SNPMiner Trials by Shray Alag

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SNPMiner SNPMiner Trials (Home Page)


Report for Mutation T790M

Developed by Shray Alag, 2020-2021.
SNP Clinical Trial Gene

There are 322 clinical trials

Clinical Trials


1 Efficacy and Safety of Almonertinib Versus Placebo as Adjuvant Therapy for Subjects With Resected Stage II-IIIB NSCLC Harboring EGFR-sensitive Mutations: A Randomized, Controlled, Double-blind, Phase 3 and Multicenter Clinical Study

To assess the efficacy and safety of Almonertinib versus placebo in patients with epidermal growth factor receptor mutation-positive (EGFRm+) stage II-IIIB non-small cell lung cancer (NSCLC), following complete tumor resection with or without adjuvant chemotherapy.

NCT04687241
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: Almonertinib
  2. Drug: Placebo Almonertinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

7. Confirmation by the central laboratory that the tumor harbors one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R), either alone or in combination with other EGFR mutations including T790M. --- L858R --- --- T790M ---

Primary Outcomes

Description: DFS is defined as the time from randomization to the recurrence of tumor as assessed by IRC or death from any cause on study. The patients will receive long-term follow-up including chest and abdominal CT every 12 weeks during Year 1, then every 24 weeks during Years 2 to 5, and every 48 weeks during Year 6 and onwards; MRI/CT of brain, and bone scan performed every 48 weeks.

Measure: DFS (Disease free survival) assessed by IRC (Independent Review Committee)

Time: From the time of randomization to recurrence of tumor or death, approximately 4 years.

Secondary Outcomes

Description: The patients will receive long-term follow-up including chest and abdominal CT every 12 weeks during Year 1, then every 24 weeks during Years 2 to 5, and every 48 weeks during Year 6 and onwards; MRI/CT of brain, and bone scan performed every 48 weeks. DFS is defined as the time from randomization to the recurrence of tumor as assessed by INVs or death from any cause on study.

Measure: DFS (Disease free survival) assessed by INVs (Investigators)

Time: From the time of randomization to recurrence of tumor or death, approximately 4 years.

Description: Defined as the proportion of patients alive and disease free at 2, 3 and 5 years, respectively, estimated from Kaplan Meier plots of the primary endpoint of DFS at the time of the primary analysis.

Measure: DFS rate at 2, 3 and 5 years assessed by IRC

Time: From the time of randomization to recurrence of tumor or death, approximately 6 years.

Description: OS is defined as the time from randomization to death due to any cause. The survival will be followed up with telephone every 24 weeks after discontinuation of the randomized treatment.

Measure: OS (Overall survival)

Time: The time from randomization to death due to any cause, approximately 8 years.

Description: OS rate at 5 years is defined as the proportion of patients alive at 5 years.

Measure: OS rate at 5 years

Time: The time from randomization to death due to any cause, approximately 8 years.

Description: AEs are graded according to CTCAE v5.0 and recorded in the case report form.

Measure: Incidence and severity of adverse events (AEs)

Time: From the screening period to 28 days after treatment completion, approximately 4 years.

Description: Defined as the pharmacokinetics exposure parameters derived from plasma concentrations of Almonertinib and its metabolite, HAS-719.

Measure: Plasma concentrations of Almonertinib and HAS-719 metabolite.

Time: From Cycle 3 (Each cycle =3 weeks) to Cycle 4, approximately 3 weeks.

2 A Multicenter, Open-Label Phase 1 Study of U3-1402 in Subjects With Metastatic or Unresectable Non-small Cell Lung Cancer

This study is designed to evaluate safety and antitumor activity of U3-1402 in two parts: Dose Escalation and Dose Expansion. In Dose Escalation, U3-1402 will be evaluated in participants with metastatic or unresectable NSCLC with epidermal growth factor receptor (EGFR) activating mutation after disease progression during/after EGFR tyrosine kinase inhibitor (TKI) therapy. In Dose Expansion, U3-1402 will be evaluated in participants with metastatic or unresectable NSCLC with EGFR activating mutation or squamous or non-squamous NSCLC (ie, without EGFR-activating mutations) with disease progression during/after systemic treatment for locally advanced or metastatic disease.

NCT03260491
Conditions
  1. Non-Small Cell Lung Cancer (NSCLC)
Interventions
  1. Drug: U3-1402
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Is willing to provide archival tumor tissue from a biopsy performed within 6 months of progression during treatment with erlotinib, gefitinib, afatinib, or osimertinib OR has at least one lesion, not previously irradiated, amenable to core biopsy and is willing to undergo screening tumor biopsy 7. Demonstrates absence of EGFR T790M mutation if treated with erlotinib, gefitinib, or afatinib. --- T790M ---

Participants with EGFR T790M mutation following treatment with erlotinib, gefitinib afatinib, or dacomitinib must have received and have documentation of radiological disease progression following treatment with osimertinib unless unable or unwilling. --- T790M ---

Primary Outcomes

Measure: Dose-limiting toxicities (DLTs) in the dose escalation period

Time: 21 days of Cycle 1

Measure: Summary of adverse events in the dose escalation period

Time: By the global end of trial date, approximately within 36 months

Description: Evaluated using RECIST 1.1

Measure: Overall response rate (ORR) assessed by Blinded Independent Central Review (BICR) Committee in the dose expansion period

Time: Approximately within 36 months

Secondary Outcomes

Measure: Maximum plasma concentration (Cmax) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose escalation period

Time: During approximately the first 84 days after dosing

Measure: Time of maximum concentration (Tmax) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose escalation period

Time: During approximately the first 84 days after dosing

Measure: Area under the serum concentration-time curve from time 0 to 8 hours (AUC[0-8]) and up to last quantifiable time (AUC[last]) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose escalation period

Time: During approximately the first 84 days after dosing

Measure: Terminal elimination rate constant (Kel) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose escalation period

Time: During approximately the first 84 days after dosing

Measure: Elimination half-life (t1/2) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose escalation period

Time: During approximately the first 84 days after dosing

Measure: Total body clearance (CL) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose escalation period

Time: During approximately the first 84 days after dosing

Measure: Volume of distribution after a single-dose (Vz) and at steady-state after multiple doses (Vss) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose escalation period

Time: During approximately the first 84 days after dosing

Description: Evaluated using RECIST 1.1

Measure: Overall response rate (ORR) in the dose escalation period

Time: Approximately within 36 months

Measure: Disease control rate (DCR) in the dose escalation period

Time: Approximately within 36 months

Measure: Duration of response (DOR) in the dose escalation period

Time: Approximately within 36 months

Measure: Time to response (TTR) in the dose escalation period

Time: Approximately within 36 months

Measure: Progression free survival (PFS) in the dose escalation period

Time: Approximately within 36 months

Measure: Overall Survival (OS) in the dose escalation period

Time: Approximately within 36 months

Measure: Summary of adverse events in the dose expansion period

Time: By the global end of trial date, approximately within 36 months

Measure: Maximum plasma concentration (Cmax) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose expansion period

Time: During approximately the first 84 days after dosing

Measure: Time of maximum concentration (Tmax) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose expansion period

Time: During approximately the first 84 days after dosing

Measure: Area under the serum concentration-time curve from time 0 to 8 hours (AUC[0-8]) and up to last quantifiable time (AUC[last]) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose expansion period

Time: During approximately the first 84 days after dosing

Measure: Terminal elimination rate constant (Kel) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose expansion period

Time: During approximately the first 84 days after dosing

Measure: Elimination half-life (t1/2) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose expansion period

Time: During approximately the first 84 days after dosing

Measure: Total body clearance (CL) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose expansion period

Time: During approximately the first 84 days after dosing

Measure: Volume of distribution after a single-dose (Vz) and at steady-state after multiple doses (Vss) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose expansion period

Time: During approximately the first 84 days after dosing

Description: Evaluated using RECIST 1.1

Measure: Overall response rate (ORR) in the dose expansion period

Time: Approximately within 36 months

Measure: Disease control rate (DCR) in the dose expansion period

Time: Approximately within 36 months

Measure: Duration of response (DOR) in the dose expansion period

Time: Approximately within 36 months

Measure: Time to response (TTR) in the dose expansion period

Time: Approximately within 36 months

Measure: Progression free survival (PFS) in the dose expansion period

Time: Approximately within 36 months

Measure: Overall Survival (OS) in the dose expansion period

Time: Approximately within 36 months

3 A Phase II Study of Combination Immunotherapy With Ipilimumab and Nivolumab in Patients With Advanced Non-small Cell Lung Cancer Resistant to Anti-PD-1-axis Therapy

The investigators propose a trial to evaluate if the addition of ipilimumab to nivolumab after primary resistance to anti- programmed death 1 (PD-1) axis therapy can lead to objective radiographic tumor regression.

NCT03262779
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Biological: combination nivolumab and ipilimumab
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

1. Patients with TKI-treated EGFR mutant NSCLC harboring the secondary EGFR T790M tumor must have received prior osimertinib 2. Patients with crizotinib-treated ALK rearranged NSCLC must have received a next generation ALK inhibitor (e.g. --- T790M ---

Primary Outcomes

Description: Objective response is defined as a complete or partial response, as determined by investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 confirmed by repeat assessment ≥4 weeks after initial documentation.

Measure: Objective response rate using RECIST v1.1 to nivolumab and ipilimumab when administered in combination to patients with pre-treated advanced NSCLC who have experienced primary resistance to anti-PD-1 axis therapy as their last line of systemic therapy.

Time: Tumor response assessment will occur every 8 weeks after initiating trial therapy for the first 24 weeks, and thereafter every 12 weeks up to 4 years.

Secondary Outcomes

Description: Progression free survival is defined as the time from the first day of nivolumab treatment until progression of disease using RECIST v1.1 and immune related Response Criteria (irRC)

Measure: Progression-free survival with nivolumab and ipilimumab when administered in combination to patients with pre- treated advanced NSCLC who have experienced primary resistance to anti-PD-1 axis therapy as their last line of systemic therapy

Time: Until disease progression, unacceptable toxicity, or study termination, up to four years.

Description: Overall survival is defined as the time from the first day of treatment until death from any cause. If a patient has not experienced death, OS will be censored at the day of last follow-up.

Measure: Overall survival (OS) with nivolumab and ipilimumab when administered in combination to patients with pre- treated advanced NSCLC who have experienced PRIMARY resistance to anti-PD-1 axis therapy as their last line of systemic therapy.

Time: Until death or day of last follow-up, up to four years from enrollment.

Description: Objective response is defined as a complete or partial response, as determined by investigator assessment using irRC and confirmed by repeat assessment ≥4 weeks after initial documentation.

Measure: Objective response rate using irRC to nivolumab and ipilimumab when administered in combination to patients with pre-treated advanced NSCLC who have experienced primary resistance to anti-PD-1 axis therapy as their last line of systemic therapy.

Time: Tumor response assessment will occur every 9 weeks after initiating trial therapy for the first 24 weeks, and thereafter every 12 weeks, up to four years.

Description: Objective response is defined as a complete or partial response, as determined by investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and immune-related Response Criteria and confirmed by repeat assessment ≥4 weeks after initial documentation.

Measure: Objective response rate in in advanced non-small cell lung cancer (NSCLC) with ACQUIRED resistance to anti-programmed death (PD)-1 axis therapy as their last line of systemic therapy.

Time: Tumor response assessment will occur every 9 weeks after initiating trial therapy for the first 24 weeks, and thereafter every 12 weeks, up to four years.

Description: Progression free survival is defined as the time from the first day of nivolumab treatment until progression of disease using RECIST v1.1 and immune related Response Criteria

Measure: Progression free survival by RECIST v1.1 with nivolumab and ipilimumab in patients with pre-treated advanced NSCLC who have experienced acquired resistance to anti-PD-1 axis therapy as their last line of systemic therapy.

Time: Until disease progression, unacceptable toxicity, or study termination, up to four years from enrollment.

Description: Overall survival is defined as the time from the first day of treatment until death from any cause. If a patient has not experienced death, OS will be censored at the day of last follow-up.

Measure: Overall survival with nivolumab and ipilimumab in patients with pre-treated advanced NSCLC who have experienced ACQUIRED resistance to anti-PD-1 axis therapy as their last line of systemic therapy.

Time: Until death or day of last follow-up (up to four years from study enrollment).

Description: Determined based on adverse events which will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0.

Measure: Safety of nivolumab and ipilimumab when administered in combination in patients with pre-treated advanced NSCLC who have experienced PRIMARY or ACQUIRED resistance to anti-PD-1 axis therapy as their last line of systemic therapy.

Time: From date of first treatment until 100 days from discontinuation of treatment.

Measure: Feasibility of sequential biopsies (performed or not performed) in patients with pre-treated advanced NSCLC who have experienced PRIMARY or ACQUIRED resistance to anti-PD-1 axis therapy as their last line of systemic therapy,

Time: Tumor biopsies will be performed just prior to initiating trial therapy, and 9 to 10 weeks after receiving first dose of trial therapy.

4 A Phase II, Open-Label, Multicenter, Single-Arm, Prospective Clinical Study to Investigate the Efficacy and Safety of Tislelizumab Combined With Chemotherapy in Non-squamous NSCLC With EGFR Sensitizing Mutation Who Failed EGFR TKI Therapy

A phase II, open-label, multicenter, single-arm, prospective clinical study to investigate the efficacy and safety of tislelizumab (anti-pd1 antibody) combined with chemotherapy in non-squamous non-small cell lung cancer patients with EGFR sensitizing mutation who failed EGFR TKI (Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor) therapy.

NCT04405674
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: Tislelizumab
  2. Drug: Carboplatin and Nab-paclitaxel
  3. Drug: Pemetrexed
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

erlotinib/afatinib/gefitinib/icotinib) are required to provide specimens after PD to confirmed absence of EGFR T790M mutation; 2) Patients with confirmed acquired T790M mutation after 1st or 2nd generation EGFR TKI (e.g. --- T790M ---

erlotinib/afatinib/gefitinib/icotinib) are required to provide specimens after PD to confirmed absence of EGFR T790M mutation; 2) Patients with confirmed acquired T790M mutation after 1st or 2nd generation EGFR TKI (e.g. --- T790M --- --- T790M ---

osimertinib) treatment as 1st line therapy are eligible regardless of their EGFR T790M mutation status. --- T790M ---

Primary Outcomes

Description: Progression-free survival (per RECIST 1.1) is defined as the time from the starting date of study drug to the date of first documentation of disease progression or death, whichever occurs first. Subjects who do not have disease progression will be censored at their last valid tumor assessment. PFS rate at 1 year as estimated by Kaplan-Meier method.

Measure: 1-Year Progression-Free Survival Rate (1-Year PFS Rate)

Time: up to 24 months after enrollment or study close

Secondary Outcomes

Description: Progression-free survival (PFS per RECIST 1.1) is defined as the time from the starting date of study drug to the date of first documentation of disease progression or death, whichever occurs first.

Measure: Progression-Free Survival (PFS)

Time: up to 24 months after enrollment or study close

Description: ORR (per RECIST 1.1) is defined as the proportion (%) of patients with at least one visit response of complete response (CR) or partial response (PR).

Measure: Objective Respond Rate (ORR)

Time: up to 24 months after enrollment or study close

Description: DCR (per RECIST 1.1) is defined as the proportion (%) of patients with at least one visit response of complete response (CR) or partial response (PR), or stable disease (SD).

Measure: Disease Control Rate (DCR)

Time: up to 24 months after enrollment or study close

Description: OS is defined as the time from the starting date of study drug to the date of death due to any cause.

Measure: Overall Survival (OS)

Time: up to 24 months after enrollment or study close

Description: DoR (per RECIST 1.1) is defined as the time from the date for first documented response of complete response (CR) or partial response (PR) to the date of first documented of disease progression or death, whichever occurs first.

Measure: Duration of Response (DoR)

Time: up to 24 months after enrollment or study close

5 Phase 2 Study of PD-1 Inhibitor JTX-4014 Alone and in Combination With Vopratelimab, an ICOS Agonist, in Biomarker-selected Subjects With Metastatic NSCLC After One Prior Platinum-containing Regimen

This is a Phase 2, open-label study to evaluate PD-1 inhibitor JTX-4014 alone and in combination with vopratelimab, an ICOS agonist, in biomarker-selected adult subjects with metastatic NSCLC who are PD-1/PD-L1 inhibitor naïve and have progressed on a platinum based chemotherapy regimen.

NCT04549025
Conditions
  1. NSCLC
Interventions
  1. Drug: JTX-4014
  2. Drug: Vopratelimab
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- Current or past participation in a study of an investigational agent or using an investigational device in the metastatic setting - Chemotherapy < 28 days prior to planned C1D1 - Prior immunotherapy including, but not limited to PD-1 or PD-L1 inhibitor mAb at any time, including JTX-4014; therapy with any mAb that specifically binds to ICOS, including vopratelimab; or chimeric antigen receptor T cell therapy - Use of anticancer therapies listed below in the metastatic setting (allowed as prior treatment for localized disease): 1. Biologic therapy 2. Targeted small molecule therapy 3. Organ transplantation, including allogeneic or autologous stem cell transplantation - Positive test for any of the following epidermal growth factor receptor gene mutations in blood or tumor: Exon 18 G719A; Exon 18 G719C; Exon 18 G719S; Exon 19 Del; Exon 20 S768I; Exon 20 T790M; Exon 20 Ins; Exon 21 L858R; Exon 21 L861Q - Prior whole brain radiation Inclusion Criteria: - Able and willing to participate and comply with all study requirements - Histologically or cytologically confirmed diagnosis of non-small cell lung cancer (NSCLC) with evaluable or measurable disease according to RECIST v1.1 with at least 1 measurable lesion - Confirmed tumor RNA signature score - Experienced progression of locally advanced or metastatic NSCLC after 1 prior systemic antineoplastic platinum-containing regimen (adjuvant therapy will count as a regimen if administered within 1 year before the relapse) - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 - Predicted life expectancy of ≥ 3 months - Adequate organ function - WOCBP must agree to use highly effective birth control Exclusion Criteria: - Concurrent anticancer treatment or subject is expected to require any other form of antineoplastic therapy while on study, either approved or investigational. --- G719A --- --- G719C --- --- G719S --- --- S768I --- --- T790M ---

- Current or past participation in a study of an investigational agent or using an investigational device in the metastatic setting - Chemotherapy < 28 days prior to planned C1D1 - Prior immunotherapy including, but not limited to PD-1 or PD-L1 inhibitor mAb at any time, including JTX-4014; therapy with any mAb that specifically binds to ICOS, including vopratelimab; or chimeric antigen receptor T cell therapy - Use of anticancer therapies listed below in the metastatic setting (allowed as prior treatment for localized disease): 1. Biologic therapy 2. Targeted small molecule therapy 3. Organ transplantation, including allogeneic or autologous stem cell transplantation - Positive test for any of the following epidermal growth factor receptor gene mutations in blood or tumor: Exon 18 G719A; Exon 18 G719C; Exon 18 G719S; Exon 19 Del; Exon 20 S768I; Exon 20 T790M; Exon 20 Ins; Exon 21 L858R; Exon 21 L861Q - Prior whole brain radiation NSCLC Carcinoma, Non-Small-Cell Lung JTX-4014 is a fully human IgG4 monoclonal antibody designed to specifically bind to PD-1 and block its interaction with its ligands, PD-L1 and PD-L2, to augment anti-tumor T cell activity. --- G719A --- --- G719C --- --- G719S --- --- S768I --- --- T790M ---

Primary Outcomes

Description: Mean percent change from baseline in all measurable lesions

Measure: Change in measurable lesion size

Time: averaged over 9 and 18 weeks

Secondary Outcomes

Description: ORR according to RECIST v1.1

Measure: ORR

Time: up to 24 months

Description: PFS according to RECIST v1.1

Measure: PFS

Time: up to 24 months

Description: Landmark progression free survival (PFS)

Measure: Landmark progression free survival (PFS)

Time: 9months

Description: Disease control rate (DCR) according to RECIST v1.1

Measure: Disease control rate (DCR)

Time: up to 24 months

Description: Median duration of response (DOR) according to RECIST v1.1

Measure: Median duration of response (DOR)

Time: up to 24 months

Description: Median overall survival (OS)

Measure: Median overall survival (OS)

Time: up to 24 months

6 A Phase 1 Study of Temozolomide in Combination With Targeted Therapy for NSCLC Patients With CNS Progression on Either Osimertinib or Lorlatinib

This trial is testing two novel combinations (temozolomide plus osimertinib OR temozolomide plus lorlatinib) which have not been evaluated in clinical trials. Thus, the exact benefits of these novel combinations are unclear. However, based on the mechanism of action of temozolomide and CNS(Central Nervous System) penetration/activity in other tumor types, it is hypothesized that adding temozolomide to osimertinib or temozolomide to lorlatinib may provide improvement in CNS disease control in patients with CNS progression on either of these latter two TKIs (Tyrosine kinase inhibitors).

NCT04541407
Conditions
  1. Non Small Cell Lung Cancer
  2. CNS Progression
Interventions
  1. Drug: Temozolomide plus Osimertinib
  2. Drug: Temozolomide plus Lorlatinib
MeSH:Disease Progression

Compound mutations are defined as 2 or more mutations in the EGFR tyrosine kinase domain with the following exceptions: 1. C797S and EGFR exon 19 deletion or EGFR exon 21 point mutation and 2. T790M mutation and EGFR exon 19 deletion or EGFR exon 21 point mutation. --- C797S --- --- T790M ---

Primary Outcomes

Description: Adverse events will be determined by the common terminology criteria for adverse events version 5.0

Measure: Adverse events

Time: Up to 3.5 years

Secondary Outcomes

Description: Central Nervous System response rate according to the Response assessment in neuro-oncology (RANO) criteria per investigator assessment. Evaluable CNS lesions may not have been previously irradiated unless they are definitively progressing following radiation and prior to enrollment on the study.

Measure: CNS response rate

Time: Up to 3.5 years

Description: Extra-CNS response rate according to response evaluation criteria in solid tumors (RECIST) v1.1 per investigator assessment.

Measure: Extra-CNS response rate

Time: Up to 3.5 years

Description: Overall response rate including both RANO criteria for CNS response rate and RECIST v1.1 for extra-CNS response rate per investigator assessment.

Measure: Overall response rate

Time: Up to 3.5 years

Description: Incidence of improvement in neurological function on two successive exams when compared to baseline as determined by one of two study neuro-oncologists

Measure: Incidence of improvement in neurological function

Time: Up to 3.5 years

Description: PFS will be defined as time from enrollment until development of CNS progressive disease according to the RANO criteria, development of extra-CNS disease progression according to RECIST v1.1 or death.

Measure: Progression free survival (PFS)

Time: Up to 3.5 years

Description: CNS PFS will be defined as time from enrollment until development of CNS progressive disease per investigator assessment according to the RANO criteria or death.

Measure: CNS PFS

Time: Up to 3.5 years

Description: Extra-CNS PFS will be defined as time from enrollment until development of progressive disease outside the CNS per investigator assessment according RECIST v1.1 or death.

Measure: Extra-CNS PFS

Time: Up to 3.5 years

Description: OS will be defined as time from enrollment until death.Patients alive at date of end of study visit will be censored for survival.

Measure: Overall Survival

Time: Up to 3.5 years

7 A Phase 2 Trial of Erlotinib Re-Challenge for Recurrent EGFR-mutant Lung Cancer in Patients Who Previously Received Adjuvant Erlotinib or Gefitinib

The purpose of this study is to measure the ability of erlotinib to effectively treat recurrent lung cancer which carries an EGFR mutation lung cancer after prior treatment with erlotinib or gefitinib received in the post-surgical or post-radiation setting.

NCT01189435
Conditions
  1. Lung Cancer
Interventions
  1. Drug: erlotinib
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

Inclusion Criteria: - A history of stage I-IIIB NSCLC - Previously underdone definitive surgery or radiation - Received prior adjuvant treatment or neoadjuvant with erlotinib or gefitinib for a total of at least 3 months at any time - Stopped adjuvant erlotinib or neoadjuvant at least 2 months prior to date of first imaging demonstrating recurrence - Pathologic evidence of recurrent lung cancer, confirmed at MSKCC EGFR sensitizing mutation (point mutation in exons 18 or 21, or deletion in exon 19) must be documented in the primary or recurrent tumor - Tissue from their recurrent tumor must be submitted for EGFR mutation testing, and to evaluate for the presence of the T790M mutation (results do not need to have been reported to be eligible) - Measurable disease by RECIST; if received prior irradiation, then must have a target lesion outside the irradiated field - Signed informed consent - Age > or = to 21 years old - Persons of reproductive potential must agree to use an adequate method of contraception throughout treatment and for at least 4 weeks after study drug is stopped Exclusion Criteria: - Prior progressive disease while receiving erlotinib or gefitinib therapy - Patients with known pre-existing interstitial lung disease - Total bilirubin greater than 1.8 mg/dl, excepting patients known to have Gilbert's syndrome - AST or ALT greater than five times the upper limit of normal - Pregnant or lactating women - Medically unfit for erlotinib therapy as determined by treating oncologist Inclusion Criteria: - A history of stage I-IIIB NSCLC - Previously underdone definitive surgery or radiation - Received prior adjuvant treatment or neoadjuvant with erlotinib or gefitinib for a total of at least 3 months at any time - Stopped adjuvant erlotinib or neoadjuvant at least 2 months prior to date of first imaging demonstrating recurrence - Pathologic evidence of recurrent lung cancer, confirmed at MSKCC EGFR sensitizing mutation (point mutation in exons 18 or 21, or deletion in exon 19) must be documented in the primary or recurrent tumor - Tissue from their recurrent tumor must be submitted for EGFR mutation testing, and to evaluate for the presence of the T790M mutation (results do not need to have been reported to be eligible) - Measurable disease by RECIST; if received prior irradiation, then must have a target lesion outside the irradiated field - Signed informed consent - Age > or = to 21 years old - Persons of reproductive potential must agree to use an adequate method of contraception throughout treatment and for at least 4 weeks after study drug is stopped Exclusion Criteria: - Prior progressive disease while receiving erlotinib or gefitinib therapy - Patients with known pre-existing interstitial lung disease - Total bilirubin greater than 1.8 mg/dl, excepting patients known to have Gilbert's syndrome - AST or ALT greater than five times the upper limit of normal - Pregnant or lactating women - Medically unfit for erlotinib therapy as determined by treating oncologist Lung Cancer Lung Neoplasms null --- T790M ---

Inclusion Criteria: - A history of stage I-IIIB NSCLC - Previously underdone definitive surgery or radiation - Received prior adjuvant treatment or neoadjuvant with erlotinib or gefitinib for a total of at least 3 months at any time - Stopped adjuvant erlotinib or neoadjuvant at least 2 months prior to date of first imaging demonstrating recurrence - Pathologic evidence of recurrent lung cancer, confirmed at MSKCC EGFR sensitizing mutation (point mutation in exons 18 or 21, or deletion in exon 19) must be documented in the primary or recurrent tumor - Tissue from their recurrent tumor must be submitted for EGFR mutation testing, and to evaluate for the presence of the T790M mutation (results do not need to have been reported to be eligible) - Measurable disease by RECIST; if received prior irradiation, then must have a target lesion outside the irradiated field - Signed informed consent - Age > or = to 21 years old - Persons of reproductive potential must agree to use an adequate method of contraception throughout treatment and for at least 4 weeks after study drug is stopped Exclusion Criteria: - Prior progressive disease while receiving erlotinib or gefitinib therapy - Patients with known pre-existing interstitial lung disease - Total bilirubin greater than 1.8 mg/dl, excepting patients known to have Gilbert's syndrome - AST or ALT greater than five times the upper limit of normal - Pregnant or lactating women - Medically unfit for erlotinib therapy as determined by treating oncologist Inclusion Criteria: - A history of stage I-IIIB NSCLC - Previously underdone definitive surgery or radiation - Received prior adjuvant treatment or neoadjuvant with erlotinib or gefitinib for a total of at least 3 months at any time - Stopped adjuvant erlotinib or neoadjuvant at least 2 months prior to date of first imaging demonstrating recurrence - Pathologic evidence of recurrent lung cancer, confirmed at MSKCC EGFR sensitizing mutation (point mutation in exons 18 or 21, or deletion in exon 19) must be documented in the primary or recurrent tumor - Tissue from their recurrent tumor must be submitted for EGFR mutation testing, and to evaluate for the presence of the T790M mutation (results do not need to have been reported to be eligible) - Measurable disease by RECIST; if received prior irradiation, then must have a target lesion outside the irradiated field - Signed informed consent - Age > or = to 21 years old - Persons of reproductive potential must agree to use an adequate method of contraception throughout treatment and for at least 4 weeks after study drug is stopped Exclusion Criteria: - Prior progressive disease while receiving erlotinib or gefitinib therapy - Patients with known pre-existing interstitial lung disease - Total bilirubin greater than 1.8 mg/dl, excepting patients known to have Gilbert's syndrome - AST or ALT greater than five times the upper limit of normal - Pregnant or lactating women - Medically unfit for erlotinib therapy as determined by treating oncologist Lung Cancer Lung Neoplasms null --- T790M --- --- T790M ---

Primary Outcomes

Description: in recurrent EGFR-mutant lung cancer, given to patients who previously received adjuvant erlotinib or gefitinib

Measure: To Examine the Objective Response Rate (ORR) of Single-agent Erlotinib

Time: 2 years

8 Pilot Trial of Molecular Profiling and Targeted Therapy for Advanced Non-Small Cell Lung Cancer, Small Cell Lung Cancer, and Thymic Malignancies

Background: - The current standard of care for advanced lung cancer and cancers of the thymus consists primarily of chemotherapy treatment. The drugs used for chemotherapy depend on the classification of the cancer in different categories that are based on the appearance of the cancer in the microscope. Though this approach has been proved to be useful in some ways, the survival rates of individuals with lung cancer and cancers of the thymus are still very poor. Recent research has shown that several genetic abnormalities play an important role in the development and growth of lung cancer and cancers of the thymus, and that it is possible to improve treatment success rates with drugs that specifically target some of the abnormal genes. Researchers are interested in determining whether it is possible to analyze the genes of patients with lung cancer and cancers of the thymus in order to provide personalized treatment with drugs that target the specific gene abnormalities. Objectives: - To evaluate the effectiveness of genetic analysis in determining targeted therapy for individuals with advanced non-small cell lung cancer, small cell lung cancer, and thymic cancer. Eligibility: - Individuals at least 18 years of age who have been diagnosed with either lung cancer or a cancer of the thymus that is not considered to be curable with the use of surgery or radiation therapy. Design: - Participants will be screened with a full medical history and physical examination, blood and urine tests, and tumor imaging studies. Participants will have a tumor biopsy or provide previously collected tumor tissue for study. - Based on the results of the tumor biopsy study, participants will be separated into different treatment groups: - Participants with EGFR gene mutation will receive a drug called erlotinib, which inhibits a protein called EGFR that is thought to be a key factor in the development and progression of some cancers. - Participants with KRAS, BRAF, HRAS, or NRAF gene mutations will receive a drug called AZD6244, which inhibits a protein called MEK that is thought to be a key factor in the development and progression of some cancers. - Participants with PIK3CA, AKT, or PTEN gene mutations will receive a drug called MK-2206, which inhibits a protein called AKT that is thought to be a key factor in the development and progression of some cancers. - Participants with KIT or PDGFRA gene mutations will receive a drug called sunitinib, which inhibits some proteins that are thought to be key factors in the development and progression of some cancers, including kidney cancer. - Participants who have ERBB2 gene mutation or amplification will receive a drug called lapatinib, which inhibits some proteins that are thought to be key factors in the development and progression of some cancers, including breast cancer. - Participants who do not have any of the genetic abnormalities described above will be offered different options for treatment, including standard of care chemotherapy or treatment with investigational agents in a different research protocol. - After 6 weeks of treatment, participants will have imaging studies to evaluate the status of their cancer. Treatment will continue as long as participants tolerate the drugs and the disease does not progress. - Participants who benefit from the first treatment but eventually develop resistance and progression of their cancer will be offered the chance to have a second tumor biopsy and undergo a different treatment for their cancer.

NCT01306045
Conditions
  1. Carcinoma, Non-Small-Cell Lung
  2. Carcinoma, Small Cell Lung
  3. Carcinoma, Thymic
Interventions
  1. Drug: AZD6244
  2. Drug: MK-2206
  3. Drug: Lapatinib
  4. Drug: Erlotinib
  5. Drug: Sunitinib
  6. Procedure: Molecular Profiling
MeSH:Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung Small Cell Lung Carcinoma Carcinoma, Small Cell Thymoma
HPO:Carcinoma Neoplasm of the lung Non-small cell lung carcinoma Small cell lung carcinoma Thymoma

- Individuals are eligible for EGFR germline mutation testing if they have: - a personal history of invasive lung cancer or one of the pre-invasive histologies associated with the development of lung cancer and more than two affected family members with invasive lung cancer or one of the pre-invasive histologies associated with the development of lung cancer; OR - a first-degree relative with a known EGFR germline mutation (EGFR exon 20 T790M, exon 21 V843I, exon 21 R831C and exon 20 R776G). --- T790M ---

Primary Outcomes

Description: The feasibility rate for the trial will be evaluated by determining the percentage of enrolled patients with a successful molecular profile determined.

Measure: To determine the feasibility of the use of tumor molecular profiling and targeted therapies in the treatment of NSCLC, SCLC, and Thymic Malignancies

Time: 5 years

Description: Efficacy will be determined by assessing if patients who have treatment assigned on the basis of their molecular profiling results will exhibit reasonable response rates to the drug selected for their particular profile.

Measure: To estimate the response rate of molecular-profile directed treatments in NSCLC, SCLC, and Thymic Malignancies

Time: 5 years

9 An Open-Label Phase 1/2 Study of Itacitinib in Combination With Osimertinib in Subjects With Locally Advanced or Metastatic Non-Small Cell Lung Cancer

The purpose of this study is to evaluate the safety and tolerability of itacitinib in combination with osimertinib in subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC).

NCT02917993
Conditions
  1. Lung Cancer
Interventions
  1. Drug: Itacitinib
  2. Drug: Osimertinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Subjects must have evidence of a T790M mutation in tumor tissue or plasma obtained after disease progression during or after treatment with an EGFR TKI. --- T790M ---

T790M mutation status from a local laboratory is acceptable; however, a tumor tissue sample or plasma sample suitable for centralized T790M mutation analysis must be available. --- T790M ---

T790M mutation status from a local laboratory is acceptable; however, a tumor tissue sample or plasma sample suitable for centralized T790M mutation analysis must be available. --- T790M --- --- T790M ---

- Any previous use of Janus kinase (JAK) inhibitor, osimertinib, or other EGFR-directed therapy for T790M-mt NSCLC. --- T790M ---

Primary Outcomes

Measure: Phase 1: Frequency, severity, and duration of adverse events (AEs)

Time: From screening through 30-35 days after end of treatment, approximately 2 years.

Measure: Phase 1: Number of subjects with dose-limiting toxicities (DLTs)

Time: Day 1 through Day 28

Description: ORR defined as the percentage of subjects who have a confirmed best overall response of complete response (CR) or partial response (PR).

Measure: Phase 2: Objective response rate (ORR) based on RECIST v1.1

Time: Screening and 8-week intervals throughout the study, approximately 2 years.

Secondary Outcomes

Measure: Phase 1 and Phase 2: Maximum plasma concentration (Cmax) of itacitinib and osimertinib when administered in combination

Time: Measured at protocol-defined study visits from Cycle 1 Day 1 through Cycle 1 Day 28.

Measure: Phase 1 and Phase 2: Area under the plasma concentration-time curve (AUC) of Itacitinib and osimertinib when administered in combination

Time: Measured at protocol-defined study visits from Cycle 1 Day 1 through Cycle 1 Day 28.

Description: Defined as the percentage of maximal tumor shrinkage observed at the lowest point (nadir) compared with baseline.

Measure: Phase 2: Depth of response (DpR) based on RECIST v1.1

Time: Screening and 8-week intervals throughout the study, approximately 2 years.

Measure: Phase 2: Progression-free survival (PFS)

Time: Interval from the first day of study treatment until disease progression or death due to any cause, approximately 3 years.

Measure: Phase 2: Overall survival (OS)

Time: Interval from the first day of study treatment until death due to any cause, approximately 3 years.

Measure: Phase 2: Frequency, severity, and duration of AEs

Time: From screening through 30-35 days after end of treatment, approximately 2 years.

10 A Phase 1 Study of BPI-15086 in Patients With Epidermal Growth Factor Receptor T790M Mutation-positive Non-Small Cell Lung Cancer Who Have Progressed on Previous EGFR Tyrosine Kinase Inhibitor Therapy

The main objective of this study is to evaluate the safety and tolerability of BPI-15086.

NCT02914990
Conditions
  1. Non-Small Cell Lung Cancer
Interventions
  1. Drug: BPI-15086
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

A Phase 1 Study of BPI-15086 in Patients With Epidermal Growth Factor Receptor T790M Mutation-positive Non-Small Cell Lung Cancer Who Have Progressed on Previous EGFR Tyrosine Kinase Inhibitor Therapy. --- T790M ---

Safety, Tolerability and Pharmacokinetic Profile of BPI-15086 in EGFR T790M Mutation-positive NSCLC Patients The main objective of this study is to evaluate the safety and tolerability of BPI-15086. --- T790M ---

icotinib, gefitinib, afatinib, neratinib, dacomitnib, or erlotinib) treatment - Patients must fulfil one of the following: - Confirmation that the tumour harbours EGFR sensitivity mutation (exon 19 deletion, L858R and L861R, G719X) - Must have experienced clinical benefit from EGFR TKIs, according to the Jackman criteria - Confirmation of T790M mutation positive after disease progression on EGFR TKIs - Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and estimated life expectancy of at least 12 weeks - Measurable lesion per Response Evaluation Criteria in Solid Tumors(RECIST1.1) --- L858R --- --- L861R --- --- T790M ---

In addition, the anti-cancer effect of BPI-15086 in EGFR T790M mutation-positive advanced NSCLC patients who have progressed on a previous EGFR tyrosine kinase inhibitor therapy will also be evaluated. --- T790M ---

Primary Outcomes

Description: Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03

Measure: Adverse events

Time: 18 months

Secondary Outcomes

Measure: Cmax

Time: 4 weeks

Measure: Half life

Time: 4 weeks

Measure: AUC

Time: 4 weeks

Measure: Objective Response Rate

Time: 12 weeks

Measure: Progression-Free Survival

Time: 18 months

11 APPLE Trial: Feasibility and Activity of AZD9291 (Osimertinib) Treatment on Positive PLasma T790M in EGFR Mutant NSCLC Patients

The phase II APPLE trial gives the opportunity to prospectively validate liquid biopsies as a new standard for testing tumor progression compared with conventional radiological procedure in EGFR mutant advanced NSCLC patients. Moreover based on the sequential T790M test during treatment the investigators will assess the predictive value of liquid biopsies. APPLE trial will examine the best strategy for delivering osimertinib (upfront versus sequential treatment after 1st generation EGFR TKI) in EGFR mutant NSCLC patients. Finally, the trial will also explore the mechanisms of acquired resistance to Osimertinib based on the results of an optional biopsy upon progression.

NCT02856893
Conditions
  1. NSCLC
Interventions
  1. Drug: Osimertinib
  2. Drug: Gefitinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

APPLE Trial: Feasibility and Activity of AZD9291 (Osimertinib) Treatment on Positive PLasma T790M in EGFR Mutant NSCLC Patients. --- T790M ---

Osimertinib Treatment on EGFR T790M Plasma Positive NSCLC Patients (APPLE) The phase II APPLE trial gives the opportunity to prospectively validate liquid biopsies as a new standard for testing tumor progression compared with conventional radiological procedure in EGFR mutant advanced NSCLC patients. --- T790M ---

Moreover based on the sequential T790M test during treatment the investigators will assess the predictive value of liquid biopsies. --- T790M ---

Proportion of patients receiving Osimertinib based on the determination of cfDNA T790M mutation positive. --- T790M ---

In case of other (than EGFR) concomitant mutations, discussion with EORTC Headquarters is mandatory; - Stage IV NSCLC; - Blood sample available for cfDNA EGFR T790M central testing; - Age ≥18 years; - EGFR TKI treatment-naïve eligible to receive first-line treatment with EGFR TKI; - Prior adjuvant and neo-adjuvant therapy is permitted (chemotherapy, radiotherapy, investigational agents) if performed more than 12 months before registration; - Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations Randomization: - Report of adequacy sample for cfDNA EGFR T790M test by central laboratory; - Prior palliative radiotherapy or surgery are allowed if completed at least 4 weeks before the randomization; - Patients with brain metastases are allowed provided they are stable (i.e. --- T790M ---

In case of other (than EGFR) concomitant mutations, discussion with EORTC Headquarters is mandatory; - Stage IV NSCLC; - Blood sample available for cfDNA EGFR T790M central testing; - Age ≥18 years; - EGFR TKI treatment-naïve eligible to receive first-line treatment with EGFR TKI; - Prior adjuvant and neo-adjuvant therapy is permitted (chemotherapy, radiotherapy, investigational agents) if performed more than 12 months before registration; - Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations Randomization: - Report of adequacy sample for cfDNA EGFR T790M test by central laboratory; - Prior palliative radiotherapy or surgery are allowed if completed at least 4 weeks before the randomization; - Patients with brain metastases are allowed provided they are stable (i.e. --- T790M --- --- T790M ---

- To determine the proportion of patients receiving Osimertinib based on the determination of cfDNA T790M mutation positive. --- T790M ---

Primary Outcomes

Measure: PFS Rate at 18 months

Time: 24 months after first patient in

Secondary Outcomes

Measure: PFS measured from switching to Osimertinib by RECIST criteria 1.1

Time: 24 months after first patient in

Measure: Proportion of patients receiving Osimertinib based on the determination of cfDNA T790M mutation positive

Time: 24 months after first patient in

Measure: Time to progression on Osimertinib

Time: through study completion

Measure: Time to symptomatic brain metastases in patients with presence of brain metastases at study entry

Time: 24 months after first patient in

Measure: Overall Response Rate (ORR) to Osimertinib

Time: 24 months after first patient in

Measure: Treatment duration

Time: 24 months after first patient in

Measure: Overall Survival (OS)

Time: 24 months after first patient in

Measure: Time to brain progression (TTBP)

Time: 24 months after first patient in

Description: Number of participants with treatment-related adverse events by CTCAE version 4.0. Adverse events, serious adverse events and adverse reactions will be monitored.

Measure: Safety

Time: 24 months after first patient in

12 A Phase 1B Study of AZD9291 in Combination With Navitoclax in EGFR-Mutant Non-Small Cell Lung Cancer Following Resistance to Initial EGFR Kinase Inhibitor

This phase Ib trial studies the side effects and best dose of osimertinib and navitoclax when given together and to see how well they work in treating patients with previously treated epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer that has spread to other places in the body (metastatic) or has not responded to previous treatment with initial EGFR kinase inhibitor. Osimertinib and navitoclax may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT02520778
Conditions
  1. Advanced Lung Non-Squamous Non-Small Cell Carcinoma
  2. Metastatic Lung Non-Squamous Non-Small Cell Carcinoma
  3. Stage III Lung Non-Small Cell Cancer AJCC v7
  4. Stage IIIA Lung Non-Small Cell Cancer AJCC v7
  5. Stage IIIB Lung Non-Small Cell Cancer AJCC v7
  6. Stage IV Lung Non-Small Cell Cancer AJCC v7
Interventions
  1. Drug: Navitoclax
  2. Drug: Osimertinib
MeSH:Carcinoma Carcinoma, Non-Small-Cell Lung
HPO:Carcinoma Non-small cell lung carcinoma

Calculated in the 20 patient expansion cohort and compared to the expected response rate of 61% in T790M+ lung cancer.. Change in plasma concentration of EGFR T790M and other EGFR mutations. --- T790M ---

Change in plasma concentration of EGFR T790M and other EGFR mutations will be studied in an exploratory fashion and compared to tumor response on imaging.. Biomarkers of apoptosis such as BCL2-like 1 (BCL-XL) and BCL2-like 11 (apoptosis facilitator) (BIM) levels in tumor tissue. --- T790M ---

Biomarkers of apoptosis such as BCL-XL and BIM levels will be measured in tumor tissue and correlated with response in an exploratory fashion, under the hypothesis that navitoclax will have greater activity in cancers with high BCL-XL levels and inadequate apoptotic response.. Inclusion Criteria: - Histologically confirmed non-squamous NSCLC, with incurable advanced or metastatic disease - Prior genotyping positive for an EGFR activating mutation (L858R, exon 19 deletion, G719X, L861Q) - Progression after prior treatment with an EGFR TKI; in addition to this one prior line of therapy, any additional prior lines of therapy are permitted; prior treatment with a third-generation EGFR TKI is allowed for the dose escalation phase, but is not permitted for the expansion cohort - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR TKI; or willing to undergo a new tumor biopsy prior to registration (for the dose escalation portion only this requirement can be waived if T790M status has already been determined using a local assay) - For the dose expansion portion only, patient must: 1) have a tumor which is EGFR-T790M positive and 2) be treatment naive to T790M-directed EGFR TKI (e.g. --- L858R --- --- L861Q --- --- T790M ---

Biomarkers of apoptosis such as BCL-XL and BIM levels will be measured in tumor tissue and correlated with response in an exploratory fashion, under the hypothesis that navitoclax will have greater activity in cancers with high BCL-XL levels and inadequate apoptotic response.. Inclusion Criteria: - Histologically confirmed non-squamous NSCLC, with incurable advanced or metastatic disease - Prior genotyping positive for an EGFR activating mutation (L858R, exon 19 deletion, G719X, L861Q) - Progression after prior treatment with an EGFR TKI; in addition to this one prior line of therapy, any additional prior lines of therapy are permitted; prior treatment with a third-generation EGFR TKI is allowed for the dose escalation phase, but is not permitted for the expansion cohort - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR TKI; or willing to undergo a new tumor biopsy prior to registration (for the dose escalation portion only this requirement can be waived if T790M status has already been determined using a local assay) - For the dose expansion portion only, patient must: 1) have a tumor which is EGFR-T790M positive and 2) be treatment naive to T790M-directed EGFR TKI (e.g. --- L858R --- --- L861Q --- --- T790M --- --- T790M ---

Biomarkers of apoptosis such as BCL-XL and BIM levels will be measured in tumor tissue and correlated with response in an exploratory fashion, under the hypothesis that navitoclax will have greater activity in cancers with high BCL-XL levels and inadequate apoptotic response.. Inclusion Criteria: - Histologically confirmed non-squamous NSCLC, with incurable advanced or metastatic disease - Prior genotyping positive for an EGFR activating mutation (L858R, exon 19 deletion, G719X, L861Q) - Progression after prior treatment with an EGFR TKI; in addition to this one prior line of therapy, any additional prior lines of therapy are permitted; prior treatment with a third-generation EGFR TKI is allowed for the dose escalation phase, but is not permitted for the expansion cohort - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR TKI; or willing to undergo a new tumor biopsy prior to registration (for the dose escalation portion only this requirement can be waived if T790M status has already been determined using a local assay) - For the dose expansion portion only, patient must: 1) have a tumor which is EGFR-T790M positive and 2) be treatment naive to T790M-directed EGFR TKI (e.g. --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- T790M ---

AZD9291, rociletinib, etc); T790M testing may be done locally or centrally on study, but if done locally, tissue must be available for central confirmation - Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) - Any number of prior therapies are allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%) - Patients must have the ability to swallow oral dosage forms - Life expectancy of greater than 3 months - Leukocytes >= 3,000/mcL - Absolute neutrophil count >= 1,500/mcL - Hemoglobin >= 8.0 g/dL - Platelets >= 100,000/mcL - Activated partial thromboplastin time (aPTT), prothrombin time (PT) =< 1.2 x upper limit of normal (ULN) - Total bilirubin =< 1.5 x ULN (patients with Gilbert's syndrome may have serum bilirubin > 1.5 x ULN) - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional ULN - Creatinine =< 2.0 mg/dL OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and navitoclax on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or navitoclax: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration) - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) for at least 3 months prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion - Intrauterine device (IUD) - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must agree to use condoms for the duration of the study and 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post-menopausal (amenorrheic for at least 12 months) - Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with a prior history of brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment - Patients who are receiving any other investigational agents - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use at least 1 week prior to receiving the 1st dose of AZD9291) medications or herbal supplements known to be potent inhibitors of cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) and potent inhibitors or inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) are ineligible; patients are eligible if they stop use of these compounds at least 1 week prior to receiving any treatment on this protocol - Patients receiving anticoagulation or anti-platelet therapy are excluded due to the risk of thrombocytopenia with navitoclax; excluded agents include heparin or low molecular weight heparin, warfarin, clopidogrel, ibuprofen and other nonsteroidal anti-inflammatory drug (NSAIDS), tirofiban, and other anticoagulants, drugs, or herbal supplements that affect platelet function; administration of heparin to keep subject's infusion lines patent is allowed; low-dose anticoagulation medications that are used to maintain the patency of a central intravenous catheter are allowed; aspirin will not be allowed within 7 days prior to the first dose of navitoclax or during navitoclax administration; however, subjects who have previously received aspirin therapy for thrombosis prevention, may resume a low dose (i.e., maximum 100 mg QD) of aspirin if platelet counts are stable (>= 50,000/mm^3) through 6 weeks of navitoclax administration; all decisions regarding treatment with aspirin therapy will be determined by the investigator in conjunction with the medical monitor - Patients with an underlying condition predisposing them to bleeding or currently exhibiting signs of clinically significant bleeding - Patients with a recent history of non-chemotherapy-induced thrombocytopenic-associated bleeding within 1 year prior to the first dose of study drug - Patients with a significant history of cardiovascular disease (e.g., myocardial infarction [MI], thrombotic or thromboembolic event in the last 6 months) - Any of the following cardiac criteria: - Mean resting corrected QT interval (QTc using Frederica's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiogram (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Congenital long QT syndrome or family history of long QT syndrome - Patients with active malignancies other than NSCLC or patients with prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded from this study because AZD9291 and navitoclax have the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with AZD9291 and navitoclax, breastfeeding should be discontinued if the mother is treated with AZD9291 and navitoclax - History of hypersensitivity to AZD9291 (or drugs with a similar chemical structure or class to AZD9291) or any excipients of these agents - Patients with human immunodeficiency virus (HIV) on antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Histologically confirmed non-squamous NSCLC, with incurable advanced or metastatic disease - Prior genotyping positive for an EGFR activating mutation (L858R, exon 19 deletion, G719X, L861Q) - Progression after prior treatment with an EGFR TKI; in addition to this one prior line of therapy, any additional prior lines of therapy are permitted; prior treatment with a third-generation EGFR TKI is allowed for the dose escalation phase, but is not permitted for the expansion cohort - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR TKI; or willing to undergo a new tumor biopsy prior to registration (for the dose escalation portion only this requirement can be waived if T790M status has already been determined using a local assay) - For the dose expansion portion only, patient must: 1) have a tumor which is EGFR-T790M positive and 2) be treatment naive to T790M-directed EGFR TKI (e.g. --- T790M ---

AZD9291, rociletinib, etc); T790M testing may be done locally or centrally on study, but if done locally, tissue must be available for central confirmation - Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) - Any number of prior therapies are allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%) - Patients must have the ability to swallow oral dosage forms - Life expectancy of greater than 3 months - Leukocytes >= 3,000/mcL - Absolute neutrophil count >= 1,500/mcL - Hemoglobin >= 8.0 g/dL - Platelets >= 100,000/mcL - Activated partial thromboplastin time (aPTT), prothrombin time (PT) =< 1.2 x upper limit of normal (ULN) - Total bilirubin =< 1.5 x ULN (patients with Gilbert's syndrome may have serum bilirubin > 1.5 x ULN) - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional ULN - Creatinine =< 2.0 mg/dL OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and navitoclax on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or navitoclax: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration) - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) for at least 3 months prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion - Intrauterine device (IUD) - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must agree to use condoms for the duration of the study and 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post-menopausal (amenorrheic for at least 12 months) - Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with a prior history of brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment - Patients who are receiving any other investigational agents - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use at least 1 week prior to receiving the 1st dose of AZD9291) medications or herbal supplements known to be potent inhibitors of cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) and potent inhibitors or inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) are ineligible; patients are eligible if they stop use of these compounds at least 1 week prior to receiving any treatment on this protocol - Patients receiving anticoagulation or anti-platelet therapy are excluded due to the risk of thrombocytopenia with navitoclax; excluded agents include heparin or low molecular weight heparin, warfarin, clopidogrel, ibuprofen and other nonsteroidal anti-inflammatory drug (NSAIDS), tirofiban, and other anticoagulants, drugs, or herbal supplements that affect platelet function; administration of heparin to keep subject's infusion lines patent is allowed; low-dose anticoagulation medications that are used to maintain the patency of a central intravenous catheter are allowed; aspirin will not be allowed within 7 days prior to the first dose of navitoclax or during navitoclax administration; however, subjects who have previously received aspirin therapy for thrombosis prevention, may resume a low dose (i.e., maximum 100 mg QD) of aspirin if platelet counts are stable (>= 50,000/mm^3) through 6 weeks of navitoclax administration; all decisions regarding treatment with aspirin therapy will be determined by the investigator in conjunction with the medical monitor - Patients with an underlying condition predisposing them to bleeding or currently exhibiting signs of clinically significant bleeding - Patients with a recent history of non-chemotherapy-induced thrombocytopenic-associated bleeding within 1 year prior to the first dose of study drug - Patients with a significant history of cardiovascular disease (e.g., myocardial infarction [MI], thrombotic or thromboembolic event in the last 6 months) - Any of the following cardiac criteria: - Mean resting corrected QT interval (QTc using Frederica's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiogram (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Congenital long QT syndrome or family history of long QT syndrome - Patients with active malignancies other than NSCLC or patients with prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded from this study because AZD9291 and navitoclax have the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with AZD9291 and navitoclax, breastfeeding should be discontinued if the mother is treated with AZD9291 and navitoclax - History of hypersensitivity to AZD9291 (or drugs with a similar chemical structure or class to AZD9291) or any excipients of these agents - Patients with human immunodeficiency virus (HIV) on antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Histologically confirmed non-squamous NSCLC, with incurable advanced or metastatic disease - Prior genotyping positive for an EGFR activating mutation (L858R, exon 19 deletion, G719X, L861Q) - Progression after prior treatment with an EGFR TKI; in addition to this one prior line of therapy, any additional prior lines of therapy are permitted; prior treatment with a third-generation EGFR TKI is allowed for the dose escalation phase, but is not permitted for the expansion cohort - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR TKI; or willing to undergo a new tumor biopsy prior to registration (for the dose escalation portion only this requirement can be waived if T790M status has already been determined using a local assay) - For the dose expansion portion only, patient must: 1) have a tumor which is EGFR-T790M positive and 2) be treatment naive to T790M-directed EGFR TKI (e.g. --- T790M --- --- L858R --- --- L861Q --- --- T790M ---

AZD9291, rociletinib, etc); T790M testing may be done locally or centrally on study, but if done locally, tissue must be available for central confirmation - Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) - Any number of prior therapies are allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%) - Patients must have the ability to swallow oral dosage forms - Life expectancy of greater than 3 months - Leukocytes >= 3,000/mcL - Absolute neutrophil count >= 1,500/mcL - Hemoglobin >= 8.0 g/dL - Platelets >= 100,000/mcL - Activated partial thromboplastin time (aPTT), prothrombin time (PT) =< 1.2 x upper limit of normal (ULN) - Total bilirubin =< 1.5 x ULN (patients with Gilbert's syndrome may have serum bilirubin > 1.5 x ULN) - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional ULN - Creatinine =< 2.0 mg/dL OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and navitoclax on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or navitoclax: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration) - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) for at least 3 months prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion - Intrauterine device (IUD) - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must agree to use condoms for the duration of the study and 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post-menopausal (amenorrheic for at least 12 months) - Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with a prior history of brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment - Patients who are receiving any other investigational agents - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use at least 1 week prior to receiving the 1st dose of AZD9291) medications or herbal supplements known to be potent inhibitors of cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) and potent inhibitors or inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) are ineligible; patients are eligible if they stop use of these compounds at least 1 week prior to receiving any treatment on this protocol - Patients receiving anticoagulation or anti-platelet therapy are excluded due to the risk of thrombocytopenia with navitoclax; excluded agents include heparin or low molecular weight heparin, warfarin, clopidogrel, ibuprofen and other nonsteroidal anti-inflammatory drug (NSAIDS), tirofiban, and other anticoagulants, drugs, or herbal supplements that affect platelet function; administration of heparin to keep subject's infusion lines patent is allowed; low-dose anticoagulation medications that are used to maintain the patency of a central intravenous catheter are allowed; aspirin will not be allowed within 7 days prior to the first dose of navitoclax or during navitoclax administration; however, subjects who have previously received aspirin therapy for thrombosis prevention, may resume a low dose (i.e., maximum 100 mg QD) of aspirin if platelet counts are stable (>= 50,000/mm^3) through 6 weeks of navitoclax administration; all decisions regarding treatment with aspirin therapy will be determined by the investigator in conjunction with the medical monitor - Patients with an underlying condition predisposing them to bleeding or currently exhibiting signs of clinically significant bleeding - Patients with a recent history of non-chemotherapy-induced thrombocytopenic-associated bleeding within 1 year prior to the first dose of study drug - Patients with a significant history of cardiovascular disease (e.g., myocardial infarction [MI], thrombotic or thromboembolic event in the last 6 months) - Any of the following cardiac criteria: - Mean resting corrected QT interval (QTc using Frederica's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiogram (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Congenital long QT syndrome or family history of long QT syndrome - Patients with active malignancies other than NSCLC or patients with prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded from this study because AZD9291 and navitoclax have the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with AZD9291 and navitoclax, breastfeeding should be discontinued if the mother is treated with AZD9291 and navitoclax - History of hypersensitivity to AZD9291 (or drugs with a similar chemical structure or class to AZD9291) or any excipients of these agents - Patients with human immunodeficiency virus (HIV) on antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Histologically confirmed non-squamous NSCLC, with incurable advanced or metastatic disease - Prior genotyping positive for an EGFR activating mutation (L858R, exon 19 deletion, G719X, L861Q) - Progression after prior treatment with an EGFR TKI; in addition to this one prior line of therapy, any additional prior lines of therapy are permitted; prior treatment with a third-generation EGFR TKI is allowed for the dose escalation phase, but is not permitted for the expansion cohort - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR TKI; or willing to undergo a new tumor biopsy prior to registration (for the dose escalation portion only this requirement can be waived if T790M status has already been determined using a local assay) - For the dose expansion portion only, patient must: 1) have a tumor which is EGFR-T790M positive and 2) be treatment naive to T790M-directed EGFR TKI (e.g. --- T790M --- --- L858R --- --- L861Q --- --- T790M --- --- T790M ---

AZD9291, rociletinib, etc); T790M testing may be done locally or centrally on study, but if done locally, tissue must be available for central confirmation - Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) - Any number of prior therapies are allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%) - Patients must have the ability to swallow oral dosage forms - Life expectancy of greater than 3 months - Leukocytes >= 3,000/mcL - Absolute neutrophil count >= 1,500/mcL - Hemoglobin >= 8.0 g/dL - Platelets >= 100,000/mcL - Activated partial thromboplastin time (aPTT), prothrombin time (PT) =< 1.2 x upper limit of normal (ULN) - Total bilirubin =< 1.5 x ULN (patients with Gilbert's syndrome may have serum bilirubin > 1.5 x ULN) - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional ULN - Creatinine =< 2.0 mg/dL OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and navitoclax on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or navitoclax: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration) - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) for at least 3 months prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion - Intrauterine device (IUD) - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must agree to use condoms for the duration of the study and 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post-menopausal (amenorrheic for at least 12 months) - Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with a prior history of brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment - Patients who are receiving any other investigational agents - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use at least 1 week prior to receiving the 1st dose of AZD9291) medications or herbal supplements known to be potent inhibitors of cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) and potent inhibitors or inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) are ineligible; patients are eligible if they stop use of these compounds at least 1 week prior to receiving any treatment on this protocol - Patients receiving anticoagulation or anti-platelet therapy are excluded due to the risk of thrombocytopenia with navitoclax; excluded agents include heparin or low molecular weight heparin, warfarin, clopidogrel, ibuprofen and other nonsteroidal anti-inflammatory drug (NSAIDS), tirofiban, and other anticoagulants, drugs, or herbal supplements that affect platelet function; administration of heparin to keep subject's infusion lines patent is allowed; low-dose anticoagulation medications that are used to maintain the patency of a central intravenous catheter are allowed; aspirin will not be allowed within 7 days prior to the first dose of navitoclax or during navitoclax administration; however, subjects who have previously received aspirin therapy for thrombosis prevention, may resume a low dose (i.e., maximum 100 mg QD) of aspirin if platelet counts are stable (>= 50,000/mm^3) through 6 weeks of navitoclax administration; all decisions regarding treatment with aspirin therapy will be determined by the investigator in conjunction with the medical monitor - Patients with an underlying condition predisposing them to bleeding or currently exhibiting signs of clinically significant bleeding - Patients with a recent history of non-chemotherapy-induced thrombocytopenic-associated bleeding within 1 year prior to the first dose of study drug - Patients with a significant history of cardiovascular disease (e.g., myocardial infarction [MI], thrombotic or thromboembolic event in the last 6 months) - Any of the following cardiac criteria: - Mean resting corrected QT interval (QTc using Frederica's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiogram (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Congenital long QT syndrome or family history of long QT syndrome - Patients with active malignancies other than NSCLC or patients with prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded from this study because AZD9291 and navitoclax have the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with AZD9291 and navitoclax, breastfeeding should be discontinued if the mother is treated with AZD9291 and navitoclax - History of hypersensitivity to AZD9291 (or drugs with a similar chemical structure or class to AZD9291) or any excipients of these agents - Patients with human immunodeficiency virus (HIV) on antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Histologically confirmed non-squamous NSCLC, with incurable advanced or metastatic disease - Prior genotyping positive for an EGFR activating mutation (L858R, exon 19 deletion, G719X, L861Q) - Progression after prior treatment with an EGFR TKI; in addition to this one prior line of therapy, any additional prior lines of therapy are permitted; prior treatment with a third-generation EGFR TKI is allowed for the dose escalation phase, but is not permitted for the expansion cohort - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR TKI; or willing to undergo a new tumor biopsy prior to registration (for the dose escalation portion only this requirement can be waived if T790M status has already been determined using a local assay) - For the dose expansion portion only, patient must: 1) have a tumor which is EGFR-T790M positive and 2) be treatment naive to T790M-directed EGFR TKI (e.g. --- T790M --- --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- T790M ---

AZD9291, rociletinib, etc); T790M testing may be done locally or centrally on study, but if done locally, tissue must be available for central confirmation - Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) - Any number of prior therapies are allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%) - Patients must have the ability to swallow oral dosage forms - Life expectancy of greater than 3 months - Leukocytes >= 3,000/mcL - Absolute neutrophil count >= 1,500/mcL - Hemoglobin >= 8.0 g/dL - Platelets >= 100,000/mcL - Activated partial thromboplastin time (aPTT), prothrombin time (PT) =< 1.2 x upper limit of normal (ULN) - Total bilirubin =< 1.5 x ULN (patients with Gilbert's syndrome may have serum bilirubin > 1.5 x ULN) - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional ULN - Creatinine =< 2.0 mg/dL OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and navitoclax on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or navitoclax: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration) - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) for at least 3 months prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion - Intrauterine device (IUD) - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must agree to use condoms for the duration of the study and 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post-menopausal (amenorrheic for at least 12 months) - Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with a prior history of brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment - Patients who are receiving any other investigational agents - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use at least 1 week prior to receiving the 1st dose of AZD9291) medications or herbal supplements known to be potent inhibitors of cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) and potent inhibitors or inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) are ineligible; patients are eligible if they stop use of these compounds at least 1 week prior to receiving any treatment on this protocol - Patients receiving anticoagulation or anti-platelet therapy are excluded due to the risk of thrombocytopenia with navitoclax; excluded agents include heparin or low molecular weight heparin, warfarin, clopidogrel, ibuprofen and other nonsteroidal anti-inflammatory drug (NSAIDS), tirofiban, and other anticoagulants, drugs, or herbal supplements that affect platelet function; administration of heparin to keep subject's infusion lines patent is allowed; low-dose anticoagulation medications that are used to maintain the patency of a central intravenous catheter are allowed; aspirin will not be allowed within 7 days prior to the first dose of navitoclax or during navitoclax administration; however, subjects who have previously received aspirin therapy for thrombosis prevention, may resume a low dose (i.e., maximum 100 mg QD) of aspirin if platelet counts are stable (>= 50,000/mm^3) through 6 weeks of navitoclax administration; all decisions regarding treatment with aspirin therapy will be determined by the investigator in conjunction with the medical monitor - Patients with an underlying condition predisposing them to bleeding or currently exhibiting signs of clinically significant bleeding - Patients with a recent history of non-chemotherapy-induced thrombocytopenic-associated bleeding within 1 year prior to the first dose of study drug - Patients with a significant history of cardiovascular disease (e.g., myocardial infarction [MI], thrombotic or thromboembolic event in the last 6 months) - Any of the following cardiac criteria: - Mean resting corrected QT interval (QTc using Frederica's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiogram (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Congenital long QT syndrome or family history of long QT syndrome - Patients with active malignancies other than NSCLC or patients with prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded from this study because AZD9291 and navitoclax have the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with AZD9291 and navitoclax, breastfeeding should be discontinued if the mother is treated with AZD9291 and navitoclax - History of hypersensitivity to AZD9291 (or drugs with a similar chemical structure or class to AZD9291) or any excipients of these agents - Patients with human immunodeficiency virus (HIV) on antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Advanced Lung Non-Squamous Non-Small Cell Carcinoma Metastatic Lung Non-Squamous Non-Small Cell Carcinoma Stage III Lung Non-Small Cell Cancer AJCC v7 Stage IIIA Lung Non-Small Cell Cancer AJCC v7 Stage IIIB Lung Non-Small Cell Cancer AJCC v7 Stage IV Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVES: I. To determine the safety and tolerability of osimertinib (AZD9291) in combination with navitoclax in patients with EGFR-mutant non-small cell lung cancer (NSCLC) following resistance to prior EGFR-tyrosine kinase inhibitor (EGFR TKI). --- T790M ---

To evaluate the feasibility of treatment with AZD9291 plus navitoclax for patients with T790M-mediated acquired resistance to EGFR TKI. --- T790M ---

Primary Outcomes

Description: Incidence of toxicity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. Frequency and severity of adverse events will be tabulated using counts and proportions detailing frequently occurring, serious and severe events of interest. Adverse events will be summarized using all adverse events experienced, although a sub-analysis may be conducted including only those adverse events in which the treating physician deems possibly, probably or definitely attributable to one or both study treatments.

Measure: Incidence of toxicity (dose escalation)

Time: Up to 2 years

Description: Will be measured as at least 50% of patients achieving the expected dose duration and intensity. The proportion of patients completing 3 courses of therapy with > 75% of total dose of each drug will be quantified. The combination dosing will be considered potentially feasible if at least 50% of patients achieve the expected dose duration and intensity (95% confidence interval 30%-70%).

Measure: Feasibility of the combination therapy in T790M+ lung cancer (dose expansion)

Time: Up to 12 weeks (3 cycles of treatment)

Secondary Outcomes

Description: Pharmacokinetic calculations will incorporate consideration of the dosing change in navitoclax between the two measurement days.

Measure: Pharmacokinetics parameters (maximum observed plasma drug concentration, area-under-the concentration-time-curve, trough drug concentration at steady state, and half-life) of osimertinib in combination with navitoclax

Time: Pre-dose, 1, 2, 4, 6, and 8 hours after navitoclax administration (day 3 of cycle 1 and day 1 of cycle 2)

Description: Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST). Calculated in the 20 patient expansion cohort and compared to the expected response rate of 61% in T790M+ lung cancer.

Measure: Objective response rate

Time: Baseline up to 30 days after completion of study drug

Description: Change in plasma concentration of EGFR T790M and other EGFR mutations will be studied in an exploratory fashion and compared to tumor response on imaging.

Measure: Change in plasma concentration of EGFR T790M and other EGFR mutations

Time: Baseline to up to 2 years

Description: Biomarkers of apoptosis such as BCL-XL and BIM levels will be measured in tumor tissue and correlated with response in an exploratory fashion, under the hypothesis that navitoclax will have greater activity in cancers with high BCL-XL levels and inadequate apoptotic response.

Measure: Biomarkers of apoptosis such as BCL2-like 1 (BCL-XL) and BCL2-like 11 (apoptosis facilitator) (BIM) levels in tumor tissue

Time: Baseline

13 Phase I, Open-Label, Two Parts Study in Chinese Patients With Advanced NSCLC Who Have Progressed Following Prior Therapy With an EGFR Tyrosine Kinase Inhibitor Agent

A Phase I, Open-Label, Two Parts Study to Assess the Safety, Tolerability,Pharmacokinetics and Preliminary Anti-tumour Activity of AZD9291 in Chinese Patients with Advanced Non-Small Cell Lung Cancer who have Progressed Following Prior Therapy with an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Agent Study Objective: 1, Primary Objective To characterise the pharmacokinetics (PK) of AZD9291 and its metabolites (AZ5104 and AZ7550) after single then multiple doses of AZD9291 administered orally once daily in Chinese patients with locally advanced or metastatic non small cell lung Cancer (NSCLC) who have progressed following prior therapy with an approved Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR TKI) agent. 2, Secondary objective(s) To investigate the safety and tolerability of AZD9291 when given orally to Chinese patients with locally advanced or metastatic NSCLC who have progressed following prior therapy with an approved EGFR TKI agent. To obtain a preliminary assessment of the anti-tumour activity of AZD9291 by evaluation of tumour response using Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1.

NCT02529995
Conditions
  1. Carcinoma, Non-Small-Cell Lung With EGFR Mutation Positive
Interventions
  1. Drug: AZD9291 40 mg
  2. Drug: AZD9291 80 mg
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

At least one lesion suitable for accurate repeated measurements 8. Females - Child bearing potential : should not be breast feeding, use adequate contraceptive measures for female patients with child-bearing potential, OR - Have evidence of non-child-bearing potential that meet one of the following criteria at screening: - Post-menopausal defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments - Women below 50 years old would be consider postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and with luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in the post-menopausal range for the institution - Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation 9. Male patients should be willing to use barrier contraception ie, condoms Exclusion Criteria: 1. Treatment with any of the following (prior to first dose of study treatment) - Treatment with an EGFR TKI within 8 days - Any investigational agents or other anticancer drugs from a previous treatment regimen or clinical study within 14 days - Previous treatment with AZD9291, or a Thr790Met (T790M) directed EGFR TKIs - Major surgery (excluding placement of vascular access) within 4 weeks - Radiotherapy : - Within 1 week if limited field of radiation for palliation of the first dose of study treatment - Within 4 weeks if receiving radiation to more than 30% of the bone marrow or with a wide field of radiation - Patients currently receiving (or unable to stop use at least 1 week) medications or herbal supplements known to be potent inhibitors or inducers of cytochrome P450 3A4 (CYP3A4) - Treatment with an investigational drug within five half-lives of the compound 2. Any unresolved toxicities from prior therapy greater than CTCAE grade 1 at the time of starting study treatment with the exception of alopecia and grade 2, prior platinum-therapy related neuropathy 3. Spinal cord compression or brain metastases unless asymptomatic, stable and not requiring steroids for at least 4 weeks prior to start of study treatment 4. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardise compliance with the protocol, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). --- Thr790Met ---

At least one lesion suitable for accurate repeated measurements 8. Females - Child bearing potential : should not be breast feeding, use adequate contraceptive measures for female patients with child-bearing potential, OR - Have evidence of non-child-bearing potential that meet one of the following criteria at screening: - Post-menopausal defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments - Women below 50 years old would be consider postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and with luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in the post-menopausal range for the institution - Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation 9. Male patients should be willing to use barrier contraception ie, condoms Exclusion Criteria: 1. Treatment with any of the following (prior to first dose of study treatment) - Treatment with an EGFR TKI within 8 days - Any investigational agents or other anticancer drugs from a previous treatment regimen or clinical study within 14 days - Previous treatment with AZD9291, or a Thr790Met (T790M) directed EGFR TKIs - Major surgery (excluding placement of vascular access) within 4 weeks - Radiotherapy : - Within 1 week if limited field of radiation for palliation of the first dose of study treatment - Within 4 weeks if receiving radiation to more than 30% of the bone marrow or with a wide field of radiation - Patients currently receiving (or unable to stop use at least 1 week) medications or herbal supplements known to be potent inhibitors or inducers of cytochrome P450 3A4 (CYP3A4) - Treatment with an investigational drug within five half-lives of the compound 2. Any unresolved toxicities from prior therapy greater than CTCAE grade 1 at the time of starting study treatment with the exception of alopecia and grade 2, prior platinum-therapy related neuropathy 3. Spinal cord compression or brain metastases unless asymptomatic, stable and not requiring steroids for at least 4 weeks prior to start of study treatment 4. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardise compliance with the protocol, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). --- Thr790Met --- --- T790M ---

Primary Outcomes

Description: Pharmacokinetics of AZD9291 after single dosing by assessment of maximum plasma AZD9291 concentration

Measure: Cmax of AZD9291 After Single Dosing

Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 metabolites (AZ5104) after single dosing by assessment of maximum plasma concentration

Measure: Cmax of AZ5104 After Single Dosing

Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 metabolites (AZ7550) after single dosing by assessment of maximum plasma concentration

Measure: Cmax of AZ7550 After Single Dosing

Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 after single dosing by assessment of area under the plasma concentration time curve from zero to infinity

Measure: AUC of AZD9291 After Single Dosing

Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 metabolites (AZ5104) after single dosing by assessment of area under the plasma concentration time curve from zero to infinity

Measure: AUC of AZ5104 After Single Dosing

Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 metabolites (AZ7550) after single dosing by assessment of area under the plasma concentration time curve from zero to infinity

Measure: AUC of AZ7550 After Single Dosing

Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.

Description: Rate and extent of absorption of single dose AZD9291 by assessment of apparent clearance following oral administration

Measure: CL/F of AZD9291 After Single Dosing

Time: PK blood samples are collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 120 hours post-dose. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 after multiple dosing by assessment of maximum plasma concentration at steady state

Measure: C(ss, Max) of AZD9291 After Multiple Dosing

Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 metabolites (AZ5104) after multiple dosing by assessment of maximum plasma concentration at steady state

Measure: C(ss, Max) of AZ5104 After Multiple Dosing

Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 metabolites (AZ7550) after multiple dosing by assessment of maximum plasma concentration at steady state

Measure: C(ss, Max) of AZ7550 After Multiple Dosing

Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 after multiple dosing by assessment of area under the plasma concentration curve from time zero to the end of the dosing interval

Measure: AUC(ss) of AZD9291 After Multiple Dosing

Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 metabolites (AZ5104) after multiple dosing by assessment of area under the plasma concentration curve from time zero to the end of the dosing interval

Measure: AUC(ss) of AZ5104 After Multiple Dosing

Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 metabolites (AZ7550) after multiple dosing by assessment of area under the plasma concentration curve from time zero to the end of the dosing interval

Measure: AUC(ss) of AZ7550 After Multiple Dosing

Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.

Description: Pharmacokinetics of AZD9291 after multiple dosing by assessment of apparent plasma clearance at steady state

Measure: CL(ss)/F of AZD9291 After Multiple Dosing

Time: PK blood samples are collected multiple times on Cycle 1 Day 8 and Cycle 2 Day 1. Results are based on data cut off of 28 Jan 2016.

Secondary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR (according to independent review) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.

Measure: Objective Response Rate (ORR)

Time: Treatment discontinuation plus 28 days or 12 months after last subject first dose (LSFD). Results are based on data cut off of 2 Nov 2016.

14 The Postoperative Adjuvant Therapy of Gefitinib for High Risk Stage Ib NSCLC Patients With EGFR Sensitive Mutation, an Open, Paired, Non-interventional, Multi-center Clinical Study

Currently, whether adjuvant therapy should be applied to Stage Ib non-small cell lung cancer (NSCLC) patients who received radical resection remains controversial. There is still no clear evidence that the postoperative adjuvant chemotherapy or other treatments can improve the survival rate for patients with stage Ib NSCLC. Tyrosine Kinase Inhibitors (TKIs) such as Gefitinib and Erlotinib are widely accepted as the first-line therapy for Epidermal growth factor receptor (EGFR) gene mutation late stage NSCLC patients. However the effect is largely uncertain for early stage patients who received surgery. The investigators aim to evaluate the effect of postoperative adjuvant use of Gefitinib for high risk stage Ib EGFR sensitive mutation NSCLC patients.

NCT02526537
Conditions
  1. NSCLC
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Patients with T790M mutations at 20 exon; 18. Woman who are pregnant or lactating. --- T790M ---

Primary Outcomes

Measure: Relapse Free Survival in 2 years

Time: Treatment period: 2 years (24 months)

Secondary Outcomes

Measure: Relapse Free Survival in 3 years

Time: Follow-up: 3 years

Measure: 5 year Overall Survival

Time: Follow-up: 5 years

Measure: Relapse Free Survival in 5 years

Time: Follow-up: 5 years

15 Open Label, Multinational, Multicenter, Real World Treatment Study of Single Agent AZD9291 for Patients With Advanced/Metastatic Epidermal Growth Factor Receptor (EGFR) T790M Mutation-Positive Non-Small Cell Lung Cancer (NSCLC) Who Have Received Prior Therapy With an EGFR Tyrosine Kinase Inhibitor (EGFR-TKI)

The aim of this study is to assess the efficacy and safety of single agent AZD9291 in a real world setting in adult patients with advanced or metastatic, epidermal growth factor receptor (EGFR) T790M mutation-positive Non-Small Cell Lung Cancer (NSCLC), who have received prior EGFR-tyrosine kinase inhibitor (TKI) therapy.

NCT02474355
Conditions
  1. Lung Cancer
Interventions
  1. Procedure: T790M+ Testing
  2. Procedure: Baseline Visit Blood & Urine Testing
  3. Procedure: Baseline ECG
  4. Procedure: Visual Slit-Lamp Testing
  5. Drug: AZD9291 Dosing
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

Open Label, Multinational, Multicenter, Real World Treatment Study of Single Agent AZD9291 for Patients With Advanced/Metastatic Epidermal Growth Factor Receptor (EGFR) T790M Mutation-Positive Non-Small Cell Lung Cancer (NSCLC) Who Have Received Prior Therapy With an EGFR Tyrosine Kinase Inhibitor (EGFR-TKI). --- T790M ---

Real World Treatment Study of AZD9291 for Advanced/Metastatic EGFR T790M Mutation NSCLC The aim of this study is to assess the efficacy and safety of single agent AZD9291 in a real world setting in adult patients with advanced or metastatic, epidermal growth factor receptor (EGFR) T790M mutation-positive Non-Small Cell Lung Cancer (NSCLC), who have received prior EGFR-tyrosine kinase inhibitor (TKI) therapy. --- T790M ---

Real World Treatment Study of AZD9291 for Advanced/Metastatic EGFR T790M Mutation NSCLC The aim of this study is to assess the efficacy and safety of single agent AZD9291 in a real world setting in adult patients with advanced or metastatic, epidermal growth factor receptor (EGFR) T790M mutation-positive Non-Small Cell Lung Cancer (NSCLC), who have received prior EGFR-tyrosine kinase inhibitor (TKI) therapy. --- T790M --- --- T790M ---

PFS will be summarized using Kaplan-Meier estimates of the median time to progression or death and quartiles with their 95% confidence intervals.. Inclusion Criteria: 1. Provision of signed and dated written informed consent by the patient or legally acceptable representative prior to any study-specific procedures 2. Adults (according to each country regulations for age of majority) 3. Locally advanced (stage IIIB) or metastatic (stage IV) EGFRm NSCLC, not amenable to curative surgery or radiotherapy, with confirmation of the presence of the T790M mutation 4. Prior therapy with an EGFR-TKI. --- T790M ---

Any of the following cardiac criteria: 1. Mean resting corrected QT interval (QTcF) > 470 ms using Fredericia's formula : 2. Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block, second degree heart block) 3. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events 7. Any unresolved toxicity from prior therapy CTCAE > grade 3 at the time of starting treatment 8. History of hypersensitivity to excipients of AZD9291 or to drugs with a similar chemical structure or class to AZD9291 Inclusion Criteria: 1. Provision of signed and dated written informed consent by the patient or legally acceptable representative prior to any study-specific procedures 2. Adults (according to each country regulations for age of majority) 3. Locally advanced (stage IIIB) or metastatic (stage IV) EGFRm NSCLC, not amenable to curative surgery or radiotherapy, with confirmation of the presence of the T790M mutation 4. Prior therapy with an EGFR-TKI. --- T790M ---

Any of the following cardiac criteria: 1. Mean resting corrected QT interval (QTcF) > 470 ms using Fredericia's formula : 2. Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block, second degree heart block) 3. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events 7. Any unresolved toxicity from prior therapy CTCAE > grade 3 at the time of starting treatment 8. History of hypersensitivity to excipients of AZD9291 or to drugs with a similar chemical structure or class to AZD9291 Lung Cancer Lung Neoplasms Objective: The primary objective of this study is to assess the efficacy and safety of single agent AZD9291 in a real world setting in adult patients with advanced or metastatic, epidermal growth factor receptor (EGFR) T790M mutation-positive Non-Small Cell Lung Cancer (NSCLC), who have received prior EGFR-tyrosine kinase inhibitor (TKI) therapy. --- T790M ---

Target patient population: Adult patients (fulfilling the definition of "age of majority" per local regulations) with locally advanced (stage IIIB) or metastatic (stage IV) NSCLC with confirmed T790M mutation, who have received prior EGFR-TKI therapy. --- T790M ---

Primary Outcomes

Description: Efficacy will be measured by the analysis of Overall Survival defined as the date of 1st dose until date of death.

Measure: Efficacy of AZD9291 by the analysis of overall survival.

Time: From first dose intake to end of study (Last subject last visit (LSLV)) (up to approximately 24 months)

Measure: Safety of AZD9291 by assessment of Serious Adverse Events, Adverse Events of special interest (Interstitial Lung Disease/pneumonitis-like events, Cardiac events)

Time: Patient receiving at least one dose until 30 days post last dose of AZD9291

Secondary Outcomes

Description: PFS will be summarized using Kaplan-Meier estimates of the median time to progression or death and quartiles with their 95% confidence intervals.

Measure: Efficacy of AZD9291 by the analysis of Progression Free Survival (PFS)

Time: from first dose intake to progression or death.

16 A Phase 1/2 Trial of Erlotinib and Onalespib Lactate in EGFR-Mutant Non-Small Cell Lung Cancer

This phase I/II trial studies the side effects and best dose of onalespib lactate when given together with erlotinib hydrochloride and to see how well they work in treating patients with EGFR-mutant non-small cell lung cancer that has come back (recurrent) or has spread to other places in the body (metastatic). Erlotinib hydrochloride and onalespib lactate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT02535338
Conditions
  1. Recurrent Lung Non-Small Cell Carcinoma
  2. Stage IV Lung Non-Small Cell Cancer AJCC v7
Interventions
  1. Drug: Erlotinib Hydrochloride
  2. Other: Laboratory Biomarker Analysis
  3. Drug: Onalespib Lactate
  4. Other: Pharmacological Study
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

TERTIARY OBJECTIVES: I. To explore plasma EGFR-mutant deoxyribonucleic acid (DNA) as a biomarker by detecting changes in plasma EGFR-mutant DNA levels (including plasma EGFR-T790M) and new mutations that may represent resistance to treatment. --- T790M ---

Primary Outcomes

Description: Will be graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0

Measure: Incidence of dose-limiting toxicities from onalespib lactate in combination with erlotinib hydrochloride (Phase I)

Time: Up to 28 days

Description: Each cohort will be independently governed by Simon's two-stage minimax design, implemented to distinguish a 25% response rate from an assumed background rate of 5%, with 10% type I and type II error rates.

Measure: Tumor response by Response Evaluation Criteria in Solid Tumors version 1.1 (Phase II)

Time: Up to at least 1 year

Secondary Outcomes

Description: Each cohort will be independently governed by Simon's two-stage minimax design, implemented to distinguish a 25% response rate from an assumed background rate of 5%, with 10% type I and type II error rates.

Measure: Tumor response by Response Evaluation Criteria in Solid Tumors version 1.1 (Phase I)

Time: Up to at least 1 year

Description: Progression-free survival will be summarized for both cohorts as time from first protocol treatment, using the product-limit, Kaplan-Meier, estimator.

Measure: Progression-free survival

Time: From start of treatment to time of progression or death, whichever occurs first, assessed up to at least 1 year

17 A Phase IIa Clinical Trial to Evaluate the Safety and Efficacy of Osimertinib (AZD9291) in First-line Patients With EGFR Mutation-positive Locally Advanced or Metastatic Non-small Cell Lung Cancer and Concomitant EGFR T790M Mutation at Time of Diagnosis

The primary goal is to evaluate the efficacy of osimertinib (AZD9291), in terms of the objective response rate in patients with advanced non-squamous NSCLC with EGFR mutations and the EGFR T790M mutation at diagnosis as defined by RECIST 1.1 criteria. Safety and efficacy will also be measured.

NCT02841579
Conditions
  1. Non-Small Cell Lung Cancer
Interventions
  1. Drug: Osimertinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

A Phase IIa Clinical Trial to Evaluate the Safety and Efficacy of Osimertinib (AZD9291) in First-line Patients With EGFR Mutation-positive Locally Advanced or Metastatic Non-small Cell Lung Cancer and Concomitant EGFR T790M Mutation at Time of Diagnosis. --- T790M ---

Osimertinib (AZD9291) in First-line Locally Advanced or Metastatic NSCLC Patients With EGFR and EGFR T790M The primary goal is to evaluate the efficacy of osimertinib (AZD9291), in terms of the objective response rate in patients with advanced non-squamous NSCLC with EGFR mutations and the EGFR T790M mutation at diagnosis as defined by RECIST 1.1 criteria. --- T790M ---

Osimertinib (AZD9291) in First-line Locally Advanced or Metastatic NSCLC Patients With EGFR and EGFR T790M The primary goal is to evaluate the efficacy of osimertinib (AZD9291), in terms of the objective response rate in patients with advanced non-squamous NSCLC with EGFR mutations and the EGFR T790M mutation at diagnosis as defined by RECIST 1.1 criteria. --- T790M --- --- T790M ---

Inclusion Criteria: - Patient aged 18 years or older - Patients with histological confirmation of locally advanced or metastatic, non-squamous non-small cell lung cancer (NSCLC) with an activating EGFR mutation and concomitant T790M mutation who are not candidates for local curative treatment. --- T790M ---

- Patients with a EGFR deletion or mutation in exon 19, exon 21 (L858R, L861Q) or exon 18 (G719X) and concomitant T790M mutation before treatment confirmed centrally. --- L858R --- --- L861Q --- --- T790M ---

- Patients with a EGFR deletion or mutation in exon 19, exon 21 (L858R, L861Q) or exon 18 (G719X) and concomitant T790M mutation before treatment that have not been confirmed centrally. --- L858R --- --- L861Q --- --- T790M ---

Non-Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung Naïve patients ≥ 18 years of age with histological confirmation of locally advanced or metastatic, non-squamous non-small cell lung cancer (NSCLC) with an activating EGFR mutation and concomitant T790M mutation. --- T790M ---

Primary objective: - To evaluate the efficacy of osimertinib (AZD9291), in terms of the objective response rate in patients with advanced non-squamous NSCLC with EGFR mutations and the EGFR T790M mutation at diagnosis as defined by RECIST 1.1 criteria. --- T790M ---

- To carry out a longitudinal analysis of EGFR mutations (including the T790M mutation) in plasma and serum. --- T790M ---

Primary Outcomes

Description: Defined as the rate of complete responses [CR] or partial responses [PR] to treatment in accordance to the guidelines of RECIST version 1.1 criteria

Measure: Objective response rate

Time: Baseline up to 78 weeks after patient entry

Secondary Outcomes

Description: Patient safety and adverse events will be assessed using the Common Terminology Criteria for Adverse Events (CTCAE) of the U.S. National Cancer Institute (NCI), version 4

Measure: Grade 3 or 4 adverse events and SAEs

Time: Baseline up to 78 weeks after patient entry

Description: Time from treatment start to the time of death due to any cause

Measure: Overall survival

Time: Baseline up to 78 weeks after patient entry

Description: Time from treatment start to the time at which the patient discontinues treatment due to any cause

Measure: Time to treatment failure

Time: Baseline up to 78 weeks after patient entry

Description: Time from the first documented response to documented disease progression or death

Measure: Duration of response

Time: Baseline up to 78 weeks after patient entry

Description: Percentage of patients with complete response, partial response or stable disease for a minimum of 24 weeks, assessed in accordance with the modified Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, during all study period from baseline up to 78 weeks after patient entry

Measure: Disease control rate

Time: Baseline up to 78 weeks after patient entry

Measure: Tumor shrinkage

Time: Baseline up to 78 weeks after patient entry

Description: Correlation ratio of mutational status and documented clinical response

Measure: Correlation ratio between mutational status and clinical response

Time: Baseline up to 78 weeks after patient entry

Measure: Tumour EGFR mutation status by histology

Time: Baseline up to 78 weeks after patient entry

Description: Measured by Percentage of patients with a positive EGFR mutation in plasma

Measure: Overall plasma EGFR mutation status

Time: Baseline up to 78 weeks after patient entry

Measure: BIM mRNA levels

Time: Baseline up to 78 weeks after patient entry

Description: Percentage of patients who develop anti-drug mutations in tumour tissue

Measure: Acquired resistance to osimertinib (AZD9291) by histology

Time: Baseline up to 78 weeks after patient entry

Description: Percentage of patients who develop anti-drug mutations in plasma

Measure: Overall plasma acquired resistance to osimertinib (AZD9291)

Time: Baseline up to 78 weeks after patient entry

18 Exploratory Phase 0/1 of Positron Emission Tomography (PET) Imaging Agent [18F]-ODS2004436 as a Marker of EGFR Mutation in Subjects With NSCLC

The development of biomarkers will lead the dynamic of personalized medicine and fill the unsatisfied needs in oncology for prediction of therapeutic response. Molecular imaging enables non invasive quantification of biomarkers. The development of molecular imaging biomarkers is closely related to the development of therapeutic molecules. Among the potential targets, kinases offer a lot of advantages: (i) they play a central role in cellular regulation, (ii) numerous kinase-specific small molecule libraries exist in biotech and pharma industry, (iii) several kinase-targeted therapies are used in clinic (imatinib, sorafenib, sunitinib…) with application across a variety of therapeutic indications. Among the imaging technologies, the Positron Emission Tomography (PET) is the most sensitive and dedicated to evaluate small molecules. However few radiotracers are available and their specificity limits their clinical use. The IMAkinib® approach is an innovative method proposed to develop new PET radiotracers adapted to current medical and economical challenges. The epidermal growth factor receptor (EGFR) is an established target for the treatment of advanced non-small cell lung cancer (NSCLC). The EGFR tyrosine kinase inhibitors (TKIs) Gefitinib (Iressa®), erlotinib (Tarceva®) and afatinib (Giotrif®) have already been approved for treatment of NSCLC harboring EGFR activating mutations (L858R or del exon 19). Unfortunately the majority of patients will develop a resistance to the TKI in the long term (6-12 months). If the mechanism of resistance is not yet fully characterized, most patients (50%) will acquire an additional T790M mutation of EGFR. TKI PET-imaging can provide a tool to determine and predict responsiveness to EGFR TKI in vivo. That is why, the investigators have selected and radiolabeled (18-Fluor) a compound targeting specifically EGFR mutated ([18F]-ODS2004436) which was further evaluated in a preclinical imaging study to determine the feasibility of TKI-PET. The investigators proved in vivo that [18F]-ODS2004436 a compound is a good candidate to evaluate the EGFR activity in human lung tumours using PET imaging.

NCT02847377
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Other: Injection of [18F]-ODS2004436 radiotracer
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

If the mechanism of resistance is not yet fully characterized, most patients (50%) will acquire an additional T790M mutation of EGFR. --- T790M ---

Primary Outcomes

Description: Sensibility will be evaluated by positron emission tomography (PET) performed on EGFR mutant patient

Measure: Evaluation of sensibility of [18F] ODS2004436

Time: 1 day

Description: Specificity will be evaluated by positron emission tomography (PET) performed on EGFR wild type patient

Measure: Evaluation of specificity of [18F] ODS2004436

Time: 1 day

Other Outcomes

Description: A follow up visit will be performed 3 days after each PET has been performed in order to register adverse events

Measure: Security

Time: 10 days

19 An Open-Label Multicenter Study of Erlotinib (Tarceva®) as First Line Therapy Until and Beyond RECIST Progression in NSCLC Patients Who Harbour EGFR Mutations

This open-label, single arm study will evaluate the safety and efficacy of Tarceva (erlotinib) as first-line therapy in participants with stage IV or recurrent non-small cell lung cancer who harbour epidermal growth factor receptor (EGFR) mutations. All participants will receive Tarceva 150 mg daily orally until disease progression or unacceptable toxicity occurs. At the investigator's discretion, participants may receive Tarceva beyond disease progression.

NCT01310036
Conditions
  1. Non-Squamous Non-Small Cell Lung Cancer
Interventions
  1. Drug: Erlotinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

This outcome measure was not assessed.. Inclusion Criteria: - Adult participants, >/= 18 years of age - Stage IV or recurrent non-small cell lung cancer (NSCLC) - Presence of mutation(s) in exon 18 through exon 21 of epidermal growth factor receptor (EGFR), (except T790M single mutation only) - Measurable disease (at least one lesion >= 10 mm in longest diameter) - Eastern Cooperative Oncology Group (ECOG) performance status 0-2 - Adequate hematological, renal and liver function Exclusion Criteria: - Patients with T790M single mutation only - Prior exposure to agents directed at the human epidermal receptor (HER) axis, e.g. --- T790M ---

This outcome measure was not assessed.. Inclusion Criteria: - Adult participants, >/= 18 years of age - Stage IV or recurrent non-small cell lung cancer (NSCLC) - Presence of mutation(s) in exon 18 through exon 21 of epidermal growth factor receptor (EGFR), (except T790M single mutation only) - Measurable disease (at least one lesion >= 10 mm in longest diameter) - Eastern Cooperative Oncology Group (ECOG) performance status 0-2 - Adequate hematological, renal and liver function Exclusion Criteria: - Patients with T790M single mutation only - Prior exposure to agents directed at the human epidermal receptor (HER) axis, e.g. --- T790M --- --- T790M ---

erlotinib, gefitinib, cetuximab, trastuzumab - Prior chemotherapy or systemic anti-cancer therapy for advanced NSCLC disease - Symptomatic or uncontrolled central nervous system (CNS) metastases - Other malignancy within the last 5 years, except for carcinoma in situ of the cervix, or basal or squamous cell carcinoma of the skin, or surgically treated localized prostate cancer, or surgically treated ductal cell carcinoma in situ of the breast - Any significant ophthalmologic abnormality - Pre-existing parenchymal lung disease such as pulmonary fibrosis - Use of coumarins (for anti-coagulation therapy the use of low molecular weight heparin is recommended instead) Inclusion Criteria: - Adult participants, >/= 18 years of age - Stage IV or recurrent non-small cell lung cancer (NSCLC) - Presence of mutation(s) in exon 18 through exon 21 of epidermal growth factor receptor (EGFR), (except T790M single mutation only) - Measurable disease (at least one lesion >= 10 mm in longest diameter) - Eastern Cooperative Oncology Group (ECOG) performance status 0-2 - Adequate hematological, renal and liver function Exclusion Criteria: - Patients with T790M single mutation only - Prior exposure to agents directed at the human epidermal receptor (HER) axis, e.g. --- T790M ---

erlotinib, gefitinib, cetuximab, trastuzumab - Prior chemotherapy or systemic anti-cancer therapy for advanced NSCLC disease - Symptomatic or uncontrolled central nervous system (CNS) metastases - Other malignancy within the last 5 years, except for carcinoma in situ of the cervix, or basal or squamous cell carcinoma of the skin, or surgically treated localized prostate cancer, or surgically treated ductal cell carcinoma in situ of the breast - Any significant ophthalmologic abnormality - Pre-existing parenchymal lung disease such as pulmonary fibrosis - Use of coumarins (for anti-coagulation therapy the use of low molecular weight heparin is recommended instead) Inclusion Criteria: - Adult participants, >/= 18 years of age - Stage IV or recurrent non-small cell lung cancer (NSCLC) - Presence of mutation(s) in exon 18 through exon 21 of epidermal growth factor receptor (EGFR), (except T790M single mutation only) - Measurable disease (at least one lesion >= 10 mm in longest diameter) - Eastern Cooperative Oncology Group (ECOG) performance status 0-2 - Adequate hematological, renal and liver function Exclusion Criteria: - Patients with T790M single mutation only - Prior exposure to agents directed at the human epidermal receptor (HER) axis, e.g. --- T790M --- --- T790M ---

Primary Outcomes

Description: PFS1 was defined as time from first dose until documented progressive disease (PD), assessed per Response Evaluation Criteria in Solid Tumors RECIST, v. 1.1, or death from any cause, whichever occurred first. PD was defined as: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; and the appearance of one or more new lesions.

Measure: Progression-free Survival Per RECIST, v. 1.1 (PFS1)

Time: Approximately 68 months

Secondary Outcomes

Description: PFS2 was defined as time from first study dose to off-erlotinib progressive disease (PD), assessed by the investigator based on overall clinical evaluation.

Measure: Progression-free Survival Per Investigator (PFS2)

Time: Approximately 68 months

Description: ORR was defined as the occurrence of either a confirmed complete (CR) or a partial response (PR, as a best overall response), as determined by RECIST, v. 1.1 criteria. CR was defined as disappearance of all target lesions. PR was defined as least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.

Measure: Objective Response Rate (ORR) for All Participants and Participants With EGFR Mutation E19del or L858R

Time: Approximately 68 months

Description: DCR was defined as CR + PR + Stable disease (SD). CR was defined as disappearance of all target lesions. PR was defined as least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study. PD was defined as: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; and the appearance of one or more new lesions.

Measure: Disease Control Rate (DCR) for All Participants and Participants With EGFR Mutation E19del or L858R

Time: Approximately 68 months

Description: PFS1 was defined as time from first dose until documented progressive disease (PD), assessed per Response Evaluation Criteria in Solid Tumors RECIST, v. 1.1, or death from any cause, whichever occurred first. PD was defined as: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; and the appearance of one or more new lesions.

Measure: Progression-free Survival for Participants With EGFR Mutation E19del or L858R Per RECIST, v. 1.1 (PFS1)

Time: Approximately 68 months

Description: OS was defined as the time from baseline to the date of death from any cause.

Measure: Overall Survival (OS) for All Participants and Participants With EGFR Mutation E19del or L858R

Time: Approximately 68 months

Description: An adverse event is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a study drug, whether or not considered related to the study drug.

Measure: Number of Participants With Adverse Events

Time: Approximately 68 months

Description: This outcome measure was not assessed.

Measure: Correlation Between EGFR Mutations in Plasma and Clinical Outcome (ORR/PFS/OS)

Time: Approximately 68 months

20 A Phase I/II Trial of Hsp 90 Inhibitor AUY-922 in Patients With Lung Adenocarcinoma With "Acquired Resistance" to EGFR Tyrosine Kinase Inhibitors

Hsp90 inhibitor AUY922 and erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. This phase I/II trial is studying the side effects and best dose of Hsp90 inhibitor AUY922 when given together with erlotinib hydrochloride and to see how well it works in treating patients with stage IIIB-IV non-small cell lung cancer.

NCT01259089
Conditions
  1. Adenocarcinoma of the Lung
  2. Non-small Cell Lung Cancer
Interventions
  1. Drug: erlotinib hydrochloride
  2. Drug: Hsp90 inhibitor AUY922
  3. Other: laboratory biomarker analysis
  4. Procedure: needle biopsy
  5. Genetic: mutation analysis
  6. Other: pharmacological study
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung Adenocarcinoma Adenocarcinoma of Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Overall survival (OS) is defined as the time from treatment initiation until death due to any cause.. Overall Survival Among Patients With Acquired Resistance With T790M Mutations (Phase II). --- T790M ---

Overall Survival (OS) will be measured from treatment initiation until death due to any cause for patients with acquired resistance with T790M mutations in the phase II portion of the study.. Inclusion Criteria: - All patients must have pathologic evidence of advanced lung adenocarcinoma (stage IIIB or stage IV) confirmed histologically/cytologically at NU, MSKCC, or DFCI and EITHER previous RECIST-defined response (CR or PR) to an EGFR-TKI (erlotinib or gefitinib) or an investigational EGFR TK inhibitor OR a documented mutation in the EGFR gene (G719X, exon 19 deletion, L858R, L861Q) - Radiographic progression by RECIST during treatment with erlotinib/gefitinib - Received treatment with erlotinib/gefitinib throughout the one month prior to enrollment and at least six months at any time - Measurable (RECIST) indicator lesion not previously irradiated - Must have undergone a biopsy after the development of acquired resistance - Karnofsky Performance Status >= 70% OR ECOG/WHO Performance Status 0-1 - Signed informed consent - Effective contraception and negative serum pregnancy test obtained within two weeks prior to the first administration of AUY922 in all pre-menopausal women (ie., last menstrual period =< 24 months ago) and women < 2 years after onset of menopause; menopause is defined as the time at which fertility ceases, where a woman has had no menstruation for > 24 months - Total bilirubin =< 1.5 x Upper Limit of Normal (ULN) - AST/SGOT and ALT/SGPT =< 3.0 x ULN, or =< 5.0 x ULN if liver metastasis present - Absolute neutrophil count (ANC) >= 1.5 x10^9/L - Hemoglobin (Hgb) >= 9g/dL - Platelets (plts) >= 100 x 10^9/L - Serum creatinine =< 1.5 x ULN or 24 hour clearance >= 50 mL/min Exclusion Criteria: - Symptomatic CNS metastases which are symptomatic and /or requiring escalating doses of steroids - Prior treatment with any HSP90 inhibitor compounds - Conventional chemotherapy, radiation or monoclonal antibodies within 4 weeks (erlotinib/gefitinib therapy within the past 4 weeks IS allowed) - Palliative radiation within 2 weeks - Unresolved diarrhea >= CTCAE grade 2 - Pregnant or lactating women - Women of childbearing potential (WCBP) (i.e. --- T790M ---

Primary Outcomes

Description: To determine the maximally tolerated dose (MTD), and recommended phase II dose of AUY922 when given in combination with erlotinib for patients with acquired resistance to erlotinib. (Phase I) Escalation of dose will be in a 3+3 design. If no dose limiting toxicities (DLTs) are seen in 3 patients enrolled at that dose level, then dose will be escalated to the next dose level and the next 3 patients will be enrolled at that dose. Alternatively, if 1 DLT is seen in 3 patients at that dose level, 3 more patients will be added at that same dose level. If 1 DLT is seen in 6 patients at that dose level, MTD will be determined to be at that dose. If more than 1 DLT is seen at that dose level, then the prior lower dose level will be the considered the MTD. DLT is defined as any of the following related to the investigational agent: Death and grade 3 and 4 specific hematological and non-hematological toxicities defined in the protocol.

Measure: Maximally Tolerated Dose (MTD) of AUY922 and Erlotinib Treatment Combination (Phase I)

Time: During the first 4 weeks of treatment for each patient.

Description: Overall response rate (ORR) will be measured per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT scan or MRI: Complete response (CR) defined as disappearance of all target lesions. Partial Response (PR), defined as >=30% decrease in the sum of the longest diameter of target lesions. Stable Disease (SD) defined as neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on study. Progressive Disease (PD) defined as having at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions

Measure: Overall Response Rate (ORR), Defined as Complete Response(CR) + Partial Response (PR) Using the Modified RECIST 1.1 Criteria for All Patients Treated at Dose of 70mg/m2 AUG922

Time: At 8 weeks from treatment initiation

Secondary Outcomes

Description: To characterize the toxicity profile for the combination of erlotinib and AUY922. Toxicity data will be collected every week for the first 28 day cycle and then every two weeks during treatment and up to 28 days after the last treatment. Adverse events will be graded according to the National Cancer Institute's Common Toxicity Criteria for adverse events version 4.0 (CTCAE v4.0). In general adverse events (AEs) will be graded according to the following: Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE

Measure: Toxicity as Assessed by NCI CTCAE Version 4.00 When AUG922 Administered at Its MTD (Phase I and II)

Time: At weeks 1 through 4 and then every 2 weeks during treatment and 30 days post last treatment for up to 2 years and half years

Description: Adverse events will be collected weekly for the first 28 day cycle and then every two weeks during treatment and up to 28 days after the last treatment. Adverse events will be graded according to the National Cancer Institute's Common Toxicity Criteria for adverse events version 4.0 (CTCAE v4.0). In general adverse events (AEs) will be graded according to the following: Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE

Measure: Incidence of Reported Adverse Events in Phase I

Time: At weeks 1 through 4 and then every 2 weeks during treatment and 30 days post last treatment, for up to 2 years and half years

Description: Median Progression Free Survival (PFS) will be calculated from time of treatment initiation until the first documentation of progressive disease. Patients will be considered to have progressive disease when CT scan or MRI show at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.

Measure: Progression-free Survival (Phase II)

Time: From the time of first treatment with AUY922 to disease progression for up to 2 years post treatment

Description: Overall survival (OS) is defined as the time from treatment initiation until death due to any cause.

Measure: Overall Survival (Phase II)

Time: From the time of first treatment with AUY922 to death, followed up to 2 years post treatment

Description: Overall Survival (OS) will be measured from treatment initiation until death due to any cause for patients with acquired resistance with T790M mutations in the phase II portion of the study.

Measure: Overall Survival Among Patients With Acquired Resistance With T790M Mutations (Phase II)

Time: From the time of first treatment with AUY922 to death, followed for up to 2 years

21 Addition of the Gamma-Secretase Inhibitor RO4929097 to Erlotinib in Patients With Advanced Non-small Cell Lung Cancer (NSCLC)

This phase I trial studies the side effects and best dose of gamma-secretase/Notch signalling pathway inhibitor RO4929097 (RO4929097) and erlotinib hydrochloride when given together in treating patients with non-small cell lung cancer that is stage IV or has come back. RO4929097 and erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT01193881
Conditions
  1. Recurrent Non-Small Cell Lung Carcinoma
  2. Stage IV Non-Small Cell Lung Cancer
Interventions
  1. Drug: Erlotinib Hydrochloride
  2. Drug: Gamma-Secretase Inhibitor RO4929097
  3. Other: Laboratory Biomarker Analysis
  4. Other: Pharmacological Study
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

(Expansion cohort) SECONDARY OBJECTIVES: I. To perform a preliminary exploratory assessment of whether probability of detectable tumor shrinkage/response correlates with pre RO4929097 presence in tumor of an activating epidermal growth factor receptor (EGFR) mutation, the T790M EGFR mutation, met proto-oncogene (c-MET) gene amplification or insulin-like growth factor 1 receptor (IGF-1R) expression or activation or various Notch pathway markers. --- T790M ---

Conduct a preliminary exploratory assessment on the expansion cohort with respect to tumor shrinkage/response of the following over the first 2 cycles of erlotinib and RO4929097 treatment with and without the presence of mutation, amplification, and activation of markers: tumor IHC scores and RPPA expression of the Notch ligand jagged 1 (Jag1), and the Notch targets hairy and enhancer of split 1 (HES1), hairy/enhancer-of-split related with YRPW motif protein 1 (HEY1); tumor IHC scores and RPPA expression of putative stem cell markers cluster of differentiation (CD)24 (decreased in stem cells), CD44, CD133, dehydrogenase and of the epithelial to mesenchymal transition (EMT) markers E-cadherin and vimentin; detectability in tumor of EGFR T790M mutations, MET amplification, and IGF-1R expression and activation; and soluble markers of angiogenesis, including stromal cell-derived factor 1 alpha (SDF-1alpha), basic fibroblastic growth factor (bFGF), cryptic epitope of collagen IV, interleukin (IL)-6, IL-8, vascular endothelial growth factor (VEGF). --- T790M ---

Conduct a preliminary exploratory assessment of whether percent tumor shrinkage/response or time to progression correlates with pre-therapy IHC and RPPA expression of Notch 1, 2, 3 and 4, the above Notch pathway and stem cell markers, with baseline detectability of T790M mutations and MET amplification, and with baseline IGF-1R expression and activation, and with change in these markers from the initial biopsy to the subsequent biopsy. --- T790M ---

Primary Outcomes

Measure: Incidence of adverse events assessed using NCI CTCAE version 4.0 (Dose escalation phase)

Time: Within 30 days of last drug dose

Measure: Maximum-tolerated dose of RO4929097 and erlotinib hydrochloride defined as the highest dose tested causing dose limiting toxicity in < 2/6 patients assessed using National Cancer Institute (NCI) CTCAE version 4.0 (Dose escalation phase)

Time: At least 3 weeks after day 1 of course 1

Description: The differences before and after treatment will be assessed using a paired-t test on the log-transformed tumor sizes and a Wilcoxon signed-rank test.

Measure: Percentage of change in expression of Notch and other tumor and blood biomarkers (Expansion cohort)

Time: Baseline to 6 weeks

Description: Will be correlated with response and baseline expression of biomarkers. The differences before and after treatment will be assessed using a paired-t test on the log-transformed tumor sizes and a Wilcoxon signed-rank test.

Measure: Percentage of tumor shrinkage (Expansion cohort)

Time: Up to 6 weeks

Measure: Response rate by RECIST 1.1 (Expansion cohort)

Time: Up to 12 weeks

Description: Will be correlated with baseline expression or biomarkers.

Measure: Time to progression (Expansion cohort)

Time: Up to 12 weeks

Other Outcomes

Measure: Efficacy of this combination in unselected patients and in patients with intrinsic or acquired erlotinib resistance (Dose escalation phase)

Time: Up to 12 weeks

Description: Correlations between Notch pathway gene polymorphisms and tumor and blood biomarkers will be assessed. Correlations between Notch pathway gene polymorphisms and tumor shrinkage/response on therapy will also be assessed.

Measure: Host Notch pathway gene polymorphisms

Time: Up to 6 weeks

Description: Exploratory assessments of correlations of tumor shrinkage and response on the combination with pre-therapy tumor expression of Notch and other tumor and blood biomarkers will be conducted.

Measure: Pre-therapy tumor expression of Notch and other tumor and blood biomarkers (Dose escalation phase)

Time: Baseline

Description: Correlations between Notch pathway markers and stem cell markers will be assessed.

Measure: Stem cell markers

Time: Up to 6 weeks

22 Development of Circulating Tumour Cell Molecular Diagnostics Using a Novel Microfluidic Device

1. To compare EGFR mutations between primary non-small cell lung cancer (NSCLC) tumours and corresponding CTCs isolated by a label-free microfluidic device-based system 2. To characterize the association between clinical response in NSCLC patients treated with gefitinib and serial changes in CTC EGFR mutations detected by a label-free microfluidic device-based system The investigators recently developed a label-free, microfluidic device for capturing circulating tumour cells (CTCs) and acquired a Fluidigm Biomark digital PCR instrument for reliable low-level DNA quantification. The overall aim of this study is to test the feasibility of using these state-of-the-art devices to reliably detect clinically relevant EGFR mutations in CTCs.

NCT01193829
Conditions
  1. Patients With Non-small Cell Lung Cancer
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

DNA will be extracted from the retrieved CTCs and tumour samples, and analyzed exon 19 deletion, L858R and T790M mutations by digital PCR on the Fluidigm Biomark according to methods described previously.23 --- L858R --- --- T790M ---

In particular, the frequency of T790M mutations in a relevant patient population is lacking, highlighting the lack of adequate analytical systems for its assessment such as the one proposed in this study. --- T790M ---


23 Almonertinib as Upfront Treatment for Uncommon EGFR Mutation Harboring Non-Small-Cell Lung Cancer Patients: A Multicenter, Open-Label, Phase II Trial

This is a Phase 2 study to evaluate the efficacy and the safety/ tolerability of Almonertinib in NSCLC patients with uncommon EGFR Mutation or EGFR exon 20 insertion mutations. Patients with EGFR exon 20 insertion mutations have to had at least one prior systemic treatment for locally advanced or metastatic NSCLC.

NCT04553887
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: Almonertinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: 1. 18-75years#ECOG PS#0-2#Life expectancy of more than 3 months#with measurable lesion ( RECIST1.1). 2. Cohort A: Patients with EGFR exon 20 insertion, failure of first-line standard chemotherapy, or intolerance to chemotherapy Cohort B: Patients with uncommen EGFR mutations but without exon 19 deletion, L858R, T790M, and exon 20 insertion 3. ≥1 target lesion that has not received radiotherapy in the past 3 months and can be accurately measured in at least 1 direction#Previously received radiation therapy, but the radiotherapy area must be <25% of the bone marrow area, and radiation therapy must have closed for at least≥4 weeks at the time of enrollment. --- L858R --- --- T790M ---

The currently approved TKIs (ie, erlotinib, gefitinib, afatinib, osimertinib) are not considered to be exon 20 insertion-selective and are permissible 1. Patients with EGFR 19 exon deletion mutation, 21 exon L858R mutation or 20 exon T790M mutation. --- L858R --- --- T790M ---

Judgment by the investigator that should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements Inclusion Criteria: 1. 18-75years#ECOG PS#0-2#Life expectancy of more than 3 months#with measurable lesion ( RECIST1.1). 2. Cohort A: Patients with EGFR exon 20 insertion, failure of first-line standard chemotherapy, or intolerance to chemotherapy Cohort B: Patients with uncommen EGFR mutations but without exon 19 deletion, L858R, T790M, and exon 20 insertion 3. ≥1 target lesion that has not received radiotherapy in the past 3 months and can be accurately measured in at least 1 direction#Previously received radiation therapy, but the radiotherapy area must be <25% of the bone marrow area, and radiation therapy must have closed for at least≥4 weeks at the time of enrollment. --- L858R --- --- T790M ---

Primary Outcomes

Description: The proportion of subjects who achieve Complete Response (CR) and Partial Response (PR) by the best response from the first dose of Almonertinib to the end of study.

Measure: Objective Response Rate

Time: To evaluate objective response rate 6-8 weeks after the initiation of Almonertinib

Secondary Outcomes

Description: The PFS time is defined as time from enrollment to locoregional or systemic recurrence, second malignancy or death due to any cause; censored observations will be the last date of : "death", "last tumor assessment", "last follow up date" or "last date in drug log"

Measure: Progression Free Survival

Time: 30 months

Description: Disease Control Rate (DCR) defined as the percentage of participants with Disease Control best overall response (complete response, partial response or stable disease).

Measure: Disease Control Rate

Time: 30 months

Description: OS was defined as time from date of enrollment to date of death due to any cause. For participants still alive at the time of analysis, OS time was censored on last date that participants were known to be alive.

Measure: Overall Survival

Time: 30 months

Description: Number of days from the date that measurement criteria are first met for CR or PR (whichever status is recorded first) until the first subsequent date that progressive disease or death is documented.

Measure: Duration of Response

Time: 30 months

Description: Number of Participants with treatment related Adverse Events as Assessed by CTCAE v5.0

Measure: Safety and Tolerability

Time: 30 months

24 A Phase Ib, Open Label, Multi-center Study to Characterize the Safety, Tolerability and Preliminary Efficacy of EGF816 in Combination With Selected Targeted Agents in EGFR Mutant NSCLC

The study purpose is to evaluate the safety, tolerability, and preliminary efficacy of the addition of INC280, trametinib, ribociclib, gefitinib, or LXH254 to EGF816 in adult patients with advanced EGFR-mutant NSCLC.

NCT03333343
Conditions
  1. EGFR-mutant Non-small Cell Lung Cancer
Interventions
  1. Drug: EGF816
  2. Drug: trametinib
  3. Drug: ribociclib
  4. Drug: LXH254
  5. Drug: INC280
  6. Drug: gefitinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- Patients who have locally advanced or metastatic NSCLC with EGFR sensitizing mutation AND an acquired T790M mutation (e.g., L858R and/or ex19del, T790M+) following progression on prior treatment with a 1st-generation EGFR TKI or 2nd-generation EGFR TKI. --- T790M ---

These patients may not have received more than 4 prior lines of antineoplastic therapy in the advanced setting, including EGFR TKI, and may not have received any agent targeting EGFR T790M mutation (i.e., 3rd-generation EGFR TKI). --- T790M ---

- Patients who have locally advanced or metastatic NSCLC with EGFR sensitizing mutation and a "de novo" T790M mutation (i.e., no prior treatment with any agent known to inhibit EGFR including EGFR TKI). --- T790M ---

- Prior therapies: - Patients who have been treated with EGFR TKI in the adjuvant setting within 6 months, unless acquired EGFR T790M is present in a tumor or blood sample obtained since the discontinuation of the EGFR TKI. - Patients who have been treated with prior EGFR TKI targeting T790M (3rd generation). --- T790M ---

- Prior therapies: - Patients who have been treated with EGFR TKI in the adjuvant setting within 6 months, unless acquired EGFR T790M is present in a tumor or blood sample obtained since the discontinuation of the EGFR TKI. - Patients who have been treated with prior EGFR TKI targeting T790M (3rd generation). --- T790M --- --- T790M ---

Primary Outcomes

Description: Assess safety and tolerability including incidence of dose limiting toxicities, adverse events, and serious adverse events.

Measure: Number of patients with adverse events and serious adverse events

Time: Every day until study end, approximately 4 years

Description: Modified objective response rate (ORR2) per RECIST v1.1 (taking as baseline the most recent assessment prior to initiating combination)

Measure: ORR2

Time: Every 8-12 weeks until study ends, approximately 4 years

Secondary Outcomes

Description: Overall response rate (ORR) per RECIST v1.1

Measure: ORR

Time: Every 8-12 weeks until study ends, approximately 4 years

Description: Time from the date of first dose of study treatment to the date of first documented disease progression (per RECIST v1.1) or death due to any cause

Measure: PFS

Time: Every 8-12 weeks until study ends, approximately 4 years

Description: Proportion of patients with best overall response of CR, PR, or SD

Measure: DCR

Time: Every 8-12 weeks until study ends, approximately 4 years

Description: Time from first documented response (PR or CR) to the date of first documented disease progression or death due to any cause

Measure: DOR

Time: Every 8-12 weeks until study ends, approximately 4 years

Measure: Time to response

Time: Every 8-12 weeks until study ends, approximately 4 years

25 AFAMOSI: Prospective, Randomized, Multicenter Phase IV Study to Evaluate the Efficacy and Safety of Afatinib Followed by Osimertinib Compared to Osimertinib in Patients With EGFRmutated/T790M Mutation Negative Non-squamous NSCLC in the First-line Setting

This randomized, open label Phase IV trial will be performed in patients with a diagnosis of advanced NSCLC (non-squamous cell histology), harboring EGFR mutation positive but T790M Mutation negative, who have no previous chemotherapy for metastatic NSCLC. Neoadjuvant or adjuvant systemic treatments had to be finished at least (≥) 6 months before study inclusion. In conclusion, this study is investigating the important clinical question whether tumor growth and long term overall survival for a patient is better controlled in a specific treatment sequence of different EGFR-inhibitors. Patients will be treated with registered compounds according to their label in both treatment arms. Thus, all patients will get an effective treatment regimen and patients who progressed on afatinib, and who developed a T790M mutation will be treated subsequently with osimertinib. Those who progressed under osimertinib or under afatinib without T790M mutation will be treated according to the current treatment guidelines with Investigator´s choice of active therapy (ICT) including but not limited to platin doublet chemotherapy.

NCT04413201
Conditions
  1. Non-squamous NSCLC
Interventions
  1. Drug: Afatinib
  2. Drug: Osimertinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

AFAMOSI: Prospective, Randomized, Multicenter Phase IV Study to Evaluate the Efficacy and Safety of Afatinib Followed by Osimertinib Compared to Osimertinib in Patients With EGFRmutated/T790M Mutation Negative Non-squamous NSCLC in the First-line Setting. --- T790M ---

AFAMOSI: Efficacy and Safety of Afatinib Followed by Osimertinib Compared to Osimertinib in Patients With EGFRmutated/T790M Mutation Negative Nonsquamous NSCLC This randomized, open label Phase IV trial will be performed in patients with a diagnosis of advanced NSCLC (non-squamous cell histology), harboring EGFR mutation positive but T790M Mutation negative, who have no previous chemotherapy for metastatic NSCLC. --- T790M ---

AFAMOSI: Efficacy and Safety of Afatinib Followed by Osimertinib Compared to Osimertinib in Patients With EGFRmutated/T790M Mutation Negative Nonsquamous NSCLC This randomized, open label Phase IV trial will be performed in patients with a diagnosis of advanced NSCLC (non-squamous cell histology), harboring EGFR mutation positive but T790M Mutation negative, who have no previous chemotherapy for metastatic NSCLC. --- T790M --- --- T790M ---

Thus, all patients will get an effective treatment regimen and patients who progressed on afatinib, and who developed a T790M mutation will be treated subsequently with osimertinib. --- T790M ---

Those who progressed under osimertinib or under afatinib without T790M mutation will be treated according to the current treatment guidelines with Investigator´s choice of active therapy (ICT) including but not limited to platin doublet chemotherapy. --- T790M ---

The main objective is to investigate whether the time to EGFR-TKI failure at 24 months is better for the treatment sequence of afatinib followed by osimertinib in the T790M positive group compared to osimertinib.. Time to EGFR-TKI failure (afatinib versus osimertinib). --- T790M ---

Inclusion Criteria: - Histologically confirmed non-squamous NSCLC harboring EGFR mutation positive but T790M mutation negative by local testing - Unresectable stage UICC ≥ IIIb or metastatic stage UICC IV disease - TKI naïve for metastatic NSCLC, neoadjuvant or adjuvant chemotherapy allowed - At least one evaluable lesion according to RECIST v1.1 - Age ≥ 18 years - ECOG performance status 0 - 2 - Adequate organ function, defined as all of the following: 1. Absolute neutrophil count (ANC) ≥ 1500/mm3. --- T790M ---

Aspartate amino transferase (AST) or alanine amino transferase (ALT) ≤ 3 times the upper limit of normal (ULN) (if related to liver metastases ≤ 5 times ULN) - Recovered from any previous therapy related toxicity to ≤ Grade 1 at before randomization (except for stable sensory neuropathy ≤ Grade 2 and alopecia) - Written informed consen Exclusion Criteria: - Any investigational drug within 30 days or hormonal anticancer treatment within 2 weeks prior to randomization (continued use of anti-androgens and/or gonadorelin analogues for treatment of prostate cancer permitted) - T790M mutation positive tumors (by local testing) - Radiotherapy within 2 weeks prior to randomization, except as follows: 1. Palliative radiation to target organs other than chest may be allowed up to 1 week prior to randomization 2. Single dose palliative treatment for symptomatic metastasis outside above allowance to be discussed with coordinating investigator prior to enrolling - Major surgery within 2 weeks before starting study treatment or scheduled for surgery during the projected course of the study - Known hypersensitivity to afatinib or osimertinib or the excipients of any of the trial drugs - History or presence of clinically relevant cardiovascular abnormalities such as 1. uncontrolled hypertension 2. congestive heart failure NYHA classification of ≥ 3 3. unstable angina or poorly controlled arrhythmia as determined by the investigator 4. Myocardial infarction within 6 months prior to randomization 5. Clinically important abnormalities in rhythm and conduction as measured by resting electrocardiogram (ECG) (e.g. --- T790M ---

Other contraindications to study treatment (Investigators opinion) or legal incapacity or limited legal capacity Inclusion Criteria: - Histologically confirmed non-squamous NSCLC harboring EGFR mutation positive but T790M mutation negative by local testing - Unresectable stage UICC ≥ IIIb or metastatic stage UICC IV disease - TKI naïve for metastatic NSCLC, neoadjuvant or adjuvant chemotherapy allowed - At least one evaluable lesion according to RECIST v1.1 - Age ≥ 18 years - ECOG performance status 0 - 2 - Adequate organ function, defined as all of the following: 1. Absolute neutrophil count (ANC) ≥ 1500/mm3. --- T790M ---

Primary Outcomes

Description: The main objective is to investigate whether the time to EGFR-TKI failure at 24 months is better for the treatment sequence of afatinib followed by osimertinib in the T790M positive group compared to osimertinib.

Measure: Time to EGFR-TKI failure within 24 months for afatinib followed by osimertinib in T790Mpositive group vs osimertinib

Time: 24 months

Secondary Outcomes

Description: Time from randomization until ICT is indicated

Measure: Time to EGFR-TKI failure (afatinib versus osimertinib)

Time: 24 months

Description: Time from randomization until disease progression according to RECIST or death

Measure: Progression-free survival (PFS: afatinib followed by osimertinib or ICT vs osimertinib followed by ICT)

Time: 24 months

Description: Survival Status

Measure: Overall Survival (OS)

Time: 24 months

Description: CR+PR according to RECIST

Measure: Response Rate (RR)

Time: 12 months

Description: CR+PR according to RECIST

Measure: Response Rate (RR)

Time: 24 months

Description: CR+PR+SD according to RECIST

Measure: Disease Control Rate (DCR)

Time: 12 months

Description: CR+PR+SD according to RECIST

Measure: Disease Control Rate (DCR)

Time: 24 months

Description: Adverse Events as assessed by intensity of the of the adverse events and the causal relation to trial medication Intensity/Severity: investigator will use the following definitions of severity in accordance with National Cancer Institute common terminology criteria for adverse events, CTCAE, version 5.0; assessment of the relationship of an adverse event to the administration of study drug is a clinical decision by the investigator Institute common terminology criteria for adverse events, CTCAE, version 5.0

Measure: Adverse Events

Time: 24 months

Description: patient-reported quality of life assessed by European Quality of Life 5 Dimensions Questionnaire (EQ-5D)

Measure: Symptom control assessed by patient-reported quality of life (QoL): EQ-5D

Time: 24 months

Description: patient-reported quality of life assessed by Questionnaire of European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)

Measure: Symptom control assessed by patient-reported quality of life (QoL): EORTC QLQ-C30

Time: 24 months

Description: EORTC QLQ-LC29

Measure: Symptom control assessed by patient-reported quality of life (QoL): EORTC QLQ-LC29

Time: 24 months

26 A Pilot Study to Assess the Concordance of Genomic Alterations Between Urine and Tissue to Develop Precision Medicine-Based Immunotherapy Approaches in High-Risk NMIBC Patients

The analysis of cell-free tumor DNA (cfDNA) in plasma has emerged as a clinically relevant predictive and prognostic biomarker in several metastatic solid malignancies, and even now represents standard-of-care for prescription of some targeted therapies in non-small cell lung cancer (blood-based T790M companion diagnostic test). cfDNA can be detected not only in plasma but also in urine, even in patients with non-invasive disease. Recent studies found that the detection of genomic alterations in plasma of urothelial bladder carcinoma patients was relatively uninformative in the localized setting. However, urine cfDNA has been shown to provide a promising resource for robust whole-genome tumor profiling in clinically localized Muscle invasive Bladder cancer (MIBC) and Non-Muscle Invasive Bladder Cancer (NMIBC). Genomic alterations using a targeted next-generation sequencing (NGS) panel have been recently documented in a series of treatment-naïve high-risk NMIBC. The investigator's aim is to determine whether liquid biopsies can be used as a new diagnostic assay to guide immunotherapeutic approaches in patients with high-risk NMIBC. The ultimate goal is to develop a "testing decision tree" to segment patients for informing on therapeutic decision and customizing treatment.

NCT04412070
Conditions
  1. Bladder Cancer
MeSH:Urinary Bladder Neoplasms
HPO:Bladder neoplasm

Assessement of the Concordance of Genomic Alterations Between Urine and Tissue in High-Risk NMIBC Patients The analysis of cell-free tumor DNA (cfDNA) in plasma has emerged as a clinically relevant predictive and prognostic biomarker in several metastatic solid malignancies, and even now represents standard-of-care for prescription of some targeted therapies in non-small cell lung cancer (blood-based T790M companion diagnostic test). --- T790M ---

Primary Outcomes

Description: concordance rate between mutations identified in the tumor

Measure: Agreement rate between urine cell-free DNA and tumor tissue mutation profile

Time: Day 0

Secondary Outcomes

Description: TMB will be calculated in the urine cell-free DNA for Each patient

Measure: Prognostic value of Tumor Mutation Burden (TMB)

Time: Day 0

27 Bevacizumab Plus EGFR Tyrosine Kinase Inhibitors in Chinese Patients With Stage IIIB-IV EGFR-mutant Non-small Cell Lung Cancer: a Prospective,Multicenter, Non-interventional,Real-world Study

This study is a prospective, multicenter, real-world study to investigate the efficacy and safety of bevacizumab plus epidermal growth factor (EGFR) Tyrosine Kinase Inhibitors in Chinese Patients With Stage IIIB/IV EGFR-mutant Non-small Cell Lung Cancer.

NCT04575415
Conditions
  1. NSCLC
Interventions
  1. Drug: Bevacizumab
  2. Drug: Erlotinib
  3. Drug: Gefitinib
  4. Drug: Icotinib
  5. Drug: Afatinib
  6. Drug: Dacomitinib
  7. Drug: Osimertinib

To evaluate the efficacy of bevacizumab combined with EGFR-TKIs in patients with NSCLC harbouring activating EGFR mutations, with or without EGFR T790M mutation,as measured by investigators assessed objective response rate using RECIST v1.1. --- T790M ---

To evaluate the efficacy of bevacizumab combined with EGFR-TKIs in patients with NSCLC harbouring activating EGFR mutations,with or without EGFR T790M mutation,as measured by investigators assessed overall survival.. Incidence of Treatment-Emergent Adverse Events using CTCAE V5.0. --- T790M ---

To evaluate the incidence of Treatment-Emergent Adverse Events of bevacizumab combined with EGFR-TKIs in patients with NSCLC harbouring activating EGFR mutations,with or without EGFR T790M mutation.. Inclusion Criteria: - Patients must meet the following criteria for study entry: 1. Signed Informed Consent Form. 2. Age≥18 years. --- T790M ---

An exon 19 deletion mutation or exon 21 L858R mutation in EGFR has been found clinically, with or without EGFR T790M mutation 5. Eastern Cooperative Oncology Group performance status 0-2 or KPS ≥60 6. --- L858R --- --- T790M ---

Primary Outcomes

Description: To evaluate the efficacy of bevacizumab combined with first-generation EGFR-TKIs in patients with EGFR-mutant NSCLC as measured by investigators

Measure: Progression-free survival (PFS) for bevacizumab plus first-generation EGFR-TKIs by investigator using RECIST v1.1

Time: This is a real-world study. The estimated median PFS for bevacizumab plus first-generation EGFR-TKIs is 18 months according to previous data.

Description: To evaluate the efficacy of bevacizumab combined with second-generation EGFR-TKIs in patients with EGFR-mutant NSCLC as measured by investigators.

Measure: Progression-free survival (PFS) for bevacizumab plus second-generation EGFR-TKIs by investigator using RECIST v1.1

Time: This is a real-world study. The estimated median PFS for bevacizumab plus second-generation EGFR-TKIs is 20 months according to previous data.

Description: To evaluate the efficacy of bevacizumab combined with third-generation EGFR-TKIs in patients with EGFR-mutant NSCLC as measured by investigators.

Measure: Progression-free survival (PFS) for bevacizumab plus third-generation EGFR-TKIs by investigator using RECIST v1.1

Time: This is a real-world study. The estimated median PFS for bevacizumab plus third-generation EGFR-TKIs is 22 months according to previous data.

Secondary Outcomes

Description: To evaluate the efficacy of bevacizumab combined with EGFR-TKIs in patients with NSCLC harbouring activating EGFR mutations, with or without EGFR T790M mutation,as measured by investigators assessed objective response rate using RECIST v1.1

Measure: Objective response rate (ORR) by investigator using RECIST v1.1

Time: Baseline overall tumor assessment can be performed up to 28 days after the first-dose of treatment. Post-baseline assessment will be performed every six weeks until 1st disease progression, through study completion, an average of 2 years.

Description: Disease control rate (DCR) will be analyzed using similar method as objective response rate.

Measure: Disease control rate (DCR) by investigator using RECIST v1.1

Time: Baseline overall tumor assessment can be performed up to 28 days after the first-dose of treatment. Post-baseline assessment will be performed every six weeks until 1st disease progression, through study completion, an average of 2 years.

Description: To evaluate the efficacy of bevacizumab combined with EGFR-TKIs in patients with NSCLC harbouring activating EGFR mutations,with or without EGFR T790M mutation,as measured by investigators assessed overall survival.

Measure: Overall survival

Time: The primary analysis on overall survival is espected to perform on 48 months of follow-up.

Description: To evaluate the incidence of Treatment-Emergent Adverse Events of bevacizumab combined with EGFR-TKIs in patients with NSCLC harbouring activating EGFR mutations,with or without EGFR T790M mutation.

Measure: Incidence of Treatment-Emergent Adverse Events using CTCAE V5.0

Time: This is a real-world study. Safety of the combination treatment is expected to perform until the study completion, an average of 1.5 years,according to CTCAE V5.0.

28 A Prospective, Multi-center, Interventional Study of Osimertinib Combined With Anlotinib in Acquired EGFR T790M Mutated NSCLC Patients With Gradual Progression on Osimertinib Treatment

EGFR T790M gatekeeper mutation accounts for approximately 60% of acquired resistance to the first- or second-generation EGFR-TKI treatment. Osimertinib, a third-generation EGFR TKI, has become the standard therapy for NSCLC patients with acquired EGFR T790M mutation. However, acquired resistance to osimertinib is still inevitable and there is no established targetable agent currently. Thus, treatment strategy for patients with acquire resistance to osimertinib remains an urgent issue. In this study, we aimed to evaluate the efficacy of osimertinib combined with anlotinib in acquired EGFR T790M mutated NSCLC patients with gradual progression on osimertinib treatment.

NCT04438902
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: osimertinib mesylate tablets and anlotinib hydrochloride capsules
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

A Prospective, Multi-center, Interventional Study of Osimertinib Combined With Anlotinib in Acquired EGFR T790M Mutated NSCLC Patients With Gradual Progression on Osimertinib Treatment. --- T790M ---

Osimertinib Combined With Anlotinib in EGFR T790M Mutated NSCLC Patients With Progression on Osimertinib Treatment EGFR T790M gatekeeper mutation accounts for approximately 60% of acquired resistance to the first- or second-generation EGFR-TKI treatment. --- T790M ---

Osimertinib Combined With Anlotinib in EGFR T790M Mutated NSCLC Patients With Progression on Osimertinib Treatment EGFR T790M gatekeeper mutation accounts for approximately 60% of acquired resistance to the first- or second-generation EGFR-TKI treatment. --- T790M --- --- T790M ---

Osimertinib, a third-generation EGFR TKI, has become the standard therapy for NSCLC patients with acquired EGFR T790M mutation. --- T790M ---

In this study, we aimed to evaluate the efficacy of osimertinib combined with anlotinib in acquired EGFR T790M mutated NSCLC patients with gradual progression on osimertinib treatment. --- T790M ---

4. Patients should be confirmed acquired EGFR T790M mutation and received osimertinib as the second line treatment, and they should have the following: (1) benefit from treatment with osimertinib initially ;(2) gradual progression on osimertinib treatment as defined by minor increment of tumor burden (≥10% but <20% in the sum of target lesions). --- T790M ---

We suppose that the combination treatment of osimertinib and anlotinib may ameliorate acquired resistance to osimertinib.This is a multi-center, open, single-arm, exploratory phase 2 trial evaluating osimertinib combined with anlotinib in acquired EGFR T790M mutated NSCLC patients with gradual progression on osimertinib treatment. --- T790M ---

Primary Outcomes

Description: PFS is defined as the time from beginning of osimertinib to disease progression on combination treatment of osimertinib and anlotinib.

Measure: progression-free survival (PFS)

Time: from the date of first dose of osimertinib until the date of disease progression,assessed up to 12 months.

Secondary Outcomes

Description: Objective Response Rate (ORR), is defined as the percentage of patients with complete response or partial response by investigator assessment as recorded in the CRF, which usually refer to Response Evaluation Criteria In Solid Tumours (RECIST) v1.1 in clinical practice.

Measure: Objective Response Rate (ORR)

Time: from the date of combination of osimertinib and anlotinib, assessed up to 6 weeks.

Description: Disease Control Rate (DCR), is defined as the percentage of patients with complete response or partial response or stable disease by investigator assessment as recorded in the CRF, which usually refer to RECIST v1.1 in clinical practice.

Measure: Disease Control Rate (DCR)

Time: from the date of combination of osimertinib and anlotinib, assessed up to 6 weeks.

Description: Incidence of Adverse Events (AEs): Incidence, severity and seriousness of adverse events, incidence of serious adverse events (SAEs), which usually be graded by CTCAE v5.0 based on current clinical practice.

Measure: Adverse events/Serious adverse events

Time: From signing ICF to 30 days after the end of treatment.

29 A Multicenter, Open-Label Phase 1 Study of DS-1205c in Combination With Osimertinib in Subjects With Metastatic or Unresectable EGFR-Mutant Non-Small Cell Lung Cancer

This study has two parts: dose escalation and dose expansion. The primary objectives are: - For Dose Escalation, to assess the safety and tolerability of DS-1205c when combined with osimertinib in the study population and to determine the recommended dose for expansion of DS-1205c when combined with osimertinib in the study population - For Dose Expansion, to assess the safety and tolerability of DS-1205c when combined with osimertinib in the study population In Dose Escalation, after a 7-day run in period (Cycle 0), there will be 21-day cycles (Cycle 1 onward). In Dose Expansion, there will be 21-day cycles. The number of treatment cycles is not fixed in this study. Participants will continue study treatment until they decide not to (withdraw consent), their disease gets worse [progressive disease (PD)], or side effects become unacceptable (unacceptable toxicity).

NCT03255083
Conditions
  1. Non-small Cell Lung Cancer (NSCLC)
Interventions
  1. Drug: DS-1205c
  2. Drug: Osimertinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

9. Demonstrates absence of EGFR T790M. --- T790M ---

Primary Outcomes

Measure: Number of participants with dose-limiting toxicities (DLTs) when taking DS-1205c in combination with osimertinib during dose escalation

Time: within 28 days

Description: Categories: during dose escalation, during dose expansion

Measure: Number of participants with clinically significant safety measures when taking DS-1205c in combination with osimertinib

Time: within 36 months

Secondary Outcomes

Description: DS-1205a is the free form of DS-1205c when DS-1205c is administered alone

Measure: Area under the plasma concentration time curve (AUC) for DS-1205a

Time: during Cycle 0 of the dose escalation period (within 28 days)

Measure: Maximum observed analyte concentration (Cmax) of DS-1205a

Time: during Cycle 0 of the dose escalation period (7 days)

Measure: Actual sampling time to reach Cmax (Tmax) of DS-1205a

Time: during Cycle 0 of the dose escalation period (7 days)

Measure: Area under the analyte concentration versus time curve during a dosing interval (AUCtau) of DS-1205a

Time: during Cycle 0 of the dose escalation period (7 days)

Measure: Minimum observed analyte concentration prior to the beginning, or at the end, of a dosing interval (Ctrough) of DS-1205a

Time: during Cycle 0 of the dose escalation period (7 days)

Description: Categories: DS-1205a, osimertinib, and osimertinib active metabolites (AZ5104 and AZ7550)

Measure: Cmax during a dosing interval (Tau) at steady state (Cmax,ss)

Time: during the dose expansion period, within 36 months

Description: Categories: DS-1205a, osimertinib, and osimertinib active metabolites (AZ5104 and AZ7550)

Measure: Plasma concentration of DS-1205a versus time

Time: during the dose expansion period, within 36 months

Description: Categories: DS-1205a, osimertinib, and osimertinib active metabolites (AZ5104 and AZ7550)

Measure: Tmax

Time: during the dose expansion period, within 36 months

Description: Categories: DS-1205a, osimertinib, and osimertinib active metabolites (AZ5104 and AZ7550)

Measure: Ctrough

Time: during the dose expansion period, within 36 months

Description: Categories: DS-1205a, osimertinib, and osimertinib active metabolites

Measure: AUCtau

Time: during the dose expansion period, within 36 months

Description: Objective response rate is calculated as the number of participants with best objective response [complete response (CR) or partial response (PR) determined by Investigator assessment based on Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1], divided by the number of participants in the analysis population.

Measure: Objective response rate (ORR), graded according to RECIST version 1.1

Time: within 36 months

Measure: Change from baseline in size of target lesion(s)

Time: within 36 months

Description: DOR is defined as the time from documentation of tumor response [either CR or PR] to disease progression

Measure: Duration of response (DOR)

Time: within 36 months

Description: DCR is defined as the sum of CR rate, PR rate, and stable disease (SD) rate

Measure: Disease control rate (DCR)

Time: first dose to 36 months

Description: PFS is defined as the time from the date of the first dose to the earlier of the dates of the first objective documentation of radiographic PD, or death due to any cause

Measure: Progression-free survival (PFS)

Time: baseline to objective disease progression or death from any cause (within 36 months)

Measure: Overall survival (OS)

Time: baseline to death from any cause (within 36 months)

30 An Open Label, Multicenter, Phase II Study of AZD9291 in Non-small Cell Lung Cancer (NSCLC) Patients Harboring T790M Mutation Who Failed EGFR TKIs and With Brain and/or Leptomeningeal Metastasis

AZD9291 is an oral potent irreversible EGFR TKI selective for sensitizing EGFR mutation and T790M resistance mutation but sparing wild-type EGFR. Preclinical studies indicate that AZD9291 has significant exposure in the brain and activity against EGFR mutant brain metastasis. In addition, anti-tumor activities of AZD9291 in patients with advanced stage EGFR mutant NSCLC including patients with brain metastasis have been reported in an ongoing Phase I study. More recently, AZD9291 at a dose of 160mg also showed promising efficacy in heavily pre-treated patients with leptomeningeal disease from EGFR mutant NSCLC. Among 11 evaluable for response, 6 patients had LM imaging improvement and 3 out of 7 patients with abnormal neurological exam at baseline had symptomatic improvement. Compared to AZD9291, other 3rd generation EGFR TKIs, rociletinib or HM61713 has not been reported to be effective in most of CNS disease of NSCLC. Further, previous studies with AZD9291 showed anecdotal case series or undetermined for T790M mutation status, indicating more systematic study is warranted. Based on these data, the investigators are going to conduct phase II study of AZD9291 in NSCLC patients harboring T790M mutation who failed EGFR TKIs and brain and/or leptomeningeal metastasis.

NCT03257124
Conditions
  1. Non-Small Cell Lung Cancer With EGFR T790M Mutation
  2. With Brain and/or Leptomeningeal Metastasis
  3. Failed Tyrosine Kinase Inhibitors
Interventions
  1. Drug: AZD9291
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung Neoplasm Metastasis Meningeal Carcinomatosis
HPO:Neoplasm of the lung Non-small cell lung carcinoma

An Open Label, Multicenter, Phase II Study of AZD9291 in Non-small Cell Lung Cancer (NSCLC) Patients Harboring T790M Mutation Who Failed EGFR TKIs and With Brain and/or Leptomeningeal Metastasis. --- T790M ---

Study of AZD9291 in NSCLC Patients Harboring T790M Mutation Who Failed EGFR TKI and With Brain and/or LMS AZD9291 is an oral potent irreversible EGFR TKI selective for sensitizing EGFR mutation and T790M resistance mutation but sparing wild-type EGFR. --- T790M ---

Study of AZD9291 in NSCLC Patients Harboring T790M Mutation Who Failed EGFR TKI and With Brain and/or LMS AZD9291 is an oral potent irreversible EGFR TKI selective for sensitizing EGFR mutation and T790M resistance mutation but sparing wild-type EGFR. --- T790M --- --- T790M ---

Further, previous studies with AZD9291 showed anecdotal case series or undetermined for T790M mutation status, indicating more systematic study is warranted. --- T790M ---

Based on these data, the investigators are going to conduct phase II study of AZD9291 in NSCLC patients harboring T790M mutation who failed EGFR TKIs and brain and/or leptomeningeal metastasis. --- T790M ---

Adverse events will be measured by the CTCAE scale, version 4.. Exploratory analysis of EGFR mutation/T790M. --- T790M ---

Exploratory analysis of EGFR mutation/T790M in tissue, plasma or cerebrospinal fluid (CSF). --- T790M ---

Inclusion Criteria: - EGFR activating mutant NSCLC patients who failed EGFR TKIs (gefitinib, erlotinib, or afatinib) and develop CNS disease (BM and/or LM) with T790M mutation either tissue or plasma. --- T790M ---

- Past medical history of interstitial lung disease, drug induced interstitial lung disease, radiation pneumonitis which required steroid treatment - History of hypersensitivity to AZD9291 - Known intracranial haemorrahge which is unrelated to tumor Refractory nausea and vomiting Inclusion Criteria: - EGFR activating mutant NSCLC patients who failed EGFR TKIs (gefitinib, erlotinib, or afatinib) and develop CNS disease (BM and/or LM) with T790M mutation either tissue or plasma. --- T790M ---

- Past medical history of interstitial lung disease, drug induced interstitial lung disease, radiation pneumonitis which required steroid treatment - History of hypersensitivity to AZD9291 - Known intracranial haemorrahge which is unrelated to tumor Refractory nausea and vomiting Non-Small Cell Lung Cancer With EGFR T790M Mutation With Brain and/or Leptomeningeal Metastasis Failed Tyrosine Kinase Inhibitors Lung Neoplasms Carcinoma, Non-Small-Cell Lung Neoplasm Metastasis Meningeal Carcinomatosis 1. --- T790M ---

Primary end points - Overall response rate (ORR) in CNS -brain metastasis cohort - Overall survival - Leptomeningeal with or without brain metastasis cohort 2. Secondary end points - Whole body disease control rate (DCR) - Time to brain progression - Progression free survival (PFS) in BM cohort - Overall survival (OS) - Adverse events (AEs) - Exploratory analysis of EGFR mutation/T790M in tissue, plasma or cerebrospinal fluid (CSF) 3. Treatment AZD9291 160mg po daily (1 cycle of 28 days) 4. Total patient sample size Eligible patients will be divided into two cohorts, brain metastasis (BM) cohort and leptomeningeal metastasis (LM) with or without BM cohort. --- T790M ---

Primary Outcomes

Description: At least one visit response of CR (complete response) or PR (partial response) that is confirmed at least 4 weeks later by using RECIST 1.1 criteria

Measure: Overall response rate (ORR) in CNS -brain metastasis cohort

Time: December, 2019 (one-year follow-up from last patient -in)

Description: From the date of study start to the date of all cause death

Measure: Overall survival - Leptomeningeal with or without brain metastasis cohort

Time: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months

Secondary Outcomes

Description: At least one visit response of CR (complete response), PR (partial response) or SD (stable disease) that is confirmed at least 4 weeks later by using RECIST 1.1 criteria.

Measure: Whole body disease control rate (DCR)

Time: December, 2019 (one-year follow-up from last patient -in)

Description: Time to brain progression is measured from the date of start of study to the date of progression of BM or LM.

Measure: Time to brain progression

Time: December, 2019 (one-year follow-up from last patient -in)

Description: measured from the date of start of study to the date of disease progression or death from any cause.

Measure: Progression free survival (PFS) in BM cohort

Time: December, 2019 (one-year follow-up from last patient -in)

Description: OS is measured from the date of start of study to the date of death from any cause

Measure: Overall survival (OS)

Time: December, 2019 (one-year follow-up from last patient -in)

Description: Adverse events will be measured by the CTCAE scale, version 4.

Measure: Adverse events (AEs)

Time: December, 2019 (one-year follow-up from last patient -in)

Description: Exploratory analysis of EGFR mutation/T790M in tissue, plasma or cerebrospinal fluid (CSF)

Measure: Exploratory analysis of EGFR mutation/T790M

Time: December, 2019 (one-year follow-up from last patient -in)

31 A Phase II Study of Nivolumab in Combination With Carboplatin and Pemetrexed, or Nivolumab in Combination With Ipilimumab, in Patients With Advanced, EGFR-mutant or ALK-rearranged, Non-Small Cell Lung Cancer

This research study is studying a drug intervention as a possible treatment for lung cancer. The drugs involved in this study are: - Nivolumab - Carboplatin - Pemetrexed - Ipilimumab

NCT03256136
Conditions
  1. Lung Cancer
Interventions
  1. Drug: Carboplatin
  2. Drug: Nivolumab
  3. Drug: pemetrexed
  4. Drug: Ipilimumab
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

- EGFR-mutant NSCLC: EGFR activating gene mutation (e.g., L858R, exon 19 deletion) as well as a T790M mutation per local testing. --- L858R --- --- T790M ---

- EGFR-mutant NSCLC (cohorts A and C): Participants must have progressed on or after 1 or more third-generation, T790M mutant-selective EGFR-TKI(s). --- T790M ---

Primary Outcomes

Description: Complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

Measure: Objective Response Rate (ORR), Presented in Numbers of Participants

Time: Up to approximately 2 years

Secondary Outcomes

Description: The number of patients that achieved either complete response (CR), partial response (PR), or stable disease (SD) per RECIST version 1.1 Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on study.

Measure: Disease Control Rate (DCR), Presented in Numbers of Participants

Time: Up to approximately 2 years

Description: Time from initiation of the study drugs to progression or death, whichever occurs first. Disease progression was assessed via RECIST 1.1 Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study(this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note:the appearance of one or more new lesions is also considered progression). Confidence Intervals (CIs) were calculated using the Kaplan Meier (KM) method

Measure: Progression Free Survival (PFS)

Time: From the start of treatment until disease progression or death due to any cause, up to approximately 2 years

Description: Time from initiation of the study drugs to date of death due to any cause. CIs are the KM estimate CIs.

Measure: Overall Survival (OS)

Time: From the start of treatment until death due to any cause, up to approximately 2 years

Description: Time from the first documentation of objective tumor response (CR or PR) to the first documentation of objective tumor progression or death due to any cause, whichever occurs first Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study(this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note:the appearance of one or more new lesions is also considered progression).

Measure: Duration Of Response

Time: From the first documented response until disease progression or death, up to approximately 2 years

32 Study of Epithelial Growth Factor Receptor Mutations in Tumor Specimens and Blood Samples From Patients With Non-Small Cell Lung Cancer Enrolled on Clinical Trial CASE-2507

RATIONALE: Studying samples of blood and tissue from patients with cancer in the laboratory may help doctors learn more about changes that occur in DNA and RNA and identify biomarkers related to cancer. PURPOSE: This laboratory study is looking at biomarkers in tumor tissue and blood samples from patients with non-small cell lung cancer.

NCT00907699
Conditions
  1. Lung Cancer
Interventions
  1. Genetic: DNA analysis
  2. Genetic: RNA analysis
  3. Genetic: fluorescence in situ hybridization
  4. Genetic: gene expression analysis
  5. Genetic: mutation analysis
  6. Genetic: polymerase chain reaction
  7. Genetic: reverse transcriptase-polymerase chain reaction
  8. Other: laboratory biomarker analysis
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Predictive value of T790M mutation status of the second biopsy (before maintenance therapy on CASE-2507) on progression-free survival (PFS). --- T790M ---

Difference of PFS between those with and without T790M mutation. --- T790M ---

Difference of clinical response rate between T790M mutation statuses. --- T790M ---

Association between T790M mutation and baseline clinical-pathological factors and smoking status. --- T790M ---

Primary Outcomes

Measure: Predictive value of T790M mutation status of the second biopsy (before maintenance therapy on CASE-2507) on progression-free survival (PFS)

Time: At the time of the second biopsy or surgical procedures

Measure: Difference of PFS between those with and without T790M mutation

Time: At the time of the second biopsy or surgical procedures

Measure: Difference of clinical response rate between T790M mutation statuses

Time: At the time of the second biopsy or surgical procedures

Measure: Predictive value of mutation status on clinical response

Time: At the time of the second biopsy or surgical procedures

Measure: Association between T790M mutation and baseline clinical-pathological factors and smoking status

Time: At the time of the second biopsy or surgical procedures

33 Open-Label, Randomized Trial of Nivolumab (BMS-936558) Plus Pemetrexed/Platinum or Nivolumab Plus Ipilimumab (BMS-734016) vs Pemetrexed Plus Platinum in Stage IV or Recurrent Non-Small Cell Lung Cancer (NSCLC) Subjects With Epidermal Growth Factor Receptor (EGFR) Mutation Who Failed 1L or 2L EGFR Tyrosine Kinase Inhibitor Therapy

The main purpose of this study is to determine whether nivolumab + chemotherapy is effective as compared to chemotherapy in the treatment of patients with EGFR mutation, NSCLC who failed first line (1L) or second-line (2L) EGFR TKI therapy.

NCT02864251
Conditions
  1. Non-Small-Cell Lung Carcinoma
Interventions
  1. Biological: Nivolumab
  2. Biological: Ipilimumab
  3. Drug: Pemetrexed
  4. Drug: Cisplatin
  5. Drug: Carboplatin
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- No evidence of exon 20 T790M mutation obtained at progression on prior first- or second-generation EGFR TKI therapy. --- T790M ---

For participants who were treated with osimertinib, T790M testing is not required. --- T790M ---

- Eastern Cooperative Group (ECOG) Performance Status 0-1 - Life expectancy is at least 3 months Exclusion Criteria: - Known EGFR mutation, T790M positive who failed 1L first- or second-generation TKI should receive osimertinib first as the standard of care (SOC). --- T790M ---

Primary Outcomes

Measure: Progression free survival (PFS) assessed by blinded independent central review (BICR)

Time: up to 47 months

Secondary Outcomes

Measure: Overall survival (OS)

Time: Up to 74 months

Measure: Objective response rate (ORR) per response evaluation criteria in solid tumors (RECIST) 1.1 by BICR

Time: Up to 47 months

Measure: Duration of response (DOR) by BICR

Time: Up to 47 months

Measure: Progression free survival (PFS) rate by BICR

Time: Up to 47 months

34 A Phase I/II, Open-Label, Safety, Pharmacokinetic and Efficacy Study of Ascending Doses of Oral CK-101 in Patients With Advanced Solid Tumors

CK-101 is a novel, potent, small molecule tyrosine kinase inhibitor (TKI) that selectively targets mutant forms of the epidermal growth factor receptor (EGFR) while sparing wild-type (WT) EGFR. The purpose of the study is to evaluate the pharmacokinetic (PK) and safety profile of oral CK-101; to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of oral CK-101; to assess the safety and efficacy of CK-101 in treatment-naive NSCLC patients known to have activating EGFR mutations and previously treated NSCLC patients known to have the T790M EGFR mutation.

NCT02926768
Conditions
  1. Lung Neoplasms
  2. Carcinoma, Non-Small-Cell Lung
  3. Lung Diseases
  4. Adenocarcinoma
Interventions
  1. Drug: CK-101
MeSH:Carcinoma, Non-Small-Cell Lung Lung Neoplasms Lung Diseases
HPO:Abnormal lung morphology Neoplasm of the lung Non-small cell lung carcinoma

The purpose of the study is to evaluate the pharmacokinetic (PK) and safety profile of oral CK-101; to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of oral CK-101; to assess the safety and efficacy of CK-101 in treatment-naive NSCLC patients known to have activating EGFR mutations and previously treated NSCLC patients known to have the T790M EGFR mutation. --- T790M ---

All patients must have evidence of radiological disease progression on or following the last treatment administered; and 3. with documented evidence of EGFR T790M mutation determined by PCR-based testing of the tumor tissue or plasma sample following disease progression on most recent treatment regimen (irrespective of whether this is EGFR TKI or chemotherapy). --- T790M ---

- Refusal to use adequate contraception for fertile patients (females and males) - Presence of any serious or unstable concomitant systemic disorder incompatible with the clinical study - Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection Lung Neoplasms Carcinoma, Non-Small-Cell Lung Lung Diseases Adenocarcinoma Carcinoma, Non-Small-Cell Lung Lung Neoplasms Lung Diseases This is a first-in-human, two-part, open-label, safety, pharmacokinetic, and efficacy study of oral CK-101 administered daily in ascending doses in patients with advanced solid tumor cancer, followed by a Phase 2 portion at the recommended Phase 2 dose (RP2D) in previously treated non-small cell lung cancer (NSCLC) patients who have documented evidence of EGFR T790M mutation and have failed treatment with a first-line EGFR inhibitor. --- T790M ---

Primary Outcomes

Measure: Phase I: Incidence of dose-limiting toxicities (DLTs)

Time: From baseline (first dose) to 28 days after last dose, expected average 6 months

Measure: Phase II: Objective response rate (ORR): Defined as the rate of complete responses [CR] or partial responses [PR] per RECIST Version 1.1 as assessed by an independent central review

Time: From baseline (first dose) until disease progression or withdrawal from study, expected average 10 months

Secondary Outcomes

Measure: Phase II: Evaluation of tumor response based on disease control rate as assessed by RECIST 1.1

Time: From baseline (first dose) until disease progression or withdrawal from study, expected average 10 months

Measure: Phase II: Evaluation of tumor response based on duration of response as assessed by RECIST 1.1

Time: From baseline (first dose) until disease progression or withdrawal from study, expected average 10 months

Measure: Phase II: Evaluation of tumor response based on tumor shrinkage as assessed by RECIST 1.1

Time: From baseline (first dose) until disease progression or withdrawal from study, expected average 10 months

Measure: Phase II: Evaluation of tumor response based on progression free survival as assessed by RECIST 1.1

Time: From baseline (first dose) until disease progression or withdrawal from study, expected average 10 months

Measure: Phase I: Change from baseline in QT/QTc interval

Time: Cycle 1 Day 1 until disease progression or withdrawal from study, expected average 10 months

Measure: Phase I: Plasma concentrations of CK-101 following dosing with CK-101 as assessed by area under the curve

Time: Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycle 2

Measure: Phase I: Plasma concentrations of CK-101 following dosing with CK-101 as assessed by maximum concentration

Time: Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycle 2

Measure: Phase I: Plasma concentrations of CK-101 following dosing with CK-101 as assessed by elimination half-life

Time: Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycle 2

35 Clinical Study of Yiqi-yangyin-jiedu Decoction Combined With Gefitinib in Advanced Pulmonary Adenocarcinoma Patients With Activating EGFR Mutation

The investigators performed a multi-centered, randomized, double blinded, placebo-controlled, prospective clinical trial on the effect of Yiqi-yangyin-jiedu decoction (YYJD), a chinese herbal medicine (CHM) formula combined with gefitinib to prolong the progression free survival (PFS) of advanced pulmonary adenocarcinoma patients with activating EGFR mutation (exon19del or exon21L858R). The investigators plan to enroll 198 cases in 3 years (99 cases for gefitinib, 99 cases for gefitinib plus YYJD), expecting that combination therapy has a better efficacy on prolonging PFS, overall survival, improving quality of life(QOL).

NCT02929693
Conditions
  1. Cancer
Interventions
  1. Drug: gefitinib
  2. Drug: Yiqi-yangyin-jiedu decoction
  3. Drug: placebo
MeSH:Adenocarcinoma Adenocarcinoma of Lung

In approximately 60% of patients, the mechanism of acquired resistance is the development of an additional EGFR mutation, EGFR T790M. --- T790M ---

Although AZD9291 (AstraZeneca), a third-generation EGFR-TKI is reported with a response rate of 61% in NSCLC patients with EGFR T790M and a mPFS of 9.6 months, resistance to third-generation inhibitors mediated by EGFR C797S mutation is inevitable. --- T790M ---

Primary Outcomes

Description: Time from start of the study treatment to date of objective tumour progression (excluding clinical deterioration without evidence of objective progression).

Measure: Progression-free survival (PFS)

Time: 2 months

Secondary Outcomes

Description: interval time from the first date of randomization to that of death for any reason, the end of the study, or loss of follow-up

Measure: Overall survival (OS)

Time: 2 months

Description: The ORR (complete response (CR) plus partial response (PR)) was determined by the Response Evaluation Criteria In Solid Tumors (RECIST) (Eisenhauer et al, 2009) version 1.1.in Solid Tumors (RECIST1.1).

Measure: Objective response rate (ORR)

Time: 2 months

Description: QOL is assessed using Functional Assessment of Cancer therapy-lung (FACT-L) questionnaire .

Measure: Quality of life (QOL)

Time: 2 months

Description: Safety assessment is evaluated according to Common Toxicity Criteria (CTC 3.0).

Measure: Safety assessment evaluated according to Common Toxicity Criteria

Time: 2 months

36 Adjuvant Erlotinib Intercalating Chemotherapy or Adjuvant Chemotherapy Alone in NSCLC With Common EGFR Mutation

This study will be performed as a local multicenter, randomized, phase III clinical study. It will compare the adjuvant chemotherapy in Stage IB-IIIA NSCLC with common EGFR mutation (Exon 19 deletion or L858R) who underwent total resection and the Erlotinib-Intercalation adjuvant chemotherapy with the chemotherapy alone. The patients will be randomly assigned to the Intercalation combination chemotherapy regimen and the chemotherapy alone regimen at the ratio of 1:1. The treatment regimen of each arm is as follows.

NCT02795884
Conditions
  1. NSCLC
Interventions
  1. Drug: intercalation therapy using pemetrexed, cisplatin and erlotinib
  2. Drug: Vinorelbine, cisplatin
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- Age to be ≥ 19 years old - Patients with Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 - Patients who are not pregnant or breastfeeding - Appropriate functions of bone marrow, liver and kidney, when assessed with the following requirements of the laboratory tests to be conducted within 14 days before the initial dose of the study drug: - Absolute neutrophil count (ANC) ≥ 1.5 x 109/L - Platelet count ≥ 100 x 109/L - Total bilirubin ≤ 1.5 times greater than the upper limit of normal - ALT and AST ≤ 2.5 times greater than the upper limit of normal - Alkaline phosphatase ≤ 2.5 times greater than the upper limit of normal - INR and PTT ≤ 1.5 times greater than the upper limit of normal - Appropriate renal function: Serum creatinine ≤ 1.25 × upper limit of normal, or serum creatinine clearance according to Cockcroft-Gault formula(below) ≥50 mL/min Woman CrCl = (140- age [years old]) x weight (kg) x 0.85 72 x serum creatinine (mg/dL) Man CrCl = (140- age [years old]) x weight (kg) x 1.00 72 x serum creatinine (mg/dL) - Patients who are capable of complying with the clinical study protocol and who can take medication orally - Patient who can hear sufficient explanation and sign on the informed consent form Exclusion Criteria: - Any subject who shows any of the following criteria should be excluded from this clinical study: - Patient identified with T790M mutation - Treatable with topical treatments (radiotherapy or surgery) - Previous treatment to inhibit the human epidermal growth factor receptor (EGFR) (e.g. --- T790M ---

Primary Outcomes

Description: Time from randomization to disease recurrence or death of any cause

Measure: Disease-free survival (DFS)

Time: 3 years

Secondary Outcomes

Measure: Overall survival (OS)

Time: 3 years

Measure: Treatment-related adverse events assessed by CTCAE v4.0

Time: 3 years

37 A Phase III, Multi-Centre, Open Label, Randomized Study to Assess the Efficacy and Safety of AZD9291 in Combination With MEDI4736 Versus AZD9291 Monotherapy in Patients With Locally Advanced or Metastatic Epidermal Growth Factor Receptor T790M Mutation-positive Non-Small Cell Lung Cancer Who Have Received Prior Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy (CAURAL)

A Phase III, Multi-Centre, Open Label, Randomized Study to Assess the Efficacy and Safety of AZD9291 in Combination with MEDI4736 versus AZD9291 Monotherapy in patients with Locally Advanced or Metastatic Epidermal Growth Factor Receptor T790M mutation-positive Non-Small Cell Lung Cancer who have received Prior Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy

NCT02454933
Conditions
  1. Locally Advanced or Metastatic EGFR T790M+ NSCLC
Interventions
  1. Drug: AZD9291
  2. Drug: MEDI4736
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

A Phase III, Multi-Centre, Open Label, Randomized Study to Assess the Efficacy and Safety of AZD9291 in Combination With MEDI4736 Versus AZD9291 Monotherapy in Patients With Locally Advanced or Metastatic Epidermal Growth Factor Receptor T790M Mutation-positive Non-Small Cell Lung Cancer Who Have Received Prior Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy (CAURAL). --- T790M ---

Study of AZD9291 Plus MEDI4736 Versus AZD9291 Monotherapy in NSCLC After Previous EGFR TKI Therapy in T790M Mutation Positive Tumours A Phase III, Multi-Centre, Open Label, Randomized Study to Assess the Efficacy and Safety of AZD9291 in Combination with MEDI4736 versus AZD9291 Monotherapy in patients with Locally Advanced or Metastatic Epidermal Growth Factor Receptor T790M mutation-positive Non-Small Cell Lung Cancer who have received Prior Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy Number of Subjects With Adverse Events (AEs) as a Measure of the Safety and Tolerability of Osimertinib in Combination With Durvalumab. --- T790M ---

Study of AZD9291 Plus MEDI4736 Versus AZD9291 Monotherapy in NSCLC After Previous EGFR TKI Therapy in T790M Mutation Positive Tumours A Phase III, Multi-Centre, Open Label, Randomized Study to Assess the Efficacy and Safety of AZD9291 in Combination with MEDI4736 versus AZD9291 Monotherapy in patients with Locally Advanced or Metastatic Epidermal Growth Factor Receptor T790M mutation-positive Non-Small Cell Lung Cancer who have received Prior Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy Number of Subjects With Adverse Events (AEs) as a Measure of the Safety and Tolerability of Osimertinib in Combination With Durvalumab. --- T790M --- --- T790M ---

- Patients must have central lab confirmation of tumour T790M status from a biopsy taken after disease progression on the most recent treatment regimen. --- T790M ---

Only patients with T790M+ will be included in the study - At least one lesion, not previously irradiated and not chosen for biopsy during the study screening period, that can be accurately measured at baseline as ≥ 10mm in the longest diameter (except lymph nodes which must have short axis ≥ 15mm) with computerised tomography (CT) or magnetic resonance imaging (MRI) which is suitable for accurate repeated measurements - World Health Organisation (WHO) performance status 0-1 with no deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks - Females of child-bearing potential using contraception; negative pregnancy test Exclusion Criteria: - Treatment with an EGFR-TKI within 5x half-life of study entry; any cytotoxic chemotherapy, investigational agents or other anticancer drugs within 14 days of study entry; current treatment with potent inhibitors/inducers of cytochrome P450 3A4 (CYP3A4); previous treatment with AZD9291 (or other agents specifically targeted against EGFR T790M mutation positive NSCLC); Prior neo-adjuvant or adjuvant chemotherapy treatment within 6 months of starting 1st EGFR TKI treatment; prior exposure to immune-mediated therapy including, but not limited to, other anti cytotoxic T-lymphocyte-associated antigen 4 (anti CTLA-4), anti- programmed cell death 1 (anti-PD-1), anti- programmed cell death ligand 1 (anti-PD-L1), and anti-programmed cell death ligand 2 (anti-PD-L2) antibodies, excluding therapeutic anticancer vaccines; radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks; major surgery within 4 weeks; - Current or prior use of immunosuppressive medication within 14 days before the first dose of MEDI4736 (excluding intranasal, inhaled, topical steroids, or local steroid injections) - Unresolved toxicities from prior therapy - History of active primary immunodeficiency - Unstable brain metastases or spinal cord compression - Severe/uncontrolled systemic diseases, including uncontrolled hypertension, renal transplant, bleeding diatheses or infection - Cardiac disease - Ophthalmological conditions - Refractory nausea/vomiting, chronic gastrointestinal diseases or bowel resection - Past history of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease. --- T790M ---

- History of another primary malignancy - Active or prior documented autoimmune or inflammatory disorders within the past 3 years prior to the start of treatment - History of organ transplant that requires use of immunosuppressive medications - Known history of tuberculosis - Receipt of live, attenuated vaccine within 30 days prior to the first dose of MEDI4736 - Inadequate bone marrow reserve or organ function Locally Advanced or Metastatic EGFR T790M+ NSCLC Carcinoma, Non-Small-Cell Lung This a phase III, Multi Centre, Open Label, Randomized, Study to Assess the Efficacy and Safety of AZD9291 (80 mg, orally, once daily) in Combination with MEDI4736 (10 mg/kg (IV) infusion q2w) versus AZD9291 Monotherapy (80 mg, orally, once daily) in patients with a confirmed diagnosis of Epidermal Growth Factor Receptor (EGFR) T790M mutation positive NSCLC, who have progressed following prior therapy with an approved Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI) agent. --- T790M ---

A mandatory biopsy will be needed for central testing of T790M mutation status following confirmed disease progression on the most recent treatment regimen. --- T790M ---

Primary Outcomes

Description: As a measure of the safety and tolerability of osimertinib in combination with durvalumab the number of subjects who experienced any treatment emergent AE (TEAE), any causally related AE, any serious AE (SAE), and any causally related SAE are presented.

Measure: Number of Subjects With Adverse Events (AEs) as a Measure of the Safety and Tolerability of Osimertinib in Combination With Durvalumab

Time: From Baseline up to 3 months after the last dose (up to 24 months).

38 A Phase 2 Study of TH-4000 (Tarloxotinib) in Patients With EGFR-Mutant, T790M-Negative, Advanced Non-Small Cell Lung Cancer Progressing on an EGFR Tyrosine Kinase Inhibitor

This phase 2 study is designed to evaluate the safety and activity of TH-4000 (Tarloxotinib), a hypoxia-activated prodrug, in patients with EGFR-Mutant, T790M-Negative, Advanced non-small cell lung cancer (NSCLC).

NCT02454842
Conditions
  1. Non-small Cell Lung Cancer
  2. NSCLC
  3. Non-squamous NSCLC
Interventions
  1. Drug: TH-4000 (Tarloxotinib)
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

A Phase 2 Study of TH-4000 (Tarloxotinib) in Patients With EGFR-Mutant, T790M-Negative, Advanced Non-Small Cell Lung Cancer Progressing on an EGFR Tyrosine Kinase Inhibitor. --- T790M ---

Study for Treatment of Patients With EGFR Mutant, T790M-negative NSCLC This phase 2 study is designed to evaluate the safety and activity of TH-4000 (Tarloxotinib), a hypoxia-activated prodrug, in patients with EGFR-Mutant, T790M-Negative, Advanced non-small cell lung cancer (NSCLC). --- T790M ---

Study for Treatment of Patients With EGFR Mutant, T790M-negative NSCLC This phase 2 study is designed to evaluate the safety and activity of TH-4000 (Tarloxotinib), a hypoxia-activated prodrug, in patients with EGFR-Mutant, T790M-Negative, Advanced non-small cell lung cancer (NSCLC). --- T790M --- --- T790M ---

Key Eligibility Criteria: - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - Confirmed recurrent Stage IV NSCLC which progressed while on treatment with EGFR TKI - Measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) - Documented evidence of an EGFR mutation known to be associated with an EGFR TKI sensitivity - No T790M mutation or small cell transformation including an assessment from tumor biopsy obtained while on or subsequent to the most recent EGFR TKI therapy - Acceptable laboratory results as indicated by protocol - Acceptable cardiac function as indicated by protocol Key Exclusion Criteria: - Receiving medication that prolongs QT interval, with a risk of causing Torsades de Pointes (TdP) unless ECG meets inclusion criteria while on a stable dose of the medication - Family history of long QTc syndrome - Symptomatic central nervous system (CNS) lesions - Radiation therapy within 2 weeks prior to the first dose of study medication - Major surgery within 4 weeks or minor surgery within 2 weeks prior to the first dose of study medication - Concurrent active malignancy requiring systemic treatment - Any other serious uncontrolled medical disorders or psychological conditions that may interfere with study conduct including but not limited to: clinically significant active infection (e.g., tuberculosis, viral hepatitis, human immunodeficiency virus [HIV]), recent (within 6 months) myocardial infarction or unstable angina, congestive heart failure, poorly-controlled hypertension or diabetes, concurrent active malignancy, or psychiatric condition that may interfere with the patient's ability to follow study procedures - Pregnant or breast-feeding Key Eligibility Criteria: - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - Confirmed recurrent Stage IV NSCLC which progressed while on treatment with EGFR TKI - Measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) - Documented evidence of an EGFR mutation known to be associated with an EGFR TKI sensitivity - No T790M mutation or small cell transformation including an assessment from tumor biopsy obtained while on or subsequent to the most recent EGFR TKI therapy - Acceptable laboratory results as indicated by protocol - Acceptable cardiac function as indicated by protocol Key Exclusion Criteria: - Receiving medication that prolongs QT interval, with a risk of causing Torsades de Pointes (TdP) unless ECG meets inclusion criteria while on a stable dose of the medication - Family history of long QTc syndrome - Symptomatic central nervous system (CNS) lesions - Radiation therapy within 2 weeks prior to the first dose of study medication - Major surgery within 4 weeks or minor surgery within 2 weeks prior to the first dose of study medication - Concurrent active malignancy requiring systemic treatment - Any other serious uncontrolled medical disorders or psychological conditions that may interfere with study conduct including but not limited to: clinically significant active infection (e.g., tuberculosis, viral hepatitis, human immunodeficiency virus [HIV]), recent (within 6 months) myocardial infarction or unstable angina, congestive heart failure, poorly-controlled hypertension or diabetes, concurrent active malignancy, or psychiatric condition that may interfere with the patient's ability to follow study procedures - Pregnant or breast-feeding Non-small Cell Lung Cancer NSCLC Non-squamous NSCLC Lung Neoplasms Carcinoma, Non-Small-Cell Lung A single arm open label multi-center Phase 2 study in which the pharmacokinetics, safety, tolerability and efficacy of TH-4000 (Tarloxotinib) will be assessed in patients with EGFR mutant, T790M negative advanced NSCLC. --- T790M ---

Key Eligibility Criteria: - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - Confirmed recurrent Stage IV NSCLC which progressed while on treatment with EGFR TKI - Measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) - Documented evidence of an EGFR mutation known to be associated with an EGFR TKI sensitivity - No T790M mutation or small cell transformation including an assessment from tumor biopsy obtained while on or subsequent to the most recent EGFR TKI therapy - Acceptable laboratory results as indicated by protocol - Acceptable cardiac function as indicated by protocol Key Exclusion Criteria: - Receiving medication that prolongs QT interval, with a risk of causing Torsades de Pointes (TdP) unless ECG meets inclusion criteria while on a stable dose of the medication - Family history of long QTc syndrome - Symptomatic central nervous system (CNS) lesions - Radiation therapy within 2 weeks prior to the first dose of study medication - Major surgery within 4 weeks or minor surgery within 2 weeks prior to the first dose of study medication - Concurrent active malignancy requiring systemic treatment - Any other serious uncontrolled medical disorders or psychological conditions that may interfere with study conduct including but not limited to: clinically significant active infection (e.g., tuberculosis, viral hepatitis, human immunodeficiency virus [HIV]), recent (within 6 months) myocardial infarction or unstable angina, congestive heart failure, poorly-controlled hypertension or diabetes, concurrent active malignancy, or psychiatric condition that may interfere with the patient's ability to follow study procedures - Pregnant or breast-feeding Key Eligibility Criteria: - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - Confirmed recurrent Stage IV NSCLC which progressed while on treatment with EGFR TKI - Measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) - Documented evidence of an EGFR mutation known to be associated with an EGFR TKI sensitivity - No T790M mutation or small cell transformation including an assessment from tumor biopsy obtained while on or subsequent to the most recent EGFR TKI therapy - Acceptable laboratory results as indicated by protocol - Acceptable cardiac function as indicated by protocol Key Exclusion Criteria: - Receiving medication that prolongs QT interval, with a risk of causing Torsades de Pointes (TdP) unless ECG meets inclusion criteria while on a stable dose of the medication - Family history of long QTc syndrome - Symptomatic central nervous system (CNS) lesions - Radiation therapy within 2 weeks prior to the first dose of study medication - Major surgery within 4 weeks or minor surgery within 2 weeks prior to the first dose of study medication - Concurrent active malignancy requiring systemic treatment - Any other serious uncontrolled medical disorders or psychological conditions that may interfere with study conduct including but not limited to: clinically significant active infection (e.g., tuberculosis, viral hepatitis, human immunodeficiency virus [HIV]), recent (within 6 months) myocardial infarction or unstable angina, congestive heart failure, poorly-controlled hypertension or diabetes, concurrent active malignancy, or psychiatric condition that may interfere with the patient's ability to follow study procedures - Pregnant or breast-feeding Non-small Cell Lung Cancer NSCLC Non-squamous NSCLC Lung Neoplasms Carcinoma, Non-Small-Cell Lung A single arm open label multi-center Phase 2 study in which the pharmacokinetics, safety, tolerability and efficacy of TH-4000 (Tarloxotinib) will be assessed in patients with EGFR mutant, T790M negative advanced NSCLC. --- T790M --- --- T790M ---

Key Eligibility Criteria: - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - Confirmed recurrent Stage IV NSCLC which progressed while on treatment with EGFR TKI - Measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) - Documented evidence of an EGFR mutation known to be associated with an EGFR TKI sensitivity - No T790M mutation or small cell transformation including an assessment from tumor biopsy obtained while on or subsequent to the most recent EGFR TKI therapy - Acceptable laboratory results as indicated by protocol - Acceptable cardiac function as indicated by protocol Key Exclusion Criteria: - Receiving medication that prolongs QT interval, with a risk of causing Torsades de Pointes (TdP) unless ECG meets inclusion criteria while on a stable dose of the medication - Family history of long QTc syndrome - Symptomatic central nervous system (CNS) lesions - Radiation therapy within 2 weeks prior to the first dose of study medication - Major surgery within 4 weeks or minor surgery within 2 weeks prior to the first dose of study medication - Concurrent active malignancy requiring systemic treatment - Any other serious uncontrolled medical disorders or psychological conditions that may interfere with study conduct including but not limited to: clinically significant active infection (e.g., tuberculosis, viral hepatitis, human immunodeficiency virus [HIV]), recent (within 6 months) myocardial infarction or unstable angina, congestive heart failure, poorly-controlled hypertension or diabetes, concurrent active malignancy, or psychiatric condition that may interfere with the patient's ability to follow study procedures - Pregnant or breast-feeding Key Eligibility Criteria: - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - Confirmed recurrent Stage IV NSCLC which progressed while on treatment with EGFR TKI - Measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) - Documented evidence of an EGFR mutation known to be associated with an EGFR TKI sensitivity - No T790M mutation or small cell transformation including an assessment from tumor biopsy obtained while on or subsequent to the most recent EGFR TKI therapy - Acceptable laboratory results as indicated by protocol - Acceptable cardiac function as indicated by protocol Key Exclusion Criteria: - Receiving medication that prolongs QT interval, with a risk of causing Torsades de Pointes (TdP) unless ECG meets inclusion criteria while on a stable dose of the medication - Family history of long QTc syndrome - Symptomatic central nervous system (CNS) lesions - Radiation therapy within 2 weeks prior to the first dose of study medication - Major surgery within 4 weeks or minor surgery within 2 weeks prior to the first dose of study medication - Concurrent active malignancy requiring systemic treatment - Any other serious uncontrolled medical disorders or psychological conditions that may interfere with study conduct including but not limited to: clinically significant active infection (e.g., tuberculosis, viral hepatitis, human immunodeficiency virus [HIV]), recent (within 6 months) myocardial infarction or unstable angina, congestive heart failure, poorly-controlled hypertension or diabetes, concurrent active malignancy, or psychiatric condition that may interfere with the patient's ability to follow study procedures - Pregnant or breast-feeding Non-small Cell Lung Cancer NSCLC Non-squamous NSCLC Lung Neoplasms Carcinoma, Non-Small-Cell Lung A single arm open label multi-center Phase 2 study in which the pharmacokinetics, safety, tolerability and efficacy of TH-4000 (Tarloxotinib) will be assessed in patients with EGFR mutant, T790M negative advanced NSCLC. --- T790M --- --- T790M --- --- T790M ---

Primary Outcomes

Measure: Number of participants with response rate as evaluated by RECIST criteria

Time: Approximately 12 months

Secondary Outcomes

Measure: Incidence of adverse events (AEs)

Time: Up to 30 days after last dose

Measure: Type of adverse events (AEs)

Time: Up to 30 days after last dose

Measure: Severity of adverse events (AEs)

Time: Up to 30 days after last dose

Measure: Duration of response (DOR) calculated for all patients achieving an objective response

Time: Approximately 12 months

Measure: Progression-free survival (PFS)

Time: Approximately 12 months

Measure: Overall Survival (OS)

Time: Approximately 12 months

Description: Time to peak plasma concentration (Tmax), maximum plasma concentration (Cmax), area under concentration-time curve (AUC)

Measure: Time to peak plasma concentration (Tmax)

Time: Cycle 1 Day 1 predose and up to 24 hours post dose

Measure: Maximum plasma concentration (Cmax)

Time: Cycle 1 Day 1 predose and up to 24 hours post dose

Measure: Area under concentration-time curve (AUC)

Time: Cycle 1 Day 1 predose and up to 24 hours post dose

Measure: QTc Interval

Time: Screening, Cycle 1 Day 1, 8, 15 & 22, Day 1 of subsequent cycles

Other Outcomes

Measure: Hypoxic volume as measured by Positron Emission Tomography (PET) hypoxia imaging

Time: Baseline

39 Pilot Study of Local Therapies for Oligometastatic Non-Small Cell Lung Cancer Harboring Sensitizing EGFR Mutations

This study will test if local therapies in addition to erlotinib can improve responses and delay the time until new treatment is required. This study will also collect blood samples for research blood tests.

NCT02450591
Conditions
  1. Oligometastatic Lung Adenocarcinoma
Interventions
  1. Drug: Erlotinib
  2. Other: Local Therapies
MeSH:Adenocarcinoma of Lung

- For women of child-bearing potential, negative pregnancy test within 14 days prior to starting treatment - Men and women of childbearing age must be willing to use effective contraception while on treatment and for at least 3 months thereafter Exclusion Criteria: - Treatment with erlotinib prior to developing metastatic disease - Patients with activating but not sensitizing mutations (exon 20 insertions, EGFR T790M) - Malignant pleural effusion or pleural disease - Leptomeningeal disease - Any site of disease that is not amenable to definitively local therapy including surgery or radiation therapy - Women who are breastfeeding or pregnant - Concurrent malignancies other than non-melanoma skin cancer that require active ongoing treatment. --- T790M ---

Primary Outcomes

Description: At least five patients will need to complete local therapy within 2 years of the study being open to accrual for the primary endpoint to be met.

Measure: Feasibility as Measured by at Least Five Patients Will Need to Complete Local Therapy.

Time: 2 years

40 A Multi-center, AZD9291 Expanded Access Program for the Treatment of Patients With Advanced/Metastatic EGFR T790M Mutation-positive Non-small Cell Lung Cancer (NSCLC) Who Have Received Prior EGFR TKI Therapy

To provide access to AZD9291 for adult patients with advanced/metastatic, epidermal growth factor receptor T790M mutation-positive non-small cell lung cancer.

NCT02451852
Conditions
  1. EGFR T790M Mutation Positive NSCLC
Interventions
  1. Drug: AZD9291

A Multi-center, AZD9291 Expanded Access Program for the Treatment of Patients With Advanced/Metastatic EGFR T790M Mutation-positive Non-small Cell Lung Cancer (NSCLC) Who Have Received Prior EGFR TKI Therapy. --- T790M ---

AZD9291 US Expanded Access Program To provide access to AZD9291 for adult patients with advanced/metastatic, epidermal growth factor receptor T790M mutation-positive non-small cell lung cancer. --- T790M ---

Inclusion Criteria: - Provision of signed and dated, written informed consent prior to any treatment protocol-specific procedures - Patients aged at least 18 years - Locally advanced or metastatic EGFRm NSCLC, not amenable to curative surgery or radiotherapy with confirmation of the presence of the T790M mutation - Two lines of prior therapy including at least one EGFR TKI - World Health Organization (WHO) performance status 0-2. --- T790M ---

- Patients with symptomatic CNS metastases who are neurologically unstable - Past medical history of ILD, drug-induced ILD, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active ILD - Any of the following cardiac criteria: 1. Mean resting corrected QT interval (QTc using Fredericia's formula) > 470 msec 2. Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block, second degree heart block) 3. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval - Any unresolved toxicity from prior therapy Common Terminology Criteria for Adverse Events (CTCAE) > grade 3 at the time of starting treatment in the access program - History of hypersensitivity to AZD9291 (or drugs with a similar chemical structure or class to AZD9291) or any excipients of these agents - Males and females of reproductive potential who are not using an effective method of birth control and females who are pregnant or breastfeeding or have a positive (urine or serum) pregnancy test prior to access program entry Inclusion Criteria: - Provision of signed and dated, written informed consent prior to any treatment protocol-specific procedures - Patients aged at least 18 years - Locally advanced or metastatic EGFRm NSCLC, not amenable to curative surgery or radiotherapy with confirmation of the presence of the T790M mutation - Two lines of prior therapy including at least one EGFR TKI - World Health Organization (WHO) performance status 0-2. --- T790M ---

- Patients with symptomatic CNS metastases who are neurologically unstable - Past medical history of ILD, drug-induced ILD, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active ILD - Any of the following cardiac criteria: 1. Mean resting corrected QT interval (QTc using Fredericia's formula) > 470 msec 2. Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block, second degree heart block) 3. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval - Any unresolved toxicity from prior therapy Common Terminology Criteria for Adverse Events (CTCAE) > grade 3 at the time of starting treatment in the access program - History of hypersensitivity to AZD9291 (or drugs with a similar chemical structure or class to AZD9291) or any excipients of these agents - Males and females of reproductive potential who are not using an effective method of birth control and females who are pregnant or breastfeeding or have a positive (urine or serum) pregnancy test prior to access program entry EGFR T790M Mutation Positive NSCLC - This is a multi-center, AZD9291 expanded access protocol for the treatment of adult patients with advanced/metastatic EGFR T790M mutation-positive non-small cell lung cancer (NSCLC) who have received prior EGFR TKI therapy and at least one additional line of therapy (≥ 3rd line). --- T790M ---

- Patients with symptomatic CNS metastases who are neurologically unstable - Past medical history of ILD, drug-induced ILD, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active ILD - Any of the following cardiac criteria: 1. Mean resting corrected QT interval (QTc using Fredericia's formula) > 470 msec 2. Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block, second degree heart block) 3. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval - Any unresolved toxicity from prior therapy Common Terminology Criteria for Adverse Events (CTCAE) > grade 3 at the time of starting treatment in the access program - History of hypersensitivity to AZD9291 (or drugs with a similar chemical structure or class to AZD9291) or any excipients of these agents - Males and females of reproductive potential who are not using an effective method of birth control and females who are pregnant or breastfeeding or have a positive (urine or serum) pregnancy test prior to access program entry EGFR T790M Mutation Positive NSCLC - This is a multi-center, AZD9291 expanded access protocol for the treatment of adult patients with advanced/metastatic EGFR T790M mutation-positive non-small cell lung cancer (NSCLC) who have received prior EGFR TKI therapy and at least one additional line of therapy (≥ 3rd line). --- T790M --- --- T790M ---


41 Pemetrexed Disodium and Cisplatin Chemotherapy Combined With Synchronous Gefitinib vs Chemotherapy Alone as Adjuvent Therapy in Patient With Stage II-IIIA, Epidermal Growth Factor Receptor Mutant Expressing Lung Adenocarcinoma

This randomized phase III trial is studying gefitinib and synchronous pemetrexed/cisplatin chenmotherapy to see how well it works compared to pemetrexed/cisplatin chenmotherapy alone in treating patients who have undergone surgery for stage II-IIIA(N1-N2) lung adenocarcinoma with EGFR activating mutation in Asian population.

NCT02518802
Conditions
  1. Lung Neoplasms
Interventions
  1. Drug: Gefitinib
  2. Drug: Pemetrexed
MeSH:Adenocarcinoma Lung Neoplasms Adenocarcinoma of Lung
HPO:Neoplasm of the lung

pyrexia of or 38.0℃ over) - Patients who harbouring exon 20 T790M mutation. --- T790M ---

Primary Outcomes

Description: To evaluate the disease free survival of synchronous therapy versus combination of Pemetrexed plus Cisplatin as adjuvant treatment for pathological stage II-IIIA(N1-N2) lung adenocarcinoma with EGFR mutation.Disease free survival (DFS)- defined as the time from randomization to the first documented disease progression or death, whichever occurs first.

Measure: Disease free survival

Time: From date of randomization to the first documented disease progression or death, whichever occurs first, assessed up to 3 and 5 years.

Secondary Outcomes

Description: To evaluate the overall survival of synchronous therapy versus combination of Pemetrexed plus Cisplatin as adjuvant treatment for stage II-IIIA(N1-N2) lung adenocarcinoma with EGFR mutation.

Measure: Overall survival

Time: From date of randomization to the first documented death, assessed up to 5 years.

Description: The safety and tolerability profile of gefitinib at a 250 mg daily dose relative to that of Chemotherapy.

Measure: Number of Participants with Adverse Events

Time: In the period of Gefitinib 250 mg/day oral daily for 24 months. Pemetrexed 500 mg/m2 intravenous infusion on day 1, Cisplatin 75 mg/m2 on day 1 for 4 cycles.

Description: Quality of life as measured by the total score and Trial Outcome Index (TOI) of the Functional Assessment of Cancer Therapy - Lung Cancer (FACT-L) questionnaire.

Measure: Quality of life

Time: In the period of Gefitinib 250 mg/day oral daily for 24 months. Pemetrexed 500 mg/m2 intravenous infusion on day 1, Cisplatin 75 mg/m2 on day 1 for 4 cycles.

42 Liquid Biopsies in Patients With Advanced Non-small Cell Lung Cancer

The goal of this project is to characterize the genetic profile of patients with advanced stage IIIB/IV non-small cell lung cancer (NSCLC) using liquid biopsies

NCT02511288
Conditions
  1. Carcinoma, Non-Small-Cell Lung
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

It is presently used in routine for detecting the EGFR mutations at diagnosis as well as for searching EGFR T790M mutation for resistant patients. --- T790M ---

Primary Outcomes

Description: Technique: ddPCR + targeted NGF, whole exome sequencing

Measure: Identification of the genetic profile in advanced or metastatic NSCLC patients using liquid biopsies (circulating tumoral DNA)

Time: 5 years

Secondary Outcomes

Description: Techniques: ddPCR + targeted NGF, whole exome sequencing

Measure: Identification of genetic biomarkers (or molecular profiles) having a potential predictive value in the treatments response

Time: 5 years

Description: Techniques: ddPCR + targeted NGF, whole exome sequencing

Measure: Detection of the ALK and ROS1 genes translocations in the circulating DNA

Time: 5 years

Description: Correlation between mutated allelic fractions or expression's modification with the treatment response. Techniques: ddPCR + targeted NGF, whole exome sequencing

Measure: Evaluation of the liquid biopsies role in the tumoral monitoring

Time: 5 years

Description: Correlation between transcriptomic and genomic factors and response to immunotherapy. Techniques: ddPCR + targeted NGF, whole exome sequencing

Measure: Evaluation of genomic and transcriptomic factors detectable in the plasma, associated to the immunotherapy response

Time: 5 years

Description: Techniques: ddPCR + targeted NGF, whole exome sequencing

Measure: Evaluation of the spatial and temporal tumor heterogeneity under targeted therapy treatment

Time: 5 years

Description: Correlation between miRNAS expression in plasma and treatment's efficacy. Techniques: miRNAs profiling using HTG technology

Measure: Evaluation of the miRNAs' expression in plasma as an epigenetic factor associated to treatments response

Time: 5 years

Description: Single cell isolation technology

Measure: Circulating tumoral cells isolation and analysis to determine the role of non-genomic and/or phenotypic factors in the treatments response.

Time: 5 years

Description: Technique: ddPCR + targeted NGF, whole exome sequencing

Measure: Evaluation of the resistance mechanisms to targeted therapies

Time: 5 years

43 A Phase III, Double-blind, Randomized, Placebo-controlled Multi-centre, Study to Assess the Efficacy and Safety of AZD9291 Versus Placebo, in Patients With Epidermal Growth Factor Receptor Mutation Positive Stage IB-IIIA Non-small Cell Lung Carcinoma, Following Complete Tumour Resection With or Without Adjuvant Chemotherapy (ADAURA).

To assess the efficacy and safety of AZD9291 versus Placebo, in patients with Epidermal Growth Factor Receptor Mutation Positive stage IB-IIIA non-small cell lung carcinoma, following complete tumour resection with or without adjuvant chemotherapy

NCT02511106
Conditions
  1. Stage IB-IIIA Non-small Cell Lung Carcinoma
Interventions
  1. Drug: AZD9291 80 mg/40 mg
  2. Drug: Placebo AZD9291 80 mg/40 mg
MeSH:Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Carcinoma Neoplasm of the lung Non-small cell lung carcinoma

5. Confirmation by the central laboratory that the tumour harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R), either alone or in combination with other EGFR mutations including T790M. --- L858R --- --- T790M ---

Primary Outcomes

Description: Defined as the time from the date of randomization until the date of disease recurrence or death (by any cause in the absence of recurrence)

Measure: Disease free survival (DFS)

Time: From date of randomization until date of disease recurrence or death (by any cause in the absence of recurrence). Estimated median time to event of 46 and 66 months for those on placebo and AZD9291, respectively.

Secondary Outcomes

Description: Defined as the proportion of patients alive and disease free at 2, 3 and 5 years, respectively, estimated from Kaplan Meier plots of the primary endpoint of DFS at the time of the primary analysis

Measure: Disease free survival (DFS) rate at 2, 3 and 5 years

Time: From date of randomization until date of disease recurrence or death (by any cause in the absence of recurrence). Estimated median time to event of 46 and 66 months for those on placebo and AZD9291, respectively.

Description: Defined as the time from the date of randomization until date of death due to any cause

Measure: Overall Survival (OS)

Time: From date of randomization until date of death due to any cause (estimated median 96 months for those on placebo)

Description: Defined as the proportion of patients alive at 5 years, estimated from a Kaplan Meier plot of OS at the time of the primary analysis

Measure: Overall Survival rate at 5 years

Time: From date of randomization until date of death due to any cause (estimated median 96 months for those on placebo)

Description: Measured by SF-36 Questionnaire consisting in 36 items that is an instrument for assessing a person's general health status over the past 28 days. The scores for each of the 8 health domain scores and for each of the physical and mental component summary measures from the SF-36 v2 will be summarized in terms of mean changes from baseline at each post-baseline assessment.

Measure: Patient health-related quality of life and symptoms (HRQoL) by SF-36v2 Health Survey

Time: From date of randomization until treatment completion or discontinuation (max. 36 months)

Description: The pharmacokinetics exposure parameters derived from plasma concentrations of AZD9291

Measure: Plasma concentrations of AZD9291

Time: From date of dosing to month 24 (approximately 24 months)

Description: The pharmacokinetics exposure parameters derived from plasma concentrations of AZ5104 and AZ7550 metabolites

Measure: Plasma concentrations of AZ5104 and AZ7550 metabolites and ratio of metabolite to AZD9291

Time: From date of dosing to month 24 (approximately 24 months)

Other Outcomes

Description: AEs graded by CTCAE version 4.0

Measure: Incidence of Adverse Events (AEs)

Time: From date of randomization until 28 days after treatment completion (max. 37 months)

44 AZD9291, an Irreversible EGFR-TKI, in Relapsed EGFR-mutated Non-small Cell Lung Cancer Patients Previously Treated With an EGFR-TKI, Coupled to Extensive Translational Studies

Phase II, single-arm study to assess the safety and efficacy of AZD9291 (80 mg, orally, once daily) in second-line (or later) patients with EGFR mutation-positive, locally advanced or metastatic NSCLC, who have progressed following treatment with an approved epidermal growth factor tyrosine kinase inhibitor agent.

NCT02504346
Conditions
  1. Lung Cancer
  2. Targeted Therapy
Interventions
  1. Drug: AZD9291
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

4. Radiological disease progression following at least one prior EGFR TKI. 5. Documented EGFR mutation known to be associated with EGFR TKI sensitivity (also including T790M). --- T790M ---

Primary Outcomes

Description: Measured by RECIST 1.1

Measure: Objective response rate

Time: 12 weeks

45 A Phase 1 Trial of MLN0128 (TAK-228) in Combination With Osimertinib (AZD9291) in Advanced EGFR Mutation Positive Non-Small Cell Lung Cancer (NSCLC) After Progression on a Previous EGFR Tyrosine Kinase Inhibitor

This phase I trial studies the side effects and best dose of sapanisertib when given together with osimertinib in treating patients with stage IV EGFR mutation positive non-small cell lung cancer that has progressed after treatment with an EGFR tyrosine kinase inhibitor. Sapanisertib and osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT02503722
Conditions
  1. Metastatic Lung Non-Small Cell Carcinoma
  2. Recurrent Lung Non-Small Cell Carcinoma
  3. Stage III Lung Non-Small Cell Cancer AJCC v7
  4. Stage IIIA Lung Non-Small Cell Cancer AJCC v7
  5. Stage IIIB Lung Non-Small Cell Cancer AJCC v7
  6. Stage IV Lung Non-Small Cell Cancer AJCC v7
Interventions
  1. Other: Laboratory Biomarker Analysis
  2. Drug: Osimertinib
  3. Other: Pharmacological Study
  4. Drug: Sapanisertib
MeSH:Carcinoma Carcinoma, Non-Small-Cell Lung
HPO:Carcinoma Non-small cell lung carcinoma

These will be listed for each patient and summarized using standard descriptive methods.. Response rate of patients with T790M- NSCLC in an expansion cohort. --- T790M ---

These will be listed for each patient and summarized using standard descriptive methods.. Disease control rate of patients with T790M- NSCLC in an expansion cohort. --- T790M ---

These will be listed for each patient and summarized using standard descriptive methods.. Progression free survival of patients with T790M- NSCLC in an expansion cohort. --- T790M ---

Primary Outcomes

Description: Toxicities will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 4 (CTCAE v4). CTCAE version 5.0 will be utilized beginning April 1, 2018.

Measure: Maximum tolerated dose of sapanisertib in combination with osimertinib in patients with EGFRmutant (m) non-small cell lung cancer (NSCLC)

Time: 28 days

Description: Toxicities will be graded according to the NCI CTCAE v4. CTCAE version 5.0 will be utilized beginning April 1, 2018.

Measure: Dose-limiting toxicity (DLT) of sapanisertib in combination with osimertinib in patients with EGFRm NSCLC

Time: 28 days

Secondary Outcomes

Description: Frequency and severity of adverse events will be tabulated using counts and proportions detailing frequently occurring, serious and severe events of interest. Adverse events will be summarized using all adverse events experienced, although a sub-analysis may be conducted including only those adverse events in which the treating physician deems possibly, probably or definitely attributable to one or both study treatments.

Measure: Non-DLTs associated with the administration of sapanisertib and osimertinib

Time: Up to 30 days after completion of study treatment

Description: PK analyses will be descriptive and will permit the evaluation of the PK profile of Tsapanisertib when combined with osimertinib.

Measure: Pharmacokinetic (PK) profiles of sapanisertib in combination with osimertinib

Time: Baseline, and at 1, 2, 4, 6, 8, and 24 hours post-sapanisertib administration, before administration and at 1, 2, 4, 6, 8, and 24 hours post-sapanisertib on day 26 of course 1; and day 1 of course 2

Description: Will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Summary statistics such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics. Treatment administered will be reported including the number of cycles, dose modifications, reason off treatment, reason off study, whether a DLT was experienced, best response, and time to progression. These will be listed for each patient and summarized using standard descriptive methods.

Measure: Response rate

Time: Up to 2 years

Description: Summary statistics such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics. Treatment administered will be reported including the number of cycles, dose modifications, reason off treatment, reason off study, whether a DLT was experienced, best response, and time to progression. These will be listed for each patient and summarized using standard descriptive methods.

Measure: Disease control rate

Time: Up to 2 years

Description: Summary statistics such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics. Treatment administered will be reported including the number of cycles, dose modifications, reason off treatment, reason off study, whether a DLT was experienced, best response, and time to progression. These will be listed for each patient and summarized using standard descriptive methods.

Measure: Progression free survival

Time: From start of treatment to time of progression or death, whichever occurs first, assessed up to 2 years

Description: Will be assessed using RECIST 1.1. Summary statistics such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics. Treatment administered will be reported including the number of cycles, dose modifications, reason off treatment, reason off study, whether a DLT was experienced, best response, and time to progression. These will be listed for each patient and summarized using standard descriptive methods.

Measure: Response rate of patients with T790M- NSCLC in an expansion cohort

Time: Up to 2 years

Description: Summary statistics such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics. Treatment administered will be reported including the number of cycles, dose modifications, reason off treatment, reason off study, whether a DLT was experienced, best response, and time to progression. These will be listed for each patient and summarized using standard descriptive methods.

Measure: Disease control rate of patients with T790M- NSCLC in an expansion cohort

Time: Up to 2 years

Description: Summary statistics such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics. Treatment administered will be reported including the number of cycles, dose modifications, reason off treatment, reason off study, whether a DLT was experienced, best response, and time to progression. These will be listed for each patient and summarized using standard descriptive methods.

Measure: Progression free survival of patients with T790M- NSCLC in an expansion cohort

Time: At 6 months

Description: Predictors of clinical outcomes will be investigated using logistic regression, Cox proportional hazards regression and or generalized estimating equations as appropriate. Potential predictors include clinical predictors and molecular correlates analyzed in tumor and blood. Descriptive statistics and plotting of data will also be used to better understand potential relationships.

Measure: Biomarkers of response and resistance to the combination, explored by studying baseline biopsies, resistance biopsies, and serial plasma deoxyribonucleic acid specimens

Time: Up to 2 years

46 A Phase II, Open Label, Single-arm Study to Assess the Safety and Efficacy of AZD9291 in Asia Pacific Patients With Locally Advanced/Metastatic Non-Small Cell Lung Cancer Whose Disease Has Progressed With Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and Whose Tumours Harbour a T790M Mutation Within the Epidermal Growth Factor Receptor Gene

A Phase II, Open Label, Single-arm Study to Assess the Safety and Efficacy of AZD9291 in Asia Pacific Patients with Locally Advanced/Metastatic Non-Small Cell Lung Cancer whose Disease has Progressed with Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and whose Tumours harbour a T790M mutation within the Epidermal Growth Factor Receptor Gene

NCT02442349
Conditions
  1. Non-Small Cell Lung Cancer
Interventions
  1. Drug: AZD9291
MeSH:Lung Neoplasms Carcinoma, Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

A Phase II, Open Label, Single-arm Study to Assess the Safety and Efficacy of AZD9291 in Asia Pacific Patients With Locally Advanced/Metastatic Non-Small Cell Lung Cancer Whose Disease Has Progressed With Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and Whose Tumours Harbour a T790M Mutation Within the Epidermal Growth Factor Receptor Gene. --- T790M ---

Phase II Single Arm Study of AZD9291 to Treat NSCLC Patients in Asia Pacific A Phase II, Open Label, Single-arm Study to Assess the Safety and Efficacy of AZD9291 in Asia Pacific Patients with Locally Advanced/Metastatic Non-Small Cell Lung Cancer whose Disease has Progressed with Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and whose Tumours harbour a T790M mutation within the Epidermal Growth Factor Receptor Gene Objective Response Rate (ORR) According to RECIST 1.1. --- T790M ---

- Patients must have central confirmation of tumour T790M mutation positive status from a biopsy sample taken after confirmation of disease progression on the most recent treatment regimen. --- T790M ---

Non-Small Cell Lung Cancer Lung Neoplasms Carcinoma, Carcinoma, Non-Small-Cell Lung This is a phase II, open label, single arm study assessing the safety and efficacy of AZD9291 (80 mg, orally, once daily) in Asia Pacific patients with a confirmed diagnosis of Epidermal Growth Factor Receptor (EGFR) sensitising mutation positive (ie, G719X, exon 19 deletion, L858R, L861Q) and T790M mutation positive (hereafter referred to as EGFRm+ and T790M+) un-resectable, locally advanced or metastatic NSCLC (Stage IIIB-IV), who have progressed on an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor(EGFR-TKI), either as first line treatment or following one line of EGFR-TKI and one line of platinum containing doublet chemotherapy. --- L858R --- --- L861Q --- --- T790M ---

Patients must agree to provide a biopsy for central confirmation of T790M mutation status following confirmed disease progression on the most recent treatment regimen. --- T790M ---

Primary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR (according to independent review) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.

Measure: Objective Response Rate (ORR) According to RECIST 1.1

Time: RECIST tumour assessments every 6 weeks from time of first dose until objective disease progression, for an average of approximately 12 months. Results are based on the data cut off of 04 March 2016 (about 18 weeks after LSFD).

Secondary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions; Stable disease (SD): Neither sufficient shrinkage to qualify as a response nor sufficient growth to qualify as progression; Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. DCR is the percentage of patients with best response of CR, PR or SD (according to independent review), prior to progression (PD) or further anti-cancer therapy.

Measure: Disease Control Rate (DCR) According to RECIST 1.1

Time: RECIST tumour assessments every 6 weeks from time first dose until date of progression, for an average of approximately 12 months. Results are based on the data cut off of 04 March 2016 (about 18 weeks after LSFD).

47 A Phase I, Multicenter, Open-Label Safety, Pharmacokinetic and Preliminary Efficacy Study of Wild-type Sparing EGFR Inhibitor, AC0010MA, in Adult Patients With Previously Treated EGFRmut and Acquired T790M Mutation Non-Small Cell Lung Cancer (NSCLC)

AC0010MA is a new, irreversible, Epidermal Growth Factor Receptor (EGFR) mutation selective Tyrosine Kinase Inhibitor. Aim at local advanced or metastatic non-small cell lung cancer patients with EGFR mutation or T790M drug-resistant mutation. The molecular mechanism: by irreversible combining the EGFR-RTKs ATP binding site of cell, selectively suppress the activities of EGFR tyrosine kinase phosphorylation, block the signal transduction pathway of EGFR and inhibit the function of ras/raf/MAPK downstream, thus block the tumor cell growth by EGFR induction, and promotes apoptosis. AC0010MA Maleate Capsules has three characters: 1. Irreversible binding to EGFR; 2. Effectively suppresses the tumor cell with EGFR mutant while has no suppression to EGFR wild-type cell; 3. Efficient suppress the tumor cell with EGFR T790M drug-resistant mutation.

NCT02448251
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: AC0010MA
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

A Phase I, Multicenter, Open-Label Safety, Pharmacokinetic and Preliminary Efficacy Study of Wild-type Sparing EGFR Inhibitor, AC0010MA, in Adult Patients With Previously Treated EGFRmut and Acquired T790M Mutation Non-Small Cell Lung Cancer (NSCLC). --- T790M ---

Aim at local advanced or metastatic non-small cell lung cancer patients with EGFR mutation or T790M drug-resistant mutation. --- T790M ---

AC0010MA Maleate Capsules has three characters: 1. Irreversible binding to EGFR; 2. Effectively suppresses the tumor cell with EGFR mutant while has no suppression to EGFR wild-type cell; 3. Efficient suppress the tumor cell with EGFR T790M drug-resistant mutation. --- T790M ---

4. Has documented evidence of an activating EGFR mutation in the tumor tissue determined by either sequencing or PCR-based technique (Part 1). 5. For Part 1 only: subjects with a positive T790M mutation are preferred, but not required. --- T790M ---

Confirmation of T790M mutation status will be determined from an archived tumor tissue sample or fresh tumor tissue sample obtained via biopsy if archived tissue is not available. --- T790M ---

In Part 2, subjects must have a confirmed, positive T790M EGFR mutation (acquired T790M EGFR mutation or "de novo" T790M EGFR mutation). --- T790M ---

In Part 2, subjects must have a confirmed, positive T790M EGFR mutation (acquired T790M EGFR mutation or "de novo" T790M EGFR mutation). --- T790M --- --- T790M ---

In Part 2, subjects must have a confirmed, positive T790M EGFR mutation (acquired T790M EGFR mutation or "de novo" T790M EGFR mutation). --- T790M --- --- T790M --- --- T790M ---

9. Has documented disease progression while receiving at least 30 days of treatment with a currently approved EGFR tyrosine kinase inhibitor (TKI) (e.g., erlotinib, gefitinib or afatinib) with intervening treatment after most recent EGFR TKI therapy (not required for "de novo" T790M EGFR mutation). --- T790M ---

Primary Outcomes

Description: To determine the safety and tolerability and to establish the maximum tolerated dose (MTD) of AC0010MA by incidence of dose limiting toxicity (DLT), defined as Grade 3 or 4 adverse events (AEs) and clinical lab abnormalities occurring within the first 28 days of treatment.

Measure: Safety and tolerability, and the maximum tolerated dose (MTD) of AC0010MA determined by incidence of dose limiting toxicity (DLT)

Time: Within the first 28 days of treatment.

Secondary Outcomes

Description: To characterize tumor response (objective response rate, ORR) and duration of response of AC0010MA as a criterion for further development of AC0010MA in this patient population.

Measure: Evaluation of tumor response and duration of response of AC0010MA ((objective response rate, ORR)

Time: within the time frame of every 8 weeks (2 cycles) for up to 3 years

Description: To evaluate pharmacokinetic parameter of AC0010MA

Measure: Maximum plasma concentration (Cmax) of AC0010MA

Time: Blood samples will be collected at pre-treatment, and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 24h post-treatment on Days 1, 8, and 28 in the first treatment cycle (QD and BID) in Phase I

Description: To evaluate pharmacokinetic parameter of AC0010MA

Measure: Time to Cmax

Time: Blood samples will be collected at pre-treatment, and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 24h post-treatment on Days 1, 8, and 28 in the first treatment cycle (QD and BID) in Phase I

Description: To evaluate pharmacokinetic parameter of AC0010MA

Measure: Terminal half-life (t1/2)

Time: Blood samples will be collected at pre-treatment, and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 24h post-treatment on Days 1, 8, and 28 in the first treatment cycle (QD and BID) in Phase I

Description: To evaluate pharmacokinetic parameter of AC0010MA

Measure: Area under the plasma concentration-time curve

Time: Blood samples will be collected at pre-treatment, and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 24h post-treatment on Days 1, 8, and 28 in the first treatment cycle (QD and BID) in Phase I

Description: To evaluate pharmacokinetic parameter of AC0010MA

Measure: Volume of distribution (V/F)

Time: Blood samples will be collected at pre-treatment, and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 24h post-treatment on Days 1, 8, and 28 in the first treatment cycle (QD and BID) in Phase I

Description: To evaluate pharmacokinetic parameter of AC0010MA

Measure: Plasma Concentration (CL/F)

Time: Blood samples will be collected at pre-treatment, and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 24h post-treatment on Days 1, 8, and 28 in the first treatment cycle (QD and BID) in Phase I

48 An Open-Label, Multicenter, Phase 1 Study With Expansion Cohorts of Ramucirumab or Necitumumab in Combination With Osimertinib in Patients With Advanced T790M-Positive EGFR-Mutant Non-Small Cell Lung Cancer After Progression on First-Line EGFR TKI Therapy

The main purpose of this study is to evaluate the safety of ramucirumab or necitumumab in combination with osimertinib in participants with non-small cell lung cancer (NSCLC).

NCT02789345
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: Ramucirumab
  2. Drug: Necitumumab
  3. Drug: Osimertinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

An Open-Label, Multicenter, Phase 1 Study With Expansion Cohorts of Ramucirumab or Necitumumab in Combination With Osimertinib in Patients With Advanced T790M-Positive EGFR-Mutant Non-Small Cell Lung Cancer After Progression on First-Line EGFR TKI Therapy. --- T790M ---

- Have T790M-positive status using a test validated and performed locally after disease progression on EGFR tyrosine kinase inhibitor (TKI) treatment. --- T790M ---

Primary Outcomes

Measure: Number of Participants with Dose Limiting Toxicities (DLTs)

Time: Up to Two Cycles (Up to 21 Day Cycles)

Secondary Outcomes

Measure: Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab

Time: Day 1 Cycle 2 to Day 1 Cycle 13 (14 Day Cycles)

Measure: PK: Cmin of Necitumumab

Time: Day 1 Cycle 3 to Day 1 Cycle 9 (21 Day Cycles)

Measure: Objective Response Rate (ORR): Percentage of Participants with a Complete Response (CR) or Partial Response (PR)

Time: Baseline to Objective Disease Progression (Approximately 30 Months)

Measure: Disease Control Rate (DCR): Percentage of Participants with CR, PR or Stable Disease (SD)

Time: Baseline to Objective Disease Progression (Approximately 30 Months)

Measure: Duration of Response (DoR)

Time: Date of CR or PR to Date of Objective Disease Progression or Death from Any Cause (Approximately 30 Months)

Measure: Progression Free Survival (PFS)

Time: Baseline to Measured Progressive Disease or Death from Any Cause (Approximately 30 Months)

Measure: Overall Survival (OS)

Time: Baseline to Death from Any Cause (Approximately 30 Months)

49 A Phase II Trial of Hypofractionated Radiotherapy for Limited Metastatic NSCLC Harboring Sensitizing EGFR Mutations After First Line TKI Therapy

To evaluate the efficacy and toxicity of patients treated with hypofractionated radiotherapy for limited metastatic NSCLC harboring sensitizing EGFR mutations after first line TKI therapy. An exploratory biomarker analysis in blood and tumor samples is also planned.

NCT02788058
Conditions
  1. Lung Adenocarcinoma
  2. EGFR Positive Non-small Cell Lung Cancer
Interventions
  1. Drug: EGFR-TKI
  2. Radiation: Thoracic Hypofractionated Radiotherapy
MeSH:Adenocarcinoma Adenocarcinoma of Lung

Frequency of T790M mutation before treatment detected by ctDNA. --- T790M ---

Abundance of T790M mutation before treatment detected by ctDNA. --- T790M ---

Frequency of T790M mutation after radiotherapy detected by ctDNA. --- T790M ---

Abundance of T790M mutation after radiotherapy detected by ctDNA. --- T790M ---

Frequency of T790M mutation after 1 year detected by ctDNA. --- T790M ---

Abundance of T790M mutation after 1 year detected by ctDNA. --- T790M ---

Two reasons can be used to explain the formation of the residual lesion:1)there is a subgroup of cancer cells that are not sensitive to TKI therapy because of tumor heterogeneity, like de novo T790M mutation; 2)some cancer cells can keep static state during the beginning treatment, and then develops acquired resistance to TKI therapy under the long-term drug pressure and continue to re-proliferation. --- T790M ---

Primary Outcomes

Measure: Progression free survival

Time: 3 years

Secondary Outcomes

Measure: Frequency of T790M mutation before treatment detected by ctDNA

Time: 1 months

Measure: Abundance of T790M mutation before treatment detected by ctDNA

Time: 1 months

Measure: Frequency of T790M mutation after radiotherapy detected by ctDNA

Time: 3 months

Measure: Abundance of T790M mutation after radiotherapy detected by ctDNA

Time: 3 months

Measure: Frequency of T790M mutation after 1 year detected by ctDNA

Time: 1 year

Measure: Abundance of T790M mutation after 1 year detected by ctDNA

Time: 1 year

Description: We will assess the rate of symptomatic radiation pneumonitis in patients who received the radiation therapy.

Measure: Rate of CTCAE grade 2 or higher radiation pneumonitis

Time: 1 years

Description: FACT-E score at the 4 months after docetaxel consolidation therapy

Measure: To assess the short-term quality of life (QOL)

Time: 4 months

50 A Phase 2 Study of XL647 in Subjects With Non-Small Cell Lung Cancer Who Have Progressed After Responding to Treatment With Either Gefitinib or Erlotinib

The purpose of this study is to determine the best confirmed response rate of daily administration of the multiple receptor tyrosine kinase (RTK) inhibitor (including EGFR and VEGFR2) XL647 in subjects with NSCLC who have progressed after responding to treatment with either erlotinib or gefitinib.

NCT00522145
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Drug: XL647
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- Subjects must have: 1. documented (radiological or clinical) progressive disease (PD) following a prior response (including stable disease) to monotherapy with erlotinib or gefitinib that was administered for at least 12 weeks prior to progression OR 2. a documented T790M EGFR mutation - Measurable disease defined according to RECIST - ECOG performance status of 0 or 1. - Sexually active subjects must use an accepted method of contraception during the course of the study. --- T790M ---

Primary Outcomes

Measure: Determine the best confirmed response rate

Time: Inclusion until disease progression

Secondary Outcomes

Measure: Safety and tolerability of XL647 administered daily

Time: First treatment until 30 day post last treatment

Measure: Progression-free survival, duration of response, and overall survival

Time: Incusion until disease progression

Measure: Further characterize the pharmacokinetic (PK) parameters

Time: Every 8 weeks after Day 57 until disease progression

51 A Single Arm, Phase II Study of Atezolizumab (MPDL3280A, Anti-PD-L1 Antibody) in Combination With Bevacizumab in Patients With EGFR Mutation Positive Stage IIIB/IV Non-Squamous Non-Small Cell Lung Cancer Pretreated With Epidermal Growth Factor Receptor Tyrosine-Kinase Inhibitors

This is an open-label, single-arm, phase II, multicenter study designed to evaluated the efficacy and safety of atezolizumab in combination with bevacizumab in PD-L1-selected patients with Stage IIIB/IV Non-Squamous NSCLC harbored EGFR mutation after EGFR TKI therapy.

NCT04426825
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Drug: Atezolizumab
  2. Drug: Bevacizumab
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Patients who have progressed on or were intolerant to first- or second-generation EGFR TKIs, and who have no evidence of the EGFR T790M mutation after TKI therapy are eligible. --- T790M ---

Patients who have progressed on or were intolerant to first- or second-generation EGFR TKIs and who have evidence of the T790M mutation must have also progressed on or were intolerant to osimertinib to be eligible. --- T790M ---

Primary Outcomes

Description: PFS rate at 6 months, defined as the proportion of participants who have not experienced disease progression or death from any cause at 6 months after enrollment, as determined by the investigator according to RECIST v1.1

Measure: Progression Free Survival (PFS) Rate at 6 Months

Time: 6 months

Secondary Outcomes

Description: Objective response rate (ORR), defined as the proportion of patients with a complete response (CR) or partial response (PR) on two consecutive occasions ≥4 weeks apart, as determined by the investigator according to RECIST v1.1

Measure: Objective Response Rate (ORR)

Time: Baseline up to approximately 3 years

Description: Duration of objective response (DOR), defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause whichever occurs first, as determined by the investigator according to RECIST v1.1.

Measure: Duration of Objective Response (DOR)

Time: Baseline up to approximately 3 years

Description: Time to response (TTR), defined as the time from the start of the treatment to the first objective tumor response observed for patients who achieved CR or PR, as determined by the investigator according to RECIST v1.1.

Measure: Time to Response (TTR)

Time: Baseline up to approximately 3 years

Description: Overall survival (OS) after enrollment, defined as the time from enrollment to death from any cause.

Measure: Overall Survival (OS)

Time: Baseline until death due to any cause (up to approximately 3 years)

Description: Progression-free survival (PFS), defined as the time from enrollment to the first occurrence of disease progression or death from any cause, whichever occurs first, as determined by the investigator according to RECIST v1.1

Measure: Progression-Free Survival (PFS)

Time: Baseline up to approximately 3 years

Description: PFS rate at 12 months, defined as the proportion of patients who have not experienced disease progression or death from any cause at 12 months, as determined by the investigator according to RECIST v1.1.

Measure: PFS Rate at 12 Months

Time: 12 months

Description: OS rate at 1 and 2 years, defined as the proportion of patients who have not experienced death from any cause at 1 and 2 years.

Measure: OS Rate at 1 and 2 Years

Time: 1 and 2 Years

Measure: Incidence of Adverse Events

Time: Baseline up to approximately 3 years

Description: Incidence of serious and non-serious immune-related adverse events (irAEs) related to atezolizumab treatment.

Measure: Incidence of Serious and Non-Serious Immune-Related Adverse Events (irAEs)

Time: Baseline up to approximately 3 years

Description: Participants will be tested by two kits - SP 142 and SP 263. Positive results from SP142 or SP263 will be accepted. Sp142 +/Sp263- and Sp142-/ SP263+ (cutoff data is 1% positive) data will be collected to do the consistency test by x2-test.

Measure: Consistency Among in SP 142 and SP 263

Time: Baseline up to approximately 12 months

52 Phase II Study of Osimertinib With Bevacizumab for Leptomeningeal Metastasis From EGFR-mutation Non-Small Cell Lung Cancer

Leptomeningeal metastasis (LM) is a fatal complication of advanced non-small cell lung cancer (NSCLC) associated with poor prognosis and rapid deterioration of performance status. The incidence of LM is increasing, reaching 3.8% in molecularly unselected NSCLC patients, being more frequent in adenocarcinoma subtype and up to 9% in epidermal growth factor receptor mutation (EGFRm) lung cancer patients, one-third of patients have concomitant brain metastasis . This increased incidence may in part be conducive to the increased survival of patients with EGFRm advanced NSCLC since the introduction of EGFR-tyrosine kinase inhibitions (TKIs).Currently, no standard therapeutic regimen for LM has been established because of its rarity and heterogeneity[11], and no approved therapies exists to specifically target LM in patients with EGFRm NSCLC. TKIs therapy is the first-line treatment of patients with EGFRm of NSCLC. The leptomeningeal space is a sanctuary site for tumour cells and therapeutic agents due to the presence of an active blood-brain barrier (BBB), so CSF concentration is an important factor affecting treatment of LM by TKIs. Standard-dose first- and second-generation EGFR-TKIs have good systemic efficacy but sub-optimal CNS penetration, as evidenced by preclinical studies of brain distribution and clinical reports of CSF penetration[15, 16]. Osimertinib is a third-generation EGFR-TKI, irreversible, oral EGFR-TKI that potently and selectively inhibits both EGFR-TKI sensitizing and EGFR T790M resistance mutations, which has demonstrated efficacy in NSCLC CNS metastasis[17-22]. Preclinical, I/II clinical studies and AURA program (AURA extension, AURA2, AURA17 and AURA3) have shown that Osimertinib has higher brain permeability than the first- and second-generation. Bevacizumab is a recombinant humanized monoclonal antibody against vascular endothelial growth factor (VEGF), animal studies and autopsy specimens show that VEGF plays an important role in LM. VEGF and EGFR share many overlapping and parallel downstream pathways. The biological rationale shows that inhibiting of EGFR and VEGR signaling pathways could improve the efficacy of antitumor and remove the resistance of EGFR inhibition. Besides, preclinical researches have shown the similar results. Based on these, numbers of clinical trials have confirmed that VEGF inhibitors in combination with EGFR-TKI significantly prolong patients' survival.

NCT04425681
Conditions
  1. Leptomeningeal Metastasis
  2. Non-small Cell Lung Cancer
  3. EGFR Activating Mutation
Interventions
  1. Drug: Osimertinib
  2. Drug: Bevacizumab
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung Neoplasm Metastasis Neoplasms, Second Primary Meningeal Carcinomatosis
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Osimertinib is a third-generation EGFR-TKI, irreversible, oral EGFR-TKI that potently and selectively inhibits both EGFR-TKI sensitizing and EGFR T790M resistance mutations, which has demonstrated efficacy in NSCLC CNS metastasis[17-22]. --- T790M ---

Primary Outcomes

Description: Time from LM diagnosis to the first documentation of disease progression or death

Measure: LM progression-free survival

Time: up to 1 year

Description: ORR, proportion of patients with a best overall response of complete response or partial response (CR+PR)

Measure: Objective Response Rate

Time: up to 1 year

Secondary Outcomes

Description: LM-OS defined as time from LM diagnosis to death due to any cause or last follow-up

Measure: LM Overall survival

Time: Every 6 weeks, up to 2 years

Description: Proportion of patients progression-free by investigator assessment per RECIST v1.1

Measure: progression-free survival

Time: Every 6 weeks, up to 2 years

Description: Number of patients with adverse events (AEs) as a measure of safety and tolerability

Measure: adverse events

Time: Every 3 weeks, up to 2 years

53 Analysis of Re-biopsy Specimens in Advanced Non-small Cell Lung Cancer With Acquired Resistance of Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor Targeted Therapy

The objective of the study is to reveal the acquired resistance mechanism of the first and second generation Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor (EGFR-TKI) in tissue and plasma using Next Generation Sequencing (NGS) and the difference of ctDNA in plasma and DNA in biopsy samples is compared and the consistency of two samples was observed. At the same time, the sensitivity, specificity and the consistency of detecting T790M mutation using ddPCR, Cobas and NGS were compared.

NCT03309462
Conditions
  1. Lung Cancer
Interventions
  1. Device: Miseq sequencer
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

At the same time, the sensitivity, specificity and the consistency of detecting T790M mutation using ddPCR, Cobas and NGS were compared. --- T790M ---

The tissue will be divided into two parts, one part was sent to Pathology Department of Shanghai Chest Hospital and will be processed with paraffin-embedded, and for those diagnosed NSCLC, the other part will be extracted with DNA and performed NGS for the qualified DNA sample and using Cobas to detect the T790M mutation. --- T790M ---

Primary Outcomes

Description: differences of gene mutation between re-biopsy tissue sample and peripheral blood sample will be tested by NGS

Measure: Compare the differences of gene mutation between tissue sample and peripheral blood sample by NGS

Time: up to one year

54 Single-arm,Multi-center,Phase II Clinical Trial of the Efficacy and Safety of AC0010 in the Treatment of EGFR T790M Mutation-positive Patients With Advanded NSCLC

The study is a single-arm, multi-center, open-label clinical trial. The study aims to expand the sample size based on the fixed dose recommended by the results of previous dose exploration studies in order to further evaluate the study drug's efficacy and safety.

NCT03300115
Conditions
  1. Metastatic Non-small Cell Lung Cancer
Interventions
  1. Drug: AC0010
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Single-arm,Multi-center,Phase II Clinical Trial of the Efficacy and Safety of AC0010 in the Treatment of EGFR T790M Mutation-positive Patients With Advanded NSCLC. --- T790M ---

Clinical Trial of the Efficacy and Safety of AC0010 in the Treatment of EGFR T790M Patients With Advanded NSCLC The study is a single-arm, multi-center, open-label clinical trial. --- T790M ---

To assess the overall objective response rate (ORR) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).. DoR (Duration of Response). --- T790M ---

To assess the duration of response (DOR) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).. PFS (Progression-free survival). --- T790M ---

To assess the progression-free survival (PFS) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).. DCR (Disease control rate). --- T790M ---

To assess the disease control rate (DCR) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).. OS (Overall survival). --- T790M ---

To assess the overall survival (OS) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).. --- T790M ---

To assess the safety of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).. Inclusion Criteria: 1. Aged 18-75 years (including 18 and 75 years old). --- T790M ---

The number of CNS metastases focus≤2, maximum diameter <10mm. 5. Document prove EGFR mutation before treatment of EGFR TKI, or show clinical benefit after treatment of EGFR TKI (PR, CR evaluation according to RECIST or more than half-year SD duration); tumor tissue proved to be EGFR T790M positive mutation by center lab after last treatment. --- T790M ---

7. Patients who have previously received first-generation EGFR-TKI (erlotinib, gefitinib, ectectin) treatment and developed resistance and are only allowed to have received one chemotherapy regimen (maintenance treatment with the same drug is allowed; but maintenance treatment with a different drug is not allowed), or are positive for primary T790M mutation but have not received treatment or have only received first-line treatment. --- T790M ---

Primary Outcomes

Description: To assess the overall objective response rate (ORR) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).

Measure: ORR(Objective Response Rate)

Time: Every 6 weeks from time of first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 12 months.

Secondary Outcomes

Description: To assess the duration of response (DOR) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).

Measure: DoR (Duration of Response)

Time: Every 6 weeks from time of first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 12 months.

Description: To assess the progression-free survival (PFS) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).

Measure: PFS (Progression-free survival)

Time: Every 6 weeks from time of first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 12 months.

Description: To assess the disease control rate (DCR) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).

Measure: DCR (Disease control rate)

Time: Every 6 weeks from time of first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 12 months.

Description: To assess the overall survival (OS) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).

Measure: OS (Overall survival)

Time: Every 6 weeks from time of first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 12 months.

Description: To assess the safety of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).

Measure: The lung cancer symptoms and health-related quality of life (HRQoL)

Time: Every 3 weeks from time of first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months.

55 A Phase II, Open-label, Single-arm, Multicenter, Efficacy and Safety of 80mg Osimertinib in Patients With Leptomeningeal Metastases(LM) Associated With EGFR Mutation-positive Non-small Cell Lung Cancer(NSCLC)

This will be a Phase II, open-label, single-arm, multicenter study of the efficacy and safety of osimertinib (80 mg orally once daily) in patients with LM associated with EGFRm+ NSCLC.

NCT04563871
Conditions
  1. Non-small Cell Lung Cancer (NSCLC)
Interventions
  1. Drug: 80mg Osimertinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

3. Male and female patients must be at least 18 years of age. 4. Patients must have documented (only allowed for EGFRm+ [exon 19 deletions or L858R] in pre-treated patients) and/or confirmed central/local test result showing eligible EGFR mutation status as specified below: - EGFR TKI pre-treated patients: EGFRm+ (exon 19 deletions or L858R), along with valid T790M mutation status 5. --- L858R --- --- L858R --- --- T790M ---

6. EGFR TKI pre-treated patients must have had at least 1 prior EGFR TKI (eg, gefitinib, erlotinib, icotinib, dacomitinib or afatinib) and may have had other lines of therapy 7. If the patients is T790M negative, EXC must be stable following previous EGFR TKI treatment. --- T790M ---

EXC progression is allowed if patients are T790M positive patients 8. ECOG/WHO performance status 0 to 2 with no deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks. --- T790M ---

Exclusion Criteria: 1. EGFR TKI pre-treated patients whose T790M mutation status cannot be determined. --- T790M ---

2. EGFR TKI pre-treated patients with progressing EXC disease who are T790M mutation-negative. --- T790M ---

Patient has previously participated in the present study, except for rescreened patients with T790M mutation-negative disease who were previously screened but were excluded due to progressing EXC disease that has subsequently been stabilized. --- T790M ---

Primary Outcomes

Description: To investigate the efficacy of osimertinib on LM as measured by OS

Measure: Overall survival

Time: Up to 30 months

Secondary Outcomes

Description: BICR(Blinded independent central review) assessments, based on neuroimaging RANO-LM

Measure: LM ORR(Objective response rate)

Time: Up to 30 months

Description: BICR(Blinded independent central review) assessments, based on neuroimaging RANO-LM

Measure: LM DoR(Duration of response)

Time: Up to 30 months

Description: BICR(Blinded independent central review) assessments, based on neuroimaging RANO-LM

Measure: LM DCR(Disease control rate)

Time: Up to 30 months

Description: BICR(Blinded independent central review) assessments, based on neuroimaging RANO-LM

Measure: LM PFS(Progression-free survival)

Time: Up to 30 months

Description: To investigate the efficacy of osimertinib in patients with LM associated with EGFRm+ NSCLC on the CSF cytological clearance

Measure: CSF response rate based on CSF cytology

Time: Up to 30 months

56 An Open-label Phase 1 Trial to Evaluate the Safety and Tolerability of a Modified Vaccinia Ankara (MVA) Priming Followed by Fowlpox Booster Vaccines Modified to Express Brachyury and T-cell Costimulatory Molecules (MVA-BN-Brachyury/FPV-Brachyury)

An open-label Phase 1 trial to evaluate the safety and tolerability of MVA-BN-Brachyury priming and FPV-Brachyury boost vaccines modified to express brachyury and T-cell costimulatory molecules in patients with a metastatic or unresectable locally advanced malignant solid tumor. Subjects will be given the following subcutaneous doses: two prime doses with MVA-BN-Brachyury and monthly boost doses with FPV-Brachyury for 6 months. The study will last approximately 104 weeks before starting long term follow up (FU).

NCT03349983
Conditions
  1. Safety Issues
Interventions
  1. Biological: MVA-BN-Brachyury/ FPV-Brachyury

Patients with T790M mutations may continue receiving osimertinib while receiving vaccine. --- T790M ---

Primary Outcomes

Description: Fraction of patients who experience a (Dose Limiting Toxicity) DLT.

Measure: Patients with Dose Limiting Toxicity

Time: up to 8 weeks

57 A Phase 2, Multi-center, Open Label Study of NIR178 in Combination With PDR001 in Patients With Selected Advanced Solid Tumors and Non-Hodgkin Lymphoma

The purpose of this phase 2 study is to evaluate the efficacy and safety of NIR178 in combination with PDR001 in multiple solid tumors and diffuse large B-cell lymphoma (DLBCL) and further explore schedule variations of NIR178 to optimize immune activation through inhibition of A2aR.

NCT03207867
Conditions
  1. NSCLC, Non Small Cell Lung Cancer
  2. RCC, Renal Cell Cancer
  3. Pancreatic Cancer
  4. Urothelial Cancer
  5. Head and Neck Cancer
  6. DLBCL, Diffused Large B Cell Lymphoma
  7. MSS, Microsatellite Stable Colon Cancer
  8. TNBC, Triple Negative Breast Cancer
  9. Melanoma
  10. mCRPC, Metastatic Castration Resistant Prostate Cancer
Interventions
  1. Drug: NIR178
  2. Drug: PDR001
MeSH:Lymphoma Lymphoma, Non-Hodgkin Triple Negative Breast Neoplasms Carcinoma, Renal Cell
HPO:Clear cell renal cell carcinoma Lymphoma Non-Hodgkin lymphoma Papillary renal cell carcinoma Renal cell carcinoma

Patients with EGFR positive NSCLC with a T790M mutation must have progressed on osimertinib or discontinued due to toxicity. --- T790M ---

Primary Outcomes

Description: Response assessed by RECIST v1.1 (for solid tumors), Cheson (for DLBCL) or PCWG3 criteria (for mCRPC)

Measure: Determine the overall response rate

Time: Every 8 weeks for first 40 weeks

Description: Response assessed by RECIST v1.1 (for solid tumors), Cheson (for DLBCL) or PCWG3 criteria (for mCRPC)

Measure: Determine the overall response rate

Time: Every 12 weeks after the first 40 weeks until disease progression or study discontinuation (an average of 6 months)

Description: Response assessed by RECIST v1.1 (for solid tumors), Cheson (for DLBCL), or PCWG3 criteria (for mCRPC)

Measure: Determine the overall response rate

Time: Baseline

Secondary Outcomes

Description: Proportion of patients with a best overall response of CR or PR or SD

Measure: Determine the disease control rate (DCR)

Time: Baseline

Description: Time from first documented response to disease progression

Measure: Determine the duration of response (DoR)

Time: Baseline

Description: Time from start of treatment to date of death due to any reason

Measure: Determine the overall survival rate (OR)

Time: Every 12 weeks until end of study for at least 24 months from the start date of the study treatment

Description: Time from start of treatment to date of the first documented progression or death in months

Measure: Progression free survival (PFS)

Time: Baseline

Description: Type, frequency, and severity of AEs and SAEs; Frequency of dose interruptions, reductions and discontinuation, Dose intensity

Measure: Safety and tolerability of the NIR178 and PDR001 combination

Time: Date of consent to end of study (An average of 24 months)

Description: Change from baseline in TILs by immunohistochemistry (IHC) (such as CD8)

Measure: Characterize changes in the immune infiltrate in tumors

Time: Screening

Description: Presence and/or concentration of anti-PDR001 antibodies

Measure: Presence and/or concentration of anti-PDR001 antibodies

Time: Starting from the first dose of study treatment to Cycle 6 Day 1

Description: Plasma concentration time profiles of NIR178 and its metabolites

Measure: Pharmacokinetics: Area under plasma concentration versus time curve (AUC) (NIR178)

Time: Starting from the first dose of study treatment to Cycle 6 Day 1

Description: Plasma concentration time profiles of PDR001

Measure: Pharmacokinetics: Area under the plasma concentration versus time curve (AUC) (PDR001)

Time: End of treatment and as needed (an average of 6 months)

Description: Plasma concentration time profiles of NIR178

Measure: Plasma concentration Vs Time profiles (NIR178)

Time: End of treatment and as needed (an average of 6 months)

Description: Plasma concentration time profiles of PDR001

Measure: Plasma concentration Vs Time profiles (PDR001)

Time: End of treatment and as needed (an average of 6 months)

Description: Plasma concentration time profiles of NIR178

Measure: Peak plasma concentration- Cmax (NIR178)

Time: End of treatment and as needed (an average of 6 months)

Description: Plasma concentration time profiles of PDR001

Measure: Peak plasma concentration- Cmax (PDR001)

Time: End of treatment and as needed (an average of 6 months)

Description: Plasma concentration time profiles of NIR178

Measure: Time of maximum concentration observed- Tmax (NIR178)

Time: End of treatment and as needed (an average of 6 months)

Description: Plasma concentration time profiles of PDR001

Measure: Time of maximum concentration observed- Tmax (PDR001)

Time: End of treatment and as needed (an average of 6 months)

Description: Proportion of patients with a best overall response of CR or PR or SD

Measure: Determine the disease control rate (DCR)

Time: Every 8 weeks for first 40 weeks

Description: Proportion of patients with a best overall response of CR or PR or SD

Measure: Determine the disease control rate (DCR)

Time: Every 12 weeks after the first 40 weeks until disease progression

Description: Time from first documented response to disease progression

Measure: Determine the duration of response (DoR)

Time: Until study discontinuation (an average of 6 months)

Description: Time from first documented response to disease progression

Measure: Determine the duration of response (DoR)

Time: Every 8 weeks for first 40 weeks

Description: Time from start of treatment to date of the first documented progression or death in months

Measure: Progression free survival (PFS)

Time: Until study discontinuation (an average of 6 months)

Description: Time from start of treatment to date of the first documented progression or death in months

Measure: Progression free survival (PFS)

Time: Every 8 weeks for first 40 weeks

Description: Change from baseline in TILs by immunohistochemistry (IHC) (such as CD8)

Measure: Characterize changes in the immune infiltrate in tumors

Time: Cycle 6 Day 1

Description: Change from baseline in TILs by immunohistochemistry (IHC) (such as CD8)

Measure: Characterize changes in the immune infiltrate in tumors

Time: Cycle 1 Day 8

Description: Change from baseline in TILs by immunohistochemistry (IHC) (such as CD8)

Measure: Characterize changes in the immune infiltrate in tumors

Time: Cycle 3 Day 1

Description: Presence and/or concentration of anti-PDR001 antibodies

Measure: Presence and/or concentration of anti-PDR001 antibodies

Time: End of treatment and as needed (an average of 6 months)

Description: Plasma concentration time profiles of NIR178 and its metabolites

Measure: Pharmacokinetics: Area under plasma concentration versus time curve (AUC) (NIR178)

Time: End of treatment and as needed (an average of 6 months)

Description: Plasma concentration time profiles of NIR178

Measure: Plasma concentration Vs Time profiles (NIR178)

Time: Starting from the first dose of study treatment to Cycle 6 Day 1

Description: Plasma concentration time profiles of PDR001

Measure: Plasma concentration Vs Time profiles (PDR001)

Time: Starting from the first dose of study treatment to Cycle 6 Day 1

Description: Plasma concentration time profiles of NIR178

Measure: Peak plasma concentration- Cmax (NIR178)

Time: Starting from the first dose of study treatment to Cycle 6 Day 1

Description: Plasma concentration time profiles of PDR001

Measure: Peak plasma concentration- Cmax (PDR001)

Time: Starting from the first dose of study treatment to Cycle 6 Day 1

Description: Plasma concentration time profiles of NIR178

Measure: Time of maximum concentration observed- Tmax (NIR178)

Time: Starting from the first dose of study treatment to Cycle 6 Day 1

Description: Plasma concentration time profiles of PDR001

Measure: Time of maximum concentration observed- Tmax (PDR001)

Time: Starting from the first dose of study treatment to Cycle 6 Day 1

Description: Proportion of patients with a best overall response of CR or PR or SD

Measure: Determine the disease control rate (DCR)

Time: Until study discontinuation (an average of 6 months)

Description: Proportion of patients with a best overall response of CR or PR or SD

Measure: Determine the duration of response (DoR)

Time: Every 12 weeks after the first 40 weeks until disease progression

Description: Time from start of treatment to date of the first documented progression or death in months

Measure: Progression free survival (PFS)

Time: Every 12 weeks after the first 40 weeks until disease progression

58 A Phase II Trial of Adjuvant Erlotinib in Patients With Resected, Early Stage Non-Small Cell Lung Cancer (NSCLC) With Confirmed Mutations in the Epidermal Growth Factor Receptor (EGFR)

In this research study erlotinib will be given to eligible participants whose lung cancer has been removed by surgery. Eligible patients have adenocarcinoma, a type of non-small lung cancer, and must have 1 or more of the following characteristics: be female, be of Asian or Pacific Rim descent and/or be a never smoker. The potential participant's tumor will be examined for Epidermal growth factor (EGFR) mutations. EGFR is a protein that is overexpressed in most non-small cell lung cancers. Some EGFR has been found to have specific mutations and the participant must have one of these mutations in his tumor. Erlotinib blocks this protein and may control tumor growth and increase survival. Previous research has shown that erlotinib is most effective for people who have these specific mutations in the EGFR.

NCT00567359
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: Erlotinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- 18 years of age or older - Tumor samples must have either exon 19 deletion mutations or the exon 21 L858R point mutation - ECOG Performance status of 0,1, or 2 - Adequate organ function as outlined in protocol Exclusion Criteria: - Radiographic evidence of recurrent NSCLC prior to erlotinib treatment - Confirmed T790M resistance mutation in the primary tumor sample - Prior exposure to EGFR tyrosine kinase inhibitors - Known hypersensitivity to erlotinib, gefitinib, or any closely related drug - Pregnant or breastfeeding women - Any evidence of clinically active interstitial lung disease - Current use of enzyme-inducing anti-epileptic drugs, including carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, and primidone - Evidence of any other significant clinical disorder or laboratory finding that makes it undesirable for the patient to participate in the study - Use of any non-FDA approved or investigational agent within 2 weeks of enrolling onto the trial, or failure to recover from the side effects of any of these agents Inclusion Criteria: - Pathologically confirmed diagnosis of NSCLC of adenocarcinoma histology - Stage IA-B, IIA-B, or IIIA by the American Joint Committee on Cancer 7th edition staging criteria - Patients must have undergone surgical resection with curative intent within 6 months of enrollment - Sufficient tumor tissue available for EGFR mutation analysis - At least ONE of the following patient characteristics: previously detected deletion 19 or L858R EGFR mutation, female sex, history of never smoking, or Asian/Pacific Rim ethnicity (to be enrolled in the screening portion of trial). --- L858R --- --- T790M ---

- 18 years of age or older - Tumor samples must have either exon 19 deletion mutations or the exon 21 L858R point mutation - ECOG Performance status of 0,1, or 2 - Adequate organ function as outlined in protocol Exclusion Criteria: - Radiographic evidence of recurrent NSCLC prior to erlotinib treatment - Confirmed T790M resistance mutation in the primary tumor sample - Prior exposure to EGFR tyrosine kinase inhibitors - Known hypersensitivity to erlotinib, gefitinib, or any closely related drug - Pregnant or breastfeeding women - Any evidence of clinically active interstitial lung disease - Current use of enzyme-inducing anti-epileptic drugs, including carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, and primidone - Evidence of any other significant clinical disorder or laboratory finding that makes it undesirable for the patient to participate in the study - Use of any non-FDA approved or investigational agent within 2 weeks of enrolling onto the trial, or failure to recover from the side effects of any of these agents Non-small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung - Erlotinib is a pill taken daily and participants may continue to receive erlotinib for up to two years, as long as the cancer does not return and they do not experience any unacceptable side effects. --- L858R --- --- T790M ---

Primary Outcomes

Description: The number of participants alive and free from disease recurrence 2 years after enrollment. Participants were monitored for disease recurrence with the use of surveillance radiographs. When possible and medically appropriate, tissue biopsies were obtained to prove recurrence.

Measure: 2-year Disease-free Survival

Time: 2 years

Secondary Outcomes

Description: Adverse events were assessed using Common Terminology Criteria for Adverse Events (CTCAE 3.0) from the start of treatment until 30 days after the end of treatment. Serious adverse events were defined as adverse events that were grade 3 or greater and deemed to be possibly, probably or definitely related to the study treatment.

Measure: Number of Participants With Treat Related Serious Adverse Events

Time: From the start of treatment until 30 days after the end of treatment, up 13 months total

Description: The median amount of time from the time of registration until death due to any cause

Measure: Median Overall Survival

Time: From the time of registration until death, up to approximately 9 years

Description: The median amount of time measured from the time of registration until the time of disease recurrence or death.

Measure: Median Disease Free Survival

Time: From registration to disease recurrence or death, up to approximately 9 years

59 Registry for the EVolution Of LUng Cancer Therapy Implementation and Outcomes Now

REVOLUTION will be a US multicenter observational registry in scope and governed by a steering committee of approximately 8 experts in NSCLC and outcomes research. The primary goal of the registry is characterizing patterns of use for NSCLC therapy. REVOLUTION will be a multicenter registry enrolling approximately 2,500 patients. Additional patients limited to those with EGFR mutations may be enrolled following the initial study period as needed to ensure adequate sample sizes needed to examine primary questions of interest in the EGFR mutant population. Patients will be enrolled over a three year period across approximately 25 geographically diverse academic as well as community based sites within the US. The five year follow-up period will ensure robust survival data for correlations with clinical, tumor, and treatment variables. The target of 2,500 patients is meant to ensure adequate numbers of NSCLC patients with particular characteristics of interest including patients with adenocarcinoma, and EGFR mutations and effectively evaluate these patients with respect to key outcomes of interest including overall survival, time to progression, stage at progression, secondary metastases including brain metastases (at diagnosis and progression), comorbidity burden, and performance status at index date. The study design allows a cross-sectional perspective with collection of detailed patient and clinical characteristics at enrollment followed by longitudinal assessment of clinician and patient-reported endpoints every three months. Centralized follow-up will be conducted by having sites upload patient data following each visit via the web-based data system, with patients who do not show up for site visits being contacted via telephone by the Duke Clinical Research Institute (DCRI) call center. Site recruitment and patient enrollment will be weighted based upon provider specialty and ability to enroll patients with NSCLC with the specified inclusion criteria.

NCT02835599
Conditions
  1. Non-Small-Cell Lung Cancer
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

Characterize the current landscape of actionable mutations in the general clinical population and identify additional factors such as demographics, smoking history, and disease characteristics that predict the presence of actionable mutations as well as the development of T790M mutations in patients with EGFR mutated disease at initial presentation.. Assessment of patient hospitalizations.. Assess quality of life (QOL) associated with various treatment regimens and the association of severe complications (i.e. --- T790M ---

Primary Outcomes

Description: Characterize current practice patterns for the care of patients with NSCLC, with a special emphasis on pharmacotherapy (i.e. chemotherapy, targeted agents, and immunotherapy) and patients with EGFR mutated disease. These data will include treatment, molecular test administration and results, provider decisions and patient preferences, and explore the determinants of each.

Measure: Assessment of treatment decisions using molecular testing and results, provider decisions and patient preferences.

Time: Time from first patient enrolled to data cut of assessed approximately every 6 months up to 72 months.

Description: Compare progression-free survival, overall survival, and duration of response associated with targeted therapies, immune checkpoint inhibitors, and cytotoxic chemotherapy in NSCLC and EGFR mutated disease.

Measure: Assessment of progression-free survival

Time: Time from first patient enrolled to data cut of assessed approximately every 6 months up to 72 months.

Description: Compare progression-free survival, overall survival, and duration of response associated with targeted therapies, immune checkpoint inhibitors, and cytotoxic chemotherapy in NSCLC and EGFR mutated disease.

Measure: Assessment of overall survival

Time: Time from first patient enrolled to data cut of assessed approximately every 6 months up to 72 months.

Description: Compare of progression-free survival, overall survival, and duration of response associated with targeted therapies, immune checkpoint inhibitors, and cytotoxic chemotherapy in NSCLC and EGFR mutated disease.

Measure: Assessment of treatments.

Time: Time from first patient enrolled to data cut of assessed approximately every 6 months up to 72 months.

Secondary Outcomes

Description: Assessments will be aggregated to quantify total, treatment-related, and toxicity-related health care resource utilization and associated financial burden at the population level (not at the individual patient level) using a three-pronged approach including 1) costs extracted from site billing claims, 2) payments obtained from Medicare claims and 3) both objective and subjective measures of patient financial burden to be collected alongside PROs.

Measure: Assessment of billing claims data.

Time: Time from first patient enrolled to data cut of assessed approximately every 6 months up to 72 months.

Description: Characterize the current landscape of actionable mutations in the general clinical population and identify additional factors such as demographics, smoking history, and disease characteristics that predict the presence of actionable mutations as well as the development of T790M mutations in patients with EGFR mutated disease at initial presentation.

Measure: Assessment of patient demographics, smoking history and disease characteristics

Time: Time from first patient enrolled to data cut of assessed approximately every 6 months up to 72 months.

Description: Assess quality of life (QOL) associated with various treatment regimens and the association of severe complications (i.e. hospitalizations, emergency room visits) with treatment.

Measure: Assessment of patient hospitalizations.

Time: Time from first patient enrolled to data cut of assessed approximately every 6 months up to 72 months.

Description: Assess patient reported outcomes associated with commonly used targeted, immune, and cytotoxic therapies and additionally measures of patient reported objective and subjective financial burden as a result of their cancer treatment.

Measure: Assessment of targeted, immune, and cytotoxic therapies

Time: Time from first patient enrolled to data cut of assessed approximately every 6 months up to 72 months.

Description: Assess patient reported outcomes associated with commonly used targeted, immune, and cytotoxic therapies and additionally measures of patient reported objective and subjective financial burden as a result of their cancer treatment.

Measure: Assessment of financial burden related to treatment

Time: Time from first patient enrolled to data cut of assessed approximately every 6 months up to 72 months.

Description: Characterize and describe the NSCLC patient population as a whole and by EGFR mutation status, with emphasis on demographics and comorbidities.

Measure: Assessment of EGFR mutation status.

Time: Time from first patient enrolled to data cut of assessed approximately every 6 months up to 72 months.

Description: Bank archived tissue specimens for future assessment of molecular markers identified in this or other relevant studies.

Measure: Assessment of molecular markers using tissue specimens.

Time: Time from first patient enrolled up to study completion, approximately 3 years.

Description: Analyze other specimens (eg blood) for future assessment of molecular markers.

Measure: Assessment of molecular markers using blood specimens

Time: Time from first patient enrolled up to study completion, approximately 3 years.

Description: Assessments will be aggregated to quantify total, treatment-related, and toxicity-related health care resource utilization and associated financial burden at the population level (not at the individual patient level) using a three-pronged approach including 1) costs extracted from site billing claims, 2) payments obtained from Medicare claims and 3) both objective and subjective measures of patient financial burden to be collected alongside PROs.

Measure: Assessment of costs extracted from site billing claims

Time: Time from first patient enrolled to data cut of assessed approximately every 6 months up to 72 months.

Description: Assessments will be aggregated to quantify total, treatment-related, and toxicity-related health care resource utilization and associated financial burden at the population level (not at the individual patient level) using a three-pronged approach including 1) costs extracted from site billing claims, 2) payments obtained from Medicare claims and 3) both objective and subjective measures of patient financial burden to be collected alongside PROs.

Measure: Assessment of patient financial burden using the Patient reported objective and subjective measures of financial toxicity patient questionnaire

Time: Time from first patient enrolled to data cut of assessed approximately every 6 months up to 72 months.

Other Outcomes

Description: Generate empiric evidence to assess current NSCLC treatment paradigms with and without EGFR mutations, including combination therapy, and hypothesize rational alternative treatment sequences to optimize the care of patients treated in general clinical practice.

Measure: Assessment of patient treatments

Time: Time from first patient enrolled up to 3 years.

Description: Characterize patterns of care and outcomes in patients with aggressive disease and poor baseline health. Specifically, we will explore variation in the management and outcomes of patients with higher baseline health risk (i.e. multiple comorbidities, low socioeconomic status) as well as those who present with more advanced disease (e.g. multiple metastases, symptomatic disease, weight loss). Through completion of this objective we hope to help inform personalized risk-benefit assessment for patients whose management is challenging yet are not represented within most clinical trials.

Measure: Evaluate multiple comorbidities and low socioeconomic status

Time: Time from first patient enrolled up to 3 years

Description: Characterize patterns of care and outcomes in patients with aggressive disease and poor baseline health. Specifically, we will explore variation in the management and outcomes of patients with higher baseline health risk (i.e. multiple comorbidities, low socioeconomic status) as well as those who present with more advanced disease (e.g. multiple metastases, symptomatic disease, weight loss). Through completion of this objective we hope to help inform personalized risk-benefit assessment for patients whose management is challenging yet are not represented within most clinical trials.

Measure: Evaluate patients with advanced disease (e.g. multiple metastases, symptomatic disease, weight loss)

Time: Time from first patient enrolled up to 3 years

60 A Phase II Trial of AZD9291 (Osimertinib) With or Without Bevacizumab in Patients With EGFR Mutation Positive NSCLC and Brain Metastases

This phase II trial studies how well osimertinib with or without bevacizumab works in treating patients with EGFR positive non-small cell lung cancer that has spread to the brain (brain metastases). Osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Bevacizumab may stop or slow non-small cell lung cancer by blocking the growth of new blood vessels necessary for tumor growth. Giving osimertinib with or without bevacizumab may work better in treating patients with non-small cell lung cancer.

NCT02971501
Conditions
  1. Metastatic Lung Non-Small Cell Carcinoma
  2. Metastatic Malignant Neoplasm in the Brain
  3. Stage IV Lung Non-Small Cell Cancer AJCC v7
Interventions
  1. Biological: Bevacizumab
  2. Other: Laboratory Biomarker Analysis
  3. Drug: Osimertinib
MeSH:Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm Non-small cell lung carcinoma

TRANSLATIONAL OBJECTIVES: I. To investigate mechanisms of sensitivity and resistance to combination AZD9291 (osimertinib) plus bevacizumab versus AZD9291 (osimertinib) by molecularly characterizing tumor samples including T790M status. --- T790M ---

Primary Outcomes

Description: The two study arms will be compared for PFS with Kaplan-Meier estimates and log-rank tests. The Rothman confidence interval (CI), and the simultaneous confidence bands will be reported. In addition, the possible risk factors will be compared for survival with log-rank test. For multivariate analysis, the proportional hazards Cox model will be applied to investigate potential prognostic factors, such as age and stage of disease of the PFS data. The adjusted p-values of the hazard ratios and the adjusted 95% confidence interval will be reported.

Measure: Progression free survival (PFS)

Time: From start of treatment to time of progression (in CNS or non-CNS disease) or death, whichever occurs first, assessed up to 2 years

Secondary Outcomes

Description: The two study arms will be compared for OS with Kaplan-Meier estimates and log-rank tests. The Rothman CI, and the simultaneous confidence bands will be reported. In addition, the possible risk factors will be compared for survival with log-rank test. For multivariate analysis, the proportional hazards Cox model will be applied to investigate potential prognostic factors, such as age and stage of disease of the OS data. The adjusted p-values of the hazard ratios and the adjusted 95% confidence interval will be reported.

Measure: Overall survival (OS)

Time: From start of treatment to death, assessed up to 2 years

Description: The two study arms will be compared for OS with Kaplan-Meier estimates and log-rank tests. The Rothman CI, and the simultaneous confidence bands will be reported. In addition, the possible risk factors will be compared for survival with log-rank test. For multivariate analysis, the proportional hazards Cox model will be applied to investigate potential prognostic factors, such as age and stage of disease of the OS data. The adjusted p-values of the hazard ratios and the adjusted 95% confidence interval will be reported.

Measure: OS rate

Time: At 12 months

Description: Assessed by Common Terminology Criteria for Adverse Events. Adverse medical events will be tabulated. National Cancer Institute toxicity grade 1 to grade 4 laboratory abnormalities will be listed.

Measure: Incidence of adverse events

Time: Up to 2 years

Description: Will be estimated using the 95% confidence CI based on Wilson's method. The Wilcoxon rank sum test and Fisher's exact test will be applied to study the association between the response status and the continuous and categorical variables respectively.

Measure: Overall response rate

Time: Up to 2 years

Description: Will be estimated using the 95% confidence CI based on Wilson's method. The Wilcoxon rank sum test and Fisher's exact test will be applied to study the association between the response status and the continuous and categorical variables respectively.

Measure: Intracranial response rate

Time: Up to 2 years

Description: Will be assessed by Response Assessment in Neuro-Oncology Brain Metastases.

Measure: Time to intracranial progression

Time: Up to 2 years

Measure: Brain metastasis response rate

Time: Up to 2 years

Measure: Time to central nervous system (CNS) progression

Time: From start of treatment to time of progression in the CNS, assessed up to 2 years

Description: Assessed by Response Assessment in Neuro-Oncology Criteria-Glioblastoma Multiforme. Will be estimated using the 95% confidence interval CI based on Wilson's method. The Wilcoxon rank sum test and Fisher's exact test will be applied to study the association between the response status and the continuous and categorical variables respectively. The generalized non-linear model and logistic regression will be applied for multivariable data analysis. The adjusted p-value and 95% CI of the odds ratios will be reported.

Measure: Intracranial response

Time: Up to 2 years

Description: Will be determined by investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1.

Measure: Objective response defined as a complete or partial response

Time: Up to 2 years

Other Outcomes

Description: Analysis will be completed using Lasso-based elastic net method.

Measure: Molecular characterization

Time: Up to 2 years

Description: Analysis will be completed using Lasso-based elastic net method.

Measure: Circulating tumor deoxyribonucleic acid assessed in plasma

Time: Up to 2 years

Description: Analysis will be completed using Lasso-based elastic net method.

Measure: Angiogenic signature assessed in plasma by multiplex panel array

Time: Up to 2 years

Description: Analysis will be completed using Lasso-based elastic net method.

Measure: Biomarker analysis of angiogenesis and signaling pathways

Time: Up to 2 years

Description: Analysis will be completed using Lasso-based elastic net method.

Measure: Changes in the tumor immune microenvironment

Time: Baseline to 2 years

61 Open Label, Multi-center, Prospective Study to Investigate the Efficacy and Safety of AZD9291 in Brain Metastases From Patients With EGFR T790M Positive NSCLC Who Have Received Prior Therapy With an EGFR-TKI

The study aims to investigate the efficacy and safety of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI.

NCT02972333
Conditions
  1. EGFR-TKI Resistant Mutation
  2. Nonsmall Cell Lung Cancer
  3. AZD9291
  4. Brain Metastases
Interventions
  1. Drug: AZD9291 80mg oral each day
  2. Radiation: Radiation therapy
MeSH:Neoplasm Metastasis Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Open Label, Multi-center, Prospective Study to Investigate the Efficacy and Safety of AZD9291 in Brain Metastases From Patients With EGFR T790M Positive NSCLC Who Have Received Prior Therapy With an EGFR-TKI. --- T790M ---

Open Label, Prospective Study to Investigate Efficacy and Safety of AZD9291 in BM From NSCLC Patients With EGFR T790M The study aims to investigate the efficacy and safety of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI. --- T790M ---

Open Label, Prospective Study to Investigate Efficacy and Safety of AZD9291 in BM From NSCLC Patients With EGFR T790M The study aims to investigate the efficacy and safety of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI. --- T790M --- --- T790M ---

To assess the efficacy of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI by PFSo. --- T790M ---

To further assess the efficacy of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI in pre-specified patient subgroups, e.g. --- T790M ---

To evaluate the safety and tolerability profile of AZD9291 and subgroups such as AZD9291 single regimen, AZD9291(before or after radiotherapy) with radiotherapy and etc. in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI.. QoL. --- T790M ---

AZD9291 single regimen, AZD9291(before or after radiotherapy) with radiotherapy etc. in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI.. Cognitive function. --- T790M ---

AZD9291 single regimen, AZD9291(before or after radiotherapy) with radiotherapy etc. in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI.. T790M mutation positive rate. --- T790M ---

AZD9291 single regimen, AZD9291(before or after radiotherapy) with radiotherapy etc. in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI.. T790M mutation positive rate. --- T790M --- --- T790M ---

To investigate the effect of AZD9291 on the inhibition of proof of mechanism biomarkers (to include, but not limited to EGFR T790M) in cell pellets from pre- and post-treatment CSF samples in comparison with blood samples.. Concordance of T790M status between CSF and plasma. --- T790M ---

To investigate the effect of AZD9291 on the inhibition of proof of mechanism biomarkers (to include, but not limited to EGFR T790M) in cell pellets from pre- and post-treatment CSF samples in comparison with blood samples.. Concordance of T790M status between CSF and plasma. --- T790M --- --- T790M ---

To investigate the effect of AZD9291 on the inhibition of proof of mechanism biomarkers (to include, but not limited to EGFR T790M) in cell pellets from pre- and post-treatment CSF samples in comparison with blood samples.. Change of imputed ctDNA concentration before and after treatment. --- T790M ---

To investigate the effect of AZD9291 on the inhibition of proof of mechanism biomarkers (to include, but not limited to EGFR T790M) in cell pellets from pre- and post-treatment CSF samples in comparison with blood samples.. Proportion of each genetic mutation. --- T790M ---

To investigate the effect of AZD9291 on the inhibition of proof of mechanism biomarkers (to include, but not limited to EGFR T790M) in cell pellets from pre- and post-treatment CSF samples in comparison with blood samples.. Change from baseline in glucose and protein levels. --- T790M ---

To explore potential relation between relevant efficacy measures, biomarkers or safety variables and plasma or CSF concentration of AZD9291 (or metabolites).. Inclusion Criteria: 1. Provision of signed and dated written informed consent by the patient or legally acceptable representative prior to any study-specific procedures 2. Metastatic (stage IV) EGFRm NSCLC, not amenable to curative surgery or radiotherapy, with confirmation of the presence of the T790M mutation. --- T790M ---

Inclusion Criteria: 1. Provision of signed and dated written informed consent by the patient or legally acceptable representative prior to any study-specific procedures 2. Metastatic (stage IV) EGFRm NSCLC, not amenable to curative surgery or radiotherapy, with confirmation of the presence of the T790M mutation. --- T790M ---

EGFR-TKI Resistant Mutation Nonsmall Cell Lung Cancer AZD9291 Brain Metastases Neoplasm Metastasis Carcinoma, Non-Small-Cell Lung Patients with confirmed EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI and concurrent with brain metastasis will be enrolled into the study. --- T790M ---

Primary Outcomes

Description: To assess the efficacy of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI by PFSo

Measure: PFSo (overall progression free survival)

Time: 2 years

Secondary Outcomes

Description: To further assess the efficacy of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI in pre-specified patient subgroups, e.g. AZD9291 single regimen, AZD9291 (before or after radiotherapy) with radiotherapy etc.

Measure: PFSe (extracranial progression-free survival)

Time: 2 years

Description: To further assess the efficacy of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI in pre-specified patient subgroups, e.g. AZD9291 single regimen, AZD9291 (before or after radiotherapy) with radiotherapy etc.

Measure: PFSi (intracranial progression-free survival)

Time: 2 years

Description: To further assess the efficacy of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI in pre-specified patient subgroups, e.g. AZD9291 single regimen, AZD9291 (before or after radiotherapy) with radiotherapy etc.

Measure: ORRo (overall objective response rate)

Time: 2 years

Description: To further assess the efficacy of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI in pre-specified patient subgroups, e.g. AZD9291 single regimen, AZD9291 (before or after radiotherapy) with radiotherapy etc.

Measure: ORRe (extracranial objective response rate)

Time: 2 years

Description: To further assess the efficacy of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI in pre-specified patient subgroups, e.g. AZD9291 single regimen, AZD9291 (before or after radiotherapy) with radiotherapy etc.

Measure: ORRi (intracranial objective response rate)

Time: 2 years

Description: To further assess the efficacy of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI in pre-specified patient subgroups, e.g. AZD9291 single regimen, AZD9291 (before or after radiotherapy) with radiotherapy etc.

Measure: DCRo (overall disease control rate)

Time: 2 years

Description: To further assess the efficacy of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI in pre-specified patient subgroups, e.g. AZD9291 single regimen, AZD9291 (before or after radiotherapy) with radiotherapy etc.

Measure: DCRe (extracranial disease control rate)

Time: 2 years

Description: To further assess the efficacy of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI in pre-specified patient subgroups, e.g. AZD9291 single regimen, AZD9291 (before or after radiotherapy) with radiotherapy etc.

Measure: DCRi (intracranial disease control rate)

Time: 2 years

Description: To further assess the efficacy of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI in pre-specified patient subgroups, e.g. AZD9291 single regimen, AZD9291 (before or after radiotherapy) with radiotherapy etc.

Measure: DoRo (overall duration of response)

Time: 3 years

Description: To further assess the efficacy of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI in pre-specified patient subgroups, e.g. AZD9291 single regimen, AZD9291 (before or after radiotherapy) with radiotherapy etc.

Measure: DoRe (extracranial duration of response)

Time: 2 years

Description: To further assess the efficacy of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI in pre-specified patient subgroups, e.g. AZD9291 single regimen, AZD9291 (before or after radiotherapy) with radiotherapy etc.

Measure: DoRi (intracranial duration of response)

Time: 2 years

Description: To further assess the efficacy of AZD9291 in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI in pre-specified patient subgroups, e.g. AZD9291 single regimen, AZD9291 (before or after radiotherapy) with radiotherapy etc.

Measure: OS(overall survival)

Time: 3 years

Description: To evaluate the safety and tolerability profile of AZD9291 and subgroups such as AZD9291 single regimen, AZD9291(before or after radiotherapy) with radiotherapy and etc. in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI.

Measure: Adverse events/Serious adverse events

Time: 2 years

Description: To assess disease-related symptoms and QoL in overall population as well as in pre-specified subgroups, e.g. AZD9291 single regimen, AZD9291(before or after radiotherapy) with radiotherapy etc. in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI.

Measure: QoL

Time: 2 years

Description: To assess disease-related symptoms and cognitive function in overall population as well as in pre-specified subgroups, e.g. AZD9291 single regimen, AZD9291(before or after radiotherapy) with radiotherapy etc. in brain metastases from patients with EGFR T790M positive NSCLC who have received prior therapy with an EGFR-TKI.

Measure: Cognitive function

Time: 2 years

Other Outcomes

Description: To investigate the effect of AZD9291 on the inhibition of proof of mechanism biomarkers (to include, but not limited to EGFR T790M) in cell pellets from pre- and post-treatment CSF samples in comparison with blood samples.

Measure: T790M mutation positive rate

Time: 2 years

Description: To investigate the effect of AZD9291 on the inhibition of proof of mechanism biomarkers (to include, but not limited to EGFR T790M) in cell pellets from pre- and post-treatment CSF samples in comparison with blood samples.

Measure: Concordance of T790M status between CSF and plasma

Time: 2 years

Description: To investigate the effect of AZD9291 on the inhibition of proof of mechanism biomarkers (to include, but not limited to EGFR T790M) in cell pellets from pre- and post-treatment CSF samples in comparison with blood samples.

Measure: Change of imputed ctDNA concentration before and after treatment

Time: 2 years

Description: To investigate the effect of AZD9291 on the inhibition of proof of mechanism biomarkers (to include, but not limited to EGFR T790M) in cell pellets from pre- and post-treatment CSF samples in comparison with blood samples.

Measure: Proportion of each genetic mutation

Time: 2 years

Description: To evaluate the changes from baseline in CSF biochemistry to support the demonstration of the anti-tumour effect of AZD9291 in addition to CSF cytology.

Measure: Change from baseline in glucose and protein levels

Time: 2 years

Description: To evaluate the changes from baseline in CSF biochemistry to support the demonstration of the anti-tumour effect of AZD9291 in addition to CSF cytology.

Measure: Change from baseline in tumor cell count

Time: 2 years

Description: To explore potential relation between relevant efficacy measures, biomarkers or safety variables and plasma or CSF concentration of AZD9291 (or metabolites).

Measure: AZD9291 concentration level in CSF/plasma

Time: 2 years

62 Safety, Tolerability, Pharmacokinetics and Anti-tumour Activity of Alflutinib in Patients With Advanced Non Small Cell Lung Cancer Who Progressed on Prior Therapy With an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Agent

Alflutinib Mesylate Tablets is a Epidermal Growth Factor Receptor (EGFR) mutation selective Tyrosine Kinase Inhibitor which can efficient suppress the EGFR T790M drug-resistant mutation tumor cell in Xenograft mouse model. This study aims at local advanced or metastatic non-small cell lung cancer patients with T790M drug-resistant mutation.

NCT02973763
Conditions
  1. NSCLC
Interventions
  1. Drug: Alflutinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Safety, Tolerability, Pharmacokinetics and Anti-tumour Activity of Alflutinib in Advanced Non Small Cell Lung Cancer Alflutinib Mesylate Tablets is a Epidermal Growth Factor Receptor (EGFR) mutation selective Tyrosine Kinase Inhibitor which can efficient suppress the EGFR T790M drug-resistant mutation tumor cell in Xenograft mouse model. --- T790M ---

This study aims at local advanced or metastatic non-small cell lung cancer patients with T790M drug-resistant mutation. --- T790M ---

Primary Outcomes

Description: Assessed by number and severity of adverse events as recorded on the case report form, vital signs, laboratory variables, physical examination, electrocardiogram, ophthalmic examinations, RECIST1.1, and NCI CTCAE v4.03

Measure: Incidence and Severity of Treatment-Emergent Adverse Events

Time: Adverse events will be collected from baseline until 28 days after the last dose

Secondary Outcomes

Description: Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day 1 to figure out Cmax.

Measure: Maximum Plasma Concentration [Cmax] of single dose Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day 1 to figure out tmax.

Measure: Peak Plasma Time [tmax] of single dose Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day1 to figure out AUC.

Measure: Area under the plasma concentration versus time curve (AUC) of single dose Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day 1 to figure out terminal rate constant.

Measure: Terminal rate constant of single dose Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day 1 to figure out clearance.

Measure: Clearance of single dose Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day 1 to figure out half life.

Measure: Half life of single dose Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day 1 to figure out volume of distribution.

Measure: Volume of distribution of single dose Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Collect plasma concentrations of Alflutinib and 2 metabolites following single dose at designated time points of Day 1 to figure out mean resistance time.

Measure: Mean resistance time of single dose Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Cmax of Alflutinib and 2 metabolites at steady state following multiple doses.

Measure: Steady state Cmax of multiple doses Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: tmax of Alflutinib and 2 metabolites at steady state following multiple doses.

Measure: Steady state tmax of multiple doses Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Cmin of Alflutinib and 2 metabolites at steady state following multiple doses.

Measure: Steady state Cmin (Minimum Plasma Concentration) of multiple doses Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: AUC of Alflutinib and 2 metabolites at steady state following multiple doses.

Measure: Steady state AUC of multiple doses Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Clearance of Alflutinib and 2 metabolites at steady state following multiple doses.

Measure: Steady state clearance of multiple doses Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Accumulation ratio of Alflutinib and 2 metabolites following multiple doses.

Measure: Accumulation ratio of multiple doses Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Time dependency of Alflutinib and 2 metabolites following multiple doses.

Measure: Time dependency of multiple doses Alflutinib and 2 metabolites

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8, 15. Cycle 2 D1- pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72 hours post dose)

Description: Evaluation of objective response rate assessed by RECIST 1.1

Measure: Objective response rate of Alflutinib

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, expected average 6 months

Description: Duration of response assessed by RECIST 1.1

Measure: Duration of response of Alflutinib

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, expected average 6 months

Description: Progression of tumor was assessed by RECIST 1.1 thereby to evaluate progression free survival

Measure: Progression free survival of Alflutinib

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, expected average 6 months

Description: Progression of tumor was assessed by RECIST 1.1 thereby to evaluate disease progression rate

Measure: Disease progression rate of Alflutinib

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, expected average 6 months

Description: Clinical benefit rate was calculated by adding up complete remission, partial remission and stabilization of disease assessed by RECIST 1.1

Measure: Clinical benefit rate of Alflutinib

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, expected average 6 months

63 TAURAS - T790 AURA ScreenFailure SOC Registry Study

The aim of this study is to evaluate clinical outcomes of 2nd line therapy in NSCLC patients without the T790M mutation, both independently and when compared indirectly with NSCLC patients with the T790M mutation in the T STAR non interventional study (D5160R00001). The patient population in the TAURAS study will consist of patients who fail screening for AURA3 (D5160C00003) due to a T790M mutation not detected using the central cobas® EGFR Mutation Test (Roche Molecular Systems).

NCT02405247
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Other: Patient Reported Outcome (PRO)
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

TAURAS - T790 AURA ScreenFailure SOC Registry Study The aim of this study is to evaluate clinical outcomes of 2nd line therapy in NSCLC patients without the T790M mutation, both independently and when compared indirectly with NSCLC patients with the T790M mutation in the T STAR non interventional study (D5160R00001). --- T790M ---

TAURAS - T790 AURA ScreenFailure SOC Registry Study The aim of this study is to evaluate clinical outcomes of 2nd line therapy in NSCLC patients without the T790M mutation, both independently and when compared indirectly with NSCLC patients with the T790M mutation in the T STAR non interventional study (D5160R00001). --- T790M --- --- T790M ---

The patient population in the TAURAS study will consist of patients who fail screening for AURA3 (D5160C00003) due to a T790M mutation not detected using the central cobas® EGFR Mutation Test (Roche Molecular Systems). --- T790M ---

Patients from Japan aged at least 20 years 3. Patients who have been considered ineligible for entry into the AZD9291 AURA3 registration trial as a result of their tumour not harbouring the T790M mutation, according to the cobas EGFR test of a biopsy taken following the latest line of therapy, at a central testing lab participating in the D5160C00003 (AURA3) study. --- T790M ---

6. Patients with an invalid or unsuccessful T790M mutation test result during screening for AURA3. --- T790M ---

Biopsy tissue is collected to assess T790M mutation status. --- T790M ---

The primary objectives of the NIS study in NSCLC patients who have progressed on a previous EGFR-TKI (with no intervening chemotherapy) and who do not harbour the T790M mutation (according to central analysis using the Roche cobas® EGFR Mutation Test), are: - To estimate overall survival - To estimate disease progression (as assessed and defined by physician) - To estimate partial, complete, and overall response rates by line of therapy (as assessed and defined by physician) - To describe treatment patterns for 2nd line and beyond, including time on treatment by line of therapy and time to subsequent therapies (or death) - To describe health resource utilization patterns (e.g., hospitalizations, emergency room visits) - To capture patient reported symptoms, functioning and health-related quality of life (HRQoL) data using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 items (EORTC QLQ-C30), and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 items (EORTC QLQ-LC13) - To capture health state utilities using the EQ-5D-5L questionnaire --- T790M ---

Primary Outcomes

Description: This will be assessed as the time from start of 2nd line therapy until the date of disease progression or death by any cause.

Measure: Progression Free Survival

Time: 24 months from last subject in

Description: This will be assessed as the time from start of 2nd line therapy until the date of disease progression or death (by any cause in the absence of progression). To assess efficacy of 2nd line treatment and beyond.

Measure: Response to Therapy as assessed by the physician

Time: 24 months from last subject in

Description: This will be assessed as the time from start date of line of therapy to end date of line of therapy or death date. To describe treatment patterns for 2nd line and beyond.

Measure: Time on treatment by line of therapy and between therapies

Time: 24 months from last subject in

Description: This will be assessed as the number and Time from the dates of admission and exit of attendance. To describe Healthcare resource utilization for 2nd line treatment and beyond.

Measure: Admission of planned/unplanned hospitalizations, emergency department visits and outpatient/physician visit

Time: 24 months from last subject in

Description: For each of the symptoms in EORTC QLQ-LC13 and EORTC QLQ-C30, Time from inclusion until the date of first clinically meaningful symptom deterioration or death by any cause in the absence of a clinically meaningful symptom deterioration. To assess the impact of 2nd and subsequent lines of therapy on patients' disease-related symptoms and health related quality of life.

Measure: Time to symptom deterioration

Time: 24 months from last subject in

Description: This will be assessed as the number of patients with two consecutive assessments, which showed a clinically meaningful improvement in that symptom from baseline. To assess the impact of 2nd and subsequent lines of therapies on patients' disease-related symptoms and health related quality of life.

Measure: Symptom Improvement Rate

Time: 24 months from last subject in

Description: This will be assessed as the time from the start date of 2nd line chemotherapy until death due to any cause.

Measure: Overall Survival

Time: 24 months from last subject in

64 An Expanded Access Protocol of Oral Rociletinib (CO-1686) as Epidermal Growth Factor Receptor (EGFR)-Directed Therapy for Patients With EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC) With the T790M Resistance Mutation

To provide access to rociletinib for patients with advanced or metastatic EGFR-mutant NSCLC who have been treated previously with EGFR directed therapy and have evidence of a T790M mutation (T790M+).

NCT02547675
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: Rociletinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

An Expanded Access Protocol of Oral Rociletinib (CO-1686) as Epidermal Growth Factor Receptor (EGFR)-Directed Therapy for Patients With EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC) With the T790M Resistance Mutation. --- T790M ---

Rociletinib (CO-1686) USA Expanded Access Program To provide access to rociletinib for patients with advanced or metastatic EGFR-mutant NSCLC who have been treated previously with EGFR directed therapy and have evidence of a T790M mutation (T790M+). --- T790M ---

Key Inclusion Criteria: - Unresectable locally advanced or metastatic NSCLC with EGFR activating mutation (excluding exon 20 insertion) and presence of the T790M mutation - Prior treatment with an approved or experimental EGFR-directed therapy - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - Adequate hematological and biological function - Written informed consent on an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved ICF before any study-specific evaluation Key Exclusion Criteria: - Eligibility for other enrolling clinical trials of rociletinib - Leptomeningeal carcinomatosis or other untreated or symptomatic CNS metastases (asymptomatic CNS metastases allowed if clinically stable without requirement for steroid dose increase for at least 4 weeks) - History of prior interstitial lung disease - Concurrent use of QT-prolonging medication - Cardiac abnormalities: - Clinically significant abnormal 12-lead ECG, QT interval corrected using Fridericia's method (QTcF) > 450 ms - Inability to measure QT interval on ECG - Personal or family history of long QT syndrome - Implantable pacemaker or implantable cardioverter defibrillator - Resting bradycardia < 55 beats/min - Presence of serious or unstable concomitant systemic disorder incompatible with the clinical study (eg, substance abuse, uncontrolled intercurrent illness including active infection, arterial thrombosis, symptomatic pulmonary embolism, and other active malignancy associated with life expectancy of less than 1 year) - Pregnant or breastfeeding females and male or female patients who refuse to use adequate contraception during the study and for 12 weeks after the last dose of rociletinib - Any contraindication, allergy, or hypersensitivity to rociletinib or excipients Key Inclusion Criteria: - Unresectable locally advanced or metastatic NSCLC with EGFR activating mutation (excluding exon 20 insertion) and presence of the T790M mutation - Prior treatment with an approved or experimental EGFR-directed therapy - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - Adequate hematological and biological function - Written informed consent on an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved ICF before any study-specific evaluation Key Exclusion Criteria: - Eligibility for other enrolling clinical trials of rociletinib - Leptomeningeal carcinomatosis or other untreated or symptomatic CNS metastases (asymptomatic CNS metastases allowed if clinically stable without requirement for steroid dose increase for at least 4 weeks) - History of prior interstitial lung disease - Concurrent use of QT-prolonging medication - Cardiac abnormalities: - Clinically significant abnormal 12-lead ECG, QT interval corrected using Fridericia's method (QTcF) > 450 ms - Inability to measure QT interval on ECG - Personal or family history of long QT syndrome - Implantable pacemaker or implantable cardioverter defibrillator - Resting bradycardia < 55 beats/min - Presence of serious or unstable concomitant systemic disorder incompatible with the clinical study (eg, substance abuse, uncontrolled intercurrent illness including active infection, arterial thrombosis, symptomatic pulmonary embolism, and other active malignancy associated with life expectancy of less than 1 year) - Pregnant or breastfeeding females and male or female patients who refuse to use adequate contraception during the study and for 12 weeks after the last dose of rociletinib - Any contraindication, allergy, or hypersensitivity to rociletinib or excipients Non-small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung This is an open-label, multi-center study in the US, which allows for expanded access to rociletinib for patients with advanced or metastatic, EGFR-mutant T790M+ NSCLC who were previously treated with at least one prior EGFR TKI therapy (≥2nd line). --- T790M ---

Key Inclusion Criteria: - Unresectable locally advanced or metastatic NSCLC with EGFR activating mutation (excluding exon 20 insertion) and presence of the T790M mutation - Prior treatment with an approved or experimental EGFR-directed therapy - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - Adequate hematological and biological function - Written informed consent on an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved ICF before any study-specific evaluation Key Exclusion Criteria: - Eligibility for other enrolling clinical trials of rociletinib - Leptomeningeal carcinomatosis or other untreated or symptomatic CNS metastases (asymptomatic CNS metastases allowed if clinically stable without requirement for steroid dose increase for at least 4 weeks) - History of prior interstitial lung disease - Concurrent use of QT-prolonging medication - Cardiac abnormalities: - Clinically significant abnormal 12-lead ECG, QT interval corrected using Fridericia's method (QTcF) > 450 ms - Inability to measure QT interval on ECG - Personal or family history of long QT syndrome - Implantable pacemaker or implantable cardioverter defibrillator - Resting bradycardia < 55 beats/min - Presence of serious or unstable concomitant systemic disorder incompatible with the clinical study (eg, substance abuse, uncontrolled intercurrent illness including active infection, arterial thrombosis, symptomatic pulmonary embolism, and other active malignancy associated with life expectancy of less than 1 year) - Pregnant or breastfeeding females and male or female patients who refuse to use adequate contraception during the study and for 12 weeks after the last dose of rociletinib - Any contraindication, allergy, or hypersensitivity to rociletinib or excipients Key Inclusion Criteria: - Unresectable locally advanced or metastatic NSCLC with EGFR activating mutation (excluding exon 20 insertion) and presence of the T790M mutation - Prior treatment with an approved or experimental EGFR-directed therapy - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - Adequate hematological and biological function - Written informed consent on an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved ICF before any study-specific evaluation Key Exclusion Criteria: - Eligibility for other enrolling clinical trials of rociletinib - Leptomeningeal carcinomatosis or other untreated or symptomatic CNS metastases (asymptomatic CNS metastases allowed if clinically stable without requirement for steroid dose increase for at least 4 weeks) - History of prior interstitial lung disease - Concurrent use of QT-prolonging medication - Cardiac abnormalities: - Clinically significant abnormal 12-lead ECG, QT interval corrected using Fridericia's method (QTcF) > 450 ms - Inability to measure QT interval on ECG - Personal or family history of long QT syndrome - Implantable pacemaker or implantable cardioverter defibrillator - Resting bradycardia < 55 beats/min - Presence of serious or unstable concomitant systemic disorder incompatible with the clinical study (eg, substance abuse, uncontrolled intercurrent illness including active infection, arterial thrombosis, symptomatic pulmonary embolism, and other active malignancy associated with life expectancy of less than 1 year) - Pregnant or breastfeeding females and male or female patients who refuse to use adequate contraception during the study and for 12 weeks after the last dose of rociletinib - Any contraindication, allergy, or hypersensitivity to rociletinib or excipients Non-small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung This is an open-label, multi-center study in the US, which allows for expanded access to rociletinib for patients with advanced or metastatic, EGFR-mutant T790M+ NSCLC who were previously treated with at least one prior EGFR TKI therapy (≥2nd line). --- T790M --- --- T790M ---


65 Frequency and Abundance of T790M Mutation on Circulating Tumor DNA in Patients With Non-small Cell Lung Cancer After Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Treatment Failure: a Perspective Observational Study

The purpose of this study is to compare the frequency and abundance of T790M mutation among the different Clinical modes of EGFR-TKI failure.

NCT02418234
Conditions
  1. Non-small Cell Lung Cancer Stage III
  2. Non-Small-Cell Lung Cancer Metastatic
Interventions
  1. Other: mutation detection
  2. Other: ARMS and ddPCR
  3. Genetic: ctDNA analysis
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Frequency and Abundance of T790M Mutation on Circulating Tumor DNA in Patients With Non-small Cell Lung Cancer After Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Treatment Failure: a Perspective Observational Study. --- T790M ---

T790M Mutation on ctDNA in Patients With NSCLC After EGFR-TKI Failure The purpose of this study is to compare the frequency and abundance of T790M mutation among the different Clinical modes of EGFR-TKI failure. --- T790M ---

T790M Mutation on ctDNA in Patients With NSCLC After EGFR-TKI Failure The purpose of this study is to compare the frequency and abundance of T790M mutation among the different Clinical modes of EGFR-TKI failure. --- T790M --- --- T790M ---

Number of Patients With T790M Mutation Detected by Amplification Refractory Mutation System (ARMS) Assay. --- T790M ---

The investigators will describe the number of T790M mutation on ctDNA detected by ARMS assay in patients with non-small cell lung cancer (NSCLC) resistant to tyrosine kinase inhibitors (TKIs).. Abundance of T790M Mutation Detected by Digital Droplet PCR (ddPCR) Assay in Each Individual Patient. --- T790M ---

The investigators will describe the number of T790M mutation on ctDNA detected by ARMS assay in patients with non-small cell lung cancer (NSCLC) resistant to tyrosine kinase inhibitors (TKIs).. Abundance of T790M Mutation Detected by Digital Droplet PCR (ddPCR) Assay in Each Individual Patient. --- T790M --- --- T790M ---

The investigators will describe the abundance of T790M mutation on ctDNA detected by ddPCR assay in patients with NSCLC resistant to TKIs.. Number of T790M Mutation by ARMS and ddPCR Assays in Each Different Clinical Modes of TKI Failure. --- T790M ---

The investigators will describe the abundance of T790M mutation on ctDNA detected by ddPCR assay in patients with NSCLC resistant to TKIs.. Number of T790M Mutation by ARMS and ddPCR Assays in Each Different Clinical Modes of TKI Failure. --- T790M --- --- T790M ---

The investigators will describe the number of participants with T790M mutation in each different clinical mode of TKI failure by ARMS and ddPCR, and employ chi-square test to analyze the distribution of T790M mutation by ARMS and ddPCR in patients among the different Clinical modes of TKI failure.. Differences of T790M Mutation by ddPCR Among the Different Clinical Modes of TKI Failure. --- T790M ---

The investigators will describe the number of participants with T790M mutation in each different clinical mode of TKI failure by ARMS and ddPCR, and employ chi-square test to analyze the distribution of T790M mutation by ARMS and ddPCR in patients among the different Clinical modes of TKI failure.. Differences of T790M Mutation by ddPCR Among the Different Clinical Modes of TKI Failure. --- T790M --- --- T790M ---

The investigators will describe the number of participants with T790M mutation in each different clinical mode of TKI failure by ARMS and ddPCR, and employ chi-square test to analyze the distribution of T790M mutation by ARMS and ddPCR in patients among the different Clinical modes of TKI failure.. Differences of T790M Mutation by ddPCR Among the Different Clinical Modes of TKI Failure. --- T790M --- --- T790M --- --- T790M ---

The investigators will employ Analysis of Variance (ANOVA) method to analyze the differences of T790M mutation by ddPCR in patients among the different Clinical modes of TKI failure.. Inclusion Criteria: - Histologically confirmed stage IIIB/IV NSCLC. --- T790M ---

Non-small Cell Lung Cancer Stage III Non-Small-Cell Lung Cancer Metastatic Lung Neoplasms Carcinoma, Non-Small-Cell Lung An observational, non-interventional, multi-central study of comparison of the frequency and abundance of T790M mutation using both amplification refractory mutation system (ARMS) and digital droplet PCR (ddPCR) methods among the different Clinical modes of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) failure --- T790M ---

Primary Outcomes

Description: The investigators will describe the number of T790M mutation on ctDNA detected by ARMS assay in patients with non-small cell lung cancer (NSCLC) resistant to tyrosine kinase inhibitors (TKIs).

Measure: Number of Patients With T790M Mutation Detected by Amplification Refractory Mutation System (ARMS) Assay

Time: up to 2 years

Description: The investigators will describe the abundance of T790M mutation on ctDNA detected by ddPCR assay in patients with NSCLC resistant to TKIs.

Measure: Abundance of T790M Mutation Detected by Digital Droplet PCR (ddPCR) Assay in Each Individual Patient

Time: up to 2 years

Secondary Outcomes

Description: The investigators will describe the number of participants with T790M mutation in each different clinical mode of TKI failure by ARMS and ddPCR, and employ chi-square test to analyze the distribution of T790M mutation by ARMS and ddPCR in patients among the different Clinical modes of TKI failure.

Measure: Number of T790M Mutation by ARMS and ddPCR Assays in Each Different Clinical Modes of TKI Failure

Time: up to 2 years

Description: The investigators will employ Analysis of Variance (ANOVA) method to analyze the differences of T790M mutation by ddPCR in patients among the different Clinical modes of TKI failure.

Measure: Differences of T790M Mutation by ddPCR Among the Different Clinical Modes of TKI Failure

Time: up to 2 years

66 A Multicenter, Randomized, Double-Blind Study of Erlotinib in Combination With Ramucirumab or Placebo in Previously Untreated Patients With EGFR Mutation-Positive Metastatic Non-Small Cell Lung Cancer

The main purpose of this study is to evaluate the efficacy and safety of ramucirumab in combination with erlotinib as compared to placebo in combination with erlotinib in previously untreated participants with stage IV non-small cell lung cancer (NSCLC) harboring an activating epidermal growth factor receptor (EGFR) mutation (Exon 19-Del and Exon 21 L858R). Safety and tolerability of ramucirumab in combination with erlotinib will be assessed in Part A before proceeding to Part B. The purpose of Part C is to determine the efficacy and safety of ramucirumab in combination with gefitinib in previously untreated East Asian participants with EGFR mutation-positive metastatic NSCLC and of ramucirumab in combination with osimertinib in those participants whose disease progressed on ramucirumab and gefitinib and that have T790M - positive metastatic NSCLC.

NCT02411448
Conditions
  1. Metastatic Non-Small Cell Lung Cancer
Interventions
  1. Drug: Ramucirumab
  2. Drug: Placebo
  3. Drug: Erlotinib
  4. Drug: Gefitinib
  5. Drug: Osimertinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Safety and tolerability of ramucirumab in combination with erlotinib will be assessed in Part A before proceeding to Part B. The purpose of Part C is to determine the efficacy and safety of ramucirumab in combination with gefitinib in previously untreated East Asian participants with EGFR mutation-positive metastatic NSCLC and of ramucirumab in combination with osimertinib in those participants whose disease progressed on ramucirumab and gefitinib and that have T790M - positive metastatic NSCLC. --- T790M ---

Exclusion Criteria: - Known T790M EGFR mutation (not applicable for Part C Period 2). --- T790M ---

Primary Outcomes

Description: PFS is defined as the time from the date of randomization to the date of radiographically documented progressive disease (PD) based on investigator assessment, or the date of death due to any cause, whichever is first assessed via Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Progressive Disease (PD) was at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of 1 or more new lesions is also considered progression.

Measure: Part B: Progression Free Survival (PFS)

Time: Randomization to Measured Progressive Disease or Death from Any Cause (Up To 37 Months)

Description: A summary of other non-serious adverse events and all serious adverse events, regardless of causality, is located in the Reported Adverse Events Section.

Measure: Number of Participants With Treatment-Emergent Adverse Events

Time: Cycle 1 Day 1 through End of Study (Up To 3 Years)

Secondary Outcomes

Description: OS was defined as the time from the date of randomization to the date of death from any cause. For each participant who was not known to have died as of the data-inclusion cutoff date for a particular analysis,OS was censored for that analysis at the date of last contact prior to the data-inclusion cutoff date (contacts considered in the determination of last contact date include adverse event (AE) date, lesion assessment date, visit date, and last known alive date).

Measure: Part B: Overall Survival (OS)

Time: Randomization to Date of Death from Any Cause (Up To 37 Months)

Description: ORR was defined as the percentage of randomized participants achieving a best overall response of partial response (PR) or complete response (CR) assessed via Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CR was defined as the disappearance of all lesions, pathological lymph node reduction in short axis to <10 mm, and normalization of tumor marker levels of non-target lesions. PR was at least a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD) was at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of 1 or more new lesions is also considered progression.

Measure: Part B: Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Objective Response Rate [ORR])

Time: Randomization to Progressive Disease (Up To 37 Months)

Description: DCR was defined as the percentage of randomized participants achieving a best overall response of CR,PR, or stable disease(SD) assessed via Response Evaluation Criteria in Solid Tumors(RECIST) version 1.1. CR was defined as the disappearance of all lesions,pathological lymph node reduction in short axis to <10 mm, and normalization of tumor marker levels of non-target lesions.PR was at least a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters.SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Progressive Disease(PD) was at least a 20% increase in the sum of the diameters of target lesions,taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.The appearance of 1 or more new lesions is also considered progression.

Measure: Part B: Percentage of Participants With CR, PR, or Stable Disease (SD) (Disease Control Rate [DCR])

Time: Randomization to Progressive Disease (Up To 37 Months)

Description: DoR was defined as the date of first documented CR or PR (responder) to the date of progressive disease or the date of death due to any cause, whichever was earlier. If a responder was not known to have died or have progressive disease, then the participant was censored at the date of last evaluable tumor assessment.CR was defined as the disappearance of all lesions, pathological lymph node reduction in short axis to <10 mm, and normalization of tumor marker levels of non-target lesions. PR was at least a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD) was at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of 1 or more new lesions is also considered progression.

Measure: Part B: Duration of Response (DoR)

Time: Date of Complete Response (CR) or Partial Response (PR) to Date of Objective Disease Progression or Death Due to Any Cause (Up To 37 Months)

Description: Part B: Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab

Measure: Part B: Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab

Time: Cycle 2 Day 1: Predose; Cycle 4 Day 1: Predose; Cycle 7 Day 1: Predose; Cycle 14 Day 1

Description: Part B: Number of Participants With Anti-Ramucirumab Antibodies.

Measure: Part B: Number of Participants With Anti-Ramucirumab Antibodies

Time: Cycle 1 Predose through Follow-up (Up To 37 Months)

Description: The LCSS consisted of 9 items: 6 items focused on lung cancer symptoms [loss of appetite, fatigue, cough, dyspnea (shortness of breath), hemoptysis (blood in sputum), and pain] and 3 global items (symptom distress, interference with activity level, and global quality of life). Participant responses to each item were measured using visual analogue scales (VAS) with 100-millimeter (mm) lines. A higher score for any item represented a higher level of symptoms/problems. The LCSS total score was defined as the mean of all 9 items. Average symptom burden index (ASBI) was calculated as the mean of the six symptom-specific questions from the LCSS. Potential scores range from 0 (for best outcome) to 100 (for worst outcome).

Measure: Part B: Best Change From Baseline on the Lung Cancer Symptom Scale (LCSS)

Time: Baseline, End of Study (Up To 37 Months)

Description: The EQ-5D-5L is a standardized instrument used to measure self-reported health status of the participants. It consists of 5 health dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). There are 5 response levels (no problems, slight problems, moderate problems, severe problems, and extreme problems/unable to), ranging from 1 to 5 (good to bad). Dimension responses were converted to an index score using UK weights. The index scores were anchored on full health (1.0) to dead (0) with negative values assigned to health states considered worse than death.

Measure: Part B: Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score

Time: Baseline, Cycle 10 (each cycle is 2 weeks)

Description: The EQ-5D-5L is a standardized instrument used to measure self-reported health status of the participants. It consists of 5 health dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). There are 5 response levels (no problems, slight problems, moderate problems, severe problems, and extreme problems/unable to), ranging from 1 to 5 (good to bad). Dimension responses were converted to an index score using UK weights. The index scores were anchored on full health (1.0) to dead (0) with negative values assigned to health states considered worse than death.

Measure: Part B: Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score

Time: Baseline, Cycle 28 (each cycle is 2 weeks)

Description: The EQ-5D-5L is a standardized instrument used to measure self-reported health status of the participants. It consists of 5 health dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). There are 5 response levels (no problems, slight problems, moderate problems, severe problems, and extreme problems/unable to), ranging from 1 to 5 (good to bad). Dimension responses were converted to an index score using UK weights. The index scores were anchored on full health (1.0) to dead (0) with negative values assigned to health states considered worse than death.

Measure: Part B: Change From Baseline on the EuroQol 5-Dimension, 5-Level Questionnaire (EQ-5D-5L) Index Score

Time: Baseline, Cycle 40 (each cycle is 2 weeks)

67 A Phase II Study of High-dose Icotinib in Previously Treated Non-small Cell Lung Cancer Patients With Epidermal Growth Factor Receptor Mutation

The purpose of this study is to investigate whether high-dose icotinib treatment beyond disease progression is beneficial for NSCLC patients who have EGFR mutation and who have responded to EGFR TKI.

NCT02960607
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Drug: Icotinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Inclusion Criteria: - Histologically confirmed stage IIIB/IV NSCLC - Investigator confirmed progression according RECIST 1.1 during previous icotinib treatment - Patients whose tumors: - are EGFR mutation-positive or - T790M mutation-negative - Performance status: WHO 0-2 - Measurable disease according to RECIST 1.1 - at least one measureable lesion .if --- T790M ---

- Patient with uncontrolled undercurrent illness or circumstances that could limit compliance with the study Inclusion Criteria: - Histologically confirmed stage IIIB/IV NSCLC - Investigator confirmed progression according RECIST 1.1 during previous icotinib treatment - Patients whose tumors: - are EGFR mutation-positive or - T790M mutation-negative - Performance status: WHO 0-2 - Measurable disease according to RECIST 1.1 - at least one measureable lesion .if --- T790M ---

Primary Outcomes

Measure: Progression Free survival

Time: 2 years

68 Neo-adjuvant Trial With AZD9291 in EGFRm+ Stage IIIA/B NSCLC - a Phase 2 Open-label Study

Patients will receive AZD9291 at a dose of 80 mg once daily. Systemic evaluation will be done by PET-CT scan after 6 weeks. In responding patients AZD9291 will be given orally 80 mg daily for 12 weeks. Non-responding patients will receive AZD9291 for the period of 6 or 12 weeks (according to the results of response assessment at each time-point).

NCT02824952
Conditions
  1. Lung Cancer, Non-small Cell
Interventions
  1. Drug: Tagrisso
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

3. Treatment-naïve stage IIIA/B NSCLC with an activating sensitizing EGFR mutation/T790M • Uncommon sensitizing EGFR mutations are allowed. --- T790M ---

Exclusion criteria 1. EGFR TKI - resistant EGFR mutations (e.g., insertion in exon 20) 2. T790M is allowed. --- T790M ---

Primary Outcomes

Description: assessed by PET-CT

Measure: Overall Response Rate as defined by RECIST 1.1

Time: 12 weeks

Secondary Outcomes

Description: mPFS measured by Kaplan-Meier method.

Measure: mPFS measured by Kaplan-Meier method.

Time: 2 years

Description: Comparing GTV (Gross tumor volume) before and after the neoadjuvant therapy

Measure: Comparing GTV (Gross tumor volume) before and after the neoadjuvant therapy

Time: 2 years

69 A Phase 2 Trial of Dasatinib in Patients With Lung Adenocarcinoma With Acquired Resistance to Erlotinib or Gefitinib

RATIONALE: Dasatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. PURPOSE: This phase II trial is studying how well dasatinib works in treating patients with advanced lung cancer that is no longer responding to erlotinib or gefitinib.

NCT00570401
Conditions
  1. Lung Cancer
Interventions
  1. Drug: dasatinib
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

- To determine the overall response rate in patients with EGFR T790M lung adenocarcinomas treated with this drug. --- T790M ---

- To determine the progression-free survival and overall survival of patients with EGFR T790M lung adenocarcinomas treated with this drug. --- T790M ---

Primary Outcomes

Description: To determine the overall response rate in patients with acquired erlotinib hydrochloride- or gefitinibresistant advanced adenocarcinoma of the lung treated with dasatinib using the RECIST criteria. Response and progression will be evaluated in this study using the international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee.22 Changes in only the largest diameter (uni-dimensional measurement) of the tumor lesions are used in the RECIST.

Measure: Determine the Overall Objective Response

Time: 2 years

70 A Prospective Registry for Patients With Acquired Resistance to Small Molecule Kinase Inhibitors in Non-Small-Cell Lung Cancer

The purpose of this study is to try to learn more about how small molecule kinase inhibitors work in treating lung cancer. Some early studies have shown that gefitinib, erlotinib and similar drugs are more likely to work if a particular DNA change (also known as a mutation) is found in a protein that is important in lung cancer. This protein is called the epidermal growth factor receptor (EGFR). Since small molecule kinase inhibitors sometimes stop working, we would like to examine your tumor to learn why these medicines are not working as well. Your tumor will be examined for a variety of things including changes in the DNA of the EGFR. We will also sequence parts of the genes for HER2, HER3, HER4, and KRAS, other proteins thought to be important in lung cancer.

NCT00579683
Conditions
  1. Unresectable or Metastatic Non-small Cell Lung Cancer (NSCLC)
Interventions
  1. Other: Tumor core biopsy for RNA isolation
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

To more precisely characterize the frequency and clinical implications of T790M in patients with acquired resistance to small molecule kinase inhibitors.. null. --- T790M ---

Primary Outcomes

Measure: To compare EGFR gene sequence in patients upon relapse with EGFR gene sequence prior to treatment with small molecule kinase inhibitors.

Time: 2 years

Secondary Outcomes

Measure: To identify novel mutations in the tyrosine kinase domain of EGFR in patients with acquired resistance to small molecule kinase inhibitors.

Time: 2 years

Measure: To more precisely characterize the frequency and clinical implications of T790M in patients with acquired resistance to small molecule kinase inhibitors.

Time: 2 years

Measure: To identify novel mechanisms of acquired resistance to EGFR small molecule kinase inhibitors.

Time: 2 years

71 Randomised Phase 2 Study of Nivolumab Versus Nivolumab and Ipilimumab Combination in EGFR Mutant Non-small Cell Lung Cancer

The purpose of this study is to determine whether Nivolumab in combination with Ipilimumab is associated with superior response rate compared to Nivolumab alone in patients with advanced Epidermal Growth Factor Receptor (EGFR) mutation positive Non-small Cell Lung Cancer who have failed one line of standard EGFR tyrosine kinase inhibitor and not more than one line of chemotherapy regimen. This study also aims to determine predictive biomarkers of response/benefit in patients with EGFR mutation positive NSCLC.

NCT03091491
Conditions
  1. Non-Small Cell Lung Cancer
Interventions
  1. Drug: Ipilimumab
  2. Drug: Nivolumab
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Eastern Cooperative Oncology Group (ECOG) 0-2 performance status v. Progressed on one line of standard EGFR TKI and not more than one line of chemotherapy; 3rd generation EGFR TKI for patients with T790M mutation is allowed - A 14-day washout period is required for EGFR TKI for patients who received this as the last therapy before recruitment - A 28-day washout period is required for chemotherapy for patients who received this as the last therapy before recruitment. --- T790M ---

The use of 3rd generation EGFR TKI for patients with acquired mutation that substitute a threonine (T) with a methionine (M) at position 790 of exon 20 (T790M) is allowed. --- T790M ---

Primary Outcomes

Measure: Overall Response Rate

Time: From baseline until best overall response of Complete Response (CR) or Partial Response (PR), up to 2 years

Secondary Outcomes

Measure: Progression-Free Survival

Time: From time of randomisation until first documented disease progression or death due to any cause, up to 2 years

Measure: Duration of Response

Time: From time of first response until first documented disease progression or death due to any cause, up to 2 years

Measure: Overall Survival

Time: From time of randomisation until death due to any cause, up to 2 years

Description: Safety data of all adverse events and serious adverse events, will be graded according to the NCI CTCAE v 4.0.

Measure: Evaluate the toxicity profiles of Nivolumab with or without Ipilimumab by measuring the number of participants with treatment-related adverse events

Time: From the time the Informed Consent Form is signed until at least 100 days after discontinuation of dosing, up to 2 years

Measure: Evaluate capability of the addition of Ipilimumab to patients who progress on Nivolumab alone (Arm A) to achieve clinical benefit by measuring the time taken to achieve CR, PR or Stable Disease (SD)

Time: From time of first dose of Ipilimumab until best overall response of CR, PR, or SD, up to 2 years

Description: Biomarkers: PD-L1, mutational burden, microsatellite instability, blood-based biomarkers

Measure: Evaluate an array of biomarkers in predicting response to Nivolumab and/or Ipilimumab

Time: From time of first dose of study treatment until clear-cut disease progression, up to 2 years

72 Circulating Tumor DNA (ctDNA) as a Prognostic Tool in Patients With Advanced Lung Adenocarcinoma

Lung cancer is the leading cause of cancer death in the U.S. and throughout the world. Lung cancers are broadly divided histologically into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). About 25% of patients with NSCLC have stage I or II disease. The primary treatment modality is surgical resection,2 and 5-year survival rates are 65% for stage I and 41% for stage II disease. However, more than 70% of patients with NSCLC present with stage III or IV disease. Patients with stage III disease are most commonly treated with chemoradiation, and 5-year survival rate is 26%. Chemotherapy and targeted therapy are often used for stage IV disease, which has a 5-year survival rate of 4%. Tyrosine kinase inhibitor (TKI) is a targeted therapy against specific molecules in critical cell-signaling pathways involved in lung carcinogenesis. The currently available FDA approved TKIs for advanced NSCLC include afatinib, gefitinib, and erlotinib that inhibit epidermal growth factor receptor (EGFR) signaling 6 and crizotinib that inhibits anaplastic lymphoma kinase (ALK) signaling. However, only tumors that carry the corresponding oncogenic mutations (e.g., sensitizing EGFR mutations) would respond well to these TKIs. Meta-analyses of clinical trials evaluating the efficacy of gefitinib and erlotinib have demonstrated that NSCLC patients who are EGFR mutation-positive have a lower risk of disease progression when treated with an EGFR-TKI as compared to those treated with chemotherapy (HR = 0.43, 95% confidence interval, CI=0.38-0.49). EGFR-TKI, however, confers no benefits to patients who are EGFR wildtype (HR = 1.06, 95% CI=0.94-1.19). A phase III trial of crizotinib has also demonstrated the superiority of crizotinib to standard chemotherapy in ALK-positive NSCLC patients (HR = 0.49; 95% CI=0.37-0.64). In Hong Kong, as in other parts of Asia like in China and in Taiwan, other than the majority of lung cancer patients being smokers, there is also a prominence of non-smokers in lung cancer. Compared with Caucasians, there is also a relatively higher incidence of EGFR mutation in lung adenocarcinomas. The prevalence of EGFR mutation in Asian population with lung adenocarcinomas can reach up to 60% compared to at most 30% in the Caucasian population. These EGFR mutant tumors will demonstrate better response to the drug EGFR-TKI, boosting up the response rate to almost 70% compared to 30% with conventional chemotherapy for lung cancer. Even with this remarkable response, however, EGFR-TKI will eventually fail in EGFR mutant lung cancer. There is an imminent need to look for newer therapeutic targets or agents that can overcome this acquired resistance to anti-cancer drugs and to explore alternative molecular signaling pathways that could interact or enhance EGFR signaling pathways to modulate the therapeutic response in lung cancer.

NCT03090815
Conditions
  1. Adenocarcinoma of Lung (Disorder)
Interventions
  1. Genetic: Sequencing of ctDNA in plasma
MeSH:Adenocarcinoma Adenocarcinoma of Lung

Emergence of the EGFR mutation T790M occurs in about 50-70% of patients with acquired resistance to EGFR-TKIs. --- T790M ---

Primary Outcomes

Description: Types of ctDNA mutations

Measure: ctDNA mutation

Time: an average of one year

Description: Types of new ctDNA mutations

Measure: Any new ctDNA mutations

Time: an average of one year

Secondary Outcomes

Description: Quantity of ctDNA mutations

Measure: ctDNA levels [measured as copy number]

Time: an average of one year

Description: Quantity of new type ctDNA

Measure: Any new ctDNA levels [measured as copy number]

Time: an average of one year

73 An Observational, Non-interventional, Multi-center, Chart Review Study Conducted Among Patients Enrolled in an AZD9291 Early Access Program in Hong Kong, With Locally Advanced/Metastatic EGFR T790M Mutation-positive NSCLC and Prior Exposure to EGFR TKI Therapy.

To assess the efficacy of single-agent osimertinib in relation to EGFR T790M mutant allele fraction (AF) in a real-world setting.

NCT03219970
Conditions
  1. Non-small
  2. Non-small Cell Lung Cancer
Interventions
  1. Drug: Osimertinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

An Observational, Non-interventional, Multi-center, Chart Review Study Conducted Among Patients Enrolled in an AZD9291 Early Access Program in Hong Kong, With Locally Advanced/Metastatic EGFR T790M Mutation-positive NSCLC and Prior Exposure to EGFR TKI Therapy.. Efficacy and Safety of Osimertinib for HK Chinese With Metastatic T790M Mutated NSCLC-real World Setting. --- T790M ---

An Observational, Non-interventional, Multi-center, Chart Review Study Conducted Among Patients Enrolled in an AZD9291 Early Access Program in Hong Kong, With Locally Advanced/Metastatic EGFR T790M Mutation-positive NSCLC and Prior Exposure to EGFR TKI Therapy.. Efficacy and Safety of Osimertinib for HK Chinese With Metastatic T790M Mutated NSCLC-real World Setting. --- T790M --- --- T790M ---

To assess the efficacy of single-agent osimertinib in relation to EGFR T790M mutant allele fraction (AF) in a real-world setting. --- T790M ---

Association between T790M mutant status and overal survival. --- T790M ---

To assess the association of EGFR T790M mutant allele fraction (AF) level with the overall survival (OS) of subjects with advanced/metastatic EGFR T790M-positive NSCLC treated with osimertinib. --- T790M ---

To assess the association of EGFR T790M mutant allele fraction (AF) level with the overall survival (OS) of subjects with advanced/metastatic EGFR T790M-positive NSCLC treated with osimertinib. --- T790M --- --- T790M ---

To estimate OS of subjects with advanced/metastatic EGFR T790M-positive NSCLC treated with osimertinib. --- T790M ---

To estimate time to treatment discontinuation (TTD) of osimertinib for the overall study population, and for subjects with different EGFR mutation status (T790M/Exon 19 del; T790M/L858R). --- T790M ---

To estimate time to treatment discontinuation (TTD) of osimertinib for the overall study population, and for subjects with different EGFR mutation status (T790M/Exon 19 del; T790M/L858R). --- T790M --- --- T790M ---

To assess by number of adverse events of special interest which are pre-defined in protocol, as recorded on the case report form.. T790M mutation testing sample. --- T790M ---

T790M mutation testing platform. --- T790M ---

To describe the characteristics of the methods used for T790M mutation testing after disease progression on, or discontinuation of, EGFR TKI therapy in the study population. --- T790M ---

To describe treatment regimens received by study subjects before and after the start of osimertinib therapy.. Inclusion Criteria: - Patients enrolled in AZD9291 Named Patient Program in Hong Kong - Patients with confirmed advanced (locally advanced (stage IIIB) or metastatic (stage IV)) NSCLC with a positive test result for the EGFR T790M mutation - Patients who have previously received EGFR TKI therapy or discontinued an EGFR TKI at the time of enrolment in the study - Provision of written informed consent (for patients alive at the time of study enrolment) - Documented patients with trackable medical records Exclusion Criteria: - Enrolment in studies that prohibit any participation in this non-interventional study Inclusion Criteria: - Patients enrolled in AZD9291 Named Patient Program in Hong Kong - Patients with confirmed advanced (locally advanced (stage IIIB) or metastatic (stage IV)) NSCLC with a positive test result for the EGFR T790M mutation - Patients who have previously received EGFR TKI therapy or discontinued an EGFR TKI at the time of enrolment in the study - Provision of written informed consent (for patients alive at the time of study enrolment) - Documented patients with trackable medical records Exclusion Criteria: - Enrolment in studies that prohibit any participation in this non-interventional study Non-small Non-small Cell Lung Cancer Carcinoma, Non-Small-Cell Lung This study will assess the efficacy and safety of single-agent osimertinib in patients with locally advanced or metastatic EGFR T790M-positive NSCLC within the context of the early access program in Hong Kong. --- T790M ---

To describe treatment regimens received by study subjects before and after the start of osimertinib therapy.. Inclusion Criteria: - Patients enrolled in AZD9291 Named Patient Program in Hong Kong - Patients with confirmed advanced (locally advanced (stage IIIB) or metastatic (stage IV)) NSCLC with a positive test result for the EGFR T790M mutation - Patients who have previously received EGFR TKI therapy or discontinued an EGFR TKI at the time of enrolment in the study - Provision of written informed consent (for patients alive at the time of study enrolment) - Documented patients with trackable medical records Exclusion Criteria: - Enrolment in studies that prohibit any participation in this non-interventional study Inclusion Criteria: - Patients enrolled in AZD9291 Named Patient Program in Hong Kong - Patients with confirmed advanced (locally advanced (stage IIIB) or metastatic (stage IV)) NSCLC with a positive test result for the EGFR T790M mutation - Patients who have previously received EGFR TKI therapy or discontinued an EGFR TKI at the time of enrolment in the study - Provision of written informed consent (for patients alive at the time of study enrolment) - Documented patients with trackable medical records Exclusion Criteria: - Enrolment in studies that prohibit any participation in this non-interventional study Non-small Non-small Cell Lung Cancer Carcinoma, Non-Small-Cell Lung This study will assess the efficacy and safety of single-agent osimertinib in patients with locally advanced or metastatic EGFR T790M-positive NSCLC within the context of the early access program in Hong Kong. --- T790M --- --- T790M ---

To describe treatment regimens received by study subjects before and after the start of osimertinib therapy.. Inclusion Criteria: - Patients enrolled in AZD9291 Named Patient Program in Hong Kong - Patients with confirmed advanced (locally advanced (stage IIIB) or metastatic (stage IV)) NSCLC with a positive test result for the EGFR T790M mutation - Patients who have previously received EGFR TKI therapy or discontinued an EGFR TKI at the time of enrolment in the study - Provision of written informed consent (for patients alive at the time of study enrolment) - Documented patients with trackable medical records Exclusion Criteria: - Enrolment in studies that prohibit any participation in this non-interventional study Inclusion Criteria: - Patients enrolled in AZD9291 Named Patient Program in Hong Kong - Patients with confirmed advanced (locally advanced (stage IIIB) or metastatic (stage IV)) NSCLC with a positive test result for the EGFR T790M mutation - Patients who have previously received EGFR TKI therapy or discontinued an EGFR TKI at the time of enrolment in the study - Provision of written informed consent (for patients alive at the time of study enrolment) - Documented patients with trackable medical records Exclusion Criteria: - Enrolment in studies that prohibit any participation in this non-interventional study Non-small Non-small Cell Lung Cancer Carcinoma, Non-Small-Cell Lung This study will assess the efficacy and safety of single-agent osimertinib in patients with locally advanced or metastatic EGFR T790M-positive NSCLC within the context of the early access program in Hong Kong. --- T790M --- --- T790M --- --- T790M ---

In particular, osimertinib treatment efficacy will be assessed in the context of the relationship between EGFR T790M mutant AF and survival outcomes, particularly overall survival. --- T790M ---

Primary Outcomes

Description: To assess the association of EGFR T790M mutant allele fraction (AF) level with the overall survival (OS) of subjects with advanced/metastatic EGFR T790M-positive NSCLC treated with osimertinib

Measure: Association between T790M mutant status and overal survival

Time: Followed up to 2 years after last patient in

Secondary Outcomes

Description: To estimate OS of subjects with advanced/metastatic EGFR T790M-positive NSCLC treated with osimertinib

Measure: Overal survival (OS)

Time: Followed up to 2 years after last patient in

Description: To estimate response rate (RR) and disease control rate (DCR) based on physician's judgement, for the overall study population.

Measure: RR

Time: Follow up within 6 months after last patient in

Description: To estimate time to treatment discontinuation (TTD) of osimertinib for the overall study population, and for subjects with different EGFR mutation status (T790M/Exon 19 del; T790M/L858R)

Measure: TTD

Time: Followed up to 12 months after last patient in

Description: To assess by number of adverse events of special interest which are pre-defined in protocol, as recorded on the case report form.

Measure: Adverse event of special interest

Time: Followed up to 12 months after last patient in

Description: To describe what sample or biopsy collected for testing after disease progression on, or discontinuation of, EGFR TKI therapy in the study population

Measure: T790M mutation testing sample

Time: Within 14 days after enrollment date

Description: To describe the characteristics of the methods used for T790M mutation testing after disease progression on, or discontinuation of, EGFR TKI therapy in the study population

Measure: T790M mutation testing platform

Time: Within 14 days after enrollment date

Description: To describe the EGFR mutation status of study subjects after disease progression on, or discontinuation of, EGFR TKI therapy

Measure: EGFR testing mutation subtype

Time: Within 14 days after enrollment date

Description: To describe treatment regimens received by study subjects before and after the start of osimertinib therapy.

Measure: Treatment pattern

Time: Followed up to 2 years after last patient in

74 Phase I Study of Epacadostat (INCB24360) in Combination With Sirolimus in Advanced Malignancy

This is a small phase I study with dose escalation and dose expansion cohorts. The former cohort will need up to 12 subjects with advanced solid tumor to define feasibility and recommended phase 2 dose (RP2D); the latter up to 10 subjects to further define safety. Study subjects will be adults with advanced solid tumor (dose escalation) and advanced non-small cell lung cancer (NSCLC) who progressed on at least one first-line systemic therapy (dose expansion).

NCT03217669
Conditions
  1. Advanced Solid Tumor
  2. Non-small Cell Lung Cancer (NSCLC)
Interventions
  1. Drug: Epacadostat
  2. Drug: sirolimus
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- Dose escalation: subjects with advanced and unresectable solid tumor who progressed on at least one line of systemic therapy, and no approved therapy or standard therapy with demonstrated clinical benefit exists; and all subjects with T790M mutation positive NSCLC have progressed on osimertinib. --- T790M ---

Primary Outcomes

Description: Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 will be used to measure incidence of treatment-emergent adverse events.

Measure: Incidence of treatment-emergent adverse events.

Time: 28 days

Secondary Outcomes

Description: Subjects will be assessed every 8 weeks by radiologic imaging to monitor disease status.

Measure: Overall response response in subjects with NSCLC (dose expansion cohort)

Time: up to 12 months

Description: Subjects will be assessed at Week 8 by radiologic imaging to monitor disease status.

Measure: Disease control rate (DCR) >40% in subjects with NSCLC (dose expansion cohort)

Time: 2 months

Description: Subjects will be assessed every 8 weeks by radiologic imaging to monitor disease status.

Measure: Median progression free survival (mPFS) >3 months in subjects with NSCLC (dose expansion cohort)

Time: up to 12 months

Description: Subjects will be assessed every 8 weeks by radiologic imaging to monitor disease status.

Measure: Median Overall Survival (mOS) > 6 months in subjects with NSCLC (dose expansion cohort)

Time: up to 12 months

75 A Ph1b Study of Osimertinib + Alisertib or Sapanisertib for Osimertinib-Resistant EGFR Mutant Non-Small Cell Lung Cancer (NSCLC) (Crossover Study)

This phase Ib trial studies the side effects and best dose of alisertib or sapanisertib, in combination with osimertinib, in treating patients with EGFR mutated stage IIIB or IV non-small cell lung cancer that remains despite treatment with osimertinib (osimertinib resistant). Osimertinib, alisertib, and sapanisertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. The goal of part 1 of this trial is to find the highest tolerable dose of alisertib or sapanisertib in combination with osimertinib that can be given to patients with EGFR mutated non-small cell lung cancer. The goal of part 2 of this trial is to learn if the dose of alisertib or sapanisertib found in part 1 can help control EGFR mutated non-small cell lung cancer when given in combination with osimertinib.

NCT04479306
Conditions
  1. EGFR T790M Mutation Positive Non-Small Cell Lung Carcinoma
  2. Recurrent Lung Non-Small Cell Carcinoma
  3. Stage IIIB Lung Cancer AJCC v8
  4. Stage IV Lung Cancer AJCC v8
  5. Stage IVA Lung Cancer AJCC v8
  6. Stage IVB Lung Cancer AJCC v8
Interventions
  1. Drug: Alisertib
  2. Drug: Osimertinib
  3. Drug: Sapanisertib
MeSH:Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Carcinoma Neoplasm of the lung Non-small cell lung carcinoma

Estimated using the method of Kaplan and Meier.. Inclusion Criteria: - Patients must have histologically or cytologically confirmed non-small cell lung cancer - Stage IIIB/IV or recurrent non-small cell lung cancer which is not amenable to curative intent therapy - EGFR exon 21 L858R or exon 19 deletion mutation, or T790M mutation that was acquired following treatment with first or second generation tyrosine kinase inhibitor (TKI). --- L858R --- --- T790M ---

- Female patient who intend to donate eggs (ova) during the course of this study or 180 days after receiving their last dose of study drug(s) - Male patients who intend to donate sperm during the course of this study or 4 months after receiving their last dose of study drug(s) Inclusion Criteria: - Patients must have histologically or cytologically confirmed non-small cell lung cancer - Stage IIIB/IV or recurrent non-small cell lung cancer which is not amenable to curative intent therapy - EGFR exon 21 L858R or exon 19 deletion mutation, or T790M mutation that was acquired following treatment with first or second generation tyrosine kinase inhibitor (TKI). --- L858R --- --- T790M ---

- Female patient who intend to donate eggs (ova) during the course of this study or 180 days after receiving their last dose of study drug(s) - Male patients who intend to donate sperm during the course of this study or 4 months after receiving their last dose of study drug(s) EGFR T790M Mutation Positive Non-Small Cell Lung Carcinoma Recurrent Lung Non-Small Cell Carcinoma Stage IIIB Lung Cancer AJCC v8 Stage IV Lung Cancer AJCC v8 Stage IVA Lung Cancer AJCC v8 Stage IVB Lung Cancer AJCC v8 Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVES: I. Determine the safety and the recommended phase 2 dose (RP2D) of osimertinib plus alisertib II. --- T790M ---

Primary Outcomes

Description: Will employ the Bayesian optimal interval (BOIN) design to find the maximum tolerated dose (MTD) in each treatment arm. RP2D will be the same as the MTD or a lower dose level if pharmacokinetic/pharmacodynamics data indicate that the lower dose level can be as efficacious with possible lower toxicities

Measure: Recommended phase 2 dose (RP2D) of osimertinib and alisertib combination (Arm A)

Time: Up to 30 days

Description: Will employ the BOIN design to find the MTD in each treatment arm. RP2D will be the same as the MTD or a lower dose level if pharmacokinetic/pharmacodynamics data indicate that the lower dose level can be as efficacious with possible lower toxicities

Measure: RP2D of osimertinib and sapanisertib combination (Arm B)

Time: Up to 30 days

Measure: Dose-limiting toxicity (DLT)

Time: During cycle 1 (28 days)

Description: Toxicity will be evaluated according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Will be estimated with 95% confidence intervals.

Measure: Incidence of adverse events

Time: Up to 30 days after last dose

Secondary Outcomes

Description: Will be estimated with 95% confidence intervals.

Measure: Objective response rate

Time: At end of 4th cycle (1 cycle = 28 days)

Description: Estimated using the method of Kaplan and Meier.

Measure: Progression-free survival

Time: Up to 30 days after last dose

76 Phase II Trial to Evaluate Trametinib in Patients With Advanced NF1-mutant Non-small Cell Lung Cancer

Phase II trial to evaluate trametinib in patients with locally advanced non-squamous, non-small cell lung cancer (NSCLC) whose tumors harbor a non-synonymous NF-1 mutation, with progressive disease on at least one prior line of therapy.

NCT03232892
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: Trametinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

bevacizumab, ipilumimab) 4. Patients with a known activating mutation in epidermal growth factor receptor (EGFR) (Exon 19 deletion, G719A, S768I, V769L, T790M, L833F, L858R, L861Q), must have progressed or been intolerant to treatment with a first-line EGFR tyrosine kinase inhibitor (TKI) (erlotinib, afatinib, or gefitinib). --- G719A --- --- S768I --- --- V769L --- --- T790M ---

Patients whose tumors were found to have an EGFR T790M mutation must also have progressed or been intolerable to treatment with osimertinib. --- T790M ---

Primary Outcomes

Description: For participants receiving at least one dose of study treatment, the ORR is defined as the best overall response recorded from the start of the treatment until disease progression or recurrence as assessed over a 1-year period from the start of treatment. The frequency and percentages of patients with a best overall response rate of complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) will be determined. We will test the hypothesis that the ORR is greater than the null hypothesis of 10% using the Fisher's exact test.

Measure: Objective Response Rate (ORR)

Time: Up to 1 year

Secondary Outcomes

Description: The DR for Complete Response (CR) and Partial Response (PR) will be measured from the date that the best response is first recorded until the date that PD is documented. For patients who continue treatment post progression, the date of Disease Progression (PD) documentation will be used for analysis. The DR will be summarized using descriptive statistics (N, mean, standard deviation, minimum, and maximum).

Measure: Duration of Response (DR)

Time: Up to 4 years

Description: DCR will be defined as the percentage of patients who have achieved CR, PR, or SD for at least 12 weeks. The DCR will be summarized using descriptive statistics (N, mean, standard deviation, minimum, and maximum).

Measure: Disease Control Rate (DCR) According to RECIST Version 1.1 Criteria.

Time: Up to 4 years

Description: PFS will be calculated as 1+ the number of days from the first dose of study drugs to documented radiographic progression or death due to any cause over a period of 1 year. For patients who continue treatment post-progression, the date of radiographic progression will be used for PFS analysis. For patients who continue treatment post-progression, the date of radiographic progression will be used for PFS analysis. The Kaplan-Meier analysis will be used to calculate the median PFS with 95% confidence interval.

Measure: Progression Free Survival (PFS) According to RECIST Version 1.1 Criteria.

Time: Up to 1 year

Description: OS will be calculated as 1+ the number of days from the first dose of study drugs to death due to any cause over a period of 1 year. The Kaplan-Meier analysis will be used to calculate the median OS with 95% confidence interval.

Measure: Overall Survival (OS)

Time: Up to 1 year

77 A Multicentre, Open-label, Single-arm, Molecular Profiling Study of Patients With EGFR Mutation-positive Locally Advanced or Metastatic NSCLC Treated With Osimertinib

A multicentre, open-label, single-arm, molecular profiling study of patients with EGFR mutation-positive locally advanced or metastatic NSCLC treated with osimertinib.

NCT03239340
Conditions
  1. EGFR Mutation Positive Locally Advanced or Metastatic Non-Small Cell Lung Cancer
Interventions
  1. Drug: Osimertinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

PFS will additionally be analysed in patient subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, epidermal growth factor receptor (EGFR) Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived circulating tumour deoxyribonucleic acid (ctDNA).. ORR in patient subgroups defined by molecular profile. --- T790M ---

ORR will additionally be analysed in patient subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, EGFR Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived ctDNA.. TTD in patient subgroups defined by molecular profile. --- T790M ---

TTD will additionally be analysed in patient subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, EGFR Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived ctDNA.. Tumour shrinkage/depth of response in patient subgroups defined by molecular profile. --- T790M ---

Tumour shrinkage/depth of response will additionally be analysed in patient subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, EGFR Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived ctDNA.. Proportion of patients with pre-specified characteristics will be summarised by molecular profile. --- T790M ---

These will be summarized by subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, EGFR Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived ctDNA.. Adverse events graded by Common Terminology Criteria for Adverse Events version 4.0. --- T790M ---

Primary Outcomes

Description: To characterize the frequency of genetic and proteomic markers at disease progression regardless of their prevalence.

Measure: Proportion of patients with a given tumour genetic and proteomic marker at the point of disease progression as defined by the Investigator

Time: Tumour Genetic and Proteomic markers will be assessed from tissue samples collected prior to initiation of treatment and at the time of disease progression for max 4.2 years

Secondary Outcomes

Description: PFS is defined as the time from first dose of osimertinib until the date of Investigator assessed RECIST 1.1-defined progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from therapy or receives another anticancer therapy prior to progression.

Measure: Progression-free survival (PFS)

Time: At baseline and every 8 weeks from enrolment until disease progression or death or end of study for max 4.2 years

Description: ORR is defined as the number (%) of patients with at least one visit response of complete response or partial response that is confirmed at least 4 weeks later.

Measure: Objective Response Rate (ORR)

Time: At baseline and every 8 weeks from enrolment until disease progression or death or end of study for max 4.2 years

Description: DoR is defined as the time from the date of first documented response, (that is subsequently confirmed) until date of documented progression or death in the absence of disease progression, the end of response should coincide with the date of progression or death from any cause used for the PFS endpoint.

Measure: Duration of Response (DoR)

Time: From time of first documented response until date of documented progression or death in the absence of disease progression or end of study up to max 4.2 years

Description: TTD is defined as the time from the date of first dose of osimertinib to the earliest of treatment discontinuation or death.

Measure: Time toTreatment Discontinuation or Death (TTD)

Time: At every visit from enrolment to end of treatment or death or end of study for max 4.2 years

Description: TFST is defined as the time from the date of first dose of osimertinib to the earlier of the date of anticancer therapy start date following study treatment discontinuation, or death.

Measure: Time to first subsequent therapy or Death (TFST)

Time: At every visit from enrolment to start of first subsequent therapy or death or end of study for max 4.2 years

Description: Percentage of patients who have a best overall response, complete response, partial response or stable disease.

Measure: Disease Control Rate

Time: At baseline and every 8 weeks from enrolment until disease progression or death or end of study for max 4.2 years

Description: PFS will additionally be analysed in patient subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, epidermal growth factor receptor (EGFR) Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived circulating tumour deoxyribonucleic acid (ctDNA).

Measure: PFS in patient subgroups defined by molecular profile

Time: At baseline and every 8 weeks from enrolment until disease progression or death or end of study for max 4.2 years

Description: ORR will additionally be analysed in patient subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, EGFR Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived ctDNA.

Measure: ORR in patient subgroups defined by molecular profile

Time: At baseline and every 8 weeks from enrolment until disease progression or death or end of study for max 4.2 years

Description: TTD will additionally be analysed in patient subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, EGFR Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived ctDNA.

Measure: TTD in patient subgroups defined by molecular profile

Time: At every visit from enrolment to start of first subsequent therapy or death or end of study for max 4.2 years

Description: Tumour shrinkage is defined as the best change from baseline in the sum of diameters of target lesions. Tumour shrinkage/depth of response will additionally be analysed in patient subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, EGFR Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived ctDNA.

Measure: Tumour shrinkage/depth of response in patient subgroups defined by molecular profile

Time: At baseline and every 8 weeks from enrolment until disease progression or death or end of study for max 4.2 years

Description: The patient characteristics will include: gender (male/female), age (<65yrs/>65yrs), race (Asian/non Asian), and WHO Performance Status (0/1). These will be summarized by subgroups defined by molecular profile, including but not limited to: Positive pre-treatment T790M mutation, EGFR Ex 19 del or L858R mutation and EGFR Ex19 del or L858R detectable in plasma derived ctDNA.

Measure: Proportion of patients with pre-specified characteristics will be summarised by molecular profile

Time: At baseline

Other Outcomes

Description: To summarize the safety and tolerability profile of osimertinib as first-line EGFR tyrosine kinase inhibitor therapy for patients with EGFR mutation-positive locally advanced or metastatic non-small cell lung cancer

Measure: Adverse events graded by Common Terminology Criteria for Adverse Events version 4.0

Time: At every visit from signing informed consent until 28 days after last dose of study treatment

78 Detection of Either the EML4-ALK Gene Rearrangements or the T790M EGFR Mutation in the Plasma of Advanced NSCLC Patients

Demonstrate feasibility of detection of EML4-ALK fusion transcripts and T790M EGFR mutation from exosomes in the circulation of Non-Small Cell Lung Cancer (NSCLS) patients.

NCT03236675
Conditions
  1. Carcinoma, Non-Small-Cell Lung
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Detection of Either the EML4-ALK Gene Rearrangements or the T790M EGFR Mutation in the Plasma of Advanced NSCLC Patients. --- T790M ---

Detection of Either the EML4-ALK Gene Rearrangements or the T790M EGFR Mutation in the Plasma of Advanced NSCLC Patients Demonstrate feasibility of detection of EML4-ALK fusion transcripts and T790M EGFR mutation from exosomes in the circulation of Non-Small Cell Lung Cancer (NSCLS) patients. --- T790M ---

Detection of Either the EML4-ALK Gene Rearrangements or the T790M EGFR Mutation in the Plasma of Advanced NSCLC Patients Demonstrate feasibility of detection of EML4-ALK fusion transcripts and T790M EGFR mutation from exosomes in the circulation of Non-Small Cell Lung Cancer (NSCLS) patients. --- T790M --- --- T790M ---

2x2 table will be constructed to determine concordance with tissue testing.. T790M EGFR mutation by tissue assay. --- T790M ---

Patients found to be positive for T790M EGFR mutation by tissue assay. --- T790M ---

Exclusion Criteria: 1. Hepatitis (all types) in patient's medical record 2. HIV documented in patient's medical record 3. Hemoglobin < 10 mg/dL 4. Less than 18 years of age 5. Histologically confirmed NSCLC Stage I-IIIA 6. Tested negative for the presence of EML4-ALK and T790M EGFR on tissue Inclusion Criteria: 1. Participants must have histologically confirmed NSCLC, stage IIIB- IV, and have tested positive for the presence of EML4-ALK on tissue specimen, fresh or archived, using an institutionally accepted assay. --- T790M ---

Exclusion Criteria: 1. Hepatitis (all types) in patient's medical record 2. HIV documented in patient's medical record 3. Hemoglobin < 10 mg/dL 4. Less than 18 years of age 5. Histologically confirmed NSCLC Stage I-IIIA 6. Tested negative for the presence of EML4-ALK and T790M EGFR on tissue Carcinoma, Non-Small-Cell Lung Carcinoma, Non-Small-Cell Lung The goal of this study is two-fold: 1) Demonstrate feasibility of detection of EML4-ALK fusion transcripts in the circulation of NSCLC patients positive for ALK on tissue analysis, using an institutionally accepted assay; 2) Demonstrate feasibility of detection of T790M EGFR mutation in the circulation of NSCLC patients positive for T790M on tissue analysis, using an institutionally accepted assay. --- T790M ---

Exclusion Criteria: 1. Hepatitis (all types) in patient's medical record 2. HIV documented in patient's medical record 3. Hemoglobin < 10 mg/dL 4. Less than 18 years of age 5. Histologically confirmed NSCLC Stage I-IIIA 6. Tested negative for the presence of EML4-ALK and T790M EGFR on tissue Carcinoma, Non-Small-Cell Lung Carcinoma, Non-Small-Cell Lung The goal of this study is two-fold: 1) Demonstrate feasibility of detection of EML4-ALK fusion transcripts in the circulation of NSCLC patients positive for ALK on tissue analysis, using an institutionally accepted assay; 2) Demonstrate feasibility of detection of T790M EGFR mutation in the circulation of NSCLC patients positive for T790M on tissue analysis, using an institutionally accepted assay. --- T790M --- --- T790M ---

Exclusion Criteria: 1. Hepatitis (all types) in patient's medical record 2. HIV documented in patient's medical record 3. Hemoglobin < 10 mg/dL 4. Less than 18 years of age 5. Histologically confirmed NSCLC Stage I-IIIA 6. Tested negative for the presence of EML4-ALK and T790M EGFR on tissue Carcinoma, Non-Small-Cell Lung Carcinoma, Non-Small-Cell Lung The goal of this study is two-fold: 1) Demonstrate feasibility of detection of EML4-ALK fusion transcripts in the circulation of NSCLC patients positive for ALK on tissue analysis, using an institutionally accepted assay; 2) Demonstrate feasibility of detection of T790M EGFR mutation in the circulation of NSCLC patients positive for T790M on tissue analysis, using an institutionally accepted assay. --- T790M --- --- T790M --- --- T790M ---

Primary Outcomes

Description: Patients found to be positive for ALK mutation by tissue assay. ALK fusions in samples will be considered binary - positive or negative/ not assessable. 2x2 table will be constructed to determine concordance with tissue testing.

Measure: ALK mutation by tissue assay.

Time: Two years

Description: Patients found to be positive for T790M EGFR mutation by tissue assay. ALK fusions in samples will be considered binary - positive or negative/ not assessable. 2x2 table will be constructed to determine concordance with tissue testing.

Measure: T790M EGFR mutation by tissue assay

Time: Two years

79 Phase I/II Study of Nivolumab and Ipilimumab Combined With Nintedanib in Non Small Cell Lung Cancer

The main purpose of this study is to see if the combination of nivolumab, ipilimumab and nintedanib is effective in people with non- small cell lung cancer. Researchers also want to find out if the combination of nivolumab, ipilimumab and nintedanib is safe and tolerable.

NCT03377023
Conditions
  1. Non Small Cell Lung Cancer
  2. Lung Cancer, Nonsmall Cell
  3. Non Small Cell Lung Cancer Metastatic
Interventions
  1. Drug: Nivolumab
  2. Drug: Ipilimumab
  3. Drug: Nintedanib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Patients with NSCLC tumor known to harbor a genomic aberration for which FDA approved treatment is available (i.e, non-resistant EGFR mutations, EGFR T790M mutation, ALK rearrangement, ROS rearrangement, BRAF V600E mutation) are allowed to enroll if they have received prior treatment with the FDA approved targeted therapy. --- T790M ---

Patients with NSCLC tumor known to harbor a genomic aberration for which FDA approved treatment is available (i.e, non-resistant EGFR mutations, EGFR T790M mutation, ALK rearrangement, ROS rearrangement, BRAF V600E mutation) are allowed to enroll if they have received prior treatment with the FDA approved targeted therapy. --- T790M ---

Patients with NSCLC tumor known to harbor a genomic aberration for which FDA approved treatment is available (i.e, non-resistant EGFR mutations, EGFR T790M mutation, ALK rearrangement, ROS rearrangement, BRAF V600E mutation) are allowed to enroll if they have received prior treatment with the FDA approved targeted therapy - At least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. --- T790M ---

Primary Outcomes

Description: Dose escalation to determine the MTD and Recommended Phase 2 Dose (RP2D) of concurrent administration of nivolumab, ipilimumab, and nintedanib. The maximum tolerated dose (MTD) is defined as the dose with the dose limiting toxicity (DLT) rate of 30%.

Measure: Phase 1 - Maximum Tolerated Dose (MTD)

Time: Up to 12 months

Description: Objective response is defined as confirmed CR or confirmed PR based on modified RECIST guidelines version 1.1. The ORR will be estimated by calculating the proportion of patients who achieve OR; the 80% Confidence Interval (CI) and 95% CI for the OR rate will be estimated using the exact binomial distribution. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

Measure: Phase 2 - Objective Response Rate (ORR) per Treatment Arm

Time: Up to 36 months

Secondary Outcomes

Description: Disease control is defined as CR, PR, or SD based on RECIST guidelines version 1.1 with modifications. The disease control rate (DCR) will be estimated by the proportion of patients who achieve DC, and its 80% CI and 95% CI will be estimated using the exact binomial distribution. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

Measure: Phase 2: Disease Control Rate (DCR)

Time: Up to 36 months

Description: Overall survival will be determined as the time from the start of treatment with nivolumab plus ipilimumab plus nintedanib until death due to any cause. For patients who are alive at the time of data cut-off, OS will be censored on the last date when patients are known to be alive. The Kaplan-Meier method will be used to estimate the OS curve and the OS rate at time points of interest.

Measure: Phase 2: Overall Survival (OS)

Time: Up to 36 months

Description: Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).

Measure: Phase 2: Progression-free Survival (PFS)

Time: Up to 36 months

80 GioTag: Real-world Data Study on Sequential Therapy With Gi(l)Otrif®/ Afatinib as First-line Treatment Followed by Osimertinib in Patients With EGFR Mutation Positive Advanced Non-small Cell Lung Cancer

This is a non-interventional, multi-country, multi-centre cohort study based on existing data from medical records of patients with EGFR mutation-positive advanced NSCLC treated with afatinib (Gi(l)otrif®) as the first-line treatment followed by osimertinib in case the T790M resistance mutation was developed.

NCT03370770
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Drug: Afatinib
  2. Drug: Osimertinib
MeSH:Carcinoma, Non-S Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Afatinib Osimertinib Sequencing NIS This is a non-interventional, multi-country, multi-centre cohort study based on existing data from medical records of patients with EGFR mutation-positive advanced NSCLC treated with afatinib (Gi(l)otrif®) as the first-line treatment followed by osimertinib in case the T790M resistance mutation was developed. --- T790M ---

Different types of resistance mutations identified at the time of discontinuation of osimertinib treatment were systematically reviewed and categorised.. Inclusion Criteria: - Patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC) - The tumour harbours common EGFR mutations (Del19, L858R) at start of first-line treatment - Patients who initiated second-line osimertinib treatment for acquired T790M mutation at least 10 months prior to data entry, AND who were treated with afatinib (Gi(l)otrif®) in the first-line - Patients treated with osimertinib within an EAP/CUP or regular clinical practice - Age ≥ 18 years - Signed and dated written informed consent per regulations (Exemption of a written informed consent for NIS based on existing data in countries per local regulations and legal requirements) Exclusion Criteria: - Patients who received drug(s) other than osimertinib as the second-line treatment and/or patients who received drug(s) other than afatinib (Gi(l)otrif®) as the first-line treatment - Patients with active brain metastases at start of treatment (either afatinib/Gi(l)otrif® or osimertinib) Inclusion Criteria: - Patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC) - The tumour harbours common EGFR mutations (Del19, L858R) at start of first-line treatment - Patients who initiated second-line osimertinib treatment for acquired T790M mutation at least 10 months prior to data entry, AND who were treated with afatinib (Gi(l)otrif®) in the first-line - Patients treated with osimertinib within an EAP/CUP or regular clinical practice - Age ≥ 18 years - Signed and dated written informed consent per regulations (Exemption of a written informed consent for NIS based on existing data in countries per local regulations and legal requirements) Exclusion Criteria: - Patients who received drug(s) other than osimertinib as the second-line treatment and/or patients who received drug(s) other than afatinib (Gi(l)otrif®) as the first-line treatment - Patients with active brain metastases at start of treatment (either afatinib/Gi(l)otrif® or osimertinib) Carcinoma, Non-Small-Cell Lung Carcinoma, Non-S Carcinoma, Non-Small-Cell Lung null --- L858R --- --- T790M ---

Different types of resistance mutations identified at the time of discontinuation of osimertinib treatment were systematically reviewed and categorised.. Inclusion Criteria: - Patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC) - The tumour harbours common EGFR mutations (Del19, L858R) at start of first-line treatment - Patients who initiated second-line osimertinib treatment for acquired T790M mutation at least 10 months prior to data entry, AND who were treated with afatinib (Gi(l)otrif®) in the first-line - Patients treated with osimertinib within an EAP/CUP or regular clinical practice - Age ≥ 18 years - Signed and dated written informed consent per regulations (Exemption of a written informed consent for NIS based on existing data in countries per local regulations and legal requirements) Exclusion Criteria: - Patients who received drug(s) other than osimertinib as the second-line treatment and/or patients who received drug(s) other than afatinib (Gi(l)otrif®) as the first-line treatment - Patients with active brain metastases at start of treatment (either afatinib/Gi(l)otrif® or osimertinib) Inclusion Criteria: - Patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC) - The tumour harbours common EGFR mutations (Del19, L858R) at start of first-line treatment - Patients who initiated second-line osimertinib treatment for acquired T790M mutation at least 10 months prior to data entry, AND who were treated with afatinib (Gi(l)otrif®) in the first-line - Patients treated with osimertinib within an EAP/CUP or regular clinical practice - Age ≥ 18 years - Signed and dated written informed consent per regulations (Exemption of a written informed consent for NIS based on existing data in countries per local regulations and legal requirements) Exclusion Criteria: - Patients who received drug(s) other than osimertinib as the second-line treatment and/or patients who received drug(s) other than afatinib (Gi(l)otrif®) as the first-line treatment - Patients with active brain metastases at start of treatment (either afatinib/Gi(l)otrif® or osimertinib) Carcinoma, Non-Small-Cell Lung Carcinoma, Non-S Carcinoma, Non-Small-Cell Lung null --- L858R --- --- T790M --- --- L858R --- --- T790M ---

Primary Outcomes

Description: Time on treatment, which was defined as time in months from the start date of Afatinib (Gi[l]otrif®) treatment ('start date of initial dose' for First-Line Treatment) to the end date of Osimertinib treatment (maximum between 'end date of initial dose' and the last 'end date of dose modification' for Second-Line Treatment) or death date due to any cause ('date of death'). Time on treatment (months) = Time on treatment (days)/30.4375. 'Time on treatment was analysed using Kaplan-Meier method, and the median along with two-sided 90% confidence interval was displayed using the Greenwood's formula for estimation of standard errors.

Measure: Time on Treatment With Afatinib (Gi(l)Otrif®) Followed by Osimertinib

Time: Data collected from start of treatment until data entry completion, up to 96.8 months for first analysis and up to 114.1 months for the extension analysis.

Secondary Outcomes

Description: Different types of resistance mutations identified at the time of discontinuation of osimertinib treatment were systematically reviewed and categorised.

Measure: The Percentage of Participants With Different Types of Mutations After Categorisation

Time: Data collected from start of treatment until data entry completion; up to 96.8 months.

81 A Single-arm, Open-label, Phase 1b Study Evaluating the Efficacy and Safety of Olmutinib 600 mg QD in Patients With T790M-positive NSCLC After Treatment With an EGFR-TKI

The purpose of this study is to evaluate the efficacy and safety of olmutinib 600 mg QD in patients with T790M-positive non-small cell lung cancer (NSCLC) after treatment with an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI).

NCT04510415
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: Olmutinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

A Single-arm, Open-label, Phase 1b Study Evaluating the Efficacy and Safety of Olmutinib 600 mg QD in Patients With T790M-positive NSCLC After Treatment With an EGFR-TKI. --- T790M ---

Olmutinib 600 mg QD in Patients With T790M-positive NSCLC After Treatment With an EGFR-TKI The purpose of this study is to evaluate the efficacy and safety of olmutinib 600 mg QD in patients with T790M-positive non-small cell lung cancer (NSCLC) after treatment with an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). --- T790M ---

Olmutinib 600 mg QD in Patients With T790M-positive NSCLC After Treatment With an EGFR-TKI The purpose of this study is to evaluate the efficacy and safety of olmutinib 600 mg QD in patients with T790M-positive non-small cell lung cancer (NSCLC) after treatment with an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). --- T790M --- --- T790M ---

- Centrally confirmed T790M mutation positive tumor status from a tumor sample taken after confirmation of disease progression on the most recent anticancer treatment regimen. --- T790M ---

Non Small Cell Lung Cancer Carcinoma, Non-Small-Cell Lung This is a single-arm, open-label, Phase 1b study to evaluate the efficacy and safety of oral single agent olmutinib administered to patients with T790M-positive NSCLC after treatment with an EGFR-TKI. --- T790M ---

Primary Outcomes

Description: Defined as a best overall confirmed response of either CR or PR according to the RECIST version 1.1

Measure: Objective response rate (ORR)

Time: 24 months

Secondary Outcomes

Description: Defined as the proportion of patients with a documented CR, PR, and SD during the treatment cycles according to the RECIST version 1.1

Measure: Disease control rate (DCR)

Time: 24 months

Description: Defined as the interval between the date of the first observation of tumor response (CR or PR) and the date of disease progression or death

Measure: Duration of overall tumor response (DR)

Time: 24 months

Description: Defined as the time from first administration of study drug to determination of tumor progression by RECIST version 1.1 or death due to any cause, whichever occurs first

Measure: Progression-free survival (PFS)

Time: 24 months

Description: Defined as the time from first administration of study drug to determination of tumor progression by RECIST version 1.1

Measure: Time to progression (TTP)

Time: 24 months

82 SINGLE ARM STUDY TO EVALUATE THE SAFETY OF DACOMITINIB FOR THE FIRST-LINE TREATMENT OF PARTICIPANTS IN INDIA WITH METASTATIC NON-SMALL CELL LUNG CANCER WITH EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR)-ACTIVATING MUTATIONS

This is a Phase 4, open label, single arm, multi-center, prospective clinical trial of dacomitinib that will be performed in India. This study will enroll a sufficient number of participants to ensure that 100 participants are treated with dacomitinib. The primary objective of this study is to assess the safety and tolerability of dacomitinib. The secondary objective is to evaluate antitumor activity of dacomitinib by objective response rate and duration of response.

NCT04511533
Conditions
  1. Metastatic Non Small Cell Lung Cancer
Interventions
  1. Drug: Dacomitinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

2. Any other mutation other than exon 19 deletion or L858R in exon 21, with or without the presence of the exon 20 T790M mutation. --- L858R --- --- T790M ---

Primary Outcomes

Description: The incidence of adverse events will be assessed for all participants who receive at least one dose of dacomitinib, regardless of dosing interruptions or dosing compliance.

Measure: Incidence of Adverse events (AEs)

Time: From the time of first dose to 28 days post last dosing date or the date of initiation of a new anticancer therapy, whichever occurs first

Secondary Outcomes

Description: The secondary outcome measure is the treatment effect of dacomitinib as assessed by the investigator for all participants who receive at least one dose of dacomitinib without regard to tolerability or discontinuation from treatment.

Measure: Confirmed Objective Response Rate (ORR) as assessed by the investigator using Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1

Time: From time of first dose until disease progression, death or initiation of a new anticancer therapy, whichever occurs first, assessed for up to 3 years

Description: The secondary outcome measure is the treatment effect of dacomitinib as assessed by the investigator for all participants who receive at least one dose of dacomitinib without regard to tolerability or discontinuation from treatment.

Measure: Confirmed Duration of Response (DoR) as assessed by the investigator using Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1

Time: From time of first tumor response until disease progression, death or initiation of a new anticancer therapy, whichever occurs first, assessed for up to 3 years

83 A Phase Ib Open-label Clinical Trial of Continuous Once Daily Oral Treatment Using BIBW 2992 Plus Cetuximab (Erbitux®) in Patients With Non-small Cell Lung Cancer With Progression Following Prior Erlotinib (Tarceva®) or Gefitinib (Iressa®)

The primary objective of this trial is to determine the maximum tolerated dose (MTD) and recommended Phase II doses for the combination of BIBW 2992 and cetuximab in patients with non-small cell lung cancer and acquired resistance to erlotinib or gefitinib. Overall safety, pharmacokinetics and anti-tumor activity for the combination of BIBW 2992 and cetuximab in patients with non-small cell lung cancer and acquired resistance to erlotinib, gefitinib or BIBW 2992 will be evaluated as secondary objectives. Initially a standard, 3+3 dose escalation will be performed to determine the MTD of BIBW 2992 when administered together with cetuximab in patients with advanced non small cell lung cancer and acquired resistance to erlotinib or gefitinib. Subsequently, the preliminary efficacy and safety of the identified MTD of cetuximab administered with BIBW 2992 will be explored in a combo arm via a further expansion of MTD cohort up to a total of 140 EGFR mutation positive NSCLC with acquired resistance to erlotinib/gefitinib. Furthermore, the safety and preliminary anti-tumor activity of the combination therapy in EGFR mutant NSCLC patients who developed acquired resistance (AR) to BIBW 2992, will be assessed in a sequential arm. The sequential arm will use a two-stage design with an early stopping rule after 12 patients with acquired resistance to BIBW 2992 have received up to 5 courses of BIBW 2992 plus cetuximab. If no responses are seen in 12 patients during 5 courses of combination therapy, accrual in the sequential arm will stop. If 1 or more responses are observed, the sequential arm will expand up to about 40 patients.

NCT01090011
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Drug: Cetuximab
  2. Drug: Cetuximab
  3. Drug: BIBW 2992
  4. Drug: BIBW 2992
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

A tumor which harbors exon 20 insertion or de novo T790M mutation is eligible for the treatment in the sequential arm 2) Objective clinical benefit from treatment with an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR TKI) as defined by either 1. Documented partial or complete response (Response Evaluation Criteria in Solid Tumors, RECIST), or 2. Stable disease >=6 months as defined by RECIST in absence of radiographic progression after initiation of gefitinib or erlotinib; or stable disease/PR/CR >=12 weeks as defined by RECIST after initiation of BIBW 2992 3. Systemic progression of disease (RECIST v1.1) while on continuous treatment with erlotinib or gefitinib or BIBW 2992 within the last 30 days. --- T790M ---

Primary Outcomes

Description: A DLT was defined as an AE or laboratory abnormality that a) related to the study regimen; b) or met any of the following criteria: CTCAE Grade 2 or higher decrease in cardiac left ventricular function CTCAE Grade 2 diarrhea lasting for 7 or more days, despite appropriate use of standard anti-diarrheal therapy CTCAE Grade ≥3 diarrhea despite appropriate use of standard anti-diarrheal therapy for at least 2 days CTCAE Grade ≥3 nausea and/or vomiting despite appropriate use of standard anti-emetics for at least 3 days CTCAE Grade ≥3 rash despite standard medical management CTCAE Grade ≥3 fatigue lasting for more than 7 days CTCAE Grade 4 hypomagnesaemia or Grade 3 hypomagnesaemia with clinical significant sequelae All other toxicities of CTCAE Grade ≥3 (except alopecia, and allergic reaction) leading to an interruption of afatinib and/or cetuximab for more than 14 days until recovery to baseline or Grade 1, whichever was higher.

Measure: The Primary Endpoint is the Occurrence of Dose Limiting Toxicity (DLT).

Time: from day 1 treatment until progression or undue toxicity, up to 28 days

Secondary Outcomes

Description: Safety of afatinib when administered together with cetuximab as indicated by intensity and incidence of adverse events, graded according to the U.S. National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version (v) 3.0

Measure: Highest CTCAE Grade

Time: From first drug administration to 28 days after discontinuation of drug intake up to 915 days

Measure: Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters

Time: From first drug administration to 28 days after discontinuation of drug intake up to 915 days

Measure: Frequency (%) of Patients With Adverse Events Leading to Dose Reduction

Time: From first drug administration to 28 days after discontinuation of drug intake up to 915 days

Description: Frequency (%) of patients with adverse events leading to treatment discontinuation

Measure: Frequency (%) of Patients With Adverse Events Leading to Treatment Discontinuation

Time: From first drug administration to 28 days after discontinuation of drug intake up to 915 days

Measure: Frequency (%) of Patients With Adverse Events Leading to Death

Time: From first drug administration to 28 days after discontinuation of drug intake up to 915 days

Description: Frequency (%) of patients with drug-related serious adverse events

Measure: Frequency (%) of Patients With Related Serious Adverse Events

Time: From first drug administration to 28 days after discontinuation of drug intake up to 915 days

Description: Area Under the Concentration-time Curve (AUC) of Afatinib in plasma at steady state over a uniform dosing interval tau (15 days) (AUCtau,ss) after oral administration of Afatinib and cetuximab combination therapy

Measure: Area Under the Concentration-time Curve (AUC) on Day 15 of Plasma Afatinib for the Combination Arm

Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55

Description: Minimum measured concentration of Afatinib in plasma at steady state over 15 day dosing interval (Cmin,ss). Maximum measured concentration of Afatinib in plasma at steady state over 15 day dosing interval (Cmax,ss).

Measure: Concentration of Afatinib in Plasma for the Combination Arm

Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55

Description: Peak-trough fluctuation (PTF) of plasma afatinib for the combination arm. PTF = 100*(Cmax-Cmin)/Caverage where Caverage = AUC/time, where time equals 24 hours.

Measure: Peak-trough Fluctuation (PTF)

Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55

Description: Terminal half-life of Afatinib in plasma at steady state (t1/2,ss)

Measure: t1/2,ss

Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55

Description: mean residence time of Afatinib in the body at steady state after oral administration (MRTpo,ss) for 15 days

Measure: MRTpo,ss

Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55

Description: Apparent clearance of afatinib in plasma at steady state after extravascular multiple dose administration (CL/F,ss)

Measure: CL/F,ss,15

Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55

Description: Apparent volume of distribution during the terminal phase λz at steady state following extravascular administration (Vz/F,ss) for 15 days

Measure: Vz/F,ss

Time: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55

Description: Predose plasma concentrations (Cpre,ss) of Afatinib at Course 1, Visit 2, 3, 4 and 5, at Course 2, Visit 1 and 2 and at Course 3, Visit 1.

Measure: Predose Plasma Concentrations of Afatinib for the Combination Arm

Time: Up to 57 days

Description: Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD), At least a 20% increase in the sum of the longest diameter of target lesions or the appearance of new lesion(s); Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Disease control = CR + PR + SD.

Measure: Disease Control (CR, PR and Stable Disease (SD) Determined by RECIST v1.1)

Time: up to 116 weeks

Description: Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD), At least a 20% increase in the sum of the longest diameter of target lesions or the appearance of new lesion(s); Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Objective tumor response = CR + PR.

Measure: Objective Tumor Response (Complete Response [CR] and Partial Response [PR]) Determined by RECIST v1.1)

Time: up to 116 weeks

Description: Duration of objective response was measured from the time measurements criteria were met for CR/PR (whichever was first recorded) until the first date that recurrent or PD was objectively documented (taking as reference for PD the smallest measurements recorded since treatment started).

Measure: Duration of Objective Response (According to RECIST v1.1)

Time: up to 116 weeks

Description: Duration of disease control was defined as the time from the start of treatment to the time of progression or death (whichever occurred first), among patients with evidence SD, PR or CR.

Measure: Duration of Disease Control (According to RECIST v1.1)

Time: up to 116 weeks

Description: Progression-Free Survival was defined as the duration of time from start of treatment until the day of objective tumour progression confirmed by tumour imaging (PD according to RECIST 1.1) or death.

Measure: Progression-Free Survival (PFS) Time

Time: up to 116 weeks

84 A Phase I Study of Ixazomib and Erlotinib in Advanced Solid Tumor Patients

The goal of this clinical research study is to find the highest tolerable dose of the combination of ixazomib and erlotinib that can be given to patients with advanced solid tumors. The safety of these drugs will also be studied. This is an investigational study. Erlotinib is FDA approved and commercially available to treat non-small cell lung cancer, but its use in advanced solid cancer is considered investigational. Ixazomib is FDA approved. The study doctor can explain how the study drugs are designed to work. Up to 36 patients will take part in this study. All will be enrolled at MD Anderson.

NCT02942095
Conditions
  1. Solid Tumors
Interventions
  1. Drug: Ixazomib
  2. Drug: Erlotinib
MeSH:Neoplasms
HPO:Neoplasm

erlotinib or afatinib) and tested negative for EGFR T790M mutation. --- T790M ---

We will allow patients with positive EGFR T790M mutation if they have progressed on third generation anti-EGFR therapy (e.g. --- T790M ---

Primary Outcomes

Description: MTD defined by dose limiting toxicities (DLTs) that occur during the first cycle. Dose limiting toxicity (DLT) defined as Any Grade 3 or 4 non-hematologic toxicity as defined in the NCI CTCAE. Any Grade 4 hematologic toxicity lasting two weeks or longer (as defined by the NCI-CTCAE), despite supportive care. Grade 4 nausea, vomiting or diarrhea > 5 days despite maximum anti-nausea regimens.

Measure: Maximum Tolerated Dose (MTD) of Ixazomib and Erlotinib in Advanced Cancer Participants

Time: 28 days

Secondary Outcomes

Description: Tumor response of this combination per RECIST version 1.1.

Measure: Tumor Response of Ixazomib and Erlotinib in Participants with Non Small Cell Lung Cancer

Time: 8 weeks

Description: Tumor response of this combination per RECIST version 1.1.

Measure: Tumor Response of Ixazomib and Erlotinib in Participants with Pancreatic Ductal Adenocarcinoma

Time: 8 weeks

85 A Multi-centre Observational Study on Dynamic Changes of Circulating Tumor DNA in Late Stage NSCLC Patients Under Gefitinib Treatment

A multi-centre observational, non-interventional study is to dynamically monitor the changes of circulating tumor DNA (ctDNA) in late stage NSCLC patients under Gefitinib treatment.

NCT02804100
Conditions
  1. Carcinoma, Non-Small-Cell Lung
  2. Bronchial Neoplasms
  3. Carcinoma, Bronchogenic
  4. Lung Diseases
  5. Lung Neoplasms
MeSH:Carcinoma Neoplasms Carcinoma, Non-Small-Cell Lung Lung Neoplasms Carcinoma, Bronchogenic Bronchial Neoplasms Lung Diseases
HPO:Abnormal lung morphology Bronchial neoplasm Carcinoma Neoplasm Neoplasm of the lung Non-small cell lung carcinoma

- Activating EGFR mutations (G719A/C/S; Exon 19 insertion/deletion; L858R; L861Q) - Able to comply with the required protocol and followed-up procedures, and able to receive oral medications Exclusion Criteria: - Histologically confirmed small cell lung cancer or other metastatic tumors - Patient had received prior chemotherapy or EGFR-TKIs treatment - Patients who harbor Exon20 T790M mutation Inclusion Criteria: - Provision of informed consent - Histologically confirmed stage IIIB/IV NSCLC. --- G719A --- --- L858R --- --- L861Q --- --- T790M ---

- Activating EGFR mutations (G719A/C/S; Exon 19 insertion/deletion; L858R; L861Q) - Able to comply with the required protocol and followed-up procedures, and able to receive oral medications Exclusion Criteria: - Histologically confirmed small cell lung cancer or other metastatic tumors - Patient had received prior chemotherapy or EGFR-TKIs treatment - Patients who harbor Exon20 T790M mutation Carcinoma, Non-Small-Cell Lung Bronchial Neoplasms Carcinoma, Bronchogenic Lung Diseases Lung Neoplasms Carcinoma Neoplasms Carcinoma, Non-Small-Cell Lung Lung Neoplasms Carcinoma, Bronchogenic Bronchial Neoplasms Lung Diseases null --- G719A --- --- L858R --- --- L861Q --- --- T790M ---

Primary Outcomes

Measure: dynamic changes of circulating tumor DNA in late stage NSCLC patients under Gefitinib treatment

Time: 2 years

86 High Dose Weekly Use First-generation EGFR-TKI Instead of Daily Regular Dose in the Treatment of EGFR-TKI Acquired Resistance Non-small Cell Lung Cancer (NSCLC)

EGFR-TKI is the main is the first line therapy for local advanced or metastatic non-small cell lung cancer with EGFR gene mutation. The median progression free survival time is around 11 months with the first generation EGFR-TKI. Patients with acquired resistance with first generation EGFR-TKI usually with EGFR exon 20 mutation (T790M). Change the drug administration maybe prolong patients PFS and evently prolong OS.

NCT02575560
Conditions
  1. EGFR-TKI Resistant Mutation
Interventions
  1. Other: history data
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Patients with acquired resistance with first generation EGFR-TKI usually with EGFR exon 20 mutation (T790M). --- T790M ---

EGFR-TKI Resistant Mutation Carcinoma, Non-Small-Cell Lung 1st generation EGFR-TKI has reversible binding to EGFR, it also bind to T790M in a high dose which is account about 60% patients acquired resistance to the drug. --- T790M ---

Resistance patients may be benefit to a bolus drug use to block T790M gene. --- T790M ---

Primary Outcomes

Measure: Progression Free Survival Time (PFS)

Time: an average 1 year

Secondary Outcomes

Measure: Overall Response Rate(ORR)

Time: an average half year

Measure: Overall Survival Time (OS)

Time: an average 2 year

87 A Randomized Phase II/III Trial of Afatinib Plus Cetuximab Versus Afatinib Alone in Treatment-Naive Patients With Advanced, EGFR Mutation Positive Non-small Cell Lung Cancer (NSCLC)

This randomized phase II/III trial studies how well afatinib dimaleate with cetuximab works and compares it with afatinib dimaleate alone in treating patients with newly diagnosed stage IV or recurrent (has come back), epidermal growth factor receptor (EGFR) mutation positive non-small cell lung cancer. Afatinib dimaleate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as cetuximab, may block tumor growth in different ways by targeting certain cells. It is not yet known whether afatinib dimaleate is more effective when given alone or with cetuximab in treating patients with non-small cell lung cancer.

NCT02438722
Conditions
  1. Recurrent Non-Small Cell Lung Carcinoma
  2. Stage IV Non-Small Cell Lung Cancer
Interventions
  1. Drug: Afatinib Dimaleate
  2. Biological: Cetuximab
  3. Other: Laboratory Biomarker Analysis
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

To evaluate if EGFRs/EGFR T790M is lower at progression than in pre-treatment specimens among patients with results available for pre-treatment and progression, a one-sample t-test (or Wilcoxon signed-rank test) will be used to test the null hypothesis that the difference between the progression ratio and the pre-treatment ratio (or an appropriate transformation of the difference, determined after exploratory data analysis) is greater than zero in favor of the alternative that the difference is less than zero.. EGFR immunohistochemistry H-score. --- T790M ---

A landmark analysis will be used to evaluate the correlation between post-randomization biomarker values and PFS and OS (from the landmark timepoint) using a Cox proportional hazards model.. Presence of de novo EGFR T790M mutation or other molecular alterations. --- T790M ---

To evaluate if the presence of de novo T790M mutation is associated with primary resistance to afatinib dimaleate, PFS and OS will be compared between T790M mutation positive and negative patients randomized to the afatinib dimaleate monotherapy arm using a log-rank test... Ratio of sensitizing EGFR mutation to EGFR T790 mutation. --- T790M ---

To evaluate if the presence of de novo T790M mutation is associated with primary resistance to afatinib dimaleate, PFS and OS will be compared between T790M mutation positive and negative patients randomized to the afatinib dimaleate monotherapy arm using a log-rank test... Ratio of sensitizing EGFR mutation to EGFR T790 mutation. --- T790M --- --- T790M ---

To evaluate if the ratio of EGFR sensitizing mutation to EGFR T790M mutation (EGFRs/EGFR T790M) among patients with T790M is predictive for afatinib dimaleate monotherapy, analyses will be performed in a similar fashion to the evaluation of T790M among patients with measurable T790M (which defines T790M). --- T790M ---

To evaluate if the ratio of EGFR sensitizing mutation to EGFR T790M mutation (EGFRs/EGFR T790M) among patients with T790M is predictive for afatinib dimaleate monotherapy, analyses will be performed in a similar fashion to the evaluation of T790M among patients with measurable T790M (which defines T790M). --- T790M --- --- T790M ---

To evaluate if the ratio of EGFR sensitizing mutation to EGFR T790M mutation (EGFRs/EGFR T790M) among patients with T790M is predictive for afatinib dimaleate monotherapy, analyses will be performed in a similar fashion to the evaluation of T790M among patients with measurable T790M (which defines T790M). --- T790M --- --- T790M --- --- T790M ---

To evaluate if the ratio of EGFR sensitizing mutation to EGFR T790M mutation (EGFRs/EGFR T790M) among patients with T790M is predictive for afatinib dimaleate monotherapy, analyses will be performed in a similar fashion to the evaluation of T790M among patients with measurable T790M (which defines T790M). --- T790M --- --- T790M --- --- T790M --- --- T790M ---

To evaluate if the ratio of EGFR sensitizing mutation to EGFR T790M mutation (EGFRs/EGFR T790M) among patients with T790M is predictive for afatinib dimaleate monotherapy, analyses will be performed in a similar fashion to the evaluation of T790M among patients with measurable T790M (which defines T790M). --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M ---

To evaluate if the ratio of EGFR sensitizing mutation to EGFR T790M mutation (EGFRs/EGFR T790M) among patients with T790M is predictive for afatinib dimaleate monotherapy, analyses will be performed in a similar fashion to the evaluation of T790M among patients with measurable T790M (which defines T790M). --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M ---

Inclusion Criteria: - Patients must have histologically or cytologically confirmed stage IV (American Joint Committee on Cancer [AJCC] 7th Edition) or recurrent non-small cell lung cancer (NSCLC) - Patients must have documented presence of an EGFR exon 19 deltion or exon 21 (L858R) substitution mutation; T790M mutation or other molecular abnormality will be allowed as long as it accompanies one of the mutations listed above; EGFR testing must be performed using a Food and Drug Administration (FDA)-approved test or in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. --- L858R --- --- T790M ---

Crohn's disease, malabsorption, etc) - Patients must be able to swallow medication by oral route - Patients must not have a history of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA) classification of 3, unstable angina or poorly controlled arrhythmia or myocardial infarction within 6 months prior to registration; if clinically indicated, echocardiogram or multigated acquisition (MUGA) must be performed and cardiac ejection fraction must be >= 50% - Patients must not have had major surgery within 28 days prior to registration or be scheduled for surgery during the projected course of protocol treatment; tumor biopsy is allowed - Patients must not have a known history of active hepatitis B infection (defined as presence of hepatitis B surface antigen [Hep B sAg] and/ or Hep B deoxyribonucleic acid [DNA]), active hepatitis C infection (defined as presence of hepatitis C [Hep C] ribonucleic acid [RNA]) and/or known human immunodeficiency virus (HIV) seropositive - Patients must not have any other concomitant serious illness or organ system dysfunction which in the opinion of the investigator would either compromise patient safety or interfere with the evaluation of the safety of the study drug - Patients must not be planning to receive any other investigational agents during the course of protocol treatment - Patients must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to afatinib and/or cetuximab - Prestudy history and physical must be obtained with 28 days prior to registration - Patients must have Zubrod performance status of 0 - 2 - No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years - Patients must not be pregnant or nursing; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures - Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines - As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system Inclusion Criteria: - Patients must have histologically or cytologically confirmed stage IV (American Joint Committee on Cancer [AJCC] 7th Edition) or recurrent non-small cell lung cancer (NSCLC) - Patients must have documented presence of an EGFR exon 19 deltion or exon 21 (L858R) substitution mutation; T790M mutation or other molecular abnormality will be allowed as long as it accompanies one of the mutations listed above; EGFR testing must be performed using a Food and Drug Administration (FDA)-approved test or in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. --- L858R --- --- T790M ---

TERTIARY OBJECTIVES: I. To investigate the molecular mechanisms that confer benefit from afatinib and afatinib plus cetuximab by evaluating whether the presence of de novo EGFR T790M mutation or other molecular alterations in the pre-treatment tumor influence the clinical outcomes. --- T790M ---

To quantitatively assess whether the ratio of sensitizing EGFR (EGFRs) mutation to EGFR T790M influences outcome and is altered during treatment. --- T790M ---

Primary Outcomes

Measure: OS (phase III)

Time: From date of registration to date of death due to any cause, assessed up to 3 years

Measure: PFS (phase II)

Time: From date of registration to date of first documentation of progression or symptomatic deterioration or death due to any cause, assessed up to 3 years

Secondary Outcomes

Measure: PFS

Time: From date of registration to date of first documentation of progression or symptomatic deterioration or death due to any cause, assessed up to 3 years

Description: Compared between arms using a chi-squared test of independence at the 1-sided 5% level.

Measure: Response rates

Time: Up to 3 years

Measure: Time to treatment discontinuation

Time: From date of registration to date of discontinuation of treatment or death due to any cause, assessed up to 3 years

Measure: Time to treatment failure

Time: From date of registration to date of first documentation of progression or symptomatic deterioration, early discontinuation of treatment, or death due to any cause, assessed up to 3 years

Description: Assessed using a chi-squared or Fisher's exact test (as appropriate) at the 1-sided 5% level.

Measure: Toxicity rates assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0

Time: Up to 3 years

Other Outcomes

Description: For each of these markers, a one-sample t-test (or Wilcoxon signed-rank test) will be used to test the null hypothesis that the absolute difference between the copy number after progression and the copy number in the pre-treatment specimen (or an appropriate transformation of the difference, determined after exploratory data analysis) is not equal to zero.

Measure: Change in copy number alterations in MET, EGFR, and HER2, analyzed using fluorescence in situ hybridization

Time: Baseline up to 3 years (after disease progression)

Description: To evaluate if EGFRs/EGFR T790M is lower at progression than in pre-treatment specimens among patients with results available for pre-treatment and progression, a one-sample t-test (or Wilcoxon signed-rank test) will be used to test the null hypothesis that the difference between the progression ratio and the pre-treatment ratio (or an appropriate transformation of the difference, determined after exploratory data analysis) is greater than zero in favor of the alternative that the difference is less than zero.

Measure: Change in the ratio of sensitizing EGFR mutation to EGFR T790 mutation

Time: Baseline up to 3 years (at progression)

Description: To evaluate the hypothesis that H-score positive status at baseline is associated with absolute difference in PFS (and OS) among patients randomized to receive afatinib dimaleate monotherapy a test of interaction will be performed at the 1-sided 20% level.

Measure: EGFR immunohistochemistry H-score

Time: Baseline

Description: Tumor marker levels over time will be evaluated using a linear mixed model for continuous markers and using generalized estimating equations for binary markers. A landmark analysis will be used to evaluate the correlation between post-randomization biomarker values and PFS and OS (from the landmark timepoint) using a Cox proportional hazards model.

Measure: Levels of circulating tumor markers

Time: Up to 3 years

Description: To evaluate if the presence of de novo T790M mutation is associated with primary resistance to afatinib dimaleate, PFS and OS will be compared between T790M mutation positive and negative patients randomized to the afatinib dimaleate monotherapy arm using a log-rank test..

Measure: Presence of de novo EGFR T790M mutation or other molecular alterations

Time: Baseline

Description: To evaluate if the ratio of EGFR sensitizing mutation to EGFR T790M mutation (EGFRs/EGFR T790M) among patients with T790M is predictive for afatinib dimaleate monotherapy, analyses will be performed in a similar fashion to the evaluation of T790M among patients with measurable T790M (which defines T790M). Cox regression will be used to assess the predictive association of the ratio in the afatinib dimaleate monotherapy arm with both OS and PFS

Measure: Ratio of sensitizing EGFR mutation to EGFR T790 mutation

Time: Up to 3 years

88 Phase I Study to Evaluate the Safety and Tolerability of ASLAN001 in Combination With Oxaliplatin and Capecitabine or Oxaliplatin and 5-FU With Leucovorin

This is a Phase I, open-label, dose escalation study of ASLAN001 given in combination with CAPOX or mFolfox6, in patients with metastatic solid tumours, whom are suitable to receive CAPOX or mFolfox6, or with tumours that have dysregulated EGFR or HER2 signaling.

NCT02435927
Conditions
  1. Solid Tumors
Interventions
  1. Drug: ASLAN001+ CAPOX (Oxaliplatin, capecitabine)
  2. Drug: ASLAN001 + mFolfox6 (5-FU, leucovorin)

5. Patients undergoing mandatory biopsy in dose expansion of a non-DLT cohort should have any of the following: - known HER2 or EGFR dysregulation - Patients with T790M mutation will be excluded. --- T790M ---

Primary Outcomes

Measure: Maximum tolerated dose (MTD) of ASLAN001 when used in combination with Oxaliplatin and Capecitabine (CAPOX) or Oxaliplatin and 5-FU with leucovorin (mFolfox6)

Time: one year

Secondary Outcomes

Measure: Pharmacokinetic parameter Area under the plasma concentration time curve (AUC)

Time: Day 1 and Day 15 of Cycle 1 and Day 1 of Cycle 3

Measure: Pharmacokinetic parameter Maximum plasma concentration (Cmax)

Time: Day 1 and Day 15 of Cycle 1 and Day 1 of Cycle 3

Measure: Pharmacokinetic parameter Minimum (trough) plasma concentration (Cmin)

Time: Day 1 and Day 15 of Cycle 1 and Day 1 of Cycle 3

Measure: Efficacy of ASLAN001 when given in combination in CAPOX or mFolfox6 as measured by the objective response rate (ORR)

Time: one year

89 Correlation Between Epithelial Growth Factor Receptor(EGFR) Mutation Using cfDNA and CTCs in Patients With Non-Small Cell Lung Cancer

Correlation of epithelial growth factor receptor mutation in blood of lung cancer patient and clinical outcome.

NCT02422628
Conditions
  1. Lung Cancer
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

3. Tumor harboring EGFR mutation including activating mutation L858R, Del19 or/and resistant mutation T790M, or/and rare mutation G719, S768, L861 4. Treatment naive 5. Patients will receive EGFR-TKI as first line treatment. --- L858R --- --- T790M ---

3. Tumor with no EGFR mutation detected (mutation L858R, Del19 or/and resistant mutation T790M, or/and rare mutation G719, S768, L861) 4. EGFR TKI treatment naïve and without any EGFR TKI treatment in the following process ------- Exclusion criteria For exclusion in the study of NSCLC patients and control subjects should fulfill the following criteria: 1. Subjects should not enter the study if any of the following exclusion criteria are fulfilled: Involvement in the planning and/or conduct of the study (applies to staff at the study site) 2. Previous enrolment in the present study 3. --- L858R --- --- T790M ---

More than half of patients acquired resistant by new EGFR T790M resistance mutation. --- T790M ---

Primary Outcomes

Measure: Progressive disease measured by RECIST criteria after receiving 1st line EGFR-TKI

Time: 3 years

90 Phase II Study of AZD9291 in Patients With Advanced Stage Non-small Cell Lung Cancer Following Prior EGFR TKI Therapy With EGFR and T790M Mutations Detected in Plasma Circulating Tumor DNA (PLASMA)

Circulating tumor DNA (ctDNA) is a highly specific and effective biomarker for the detection of EGFR mutation status. We hypothesise AZD9291 is efficacious in patients with EGFR sensitizing mutations and T790M detected in plasma ctDNA. This is a prospective, open label, multi-centre single arm phase II study assessing the efficacy and safety of AZD9291 monotherapy in patients with stage IIIB or IV harboring sensitising EGFR mutation (exon 19 deletions or exon 21 L858R substitution mutations) and T790M who have progressed following prior treatment with an approved EGFR TKI. Approximately 106 subjects will be enrolled. All patients must have documented radiological progression on EGFR-TKI treatment and on the last treatment administered prior to enrolling in the study.

NCT02811354
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Drug: AZD9291
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Phase II Study of AZD9291 in Patients With Advanced Stage Non-small Cell Lung Cancer Following Prior EGFR TKI Therapy With EGFR and T790M Mutations Detected in Plasma Circulating Tumor DNA (PLASMA). --- T790M ---

Phase II Study of AZD9291 in Advanced Stage NSCLC With EGFR and T790M Mutations Detected in Plasma Ct-DNA Circulating tumor DNA (ctDNA) is a highly specific and effective biomarker for the detection of EGFR mutation status. --- T790M ---

We hypothesise AZD9291 is efficacious in patients with EGFR sensitizing mutations and T790M detected in plasma ctDNA. --- T790M ---

This is a prospective, open label, multi-centre single arm phase II study assessing the efficacy and safety of AZD9291 monotherapy in patients with stage IIIB or IV harboring sensitising EGFR mutation (exon 19 deletions or exon 21 L858R substitution mutations) and T790M who have progressed following prior treatment with an approved EGFR TKI. --- L858R --- --- T790M ---

Confirmation of T790M status by central lab testing from a plasma sample taken after confirmation of disease progression on the most recent treatment regimen. --- T790M ---

Carcinoma, Non-Small-Cell Lung Carcinoma, Non-Small-Cell Lung As T790M is the most common mechanism of acquired resistance to EGFR TKI, EGFR TKIs targeting T790M has been developed. --- T790M ---

Carcinoma, Non-Small-Cell Lung Carcinoma, Non-Small-Cell Lung As T790M is the most common mechanism of acquired resistance to EGFR TKI, EGFR TKIs targeting T790M has been developed. --- T790M --- --- T790M ---

AZD9291 is an oral, potent, irreversible EGFR-TKI selective for sensitizing (EGFRm) and T790M resistance mutation with a significant selectivity margin against wild-type EGFR. --- T790M ---

As a result, AZD9291 can effectively block EGFR signaling both in EGFR single mutant cells with activating EGFR mutations and in double mutant cells bearing the resistance T790M mutation. --- T790M ---

This is a prospective, open label, multi-centre single arm phase II study assessing the efficacy and safety of AZD9291 monotherapy in patients with stage IIIB or IV harboring sensitising EGFR mutation (exon 19 deletions and exon 21 L858R substitution mutations) and T790M who have progressed following prior treatment with an approved EGFR TKI. --- L858R --- --- T790M ---

Plasma sample must harbour an EGFR mutation known to be associated with EGFR TKI sensitivity (exon 19 deletion, L858R as well as presence of T790M by central lab testing from a plasma sample taken after confirmation of disease progression on the most recent treatment regimen. --- L858R --- --- T790M ---

Primary Outcomes

Measure: Objective response rate (ORR)

Time: From the time of their first treatment with daily AZD9291 till 28 days after discontinuation

Secondary Outcomes

Measure: Progression free survival (PFS)

Time: From the time of their first treatment with daily AZD9291 till 28 days after discontinuation

Measure: Duration of response (DoR)

Time: From the time of their first treatment with daily AZD9291 till 28 days after discontinuation

Measure: Disease control rate (DCR)

Time: From the time of their first treatment with daily AZD9291 till 28 days after discontinuation

Measure: Tumour shrinkage

Time: From the time of their first treatment with daily AZD9291 till 28 days after discontinuation

Measure: Overall survival (OS)

Time: From the time of their first treatment with daily AZD9291 till 28 days after discontinuation

91 Phase III Study of Osimertinib or Docetaxel-bevacizumab as Third-line Treatment in EGFR T790M Mutated Non-Small Cell Lung Cancer

Acquired epidermal growth factor receptor (EGFR) T790M mutation is the most common genetic change after resistant to first generation EGFR tyrosine kinase inhibitor (EGFR TKI) in non-small cell lung cancer. After a 10 to 14 months median progression-free survival with the treatment of first generation EGFR TKI, half of patients will get disease progression.For patients progression after treated with first line EGFR TKI and second line double bullets chemotherapy or chemotherapy then EGFR TKI, optimal third line therapy is quite critical important for benefit patients' survival. We conducted this study was aimed to compare the efficacy and toxicity between osimertinib and docetaxel-bevacizumab as the third line therapy in patients with local advanced or metastatic non-squamous cell lung cancer.

NCT02959749
Conditions
  1. Progression Free Survival
Interventions
  1. Drug: Osimertinib
  2. Drug: docetaxel, bevacizumab
MeSH:Carcinoma, Non-Small-Cell Lung Disease Progression
HPO:Non-small cell lung carcinoma

Phase III Study of Osimertinib or Docetaxel-bevacizumab as Third-line Treatment in EGFR T790M Mutated Non-Small Cell Lung Cancer. --- T790M ---

Osimertinib or Docetaxel-bevacizumab as Third-line Treatment in EGFR T790M Mutated Non-Small Cell Lung Cancer Acquired epidermal growth factor receptor (EGFR) T790M mutation is the most common genetic change after resistant to first generation EGFR tyrosine kinase inhibitor (EGFR TKI) in non-small cell lung cancer. --- T790M ---

Osimertinib or Docetaxel-bevacizumab as Third-line Treatment in EGFR T790M Mutated Non-Small Cell Lung Cancer Acquired epidermal growth factor receptor (EGFR) T790M mutation is the most common genetic change after resistant to first generation EGFR tyrosine kinase inhibitor (EGFR TKI) in non-small cell lung cancer. --- T790M --- --- T790M ---

Inclusion Criteria: - local advanced or metastatic non-small cell lung cancer - large cell lung carcinoma or adenocinoma - Previously treated by TKI-Chemotherapy or Chemotherapy-TKI - EGFR T790M positive - No uncontrolled hypertension - No active bleeding or thrombosis in recent 6 months - No previously treated with VEGF antibody Exclusion Criteria: - newly diagnosed thrombosis - anti-coagulation therapy - uncontrolled hypertension - uncontrolled nephropathy Inclusion Criteria: - local advanced or metastatic non-small cell lung cancer - large cell lung carcinoma or adenocinoma - Previously treated by TKI-Chemotherapy or Chemotherapy-TKI - EGFR T790M positive - No uncontrolled hypertension - No active bleeding or thrombosis in recent 6 months - No previously treated with VEGF antibody Exclusion Criteria: - newly diagnosed thrombosis - anti-coagulation therapy - uncontrolled hypertension - uncontrolled nephropathy Progression Free Survival Carcinoma, Non-Small-Cell Lung Disease Progression null --- T790M ---

Inclusion Criteria: - local advanced or metastatic non-small cell lung cancer - large cell lung carcinoma or adenocinoma - Previously treated by TKI-Chemotherapy or Chemotherapy-TKI - EGFR T790M positive - No uncontrolled hypertension - No active bleeding or thrombosis in recent 6 months - No previously treated with VEGF antibody Exclusion Criteria: - newly diagnosed thrombosis - anti-coagulation therapy - uncontrolled hypertension - uncontrolled nephropathy Inclusion Criteria: - local advanced or metastatic non-small cell lung cancer - large cell lung carcinoma or adenocinoma - Previously treated by TKI-Chemotherapy or Chemotherapy-TKI - EGFR T790M positive - No uncontrolled hypertension - No active bleeding or thrombosis in recent 6 months - No previously treated with VEGF antibody Exclusion Criteria: - newly diagnosed thrombosis - anti-coagulation therapy - uncontrolled hypertension - uncontrolled nephropathy Progression Free Survival Carcinoma, Non-Small-Cell Lung Disease Progression null --- T790M --- --- T790M ---

Primary Outcomes

Measure: progression free survival

Time: Average 10 months

92 Phase I/II Study of Dasatinib and Osimertinib (AZD9291) in Patients With Advanced Non-small Cell Lung Cancer With EGFR Mutations

This is a study for patients with advanced non-small cell lung cancer with changes to their cancer cells called EGFR mutations. Mutated EGFR is important in the growth of cancer cells. Medical studies have shown that patients with EGFR mutation-positive lung cancer gain more benefit from targeted therapy drugs such as EGFR inhibitors than with standard chemotherapy. However, a significant proportion of patients carrying these sensitizing mutations do not respond well to the first-generation EGFR-TKIs (erlotinib and gefitinib), indicating the existence of intrinsic resistance mechanisms. Moreover, despite initial response to EGFR-TKIs, acquired resistance is inevitable in all patients. The investigators have recently shown that Cripto-1 overexpression in EGFR mutant NSCLC contributes to the intrinsic resistance to EGFR-TKIs through activation of the SRC oncogene. They have also shown that a combination of an EGFR-TKI (both erlotinib and osimertinib) and a Src inhibitor are synergistic in Cripto-1 overexpressing tumors in the laboratory. This study will be testing a combination of two drugs, dasatinib and osimertinib, to overcome resistance to EGFR-TKIs. Osimertinib (AZD9291) is a third-generation EGFR-TKI, which selectively blocks the activity of EGFR mutants, but spares that of wild type. The advantage of using osimertinib is that it inhibits not only the sensitizing EGFR mutations, but also the T790M mutant, which is the most common mechanism of acquired resistance. Dasatinib is a potent, orally available ABL1/SRC TKI, approved for the treatment of chronic myeloid leukemia (CML) in first-line and in patients with imatinib-resistant disease or intolerant, and is being actively studied in patients with advanced solid tumors. The first part of the study will involve finding the highest dose of dasatinib that can be given with osimertinib without causing severe side effects, finding out the side effects seen by giving dasatinib at different dose levels with osimertinib, and measuring the levels of dasatinib and osimertinib in blood at different dose levels. The second part will determine the effects of the combination of dasatinib and osimertinib and determine if the amount of Cripto-1 protein in your tumor or blood makes you more likely to have a good response to the combination of dasatinib and osimertinib.

NCT02954523
Conditions
  1. EGFR Gene Mutation
  2. Nonsmall Cell Lung Cancer
Interventions
  1. Drug: Dasatinib
  2. Drug: Osimertinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

The advantage of using osimertinib is that it inhibits not only the sensitizing EGFR mutations, but also the T790M mutant, which is the most common mechanism of acquired resistance. --- T790M ---

Patients with the T790M mutation will also be eligible. --- T790M ---

The advantage of using AZD9291 is that it inhibits not only the mutants of exon-19 deletion and L858R, but also the T790M mutant, which is the most common mechanism of acquired resistance. --- L858R --- --- T790M ---

Primary Outcomes

Description: Number of patients with drug related adverse events and number of patients who can tolerate dosing of dasatinib when given in combination with osimertinib

Measure: Phase I : Number of patients with drug-related adverse events as assessed by CTCAEv4.0

Time: 9 months

Description: The rate of patients non-responding (progressive disease or stable disease lasting 4 months or less) to the combination of osimertinib and dasatinib

Measure: Phase II : Number of patients that do not progress according to RECIST v1.1

Time: 9 months

Secondary Outcomes

Description: Number of patients with treatment-related adverse events in the phase II study, who are treated at the same dose that has been selected based on the phase I part

Measure: Number of patients with treatment-related adverse events in the phase II study

Time: 18 months

Description: To describe the concentration of osimertinib when administered with dasatinib. Blood is obtained from patients before each cycle and 4 hours after start of the first 2 cycles.

Measure: Concentration of orimertinib in blood

Time: 18 months

Description: Determination of the time between the start of the experimental treatment and progression of the tumor

Measure: Progression-free survival

Time: 3 years

Description: Determination of the time between start of the experimental treatment and death

Measure: Overall survival

Time: 3 years

Description: Determination of the duration of the response to the treatment, calculated from start of treatment in case of partial response and from the declaration of complete response in case of complete response. The end of the response will be when the tumor progresses

Measure: Duration of response

Time: 3 years

93 Phase II Study of Erlotinib With or Without Hydroxychloroquine in Patients With Previously Untreated Advanced NSCLC and EGFR Mutations

The purpose of this research study is to learn if adding hydroxychloroquine (HCQ) to erlotinib helps treat non-small cell lung cancer (NSCLC). Another goal of this research study is to learn more about NSCLC and how it may respond to study treatment. Erlotinib (Tarceva) is a type of drug called a tyrosine kinase inhibitor (TKI). TKIs block a protein called the epidermal growth factor receptor (EGFR). EGFR may control tumor growth and tumor cell survival. However, although TKI drugs can work for some lung cancer patients for a period of time, eventually the tumor finds a way to resist or counteract the TKI treatment and it begins to grow again. Hydroxychloroquine (HCQ) is a drug approved by the FDA for treating malaria, rheumatoid arthritis, and several other diseases. Laboratory research suggests that when HCQ is given with a TKI, it may help delay or prevent TKI resistance from developing.

NCT00977470
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: Erlotinib
  2. Drug: Hydroxychloroquine
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Presence of the known resistance mutation T790M as detected by direct tumor sequencing is not allowed. --- T790M ---

Primary Outcomes

Description: A measure of progression-free survival in patients with advanced non small-cell lung cancer (NSCLC) and EGFR mutations treated with erlotinib as compared with patients treated with erlotinib plus hydroxychloroquine (HCQ). Disease progression is defined as at least a 20% increase in the sum of the longest diameter of target lesions, as seen on CT scan, or the appearance of one or more new lesions on CT scan.

Measure: Median Progression Free Survival

Time: From start of treatment until report of disease progression, assessed up to 10 years.

Description: This trial can detect a difference in proportions alive without progression at 9 months from 50% in the erlotinib arm to 77% in the erlotinib plus hydroxychloroquine (HCQ) arm, using an alpha of 0.15 and power of 85%, using the two-sided Likelihood Ratio test. Progression is defined as at least a 20% increase in the size of existing lesions or the appearance of one or more new lesions.

Measure: Nine-month Progression-free Survival Rate

Time: Nine months

Secondary Outcomes

Description: To evaluate the safety of treatment with erlotinib with and without hydroxychloroquine (HCQ). All participants receiving study treatment were evaluated for safety. Parameters included laboratory tests, hematological abnormalities, physical exam findings and spontaneous reports of adverse events reported by participants. Toxicities were evaluated and graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = life-threatening, Grade 5 = fatal.

Measure: Treatment Related Toxicity, > 10% Frequency, Any Grade

Time: 2 years

Description: Response is assessed via spiral CT scan, done at baseline and after every 2 cycles of study treatment. Standard RECIST (Response Evaluation Criteria in Solid Tumors) was used. Complete Response (CR) = disappearance of all target lesions; Partial Response (PR) = at least a 30% decrease in the size of target lesions, as compared to baseline; Progressive Disease (PD) = at least at 20% increase in the size of target lesions, or the appearance of one or more new lesions; Stable Disease (SD) = neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease. Response rate = CR + PR. Disease control rate = CR + PR + SD

Measure: Objective Tumor Response Rate Following Treatment With Erlotinib and With Erlotinib/HCQ.

Time: 2 years

Measure: Overall Survival of Patients Treated With Erlotinib and With Erlotinib/HCQ

Time: Until death

Other Outcomes

Description: Serial circulating tumor cell (CTC) analyses will be performed on peripheral blood and correlated with disease response.

Measure: Circulating Tumor Cell Quantification

Time: Until disease progression (median of 10.8 months)

Description: Correlation of molecular and genetic tumor characteristics with disease response. Genomic DNA will be extracted from tumor tissue and direct sequencing analysis will be performed to identify additional mutations.

Measure: EGFR Mutational Status

Time: 2 years

Description: [18F]-FMISO-PET/CT was performed on a 64-slice PET/CT scanner and tracer uptake was assessed using SUV (standardized uptake value), normalizing the radioactivity measured in tissue by the injected dose and the body weight of the patient. Mean and maximum SUV and threshold volume of FMISO uptake were measured to quantify the extent of hypoxia in the primary tumor. Imaging was performed before and after initiation of therapy with erlotinib.

Measure: Percent of Participants in Which FMISO-PET ([18F]-Fluoromisonidazole-positron Emission Tomography) is Able to Detect and Quantify Changes in Tumor Hypoxia After Erlotinib.

Time: 12 weeks

94 "T790M Mutation Testing in Blood by Different Methodologies"_RING Project

Three laboratories will participate in the study. Each laboratory will analyze the same samples by different methodologies according to the flow indicated in figure 1. This design will allow comparing the agreement performance of different methods available for T790M identification in circulating-free DNA isolated from peripheral blood.

NCT03363139
Conditions
  1. NSCLC Stage IV
Interventions
  1. Drug: Tirosin Kinase Inhibitors

"T790M Mutation Testing in Blood by Different Methodologies"_RING Project. --- T790M ---

T790M Mutation Testing in Blood by Different Methodologies Three laboratories will participate in the study. --- T790M ---

This design will allow comparing the agreement performance of different methods available for T790M identification in circulating-free DNA isolated from peripheral blood. --- T790M ---

To evaluate the agreement performance of different methodologies available in Spain for T790M identification in circulating-free DNA isolated from blood collected at the time of progression on a first or second generation TKI. --- T790M ---

Circulating free DNA from peripheral blood sample is an adequate source for T790M resistance mutation testing. --- T790M ---

Primary Outcomes

Description: To evaluate the agreement performance of different methodologies available in Spain for T790M identification in circulating-free DNA isolated from blood collected at the time of progression on a first or second generation TKI

Measure: Assess the agreement between qualitative methodologies

Time: At 12 months from the first inclusion

Secondary Outcomes

Description: To compare the cost of the different methodologies

Measure: Cost of the different methodologies

Time: At 12 months from the first inclusion

Description: To estimate the specificity and sensitivity of each cfDNA method.

Measure: Specificity and sensitivity of each cfDNA method

Time: At 12 months from the first inclusion

Other Outcomes

Description: To compare turnaround time of the different methodologies

Measure: Turnaround time of different methodologies

Time: At 12 months from the first inclusion

Description: To compare the ease of use of the different methodologies

Measure: Ease of use of different methodologies

Time: At 12 months from the first inclusion

95 A Biomarker-Integrated Targeted Therapy Study in Previously Treated Patients With Advanced Non-Small Cell Lung Cancer - (IM-BATTLE-2 Program)

This phase Ib/II trial studies the side effects and best dose of trametinib when given together with pembrolizumab and to see how well they work in treating patients with non-small cell lung cancer that has come back and spread to other places in the body, cannot be removed by surgery, or spread to nearby tissues or lymph nodes. Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving trametinib and pembrolizumab may work better in treating patients with non-small cell lung cancer.

NCT03225664
Conditions
  1. Metastatic Lung Non-Small Cell Carcinoma
  2. Recurrent Lung Non-Small Cell Carcinoma
  3. Stage III Lung Cancer AJCC v8
  4. Stage IIIA Lung Cancer AJCC v8
  5. Stage IIIB Lung Cancer AJCC v8
  6. Stage IIIC Lung Cancer AJCC v8
  7. Stage IV Lung Cancer AJCC v8
  8. Stage IVA Lung Cancer AJCC v8
  9. Stage IVB Lung Cancer AJCC v8
  10. Unresectable Lung Non-Small Cell Carcinoma
Interventions
  1. Biological: Pembrolizumab
  2. Other: Pharmacokinetic Study
  3. Drug: Trametinib
MeSH:Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Carcinoma Neoplasm of the lung Non-small cell lung carcinoma

Subjects with known EGFR sensitizing mutational status or ALK fusion must have been treated and progressed on EGFR TKIs or ALK-directed therapy, or with tumors harboring EGFR T790M mutation to have received and progressed on therapy directed at the T790M mutation (e.g. --- T790M ---

Subjects with known EGFR sensitizing mutational status or ALK fusion must have been treated and progressed on EGFR TKIs or ALK-directed therapy, or with tumors harboring EGFR T790M mutation to have received and progressed on therapy directed at the T790M mutation (e.g. --- T790M --- --- T790M ---

Primary Outcomes

Description: Each patient will have the KRAS mutation and PD-L1 status determined prior to treatment in order for stratified randomization. A futility monitoring will be carried out continuously to each stratum within each treatment arm after the primary endpoints of 6 patients have been observed in the corresponding marker groups.

Measure: Overall objective response rate evaluated according to modified Response Evaluation Criteria in Solid Tumors (RECIST 1.1 and immune related [ir]RECIST)

Time: At 6 months

96 Phase II, Multicenter, Single-arm, Open-label Study to Evaluate the Efficacy of Olmutinib(Olita®) in Patients With NSCLC Who Harboring T790M Mutation Confirmed Using DNA Extracted From Extracellular Vesicles in Bronchoalveolar Lavage Fluid

The purpose of this study is to evaluate the efficacy of Olmutinib(Olita®) in patients with T790M-positive non-small cell lung cancer (NSCLC) confirmed using DNA extracted from extracellular vesicles of bronchoalveolar lavage fluid.

NCT03228277
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: Olmutinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Phase II, Multicenter, Single-arm, Open-label Study to Evaluate the Efficacy of Olmutinib(Olita®) in Patients With NSCLC Who Harboring T790M Mutation Confirmed Using DNA Extracted From Extracellular Vesicles in Bronchoalveolar Lavage Fluid. --- T790M ---

Olmutinib Trial in T790M (+) NSCLC Patients Detected by Liquid Biopsy Using BALF Extracellular Vesicular DNA The purpose of this study is to evaluate the efficacy of Olmutinib(Olita®) in patients with T790M-positive non-small cell lung cancer (NSCLC) confirmed using DNA extracted from extracellular vesicles of bronchoalveolar lavage fluid. --- T790M ---

Olmutinib Trial in T790M (+) NSCLC Patients Detected by Liquid Biopsy Using BALF Extracellular Vesicular DNA The purpose of this study is to evaluate the efficacy of Olmutinib(Olita®) in patients with T790M-positive non-small cell lung cancer (NSCLC) confirmed using DNA extracted from extracellular vesicles of bronchoalveolar lavage fluid. --- T790M --- --- T790M ---

8. Confirmation that the extracellular vesicles (EV) extracted from bronchoalveolar lavage fluid (BALF) harbour T790M mutation (It can be replaced previous the same result throughout the follow up period before enrollment.) 9. --- T790M ---

Previous treatment with anticancer therapies, EGFR-TKI, olmutinib (HM61713), or other drugs that target T790M-positive mutant EGFR with sparing of wild-type, Osimertinib (AZD9291), Rociletinib (CO-1686), investigational agent(s) within 30 days prior to the first administration of study drug, radiotherapy 2. Treatment with a potent cytochrome P450 (CYP) 3A4 inhibitors or inducers 3. History of any other malignancy EXCEPTIONS are: - adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS) of the breast, thyroid cancer - other malignancies diagnosed prior to randomisation and treated with no evidence of disease recurrence more than 3 years 4. Any history or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure NYHA classification of III or IV, unstable angina or poorly controlled arrhythmia as determined by the investigator. --- T790M ---

Patients who had received other investigational product within 30 days prior to the first administration of study drug except for gefitinib, erlotinib, or afatinib Non Small Cell Lung Cancer Carcinoma, Non-Small-Cell Lung This is a single-arm, open-label, Phase 2 study to assess the anti-tumor efficacy of Olmutinib(Olita®) administered to patients with T790M-positive NSCLC confirmed using DNA extracted from extracellular vesicles in bronchoalveolar lavage fluid as measured by objective response rate (ORR). --- T790M ---

Primary Outcomes

Description: defined as the proportion of patients who achieved complete remission(CR) or partial remission(PR) based on RECIST version 1.1

Measure: Objective response rate (ORR)

Time: Change from baseline at every 6 weeks until disease progression or withdrawal from study, assessed up to 12 months

Secondary Outcomes

Description: defined as the proportion of patients with a documented CR, PR, and SD during the treatment cycles according to the RECIST version 1.1

Measure: Disease control rate (DCR)

Time: Change from baseline at every 6 weeks until disease progression or withdrawal from study, assessed up to 12 months

Description: defined as the time from first administration of study drug to determination of tumor progression by RECIST version 1.1 or death due to any cause, whichever occurs first

Measure: Progression-free survival (PFS)

Time: Change from baseline at every 6 weeks until disease progression or withdrawal from study, assessed up to 12 months

97 A Randomized, Double-blind, Positive Controlled Phase III Study to Evaluate the Efficacy and Safety of BPI-7711 Capsule in Locally Advanced or Recurrent/Metastatic Treatment-naïve Non-small Cell Lung Cancer Patients With EGFR Mutation

A randomized, double-blind, positive controlled phase III study to evaluate the efficacy and safety of BPI-7711 capsule in locally advanced or recurrent/metastatic treatment-naïve non-small cell lung cancer patients with EGFR mutation

NCT03866499
Conditions
  1. NSCLC
Interventions
  1. Drug: BPI-7711
  2. Drug: Gefitinib
  3. Drug: Placebo Tablet
  4. Drug: Placebo capsule
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- Primary T790M mutation-positive patient. --- T790M ---

Primary Outcomes

Description: Progression-free survival evaluated by Blinded Independent Center Review

Measure: Progression-free survival

Time: up to approximately 16 months

Secondary Outcomes

Description: Progression-free survival evaluated by investigators

Measure: Progression-free survival

Time: up to approximately 16 months

Description: Objective response rate

Measure: Objective response rate

Time: up to approximately 16 months

Description: Best objective response

Measure: Best objective response

Time: up to approximately 16 months

Description: Disease control rate

Measure: Disease control rate

Time: up to approximately 16 months

Description: Duration of response

Measure: Duration of response

Time: up to approximately 16 months

Description: Overall survival

Measure: Overall survival

Time: up to approximately 30 months

98 A Phase II Study to Assess the Safety and Efficacy of D-0316 in Patients With Locally Advanced/Metastatic Non Small Cell Lung Cancer Whose Tumors Are Epidermal Growth Factor Receptor Mutation Positive

A Phase II, Open Label, Single-arm Study to Assess the Safety and Efficacy of D-0316 in Patients with Locally Advanced/Metastatic Non Small Cell Lung Cancer whose Disease has Progressed with Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and whose Tumours are Epidermal Growth Factor Receptor Mutation and T790M Mutation Positive

NCT03861156
Conditions
  1. Solid Tumor
  2. NSCLC
  3. EGFR T790M
Interventions
  1. Drug: D-0316
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

D-0316 in Patients With EGFR Positive Non Small Cell Lung Cancer A Phase II, Open Label, Single-arm Study to Assess the Safety and Efficacy of D-0316 in Patients with Locally Advanced/Metastatic Non Small Cell Lung Cancer whose Disease has Progressed with Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and whose Tumours are Epidermal Growth Factor Receptor Mutation and T790M Mutation Positive Objective response rate based on independent radiology review. --- T790M ---

- patients must also have confirmation of tumour T790M mutation status (confirmed positive) after disease progression on the prior EGFR TKI. - Eastern cooperative oncology group performance status (ECOG PS) of 0-1. - a minimum life expectancy of 12 weeks. --- T790M ---

Solid Tumor NSCLC EGFR T790M Carcinoma, Non-Small-Cell Lung This is a phase II, open label, single arm study assessing the safety and efficacy of D-0316 (Firstly, D-0316 was orally given 75mg for a cycle(21 days), if tolerated, the dose will be increased to 100mg. --- T790M ---

Otherwise, the dose will be maintained at 75mg.) in patients with a confirmed diagnosis of Epidermal Growth Factor Receptor mutation positive and T790M mutation positive NSCLC,who have progressed following prior therapy with an approved Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI) agent. --- T790M ---

Primary Outcomes

Description: ORR per RECIST 1.1 calculated as the proportion of patients with a best overall response defined as complete response (CR) or partial response (PR).

Measure: Objective response rate based on independent radiology review

Time: 24 months

Secondary Outcomes

Description: PFS, defined as time from first dose of X-396 to progression or death due to any cause.

Measure: Progression-free survival (PFS) as assessed by independent radiology review and investigator

Time: 36 months

Description: OS, defined as time from first dose of X-396 to death due to any cause.

Measure: Overall survival (OS)

Time: 36 months

Description: DoR, defined as time from first reponse to disease progression or death

Measure: Duration of response(DoR)

Time: 24 months

Description: DCR, defined as proportion of complete response, partial response, and disease stabilization to the proportion of patients with evaluable tumors.

Measure: Disease control rate(DCR)

Time: 24 months

Description: iPFS, defined as the time between baseline brain metastases, from the date of study drug administration to the time between the onset of intracranial tumor progression or death.

Measure: Intracranial Progression-free survival(iPFS)

Time: 36 months

Description: iORR, defined as the proportion of subjects with complete intracranial response, partial intracranial response to subjects with brain metastases at baseline.

Measure: Intracranial objective response rate(iORR)

Time: 24 months

99 MELROSE: Phase 2 Study Evaluating MEchanisms of Resistance on Tumor Tissue and Liquid Biopsy in Patients With EGFR Mutated Nonpretreated Advanced Lung Cancer Receiving OSimErtinib Until and Beyond Radiological Progression : the MELROSE Trial

Osimertinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is selective for both EGFR-TKI sensitizing and T790M resistance mutations in patients with non-small-cell lung cancer. The AURA 3 study (T790M-positive advanced non-small-cell lung cancer in progression after first-line EGFR-TKI therapy, shown that the median duration of progression-free survival was significantly longer with osimertinib than with platinum therapy plus pemetrexed (10.1 months vs. 4.4 months p<0.001). In addition, clinical data show that patients with mutated EGFR NSCLC receiving osimertinib in first line, presented an objective response rate of 77 % with a disease control rate of 98 % and a median PFS was 19.3 months. Finally, The FLAURA study randomized phase 3 study clearly demonstrated the superiority of osimertinib compared with erlotinib or gefitinib in EGFR mutated nonpretreated NSCLC (median PFS of 18.9 months versus 10.2 months). However, several issues remain unknown or debated : - What are the mechanisms of resistance to osimertinib prescribed in first-line? - What are the consequences of prolonged exposure to osimertinib on the expression of markers of response to immunotherapy? - Is there an association between kinetic parameters of ctDNA (circulating tumor DNA) and prediction of response to osimertinib and/ or and prediction of therapeutic escape under osimertinib? In order to respond to all these questions, this phase II trial will be the first to systemically analyze the mechanisms of resistance to Osimertinib based on the analysis of biopsy, and collection of plasma from all patients during the course of treatment.

NCT03865511
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: TAGRISSO® 80mg (Osimertinib)
  2. Genetic: Tumor biopsies
  3. Genetic: ctDNA analysis
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

MEchanisms of Resistance in EGFR Mutated Nonpretreated Advanced Lung Cancer Receiving OSimErtib Osimertinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is selective for both EGFR-TKI sensitizing and T790M resistance mutations in patients with non-small-cell lung cancer. --- T790M ---

The AURA 3 study (T790M-positive advanced non-small-cell lung cancer in progression after first-line EGFR-TKI therapy, shown that the median duration of progression-free survival was significantly longer with osimertinib than with platinum therapy plus pemetrexed (10.1 months vs. 4.4 months p<0.001). --- T790M ---

Primary Outcomes

Description: Analyze of the proportion of patients with a given genetic marker on tumor biopsy (including, but not limited to, EGFR mutations, HER2 (Human Epidermal Growth factor receptor 2), and cMET expression and/or amplification) at the point of clinical disease progression.

Measure: Examination of the genetic profile at the point of disease progression in EGFRm+ (mutated Epidermal Growth Factor Receptor) patients receiving osimertinib as first-line EGFR TKI therapy compared to baseline.

Time: At clinical disease progression (approximately 22 months)

Secondary Outcomes

Description: Progression free survival rate at one year defined by time from first study dose to first event between Radiological Progression Disease and death, or one year if no event. The rPFS is defined according to RECIST 1.1.

Measure: Clinical objective : To assess efficacy of Osimertinib

Time: Every 3 months up to one year after first study dose

Description: Radiological Progression Free Survival (rPFS): Time from first study dose to first event between rPFS or death. The rPFS is defined according to RECIST 1.1.

Measure: Clinical objective : To assess efficacy of Osimertinib

Time: Every 3 months until radiological disease progression (approximately 22 months)

Description: Clinical Progression Free Survival (cPFS): Time from first study dose to off-osimertinib.

Measure: Clinical objective : To assess efficacy of Osimertinib

Time: Every month until clinical disease progression (approximately 22 months)

Description: Overall survival

Measure: Clinical objective : To assess efficacy of Osimertinib

Time: From first dose to end of study or date of death from any cause, whicheever comes first, assessed every 3 months (approximately 48 months)

Description: Objective Response Rate (ORR)

Measure: Clinical objective : To assess efficacy of Osimertinib

Time: every 3 months until radiological disease progression (approximately 22 months)

Description: Duration of Response (DoR): Disease Control Rate (DCR)

Measure: Clinical objective : To assess efficacy of Osimertinib: Duration of Response (DoR): Disease Control Rate (DCR)

Time: every 3 months until radiological disease progression (approximately 22 months)

Description: Monitoring of Adverse events (grade 3 and 4)

Measure: Clinical objective : To assess safety of Osimertinib with Monitoring of Adverse events (grade 3 and 4)

Time: monthly from first study dose until 15 days after last study dose

Description: By the study of the expression of molecules involved in the efficacy of check point inhibitors determined by immunohistochemistry (PD-L1; CD73; CD4; CD8) on tumor tissue collected at progression

Measure: Biological objective : To evaluate the consequence of osimertinib treatment on the expression of targets of immune check point inhibitors

Time: At baseline and at clinical disease progression (approximately 22 months)

Description: Analyze of mutation at progression on tumor tissue and ctDNA

Measure: Biological objective : To evaluate diagnostic accuracy of ctDNA to detect mutation

Time: At baseline and monthly until clinical disease progression (approximately 22 months)

Description: Analyze of the presence of tumors ctDNA at baseline, clinical progression disease

Measure: Biological objective : To observe if the presence of ctDNA at baseline is a prognostic factor of clinical progression disease

Time: At baseline and monthly until clinical disease progression (approximately 22 months)

Description: Analyze of absolute quantities of ctDNA molecules presenting the EGFR mutation identified in the tumor, clinical progression disease

Measure: Biological objective : To demonstrate that the early kinetics of ctDNA is an indicator of response to osimertinib

Time: At baseline and monthly until clinical disease progression (approximately 22 months)

Description: Serial monitoring in ctDNA of molecular alterations identified in tissues collected at progression

Measure: Biological objective : To measure the biological progression (bPFS) in patients treated with osimertinib

Time: At baseline and monthly until clinical disease progression (approximately 22 months)

Description: Analyze of the EGFR mutation identified in the tumor biopsy and in the ctDNA

Measure: Biological objective : To compare the genetic profile of the ctDNA and the tumor biopsy

Time: At baseline and at clinical disease progression (approximately 22 months)

Description: Analyze of the absolute quantities of ctDNA molecules presenting the EGFR mutation monthly, radiological and clinical progression disease

Measure: Biological objective : To compare the kinetic of appearance of EGFR mutation and radiological and clinical progression disease

Time: At baseline and monthly until clinical disease progression (approximately 22 months)

100 A Randomized Trial of Consolidative Immunotherapy With vs Without Thoracic Radiotherapy and / or Stereotactic Body Radiation Therapy (SBRT) After First-Line Systemic Therapy for Metastatic NSCLC

This phase III trial studies immunotherapy and stereotactic body radiation therapy to see how well it works compared with immunotherapy alone after first-line systemic therapy (therapy that goes throughout the body) in treating patients with stage IV non-small cell lung cancer. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Stereotactic body radiation therapy uses special equipment to position a patient and deliver radiation to tumors with high precision. This method can kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. Giving immunotherapy with stereotactic body radiation therapy may work better than immunotherapy alone in treating patients with non-small cell lung cancer.

NCT03867175
Conditions
  1. Metastatic Lung Cancer
  2. Stage IV Lung Cancer
Interventions
  1. Radiation: Stereotactic Body Radiation Therapy
  2. Biological: Pembrolizumab
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

- Patients with major activating mutations in EGFR (del19, L858R, and T790M) or ROS 1 or ALK gene rearrangements are excluded Eligibility for Randomization - Once enrolled on study, patients will have a PET/MRI brain for restaging. --- L858R --- --- T790M ---

Primary Outcomes

Description: Will be determined using the product-limit method of Kaplan and Meier. Will compare unadjusted median PFS between the 2 arms using a log-rank test. Will also use a proportional hazards model to compare progression-free survival between the two groups, adjusting for key covariates such as age, performance (Eastern Cooperative Oncology Group) status, response to initial systemic therapy versus (vs) stable disease, the presence or absence of brain metastases, PD-L1 [programmed death-ligand ] expression (< 1% vs > 50%), tumor histology (adenocarcinoma vs non-adenocarcinoma), and number of disease sites treated (1-3 sites vs 4-6 sites).

Measure: Progression-free survival (PFS) after completion of first line systemic therapy

Time: Up to 5 years

Secondary Outcomes

Description: Will be reported with an exact 95% confidence interval.

Measure: Overall Survival

Time: Up to 5 years

Description: In patients not receiving radiation, the investigators will assess progression at their known sites of disease prior to beginning first line systemic chemotherapy.

Measure: Time of Progression

Time: Baseline up to 5 years

Description: Investigators will assess the rate of failures inside and outside of radiation treatment.

Measure: Rate of Failure

Time: Baseline up to 5 years

Description: Investigators will assess the development of new sites of disease during or after immunotherapy

Measure: Number of Participants with New Sites of Disease

Time: Baseline up to 5 years

Description: All safety measures, including acute and late toxicity, will be reported using descriptive statistics (mean, median, standard deviation, proportions, and 95% confidence intervals). This will include calculating frequency/risk of adverse events by treatment site. Potential toxicities reported would include pneumonitis, esophagitis, chest wall pain, dermatologic toxicity, renal dysfunction, gastrointestinal toxicity including nausea, vomiting, and diarrhea, hepatotoxicity, and abdominal pain. These toxicities would be assessed according to site of irradiation by the treating physician and graded as per Common Terminology Criteria for Adverse Events 5.

Measure: Incidence of adverse events

Time: Up to 5 years

101 A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Phase III Study of Pemetrexed + Platinum Chemotherapy With or Without Toripalimab (JS001) in Advanced Non-small Cell Lung Cancer (NSCLC) Participants With TKI-resistant EGFR-mutated Tumors

This is a Randomized, Double-Blind, Placebo-Controlled, Multicenter, Phase III Study to evaluate the efficacy and safety of Toripalimab injection (JS001) or placebo combined with chemotherapyin Advanced Non-small Cell Lung Cancer (NSCLC) Participants with TKI-resistant EGFR-mutated Tumors; and evaluate the population with the best predictive biomarkers, i.e., positive diagnosis population. About 350 subjects with advanced non-small cell lung cancer with activated EGFR mutation will be 1:1 randomized into two groups, JS001 combined with the standard 1st-line chemotherapy will be given in the study group whereas placebo combined with standard 1st-line chemotherapy will be given in the control group. The stratification will be based on the following factors: The history of the previous lines of EGFR-TKI treament ( 1st or 2nd line of TKI vs. 3rd line of TKI vs. 1st or 2nd line of TKI + 3rd line of TKI) ; Disease stage (IIIB-C vs. IV);

NCT03924050
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: TORIPALIMAB INJECTION(JS001 )
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - Only the patients meeting all the following criteria can be eligible to participate in the trial: - Fully informed consent and signed ICF; - Age of 18-75 years; - Histologically and/or cytologically confirmed advanced or recurrent stage III B-C or IV (AJCC Version 8) NSCLC with TKI-resistant EGFR-mutated tumors, which also satisfy following conditions: Without T790M mutation in exon 20 after 1st or 2nd generation EGFR-TKI (eg, gefitinib, erlotinib, icotinib, afatinib,etc.) --- T790M ---

treatment failure;If with T790M mutation in exon 20 after 1st or 2nd generation EGFR-TKI (eg, gefitinib, erlotinib, icotinib, afatinib,etc.),participants --- T790M ---

are required to have osimertinib or other 3rd generation EGFR-TKI treatment failure prior to enrollment.Participants with osimertinib treatment failure as 1st line therapy (regardless of their EGFR T790M mutation status);Previous neoadjuvant/adjuvant chemotherapy is allowed, but the time interval between the last dose of chemotherapy and recurrence/metastasis must be at least 6 months. --- T790M ---

- With at least one measurable disease per RECIST 1.1; - Agree to provide formalin fixed tumor specimen after EGFR-TKI treatment failure or provide fresh biopsy tissue; - ECOG performance status of 0-1; - Life expectancy ≥ 3 months; - Good organ function; - Any adverse event resulting from prior treatment, surgery, or radiotherapy must return to grade 0 or 1 according to NCI-CTCAE v5.0, except for alopecia of any grade; - Willing and able to follow protocol visits, treatment plans, laboratory tests and other study procedures; - Women of childbearing potential must have negative serum pregnancy test within 3 days prior to the first dose of investigational product: Exclusion Criteria: - Exclusion of tumor histology or cytology confirmed the presence of small cell lung cancer components, or squamous cell carcinoma components of more than 10%; - Combined with other driver mutations with known therapeutic drug, including but not limited to: ALK rearrangement, ROS1 mutation, BRAF600E mutation, and KRAS mutation; - Previous systematic chemotherapy for advanced NSCLC; - Subjects with no measurable lesions; - Subjects with cancer meningitis and spinal cord compression; - Subjects with untreated central nervous system (CNS) tumor metastasis; - Subjects were previously treated with an anti-PD-1, anti-PD-L1 or anti-CTLA-4 agent; - Subjects with any active, known or suspected autoimmune disease; - Subjects who are now participating in other clinical studies or the last dose of prior investigational drug was given in < 4 weeks (or 5 half-lives) from the first investigational product administration of this study; - Subjects who were expected to receive any other antitumor therapy (eg, other maintenance therapy for NSCLC, radiotherapy, and/or surgical excision); - Subjects who received major surgery within 4 weeks prior to enrollment or were not fully recovered from prior surgery; - Subjects with other malignancies requiring concurrent treatment; - Subjects with grade II or above myocardial ischemia or myocardial infarction, or subjects with arrhythmia with poor control; - Subjects with uncontrolled pleural/pericardial effusion, or with ascites requiring repeated drainage; - Subjects with uncontrolled tumor-related pain; - Subjects with severe allergic reactions to other monoclonal antibodies and subjects with severe allergic reactions to pemetrexed, platinum or its prophylaxis; - Subjects with psychological disorder, alcohol alcoholism, drug abuse or drug dependency Inclusion Criteria: - Only the patients meeting all the following criteria can be eligible to participate in the trial: - Fully informed consent and signed ICF; - Age of 18-75 years; - Histologically and/or cytologically confirmed advanced or recurrent stage III B-C or IV (AJCC Version 8) NSCLC with TKI-resistant EGFR-mutated tumors, which also satisfy following conditions: Without T790M mutation in exon 20 after 1st or 2nd generation EGFR-TKI (eg, gefitinib, erlotinib, icotinib, afatinib,etc.) --- T790M ---

Primary Outcomes

Description: Progression free survival (PFS) evaluated by investigators according to the response evaluation criteria in solid tumors (RECIST 1.1)

Measure: PFS (Progression Free Survival) by investigator

Time: Approximately 2 years

Secondary Outcomes

Description: PFS evaluated by the Blinded Individual Review Committee (BIRC) based on RECIST1.1 criteria;

Measure: PFS (Progression Free Survival) by IRC (Independent Review Board)

Time: Approximately 2 years

Description: Objective response rate (ORR) evaluated by investigators and BIRC based on RECIST1.1;

Measure: ORR (Objective Response Rate)

Time: Approximately 2 years

Description: Duration of response (DOR) evaluated by investigators and BIRC based on RECIST1.1;

Measure: DOR (Duration of Response)

Time: Approximately 2 years

Description: Disease control rate (DCR) evaluated by investigators and BIRC based on RECIST1.1;

Measure: DCR (Disease of Response)

Time: Approximately 2 years

Description: Time to response (TTR) evaluated by investigators and BIRC based on RECIST1.1;

Measure: TTR (Time to Response)

Time: Approximately 2 years

Description: Overall survival (OS);

Measure: OS (Overall Survival) OS OS

Time: Approximately 2 years

Description: Adverse events (AEs) study drug related; serious adverse events (SAEs)study drug related; abnormal value of Lab test according to NCI-CTCAE V5.0

Measure: Incidence of AEs/SAEs

Time: Approximately 2 years

102 A Retrospective, Multicenter and Observational Study of Osimertinib Monotherapy Treatment in Subjects With Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) EGFR-T790M Mutation-positive Who Have Received the Treatment Within the Special Use Medication Program (SUMP) in Spain

This is a retrospective, multicenter and observational study of Osimertinib monotherapy treatment in Subjects with advanced or metastatic Non-Small Cell Lung Cancer (NSCLC) EGFR-T790M mutation-positive who have received the treatment within the Special Use Medication Program (SUMP) in Spain.

NCT03790397
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: Osimertinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

A Retrospective, Multicenter and Observational Study of Osimertinib Monotherapy Treatment in Subjects With Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) EGFR-T790M Mutation-positive Who Have Received the Treatment Within the Special Use Medication Program (SUMP) in Spain. --- T790M ---

Osimertinib in Subjects With Advanced Non-Small Cell Lung Cancer EGFR-T790M Mutation-positive This is a retrospective, multicenter and observational study of Osimertinib monotherapy treatment in Subjects with advanced or metastatic Non-Small Cell Lung Cancer (NSCLC) EGFR-T790M mutation-positive who have received the treatment within the Special Use Medication Program (SUMP) in Spain. --- T790M ---

Osimertinib in Subjects With Advanced Non-Small Cell Lung Cancer EGFR-T790M Mutation-positive This is a retrospective, multicenter and observational study of Osimertinib monotherapy treatment in Subjects with advanced or metastatic Non-Small Cell Lung Cancer (NSCLC) EGFR-T790M mutation-positive who have received the treatment within the Special Use Medication Program (SUMP) in Spain. --- T790M --- --- T790M ---

Inclusion Criteria: - Squamous or Non-Squamous, non-small cell lung cancer (NSCLC), Stage IIIb/IV (histologically or cytologically confirmed), EGFRm/T790M, who received osimertinib treatment within the Spanish special use medication program of Osimertinib (SUMP). --- T790M ---

Primary Outcomes

Description: To estimate the progression free survival of the Osimertinib Treatment

Measure: Progression free survival

Time: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months

103 A Phase II, Multi-centre Study, to Evaluate the Efficacy and Safety of Osimertinib Treatment for Patients With EGFR-mutated Non-small Cell Lung Cancer (NSCLC) With Brain or Leptomeningeal Metastases

Treatment of non-small cell lung cancer (NSCLC) with Epidermal Growth Factor Receptor (EGFR) mutation is mainly based on tyrosine kinase inhibitors (TKIs) targeting EGFR. 1st or 2nd generation inhibitors have been shown to be superior to chemotherapy in terms of Progression-Free Survival (PFS) when used as 1st line treatment. In case of progression at several metastatic sites, systemic treatment will be considered and will depend on the presence of the TKI resistance mutation, the T790M mutation. In the presence of the T790M mutation, osimertinib is superior to chemotherapy in terms of progression-free survival, while in the absence of the T790M mutation, platinum salt chemotherapy is recommended. In case of local progression, treatment of the site in progression by radiotherapy and/or surgery is considered. As these local treatments can cause long-term adverse effects, systemic treatments are increasingly being considered in this indication. Brain and leptomeningeal metastases are the most frequent isolated site of progression in EGFR mutated patients treated with TKI. The high frequency of isolated cerebral and leptomeningeal progression is a consequence of the lower diffusion of 1st and 2nd generation TKIs in the central nervous system (CNS). Osimertinib is a 3rd generation TKI that has the particularity of overcoming the T790M mutation and having greater brain penetration than 1st or 2nd generation TKIs, which could make it an attractive therapeutic option in the event of brain progression or leptomeningeal progression. However, its efficacy in patients with cerebral or leptomeningeal metastases is still poorly understood.

NCT04233021
Conditions
  1. Non Small Cell Lung Cancer Metastatic
  2. Leptomeningeal Metastasis
  3. Brain Metastases
  4. EGFR Activating Mutation
Interventions
  1. Drug: Osimertinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung Neoplasm Metastasis Neoplasms, Second Primary Meningeal Carcinomatosis
HPO:Neoplasm of the lung Non-small cell lung carcinoma

In case of progression at several metastatic sites, systemic treatment will be considered and will depend on the presence of the TKI resistance mutation, the T790M mutation. --- T790M ---

In the presence of the T790M mutation, osimertinib is superior to chemotherapy in terms of progression-free survival, while in the absence of the T790M mutation, platinum salt chemotherapy is recommended. --- T790M ---

In the presence of the T790M mutation, osimertinib is superior to chemotherapy in terms of progression-free survival, while in the absence of the T790M mutation, platinum salt chemotherapy is recommended. --- T790M --- --- T790M ---

Osimertinib is a 3rd generation TKI that has the particularity of overcoming the T790M mutation and having greater brain penetration than 1st or 2nd generation TKIs, which could make it an attractive therapeutic option in the event of brain progression or leptomeningeal progression. --- T790M ---

4. Testing for T790M mutation in circulating tumour DNA or tumour tissue sample at progression on the last treatment received before inclusion. --- T790M ---

Primary Outcomes

Description: Objective Response Rate at 6 months using EANO-ESMO criteria (cohort 1) and RECIST1.1 criteria (cohorts 2, 3, 4)

Measure: Objective Response Rate

Time: 6 months

Secondary Outcomes

Description: Time from enrollment until death due to any cause

Measure: Overall Survival

Time: About 24 months

Description: Time from enrollment to first observation of progression (EANO-ESMO criteria (cohort 1) and RECIST1.1 criteria (cohorts 2, 3, 4)) or date of death (from any cause)

Measure: Progression-free survival

Time: About 24 months

Description: Descriptive statistics of safety will be presented using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.

Measure: Incidence, type and severity of adverse event

Time: From time of informed consent through treatment period and up to 30 days post last dose of study treatment (about 24 months)

Description: EORTC QLQ-C30-LC13 (Qualify of Life Questionnaire C30 and Lung Cancer 13) questionnaire

Measure: Evaluate the Quality of life

Time: From time of randomisation through treatment period (about 24 months)

Description: QLQ BN20 (Brain Neoplasm N20) questionnaire

Measure: Evaluate the Quality of life

Time: From time of randomisation through treatment period (about 24 months)

104 Peripheral Circulating Blood Tumor Cells (CTC) Detection and CTC-based PD-L1 Antibody Immunofluorescence Detection to PD-1 Monoclonal Antibody SHR-1210 and Apatinib in Second-line and Back-line Treatment of Advanced NSCLC, Soft Tissue Sarcoma, Uterine Cancer Clinical Research

In this one-arm study, histologically or cytologically confirmed advanced NSCLC, uterine malignancies, and soft tissue sarcoma will be enrolled to investigate the efficacy and safety of PD-1 monoclonal antibody SHR-1210 and apatinib, at the same time, peripheral circulating blood tumor cells (CTC) detection and CTC-based PD-L1 antibody immunofluorescence detection will be performed.

NCT04239443
Conditions
  1. Advanced Non Small Cell Lung Cancer
  2. Uterine Cancer
  3. Soft Tissue Sarcoma
Interventions
  1. Drug: PD-1 inhibitor
  2. Drug: Apatinib
MeSH:Sarcoma Uterine Neoplasms
HPO:Sarcoma Soft tissue sarcoma Uterine neoplasm

Inclusion Criteria: 1. Age 18-70 years, both men and women (Uterine cancer limited to women); 2. NSCLC: Pathologically confirmed advanced (IIIB, stage IV) NSCLC with at least 1 measurable lesion that meets the RECIST v1.1 standard without local treatment, of which stage IIIb patients are incapable, unsuitable for surgery or radical radiotherapy, NSCLC patients have failed at least the first-line standard treatment or refused to receive standard treatment, or chemotherapy intolerance, Among them, patients with sensitive gene mutations must fail after TKI treatment (patients who have failed first-line or second-line treatment may participate in this study), Patients with EGFR and ALK mutations must undergo EGFR and ALK inhibitor treatment failure and EGFR T790M mutation negative, for EGFR T790M-positive patients, third-generation EGFR TKI treatment fails. --- T790M ---

Inclusion Criteria: 1. Age 18-70 years, both men and women (Uterine cancer limited to women); 2. NSCLC: Pathologically confirmed advanced (IIIB, stage IV) NSCLC with at least 1 measurable lesion that meets the RECIST v1.1 standard without local treatment, of which stage IIIb patients are incapable, unsuitable for surgery or radical radiotherapy, NSCLC patients have failed at least the first-line standard treatment or refused to receive standard treatment, or chemotherapy intolerance, Among them, patients with sensitive gene mutations must fail after TKI treatment (patients who have failed first-line or second-line treatment may participate in this study), Patients with EGFR and ALK mutations must undergo EGFR and ALK inhibitor treatment failure and EGFR T790M mutation negative, for EGFR T790M-positive patients, third-generation EGFR TKI treatment fails. --- T790M --- --- T790M ---

To the safety of the subject, or the collection of information and samples; Inclusion Criteria: 1. Age 18-70 years, both men and women (Uterine cancer limited to women); 2. NSCLC: Pathologically confirmed advanced (IIIB, stage IV) NSCLC with at least 1 measurable lesion that meets the RECIST v1.1 standard without local treatment, of which stage IIIb patients are incapable, unsuitable for surgery or radical radiotherapy, NSCLC patients have failed at least the first-line standard treatment or refused to receive standard treatment, or chemotherapy intolerance, Among them, patients with sensitive gene mutations must fail after TKI treatment (patients who have failed first-line or second-line treatment may participate in this study), Patients with EGFR and ALK mutations must undergo EGFR and ALK inhibitor treatment failure and EGFR T790M mutation negative, for EGFR T790M-positive patients, third-generation EGFR TKI treatment fails. --- T790M ---

To the safety of the subject, or the collection of information and samples; Inclusion Criteria: 1. Age 18-70 years, both men and women (Uterine cancer limited to women); 2. NSCLC: Pathologically confirmed advanced (IIIB, stage IV) NSCLC with at least 1 measurable lesion that meets the RECIST v1.1 standard without local treatment, of which stage IIIb patients are incapable, unsuitable for surgery or radical radiotherapy, NSCLC patients have failed at least the first-line standard treatment or refused to receive standard treatment, or chemotherapy intolerance, Among them, patients with sensitive gene mutations must fail after TKI treatment (patients who have failed first-line or second-line treatment may participate in this study), Patients with EGFR and ALK mutations must undergo EGFR and ALK inhibitor treatment failure and EGFR T790M mutation negative, for EGFR T790M-positive patients, third-generation EGFR TKI treatment fails. --- T790M --- --- T790M ---

Primary Outcomes

Description: Evaluated by researchers based on the RECIST 1.1 standard

Measure: Objective remission rate (ORR)

Time: 2 years

Description: Evaluated by researchers based on the RECIST 1.1 standard

Measure: Progression free survival (PFS)

Time: 2 years

Description: Evaluated by researchers based on the RECIST 1.1 standard

Measure: Overall survival (OS)

Time: 2 years

Measure: The number of Circulating Tumor Cell (CTC)

Time: 2 years

Measure: Analysis of PD-L1 expression on Circulating Tumor Cell (CTC) and tumor tissue

Time: 2 years

Secondary Outcomes

Description: Evaluated by researchers based on the RECIST 1.1 standard

Measure: Duration of response(DOR)

Time: 2 years

Description: Evaluated by researchers based on the RECIST 1.1 standard

Measure: Disease control rate(DCR)

Time: 2 years

105 An Observational Study to Evaluate AZD9291 Treatment in Patients With EGFR T790M Positive Locally Advanced or Metastatic Non-small Cell Lung Cancer Following Progression on at Least One Prior EGFR TKI Treatment

AZD9291 Early Access Program (EAP) was available in Taiwan during October 2015 to September 2016, a time period before the approval of AZD9291, to supply the unlicensed AZD9291 for the NSCLC patients who received at least one prior EGFR TKI therapy. At the end of September 2016, more than 450 patients have been under AZD9291 treatment through the EAP. This observational study aims to evaluate the clinical benefit of AZD9291 treatment for these patients who were in the EAP

NCT03457220
Conditions
  1. Non Small Cell Lung Cancer
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

An Observational Study to Evaluate AZD9291 Treatment in Patients With EGFR T790M Positive Locally Advanced or Metastatic Non-small Cell Lung Cancer Following Progression on at Least One Prior EGFR TKI Treatment. --- T790M ---

An Observational Study to Evaluate AZD9291 Treatment in Patients With T790M Positive Non-small Cell Lung Cancer AZD9291 Early Access Program (EAP) was available in Taiwan during October 2015 to September 2016, a time period before the approval of AZD9291, to supply the unlicensed AZD9291 for the NSCLC patients who received at least one prior EGFR TKI therapy. --- T790M ---

Primary Outcomes

Description: PFS is defined as the time interval (in months) from the first dose of AZD9291 in the EAP to the date of disease progression

Measure: Progression free survival (PFS)

Time: Every 12 weeks until treatment discontinuation as defined by RECIST 1.1 projected 12 months

Secondary Outcomes

Description: OS is defined as the time interval (in months) from the date of the first dose of AZD9291 in the EAP until the date of death due to any cause

Measure: Overall survival (OS)

Time: Every 12 weeks until treatment discontinuation as defined by RECIST 1.1 projected 24 months

Other Outcomes

Description: RR is defined as the percentage of subjects with the best overall response of 'responding', which is defined as complete response (CR) or partial response (PR), by investigator's assessment

Measure: Response Rate (RR)

Time: Every 12 weeks until treatment discontinuation as defined by RECIST 1.1 projected 12 months

Description: DCR is defined as the percentages of subjects who have the best overall response of CR, PR, or SD, which is determined by investigator's assessment.

Measure: Disease Control Rate (DCR)

Time: Every 12 weeks until treatment discontinuation as defined by RECIST 1.1 projected 12 months

Description: TTD is defined as the time interval (in months) from the date of the first dose of AZD9291 in the EAP until the date of the single use of AZD9291 discontinuation for any reason

Measure: Time to treatment discontinuation (TTD)

Time: Time from patient first dose to data cut off (up to 32 months)

106 Phase 1b/2 Safety, Pharmacokinetic, and Efficacy Study of G1T38 in Combination With Osimertinib in Patients With EGFR Mutation-Positive Metastatic Non-Small Cell Lung Cancer (NSCLC)

This is a study to investigate the potential clinical benefit of G1T38 as an oral therapy in combination with osimertinib in patients with EGFR mutation-positive metastatic non-small cell lung cancer. The study is an open-label design, consists of 2 parts: safety, pharmacokinetic, and dose-finding portion (Part 1), and randomized portion (Part 2). Both parts include 3 study phases: Screening Phase, Treatment Phase, and Survival Follow-up Phase. The Treatment Phase begins on the day of first dose with study treatment and completes at the Post-Treatment Visit. Approximately, 144 patients will be enrolled in the study.

NCT03455829
Conditions
  1. Carcinoma, Non-Small-Cell Lung
  2. Lung Cancer
  3. Non-small Cell Lung Cancer
Interventions
  1. Drug: G1T38
  2. Drug: Osimertinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - Confirmed EGFR mutation for non-small cell lung cancer associated with EGFR TKI sensitivity - For Part 2, EGFR T790M mutation-positive tumor status - Left ventricular ejection fraction (LVEF) ≥ institution's lower limit of the reference range - For Part 1, evaluable or measurable disease as defined by RECIST, Version 1.1 - For Part 2, measurable disease as defined by RECIST, Version 1.1 - ECOG performance status 0 to 1 - Adequate organ function Exclusion Criteria: - Prior treatment with EGFR TKI within 9 days of first study dose - For Part 1, prior treatment with more than 2 prior lines of chemotherapy for advanced NSCLC - For Part 2, prior treatment with osimertinib or other T790M active EGFR TKI - For Part 2, prior chemotherapy for advanced NSCLC - Active uncontrolled/symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease - Investigational drug within 3 months or 5 half-lives, whichever is longer, of first study dose - Concurrent radiotherapy, radiotherapy within 28 days of first study dose, previous radiotherapy to the target lesion sites, or prior radiotherapy to > 25% of bone marrow - Prior hematopoietic stem cell or bone marrow transplantation Inclusion Criteria: - Confirmed EGFR mutation for non-small cell lung cancer associated with EGFR TKI sensitivity - For Part 2, EGFR T790M mutation-positive tumor status - Left ventricular ejection fraction (LVEF) ≥ institution's lower limit of the reference range - For Part 1, evaluable or measurable disease as defined by RECIST, Version 1.1 - For Part 2, measurable disease as defined by RECIST, Version 1.1 - ECOG performance status 0 to 1 - Adequate organ function Exclusion Criteria: - Prior treatment with EGFR TKI within 9 days of first study dose - For Part 1, prior treatment with more than 2 prior lines of chemotherapy for advanced NSCLC - For Part 2, prior treatment with osimertinib or other T790M active EGFR TKI - For Part 2, prior chemotherapy for advanced NSCLC - Active uncontrolled/symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease - Investigational drug within 3 months or 5 half-lives, whichever is longer, of first study dose - Concurrent radiotherapy, radiotherapy within 28 days of first study dose, previous radiotherapy to the target lesion sites, or prior radiotherapy to > 25% of bone marrow - Prior hematopoietic stem cell or bone marrow transplantation Carcinoma, Non-Small-Cell Lung Lung Cancer Non-small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- T790M ---

Inclusion Criteria: - Confirmed EGFR mutation for non-small cell lung cancer associated with EGFR TKI sensitivity - For Part 2, EGFR T790M mutation-positive tumor status - Left ventricular ejection fraction (LVEF) ≥ institution's lower limit of the reference range - For Part 1, evaluable or measurable disease as defined by RECIST, Version 1.1 - For Part 2, measurable disease as defined by RECIST, Version 1.1 - ECOG performance status 0 to 1 - Adequate organ function Exclusion Criteria: - Prior treatment with EGFR TKI within 9 days of first study dose - For Part 1, prior treatment with more than 2 prior lines of chemotherapy for advanced NSCLC - For Part 2, prior treatment with osimertinib or other T790M active EGFR TKI - For Part 2, prior chemotherapy for advanced NSCLC - Active uncontrolled/symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease - Investigational drug within 3 months or 5 half-lives, whichever is longer, of first study dose - Concurrent radiotherapy, radiotherapy within 28 days of first study dose, previous radiotherapy to the target lesion sites, or prior radiotherapy to > 25% of bone marrow - Prior hematopoietic stem cell or bone marrow transplantation Inclusion Criteria: - Confirmed EGFR mutation for non-small cell lung cancer associated with EGFR TKI sensitivity - For Part 2, EGFR T790M mutation-positive tumor status - Left ventricular ejection fraction (LVEF) ≥ institution's lower limit of the reference range - For Part 1, evaluable or measurable disease as defined by RECIST, Version 1.1 - For Part 2, measurable disease as defined by RECIST, Version 1.1 - ECOG performance status 0 to 1 - Adequate organ function Exclusion Criteria: - Prior treatment with EGFR TKI within 9 days of first study dose - For Part 1, prior treatment with more than 2 prior lines of chemotherapy for advanced NSCLC - For Part 2, prior treatment with osimertinib or other T790M active EGFR TKI - For Part 2, prior chemotherapy for advanced NSCLC - Active uncontrolled/symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease - Investigational drug within 3 months or 5 half-lives, whichever is longer, of first study dose - Concurrent radiotherapy, radiotherapy within 28 days of first study dose, previous radiotherapy to the target lesion sites, or prior radiotherapy to > 25% of bone marrow - Prior hematopoietic stem cell or bone marrow transplantation Carcinoma, Non-Small-Cell Lung Lung Cancer Non-small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- T790M --- --- T790M ---

Inclusion Criteria: - Confirmed EGFR mutation for non-small cell lung cancer associated with EGFR TKI sensitivity - For Part 2, EGFR T790M mutation-positive tumor status - Left ventricular ejection fraction (LVEF) ≥ institution's lower limit of the reference range - For Part 1, evaluable or measurable disease as defined by RECIST, Version 1.1 - For Part 2, measurable disease as defined by RECIST, Version 1.1 - ECOG performance status 0 to 1 - Adequate organ function Exclusion Criteria: - Prior treatment with EGFR TKI within 9 days of first study dose - For Part 1, prior treatment with more than 2 prior lines of chemotherapy for advanced NSCLC - For Part 2, prior treatment with osimertinib or other T790M active EGFR TKI - For Part 2, prior chemotherapy for advanced NSCLC - Active uncontrolled/symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease - Investigational drug within 3 months or 5 half-lives, whichever is longer, of first study dose - Concurrent radiotherapy, radiotherapy within 28 days of first study dose, previous radiotherapy to the target lesion sites, or prior radiotherapy to > 25% of bone marrow - Prior hematopoietic stem cell or bone marrow transplantation Inclusion Criteria: - Confirmed EGFR mutation for non-small cell lung cancer associated with EGFR TKI sensitivity - For Part 2, EGFR T790M mutation-positive tumor status - Left ventricular ejection fraction (LVEF) ≥ institution's lower limit of the reference range - For Part 1, evaluable or measurable disease as defined by RECIST, Version 1.1 - For Part 2, measurable disease as defined by RECIST, Version 1.1 - ECOG performance status 0 to 1 - Adequate organ function Exclusion Criteria: - Prior treatment with EGFR TKI within 9 days of first study dose - For Part 1, prior treatment with more than 2 prior lines of chemotherapy for advanced NSCLC - For Part 2, prior treatment with osimertinib or other T790M active EGFR TKI - For Part 2, prior chemotherapy for advanced NSCLC - Active uncontrolled/symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease - Investigational drug within 3 months or 5 half-lives, whichever is longer, of first study dose - Concurrent radiotherapy, radiotherapy within 28 days of first study dose, previous radiotherapy to the target lesion sites, or prior radiotherapy to > 25% of bone marrow - Prior hematopoietic stem cell or bone marrow transplantation Carcinoma, Non-Small-Cell Lung Lung Cancer Non-small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- T790M --- --- T790M --- --- T790M ---

Inclusion Criteria: - Confirmed EGFR mutation for non-small cell lung cancer associated with EGFR TKI sensitivity - For Part 2, EGFR T790M mutation-positive tumor status - Left ventricular ejection fraction (LVEF) ≥ institution's lower limit of the reference range - For Part 1, evaluable or measurable disease as defined by RECIST, Version 1.1 - For Part 2, measurable disease as defined by RECIST, Version 1.1 - ECOG performance status 0 to 1 - Adequate organ function Exclusion Criteria: - Prior treatment with EGFR TKI within 9 days of first study dose - For Part 1, prior treatment with more than 2 prior lines of chemotherapy for advanced NSCLC - For Part 2, prior treatment with osimertinib or other T790M active EGFR TKI - For Part 2, prior chemotherapy for advanced NSCLC - Active uncontrolled/symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease - Investigational drug within 3 months or 5 half-lives, whichever is longer, of first study dose - Concurrent radiotherapy, radiotherapy within 28 days of first study dose, previous radiotherapy to the target lesion sites, or prior radiotherapy to > 25% of bone marrow - Prior hematopoietic stem cell or bone marrow transplantation Inclusion Criteria: - Confirmed EGFR mutation for non-small cell lung cancer associated with EGFR TKI sensitivity - For Part 2, EGFR T790M mutation-positive tumor status - Left ventricular ejection fraction (LVEF) ≥ institution's lower limit of the reference range - For Part 1, evaluable or measurable disease as defined by RECIST, Version 1.1 - For Part 2, measurable disease as defined by RECIST, Version 1.1 - ECOG performance status 0 to 1 - Adequate organ function Exclusion Criteria: - Prior treatment with EGFR TKI within 9 days of first study dose - For Part 1, prior treatment with more than 2 prior lines of chemotherapy for advanced NSCLC - For Part 2, prior treatment with osimertinib or other T790M active EGFR TKI - For Part 2, prior chemotherapy for advanced NSCLC - Active uncontrolled/symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease - Investigational drug within 3 months or 5 half-lives, whichever is longer, of first study dose - Concurrent radiotherapy, radiotherapy within 28 days of first study dose, previous radiotherapy to the target lesion sites, or prior radiotherapy to > 25% of bone marrow - Prior hematopoietic stem cell or bone marrow transplantation Carcinoma, Non-Small-Cell Lung Lung Cancer Non-small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- T790M --- --- T790M --- --- T790M --- --- T790M ---

Primary Outcomes

Measure: Dose Limiting Toxicity

Time: Cycle 1 Day -14 to Cycle 1 Day 28

Measure: Recommended Phase 2 dose

Time: 9 months

Description: All AEs, including clinical laboratory, vitals signs, physical examinations and ECGs will be analyzed in all patients receiving study drug from the signing of the informed consent until 30 days after the last dose of study medication

Measure: Number of Treatment Related Adverse Event, including Abnormal Laboratory Events

Time: 36 months

Measure: Progression free survival (PFS) using blinded independent central review (BICR)

Time: 36 months

Secondary Outcomes

Measure: Tumor response based on RECIST, Version 1.1

Time: 21 months

Measure: Pharmacokinetics of G1T38 and metabolite G1T30: Maximum Plasma Concentration (Cmax)

Time: Part 1, Cycle 1 Day -14 to Day -2. Part 2, Cycle 1 Day 15 to Cycle 2 Day 1.

Measure: Pharmacokinetics of G1T38 and metabolite G1T30: Area under Curve - plasma concentration (AUC)

Time: Part 1, Cycle 1 Day -14 to Day -2. Part 2, Cycle 1 Day 15 to Cycle 2 Day 1.

Measure: Pharmacokinetics of G1T38 and metabolite G1T30: Plasma: terminal half life (T1/2)

Time: Part 1, Cycle 1 Day -14 to Day -2. Part 2, Cycle 1 Day 15 to Cycle 2 Day 1.

Measure: Pharmacokinetics of G1T38 and metabolite G1T30: Plasma - Volume of distribution

Time: Part 1, Cycle 1 Day -14 to Day -2. Part 2, Cycle 1 Day 15 to Cycle 2 Day 1.

Measure: PFS using investigator assessment

Time: 36 months

Measure: 1-year PFS using investigator assessment and BICR

Time: 33 months

Measure: Overall survival (OS)

Time: 60 months

107 A Phase I Study of D-0316 in Patients With Advanced Non Small Cell Lung Cancer With Mutation of Epidermal Growth Factor Receptor Tyrosine Kinase

This is a phase 1 open label multicentre study of D-0316 administered orally in patients with advanced NSCLC who have progressed following prior therapy with an EGFR-TKI (Epidermal Growth Factor Receptor tyrosine kinase inhibitor agent). This is the first time this drug has ever been tested in patients, and so it will help to understand safety, tolerability, pharmacokinetics and preliminary anti-tumour activity of ascending doses of D-0316.

NCT03452150
Conditions
  1. Advanced Non Small Cell Lung Cancer
Interventions
  1. Drug: D-0316
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Confirmation that the tumour harbours an EGFR T790M mutation. --- T790M ---

Primary Outcomes

Description: Incidence of DLTs

Measure: Dose Limiting Toxicities (DLTs)

Time: Day 1 - Day 28

Description: Incidence of AEs

Measure: Adverse events

Time: Day 1 - Day 28

Description: Incidence of laboratory abnormalities

Measure: Laboratory results

Time: Day 1 - Day 28

Description: Incidence of vital sign abnormalities

Measure: Vital signs

Time: Day 1 - Day 28

Description: Incidence of ECG abnormalities

Measure: Electrocardiogram

Time: Day 1 - Day 28

Secondary Outcomes

Description: AUC: area under the plasma concentration versus time curve for D-0316

Measure: Pharmacokinetic: area under the plasma concentration versus time curve (AUC)

Time: Day 1 through 6, Cycle Day 1-Day 15

Description: Cmax: maximum plasma drug concentration of D-0316

Measure: Pharmacokinetic: maximum plasma drug concentration (Cmax)

Time: Day 1 through 6, Cycle Day 1-Day 15

Description: tmax: Time to reach the Cmax of D-0316

Measure: Pharmacokinetic: Time to reach the Cmax (Tmax)

Time: Day 1 through 6, Cycle Day 1-Day 15

Description: t1/2: apparent terminal half-life of D-0316

Measure: Pharmacokinetic: Apparent terminal half-life (t1/2)

Time: Day 1 through 6, Cycle Day 1-Day 15

Description: Antitumor activity by evaluation of tumor response assessments using Response Evaluation Criteria in Solid Tumours (RECIST 1.1)

Measure: Antitumor activity

Time: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months

108 Multicenter, Randomized and OpenⅡb Clinical Trials to Evaluate the Efficacy and Safety of Alflutinib in Locally Advanced or Metastatic Non-Small Cell Lung Cancer Patients Harbouring T790M Mutation

This study is conducted to evaluate the efficacy and safety of Alflutinib in locally advanced or metastatic non-small cell lung cancer patients harbouring T790M mutation

NCT03452592
Conditions
  1. Advanced NSCLC Patients With T790M
Interventions
  1. Drug: Alflutinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Multicenter, Randomized and OpenⅡb Clinical Trials to Evaluate the Efficacy and Safety of Alflutinib in Locally Advanced or Metastatic Non-Small Cell Lung Cancer Patients Harbouring T790M Mutation. --- T790M ---

Efficacy and Safety of Alflutinib in Locally Advanced or Metastatic Non-Small Cell Lung Cancer Patients With T790M This study is conducted to evaluate the efficacy and safety of Alflutinib in locally advanced or metastatic non-small cell lung cancer patients harbouring T790M mutation Objective response rate of Alflutinib. --- T790M ---

Efficacy and Safety of Alflutinib in Locally Advanced or Metastatic Non-Small Cell Lung Cancer Patients With T790M This study is conducted to evaluate the efficacy and safety of Alflutinib in locally advanced or metastatic non-small cell lung cancer patients harbouring T790M mutation Objective response rate of Alflutinib. --- T790M --- --- T790M ---

Evaluation of the objective response rate of Alflutinib in locally advanced or metastatic non-small cell lung cancer patients harbouring acquired T790M mutation by prior therapy with an EGFR-TKI or primary T790M mutation assessed by RECIST 1.1. --- T790M ---

Evaluation of the objective response rate of Alflutinib in locally advanced or metastatic non-small cell lung cancer patients harbouring acquired T790M mutation by prior therapy with an EGFR-TKI or primary T790M mutation assessed by RECIST 1.1. --- T790M --- --- T790M ---

Evaluation of the overall survival of Alflutinib in locally advanced or metastatic non-small cell lung cancer patients harbouring acquired T790M mutation by prior therapy with an EGFR-TKI or primary T790M mutation assessed by RECIST 1.1. --- T790M ---

Evaluation of the overall survival of Alflutinib in locally advanced or metastatic non-small cell lung cancer patients harbouring acquired T790M mutation by prior therapy with an EGFR-TKI or primary T790M mutation assessed by RECIST 1.1. --- T790M --- --- T790M ---

Evaluation of the duration of response of Alflutinib in locally advanced or metastatic non-small cell lung cancer patients harbouring acquired T790M mutation by prior therapy with an EGFR-TKI or primary T790M mutation assessed by RECIST 1.1. --- T790M ---

Evaluation of the duration of response of Alflutinib in locally advanced or metastatic non-small cell lung cancer patients harbouring acquired T790M mutation by prior therapy with an EGFR-TKI or primary T790M mutation assessed by RECIST 1.1. --- T790M --- --- T790M ---

- 3.Patients who have disease progression after continuous previous treatment of 1st/2nd-generation EGFR TKIs (evaluation according to imaging evidence, judged by research center) will be recruited and primary T790M mutation patients are allowed to have received no EGFR-targeting therapy before detection. --- T790M ---

- 4.The tissue/cell specimen collected from patients who have received the recent treatment (either TKI or chemotherapy) progression should be confirmed to T790M positive mutation by the detection of central laboratory, while no specimen collection requirements for the primary T790M mutation patients. --- T790M ---

- 4.The tissue/cell specimen collected from patients who have received the recent treatment (either TKI or chemotherapy) progression should be confirmed to T790M positive mutation by the detection of central laboratory, while no specimen collection requirements for the primary T790M mutation patients. --- T790M --- --- T790M ---

Advanced NSCLC Patients With T790M Carcinoma, Non-Small-Cell Lung This is a multicenter, randomized and open Ⅱb phase study assessing the efficacy and safety of Alflutinib at doses of 80 mg orally /once daily and 160 mg orally /once daily in patients with locally advanced or metastatic Non-small Cell Lung Cancer (NSCLC) harboring acquired T790M mutation after EGFR-TKI treatment or primary T790M mutation. --- T790M ---

Advanced NSCLC Patients With T790M Carcinoma, Non-Small-Cell Lung This is a multicenter, randomized and open Ⅱb phase study assessing the efficacy and safety of Alflutinib at doses of 80 mg orally /once daily and 160 mg orally /once daily in patients with locally advanced or metastatic Non-small Cell Lung Cancer (NSCLC) harboring acquired T790M mutation after EGFR-TKI treatment or primary T790M mutation. --- T790M --- --- T790M ---

Advanced NSCLC Patients With T790M Carcinoma, Non-Small-Cell Lung This is a multicenter, randomized and open Ⅱb phase study assessing the efficacy and safety of Alflutinib at doses of 80 mg orally /once daily and 160 mg orally /once daily in patients with locally advanced or metastatic Non-small Cell Lung Cancer (NSCLC) harboring acquired T790M mutation after EGFR-TKI treatment or primary T790M mutation. --- T790M --- --- T790M --- --- T790M ---

Primary Outcomes

Description: Evaluation of the objective response rate of Alflutinib in locally advanced or metastatic non-small cell lung cancer patients harbouring acquired T790M mutation by prior therapy with an EGFR-TKI or primary T790M mutation assessed by RECIST 1.1

Measure: Objective response rate of Alflutinib

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, whichever came first, assessed up to 52 weeks

Secondary Outcomes

Description: Progression of tumor was assessed by RECIST 1.1 thereby to evaluate progression free survival

Measure: Progression free disease of Alflutinib

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, whichever came first, assessed up to 52 weeks

Description: Evaluation of the overall survival of Alflutinib in locally advanced or metastatic non-small cell lung cancer patients harbouring acquired T790M mutation by prior therapy with an EGFR-TKI or primary T790M mutation assessed by RECIST 1.1

Measure: Overall survival of Alflutinib

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, whichever came first, assessed up to 52 weeks

Description: Evaluation of the duration of response of Alflutinib in locally advanced or metastatic non-small cell lung cancer patients harbouring acquired T790M mutation by prior therapy with an EGFR-TKI or primary T790M mutation assessed by RECIST 1.1

Measure: Duration of response of Alflutinib

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, whichever came first, assessed up to 52 weeks

Description: Progression of tumor was assessed by RECIST 1.1 thereby to evaluate disease control rate

Measure: Disease control rate of Alflutinib

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, whichever came first, assessed up to 52 weeks

Description: Clinical benefit rate was calculated by adding up complete remission, partial remission and stabilization of disease assessed by RECIST 1.1

Measure: Clinical benefit of Alflutinib

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression or withdrawal from study, whichever came first, assessed up to 52 weeks

109 Toripalimab Combined With Pemetrexed Plus Carboplatin for Treatment of Recurrent or Advanced Non-small-cell Lung Cancer With EGFR-mutation Positive and T790M Negative After Progression on EGFR-TKI Treatment:a Multi-center, Single Arm Phase II Study

JS001 combined with pemetrexed plus carboplatin for treatment of recurrent or advanced non-small-cell lung cancer with EGFR-mutation positive and T790M negative after progression on EGFR-TKI treatment:a multi-center, single arm phase II study

NCT03513666
Conditions
  1. NSCLC
Interventions
  1. Combination Product: Drug intervention
MeSH:Disease Progression

Toripalimab Combined With Pemetrexed Plus Carboplatin for Treatment of Recurrent or Advanced Non-small-cell Lung Cancer With EGFR-mutation Positive and T790M Negative After Progression on EGFR-TKI Treatment:a Multi-center, Single Arm Phase II Study. --- T790M ---

A Study of Toripalimab+ Pemetrexed Plus Carboplatin in Patients With EGFR-mutation Positive and T790M Negative After Progression on EGFR-TKI Treatment JS001 combined with pemetrexed plus carboplatin for treatment of recurrent or advanced non-small-cell lung cancer with EGFR-mutation positive and T790M negative after progression on EGFR-TKI treatment:a multi-center, single arm phase II study Objective response rate (ORR). --- T790M ---

A Study of Toripalimab+ Pemetrexed Plus Carboplatin in Patients With EGFR-mutation Positive and T790M Negative After Progression on EGFR-TKI Treatment JS001 combined with pemetrexed plus carboplatin for treatment of recurrent or advanced non-small-cell lung cancer with EGFR-mutation positive and T790M negative after progression on EGFR-TKI treatment:a multi-center, single arm phase II study Objective response rate (ORR). --- T790M --- --- T790M ---

Inclusion Criteria: Only the patients meeting all the following criteria can be eligible to participate in the trial: - Histologically and/or cytologically confirmed advanced or recurrent non-small cell lung cancer with EGFR sensitive mutation (exon 19 deletion, exon 21 L858R), and meeting the following conditions at the same time: - Previous first-line EGFR-TKI monotherapy with clinical benefit, followed by progression of disease; - No exon 20 T790M mutation after failure of EGFR-TKI therapy; - At least one measurable lesion (in accordance with RECIST 1.1); Exclusion Criteria: Patients who fulfill any of the following criteria must be excluded from the study: - Histologically or cytopathologically confirmed combined with small cell lung cancer component or squamous cell carcinoma component >10%; - Combined with other driver gene mutation with known drug therapy, including but not limited to ALK rearrangement, ROS1 mutation, BRAF600E mutation etc.; - Previous systemic chemotherapy for advanced NSCLC; - EGFR-TKI therapy within two weeks prior to enrollment; Inclusion Criteria: Only the patients meeting all the following criteria can be eligible to participate in the trial: - Histologically and/or cytologically confirmed advanced or recurrent non-small cell lung cancer with EGFR sensitive mutation (exon 19 deletion, exon 21 L858R), and meeting the following conditions at the same time: - Previous first-line EGFR-TKI monotherapy with clinical benefit, followed by progression of disease; - No exon 20 T790M mutation after failure of EGFR-TKI therapy; - At least one measurable lesion (in accordance with RECIST 1.1); Exclusion Criteria: Patients who fulfill any of the following criteria must be excluded from the study: - Histologically or cytopathologically confirmed combined with small cell lung cancer component or squamous cell carcinoma component >10%; - Combined with other driver gene mutation with known drug therapy, including but not limited to ALK rearrangement, ROS1 mutation, BRAF600E mutation etc.; - Previous systemic chemotherapy for advanced NSCLC; - EGFR-TKI therapy within two weeks prior to enrollment; NSCLC Disease Progression null --- L858R --- --- T790M ---

Inclusion Criteria: Only the patients meeting all the following criteria can be eligible to participate in the trial: - Histologically and/or cytologically confirmed advanced or recurrent non-small cell lung cancer with EGFR sensitive mutation (exon 19 deletion, exon 21 L858R), and meeting the following conditions at the same time: - Previous first-line EGFR-TKI monotherapy with clinical benefit, followed by progression of disease; - No exon 20 T790M mutation after failure of EGFR-TKI therapy; - At least one measurable lesion (in accordance with RECIST 1.1); Exclusion Criteria: Patients who fulfill any of the following criteria must be excluded from the study: - Histologically or cytopathologically confirmed combined with small cell lung cancer component or squamous cell carcinoma component >10%; - Combined with other driver gene mutation with known drug therapy, including but not limited to ALK rearrangement, ROS1 mutation, BRAF600E mutation etc.; - Previous systemic chemotherapy for advanced NSCLC; - EGFR-TKI therapy within two weeks prior to enrollment; Inclusion Criteria: Only the patients meeting all the following criteria can be eligible to participate in the trial: - Histologically and/or cytologically confirmed advanced or recurrent non-small cell lung cancer with EGFR sensitive mutation (exon 19 deletion, exon 21 L858R), and meeting the following conditions at the same time: - Previous first-line EGFR-TKI monotherapy with clinical benefit, followed by progression of disease; - No exon 20 T790M mutation after failure of EGFR-TKI therapy; - At least one measurable lesion (in accordance with RECIST 1.1); Exclusion Criteria: Patients who fulfill any of the following criteria must be excluded from the study: - Histologically or cytopathologically confirmed combined with small cell lung cancer component or squamous cell carcinoma component >10%; - Combined with other driver gene mutation with known drug therapy, including but not limited to ALK rearrangement, ROS1 mutation, BRAF600E mutation etc.; - Previous systemic chemotherapy for advanced NSCLC; - EGFR-TKI therapy within two weeks prior to enrollment; NSCLC Disease Progression null --- L858R --- --- T790M --- --- L858R --- --- T790M ---

Primary Outcomes

Description: The primary endpoint is the antitumor activities in this study

Measure: Objective response rate (ORR)

Time: 12 weeks

Secondary Outcomes

Description: Progression free survival (PFS)

Measure: PFS

Time: 18 months

Description: Overall survival (OS)

Measure: OS

Time: 18 months

Description: Duration of response (DOR)

Measure: DOR

Time: 18 months

110 A Randomized, Double-Blind, Phase 3 Study of Pemetrexed + Platinum Chemotherapy With or Without Pembrolizumab (MK-3475) in TKI-resistant EGFR-mutated Tumors in Metastatic Non-squamous Non-small Cell Lung Cancer (NSCLC) Participants (KEYNOTE-789)

The purpose of this study is to evaluate the efficacy and safety of pemetrexed plus platinum chemotherapy (carboplatin or cisplatin) with or without pembrolizumab (MK-3475; KEYTRUDA®) in the treatment of adults with the following types of tyrosine kinase inhibitor (TKI)-resistant, epidermal growth factor receptor (EGFR)-mutated, metastatic non-squamous non-small cell lung cancer (NSCLC) tumors: 1) TKI-failures (including osimertinib [TAGRISSO®] failure) with T790M-negative mutation tumors, 2) T790M-positive mutation tumors with prior exposure to osimertinib, and 3) first-line osimertinib failure regardless of T790M mutation status. The primary study hypotheses are that the combination of pembrolizumab plus chemotherapy has superior efficacy compared to saline placebo plus chemotherapy in terms of: 1) Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) based on blinded independent central review, and 2) Overall Survival (OS). This study will be considered to have met its success criteria if the combination of pembrolizumab plus chemotherapy is superior to saline placebo plus chemotherapy in terms of PFS or OS.

NCT03515837
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Biological: pembrolizumab
  2. Drug: pemetrexed
  3. Drug: carboplatin
  4. Drug: cisplatin
  5. Drug: saline solution
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Study of Pemetrexed + Platinum Chemotherapy With or Without Pembrolizumab (MK-3475) in Adults With Tyrosine Kinase Inhibitor- (TKI)-Resistant Epidermal Growth Factor Receptor- (EGFR)-Mutated Metastatic Non-squamous Non-small Cell Lung Cancer (NSCLC) (MK-3475-789/KEYNOTE-789) The purpose of this study is to evaluate the efficacy and safety of pemetrexed plus platinum chemotherapy (carboplatin or cisplatin) with or without pembrolizumab (MK-3475; KEYTRUDA®) in the treatment of adults with the following types of tyrosine kinase inhibitor (TKI)-resistant, epidermal growth factor receptor (EGFR)-mutated, metastatic non-squamous non-small cell lung cancer (NSCLC) tumors: 1) TKI-failures (including osimertinib [TAGRISSO®] failure) with T790M-negative mutation tumors, 2) T790M-positive mutation tumors with prior exposure to osimertinib, and 3) first-line osimertinib failure regardless of T790M mutation status. --- T790M ---

Study of Pemetrexed + Platinum Chemotherapy With or Without Pembrolizumab (MK-3475) in Adults With Tyrosine Kinase Inhibitor- (TKI)-Resistant Epidermal Growth Factor Receptor- (EGFR)-Mutated Metastatic Non-squamous Non-small Cell Lung Cancer (NSCLC) (MK-3475-789/KEYNOTE-789) The purpose of this study is to evaluate the efficacy and safety of pemetrexed plus platinum chemotherapy (carboplatin or cisplatin) with or without pembrolizumab (MK-3475; KEYTRUDA®) in the treatment of adults with the following types of tyrosine kinase inhibitor (TKI)-resistant, epidermal growth factor receptor (EGFR)-mutated, metastatic non-squamous non-small cell lung cancer (NSCLC) tumors: 1) TKI-failures (including osimertinib [TAGRISSO®] failure) with T790M-negative mutation tumors, 2) T790M-positive mutation tumors with prior exposure to osimertinib, and 3) first-line osimertinib failure regardless of T790M mutation status. --- T790M --- --- T790M ---

Study of Pemetrexed + Platinum Chemotherapy With or Without Pembrolizumab (MK-3475) in Adults With Tyrosine Kinase Inhibitor- (TKI)-Resistant Epidermal Growth Factor Receptor- (EGFR)-Mutated Metastatic Non-squamous Non-small Cell Lung Cancer (NSCLC) (MK-3475-789/KEYNOTE-789) The purpose of this study is to evaluate the efficacy and safety of pemetrexed plus platinum chemotherapy (carboplatin or cisplatin) with or without pembrolizumab (MK-3475; KEYTRUDA®) in the treatment of adults with the following types of tyrosine kinase inhibitor (TKI)-resistant, epidermal growth factor receptor (EGFR)-mutated, metastatic non-squamous non-small cell lung cancer (NSCLC) tumors: 1) TKI-failures (including osimertinib [TAGRISSO®] failure) with T790M-negative mutation tumors, 2) T790M-positive mutation tumors with prior exposure to osimertinib, and 3) first-line osimertinib failure regardless of T790M mutation status. --- T790M --- --- T790M --- --- T790M ---

erlotinib/afatinib/gefitinib) are required to have confirmed documented absence of EGFR T790M mutation; b) Participants with confirmed acquired T790M mutation after 1st or 2nd generation EGFR TKI (e.g. --- T790M ---

erlotinib/afatinib/gefitinib) are required to have confirmed documented absence of EGFR T790M mutation; b) Participants with confirmed acquired T790M mutation after 1st or 2nd generation EGFR TKI (e.g. --- T790M --- --- T790M ---

erlotinib/afatinib/gefitinib) are required to have osimertinib TKI treatment failure prior to enrollment; c) Participants previously failed osimertinib TKI treatment as 1st line therapy are eligible regardless of their EGFR T790M mutation status. --- T790M ---

Primary Outcomes

Description: PFS is defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurs first. PFS will be assessed by blinded independent central review (BICR) using RECIST 1.1. Per RECIST 1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions is also considered PD. The PFS for participants will be presented.

Measure: Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

Time: Up to approximately 32 months

Description: OS is defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis will be censored at the date of the last follow-up. The OS of participants will be presented.

Measure: Overall Survival (OS)

Time: Up to approximately 59 months

Secondary Outcomes

Description: ORR is defined as the percentage of participants in the analysis population who experience a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters) per RECIST 1.1. The ORR for participants will be presented.

Measure: Objective Response Rate (ORR) Per RECIST 1.1

Time: Up to approximately 32 months

Description: For participants who experience a response of CR or PR, DOR is defined as the time from the earliest date of qualifying response until earliest date of PD or death from any cause, whichever comes first. DOR will be assessed per RECIST 1.1 based on BICR. The DOR of participants who experience a CR or PR will be presented.

Measure: Duration of Response (DOR) Per RECIST 1.1

Time: Up to approximately 32 months

Description: The EORTC QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. For Global Health Status, participants are asked "How would you rate your overall health during the past week?" Individual responses are given on a 7-point scale (1=Very poor; 7=Excellent), with a higher score indicating a better outcome. The change from baseline in EORTC-QLQ-C30 score for Global Health Status will be presented.

Measure: Change from Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 Item (QLQ-C30) Global Health Status (Item 29) Scale Score

Time: Baseline and Week 12, Week 27

Description: TTD is the time from baseline to first onset of 10 points or more decrease from baseline with confirmation by the subsequent visit of 10 points or more deterioration from baseline in the composite endpoint of cough [EORTC QLQ-Lung Cancer Module 13 (LC13) Item 1; How much did you cough?], chest pain [EORTC QLQ-LC13 Item 10; Have you had pain in your chest?], or dyspnea [EORTC QLQ-C30 Item 8; Were you short of breath?]. Individual responses are given on a 4-point scale (1=Not at all; 4=Very much), with a lower score indicating a better outcome. The time to true deterioration in the composite endpoint of cough, chest pain or dyspnea will be presented.

Measure: Time to True Deterioration (TTD) in the EORTC Questionnaire Composite Endpoint of Cough, Chest Pain or Dyspnea

Time: Up to approximately 32 months

Description: An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study treatment, whether or not considered related to the use of study treatment. The number of participants who experience an AE will be presented.

Measure: Adverse Events (AEs)

Time: Up to 90 days after last dose of study treatment (Up to approximately 42 months)

Description: The number of participants who discontinue study treatment due to an AE will be presented.

Measure: Study Treatment Discontinuations Due to AEs

Time: Up to approximately 39 months

Description: The EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. For Quality of Life, participants are asked "How would you rate your overall quality of life during the past week?" Individual responses are given on a 7-point scale (1=Very poor; 7=Excellent), with a higher score indicating a better outcome. The change from baseline in EORTC-QLQ-C30 score for Quality of Life will be presented.

Measure: Change from Baseline in EORTC-QLQ-C30 Quality of Life (Item 30) Scale Score

Time: Baseline and Week 12, Week 27

111 An Observational, Multi-centre Study on EGFR T790M Mutation Testing Practices and Outcomes Conducted Among Locally Advanced/Metastatic NSCLC Patients Who Progressed on Previous EGFR Tyrosine-kinase Inhibitor (TKI) Therapy in Hong Kong

To describe the T790M mutation status of patients with locally advanced/metastatic NSCLC who progressed on previous EGFR TKI treatment in a real-world setting.

NCT03519958
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Diagnostic Test: Plasma-tissue testing
MeSH:Carcinoma, Non-Small-Cell Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

An Observational, Multi-centre Study on EGFR T790M Mutation Testing Practices and Outcomes Conducted Among Locally Advanced/Metastatic NSCLC Patients Who Progressed on Previous EGFR Tyrosine-kinase Inhibitor (TKI) Therapy in Hong Kong. --- T790M ---

Epidermal Growth Factor Receptor (EGFR) T790M Mutation Testing Practices in Hong Kong To describe the T790M mutation status of patients with locally advanced/metastatic NSCLC who progressed on previous EGFR TKI treatment in a real-world setting. --- T790M ---

Epidermal Growth Factor Receptor (EGFR) T790M Mutation Testing Practices in Hong Kong To describe the T790M mutation status of patients with locally advanced/metastatic NSCLC who progressed on previous EGFR TKI treatment in a real-world setting. --- T790M --- --- T790M ---

EGFR T790M mutation prevalance. --- T790M ---

Proportion of Valid Tissue T790M Testing Result. --- T790M ---

Proportion of study subjects who have a valid tissue/cytology T790M testing result after receiving a negative plasma test result for the T790M mutation. --- T790M ---

Proportion of study subjects who have a valid tissue/cytology T790M testing result after receiving a negative plasma test result for the T790M mutation. --- T790M --- --- T790M ---

T790M Plasma Outcome. --- T790M ---

Proportions of study subjects who are T790M plasma-negative. --- T790M ---

Proportion of study subjects who are T790M plasma-negative but T790M tissue/cytology-positive. --- T790M ---

Proportion of study subjects who are T790M plasma-negative but T790M tissue/cytology-positive. --- T790M --- --- T790M ---

Demographics of T790M-positive subjects and T790M-negative subjects. --- T790M ---

Demographics of T790M-positive subjects and T790M-negative subjects. --- T790M --- --- T790M ---

Disease characteristics of T790M-positive subjects and T790M-negative subjects. --- T790M ---

Disease characteristics of T790M-positive subjects and T790M-negative subjects. --- T790M --- --- T790M ---

Clinical Outcomes in T790M plasma-positive subejects. --- T790M ---

Clinical outcomes after osimertinib treatment between study subjects who are T790M plasma-positive. --- T790M ---

To analyze the concordance of T790M mutation status as determined by urine, plasma, and tissue/cytology T790M testing. --- T790M ---

To analyze the concordance of T790M mutation status as determined by urine, plasma, and tissue/cytology T790M testing. --- T790M --- --- T790M ---

Inclusion Criteria - Provision of written informed consent - Locally advanced (stage IIIB) or metastatic (stage IV) NSCLC, not amenable to curative surgery or radiotherapy - Confirmed EGFR sensitizing mutation (exon 19 deletion or exon 21 L858R ) in medical record - Progressed on previous EGFR TKI treatment, based on physician judgement, with or without additional lines of treatment - Suggested to undergo T790M mutation testing by treating physician, based on physician judgement Exclusion Criteria - Had been treated with osimertinib or any other 3rd generation T790M inhibitors - Enrollment in studies that prohibit participation in this observational study Inclusion Criteria - Provision of written informed consent - Locally advanced (stage IIIB) or metastatic (stage IV) NSCLC, not amenable to curative surgery or radiotherapy - Confirmed EGFR sensitizing mutation (exon 19 deletion or exon 21 L858R ) in medical record - Progressed on previous EGFR TKI treatment, based on physician judgement, with or without additional lines of treatment - Suggested to undergo T790M mutation testing by treating physician, based on physician judgement Exclusion Criteria - Had been treated with osimertinib or any other 3rd generation T790M inhibitors - Enrollment in studies that prohibit participation in this observational study Non-small Cell Lung Cancer Carcinoma, Non-Small-Cell Carcinoma, Non-Small-Cell Lung This is a multi-center, observational study of patients with locally advanced/metastatic NSCLC who progressed on previous EGFR TKI treatment. --- L858R --- --- T790M ---

Inclusion Criteria - Provision of written informed consent - Locally advanced (stage IIIB) or metastatic (stage IV) NSCLC, not amenable to curative surgery or radiotherapy - Confirmed EGFR sensitizing mutation (exon 19 deletion or exon 21 L858R ) in medical record - Progressed on previous EGFR TKI treatment, based on physician judgement, with or without additional lines of treatment - Suggested to undergo T790M mutation testing by treating physician, based on physician judgement Exclusion Criteria - Had been treated with osimertinib or any other 3rd generation T790M inhibitors - Enrollment in studies that prohibit participation in this observational study Inclusion Criteria - Provision of written informed consent - Locally advanced (stage IIIB) or metastatic (stage IV) NSCLC, not amenable to curative surgery or radiotherapy - Confirmed EGFR sensitizing mutation (exon 19 deletion or exon 21 L858R ) in medical record - Progressed on previous EGFR TKI treatment, based on physician judgement, with or without additional lines of treatment - Suggested to undergo T790M mutation testing by treating physician, based on physician judgement Exclusion Criteria - Had been treated with osimertinib or any other 3rd generation T790M inhibitors - Enrollment in studies that prohibit participation in this observational study Non-small Cell Lung Cancer Carcinoma, Non-Small-Cell Carcinoma, Non-Small-Cell Lung This is a multi-center, observational study of patients with locally advanced/metastatic NSCLC who progressed on previous EGFR TKI treatment. --- L858R --- --- T790M --- --- T790M ---

Inclusion Criteria - Provision of written informed consent - Locally advanced (stage IIIB) or metastatic (stage IV) NSCLC, not amenable to curative surgery or radiotherapy - Confirmed EGFR sensitizing mutation (exon 19 deletion or exon 21 L858R ) in medical record - Progressed on previous EGFR TKI treatment, based on physician judgement, with or without additional lines of treatment - Suggested to undergo T790M mutation testing by treating physician, based on physician judgement Exclusion Criteria - Had been treated with osimertinib or any other 3rd generation T790M inhibitors - Enrollment in studies that prohibit participation in this observational study Inclusion Criteria - Provision of written informed consent - Locally advanced (stage IIIB) or metastatic (stage IV) NSCLC, not amenable to curative surgery or radiotherapy - Confirmed EGFR sensitizing mutation (exon 19 deletion or exon 21 L858R ) in medical record - Progressed on previous EGFR TKI treatment, based on physician judgement, with or without additional lines of treatment - Suggested to undergo T790M mutation testing by treating physician, based on physician judgement Exclusion Criteria - Had been treated with osimertinib or any other 3rd generation T790M inhibitors - Enrollment in studies that prohibit participation in this observational study Non-small Cell Lung Cancer Carcinoma, Non-Small-Cell Carcinoma, Non-Small-Cell Lung This is a multi-center, observational study of patients with locally advanced/metastatic NSCLC who progressed on previous EGFR TKI treatment. --- L858R --- --- T790M --- --- T790M --- --- L858R --- --- T790M ---

Inclusion Criteria - Provision of written informed consent - Locally advanced (stage IIIB) or metastatic (stage IV) NSCLC, not amenable to curative surgery or radiotherapy - Confirmed EGFR sensitizing mutation (exon 19 deletion or exon 21 L858R ) in medical record - Progressed on previous EGFR TKI treatment, based on physician judgement, with or without additional lines of treatment - Suggested to undergo T790M mutation testing by treating physician, based on physician judgement Exclusion Criteria - Had been treated with osimertinib or any other 3rd generation T790M inhibitors - Enrollment in studies that prohibit participation in this observational study Inclusion Criteria - Provision of written informed consent - Locally advanced (stage IIIB) or metastatic (stage IV) NSCLC, not amenable to curative surgery or radiotherapy - Confirmed EGFR sensitizing mutation (exon 19 deletion or exon 21 L858R ) in medical record - Progressed on previous EGFR TKI treatment, based on physician judgement, with or without additional lines of treatment - Suggested to undergo T790M mutation testing by treating physician, based on physician judgement Exclusion Criteria - Had been treated with osimertinib or any other 3rd generation T790M inhibitors - Enrollment in studies that prohibit participation in this observational study Non-small Cell Lung Cancer Carcinoma, Non-Small-Cell Carcinoma, Non-Small-Cell Lung This is a multi-center, observational study of patients with locally advanced/metastatic NSCLC who progressed on previous EGFR TKI treatment. --- L858R --- --- T790M --- --- T790M --- --- L858R --- --- T790M --- --- T790M ---

Plasma circulating tumor DNA (ctDNA) and urine ctDNA will be analyzed by droplet digital PCR (ddPCR) for detection of T790M mutation and EGFR sensitizing mutations. --- T790M ---

Patients who are T790M plasma-negative, regardless of the urine testing results, will be recommended to undergo re-biopsy (defined as tissue sampling or cytology sampling), tissue/cytology T790M testing, and to provide a second plasma sample for a second plasma T790M test (tested by ddPCR). --- T790M ---

Patients who are T790M plasma-negative, regardless of the urine testing results, will be recommended to undergo re-biopsy (defined as tissue sampling or cytology sampling), tissue/cytology T790M testing, and to provide a second plasma sample for a second plasma T790M test (tested by ddPCR). --- T790M --- --- T790M ---

Patients who are T790M plasma-negative, regardless of the urine testing results, will be recommended to undergo re-biopsy (defined as tissue sampling or cytology sampling), tissue/cytology T790M testing, and to provide a second plasma sample for a second plasma T790M test (tested by ddPCR). --- T790M --- --- T790M --- --- T790M ---

Primary Outcomes

Description: Based on the plasma-tissue testing algorithm in NSCLC patients who progressed on previous EGFR TKI therapy

Measure: EGFR T790M mutation prevalance

Time: 3 years

Secondary Outcomes

Description: Proportion of study subjects who have a valid tissue/cytology T790M testing result after receiving a negative plasma test result for the T790M mutation

Measure: Proportion of Valid Tissue T790M Testing Result

Time: 3 years

Description: Proportions of study subjects who are T790M plasma-negative

Measure: T790M Plasma Outcome

Time: 3 years

Description: Proportion of study subjects who are T790M plasma-negative but T790M tissue/cytology-positive

Measure: False Negative Proportation

Time: 3 years

Description: reasons given for not performing re-biopsy and tissue/cytology testing after obtaining a negative plasma test result

Measure: Reasons for not performing re-biopsy

Time: 3 years

Description: Demographics of T790M-positive subjects and T790M-negative subjects

Measure: Demographics

Time: Baseline

Description: Disease characteristics of T790M-positive subjects and T790M-negative subjects

Measure: Disease Characteristics

Time: 3 years

Description: Number of particapants with complications assoicated with tissue/cytology re-biopsy

Measure: Number of particapants with complications assoicated with re-biopsy

Time: 3 years

Description: Clinical outcomes after osimertinib treatment between study subjects who are T790M plasma-positive

Measure: Clinical Outcomes in T790M plasma-positive subejects

Time: 3 years

Description: Clinical outcomes after osimertinib treatment between study subjects who are urine-positive

Measure: Clinical Outcomes in urine-positive

Time: 3 years

Description: Clinical outcomes after osimertinib treatment between study subjects who are tissue/cytology-positive

Measure: Clinical Outcomes in tissue/cytology-positive

Time: 3 years

Other Outcomes

Description: To analyze the concordance of T790M mutation status as determined by urine, plasma, and tissue/cytology T790M testing

Measure: Concordance

Time: 3 years

112 A Phase I Dose-Escalation Study of Erlotinib in Combination With Pralatrexate in Subjects With Advanced Cancer

The goal of this clinical research study is to find the highest tolerable dose of the combination of erlotinib and pralatrexate that can be given to patients with advanced cancer. The safety of the drug combination will also be studied. Pralatrexate is designed to block the body's ability to make folic acid, a protein that may help cancer tissue to develop and spread. Erlotinib hydrochloride is designed to block proteins that are thought to cause cancer cells to grow. Erlotinib may help slow the growth of tumors.

NCT01532011
Conditions
  1. Advanced Cancers
  2. Solid Tumors
Interventions
  1. Drug: Erlotinib
  2. Drug: Pralatrexate
MeSH:Neoplasms
HPO:Neoplasm

Have an EGFR-resistant mutation (as T790M in exon 20), OR III. --- T790M ---

Primary Outcomes

Description: MTD defined by dose limiting toxicities (DLTs) that occur in the first cycle. DLT defined as any Grade 3 or 4 non-hematologic toxicity as defined in the NCI Common Toxicity Criteria for Adverse Effects (CTCAE) v3.0. Grade 4 hematologic toxicity lasting 2 weeks or longer despite supportive care. Grade 4 nausea or vomiting > 5 days despite maximum anti-nausea regimens, and any other Grade 3 non-hematologic toxicity, including symptoms/signs of vascular leak or cytokine release syndrome; or any severe or life-threatening complication or abnormality not defined in NCI-CTCAE as attributable to therapy.

Measure: Maximum Tolerated Dose (MTD) of Erlotinib with Pralatrexate

Time: 8 weeks

Secondary Outcomes

Description: Tumor response defined as one or more of the following: (1) stable disease for more than or equal to 4 months, (2) decrease in measurable tumor (sentinel lesions) by more than or equal to 20% by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, (3) decrease in tumor markers by more than or equal to 25% (for example, a >/= 25% decrease in CA125 for patients with ovarian cancer), or (4) a partial response according to the Choi criteria, i.e. decrease in size by 10% or more, or a decrease in tumor density, as measured in Hounsfield units (HU), by more than or equal to 15% (28).

Measure: Tumor Response

Time: 8 weeks

113 A Randomized Phase II Trial of Erlotinib Alone or in Combination With Bevacizumab in Patients With Non-Small Cell Lung Cancer and Activating Epidermal Growth Factor Receptor Mutations

This randomized phase II trial studies how well erlotinib hydrochloride (Tarceva) with or without bevacizumab (Avastin) works in treating patients with stage IV non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. Erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, may block tumor growth in different ways by targeting certain cells. Bevacizumab may also stop the growth of NSCLC by blocking the growth of new blood vessels necessary for tumor growth. It is not yet known whether erlotinib hydrochloride is more effective when given alone or with bevacizumab in treating patients with NSCLC.

NCT01532089
Conditions
  1. EGFR Exon 19 Deletion Mutation
  2. EGFR NP_005219.2:p.L858R
  3. Lung Non-Squamous Non-Small Cell Carcinoma
  4. Stage IV Lung Non-Small Cell Cancer AJCC v7
Interventions
  1. Biological: Bevacizumab
  2. Drug: Erlotinib
  3. Drug: Erlotinib Hydrochloride
  4. Other: Laboratory Biomarker Analysis
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Agreement of EGFR mutations detected in plasma DNA with those detected in tumor DNA will be evaluated.. Prevalence of EGFR T790M Resistance Mutations From Pretreatment > Tumor Biopsies Using More Sensitive Mutation Detection Methods. --- T790M ---

The robustness of treatment effect in different subgroups will be examined in a Forest plot.. EGFR T790M Mutations. --- T790M ---

The PFS of patients with EGFR T790M mutations will be estimated and the survival difference will be tested using Cox proportional hazard model after adjusting for treatment effect. --- T790M ---

To estimate the prevalence of EGFR T790M resistance mutations from pretreatment tumor biopsies using more sensitive mutation detection methods. --- T790M ---

To investigate progression free survival of EGFR mutant NSCLC patients with and without concurrent EGFR T790M detected from pre-treatment tumor specimen using allele specific quantitative polymerase chain reaction (PCR). --- T790M ---

Primary Outcomes

Description: Progression free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death resulting from any cause, whichever comes first. Progression is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as at least a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator.

Measure: Progression Free Survival (PFS)

Time: Time from randomization to disease progression and death of any cause, whichever comes first, assessed up to 6 years

Secondary Outcomes

Description: Overall survival time is defined as the time from randomization to death due to any cause. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator.

Measure: Overall Survival

Time: Time from randomization to death of any causes, assessed up to 6 years

Description: The response rate (percentage) is the percent of patients whose best response was Complete Response (CR) or Partial Response (PR) as defined by RECIST 1.1 criteria. Percentage of successes will be estimated by 100 times the number of successes divided by the total number of evaluable patients. (CR: Disappearance of all evidence of disease, PR: Regression of measurable disease and no new sites).

Measure: Response Rate (Complete or Partial) to Each Treatment, Evaluated Using the New International Criteria Proposed by the Revised Response Evaluation Criteria in Solid Tumors Guidelines (Version 1.1)

Time: Up to 6 years

Description: Progression free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death resulting from any cause, whichever comes first. Progression is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as at least a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator by mutation type.

Measure: Progression Free Survival of Patients With Different Mutation Types (Exon Deletion 19 Versus Exon 21 L858R)

Time: From the date of randomization to the date of disease progression or death of any cause, whichever comes first, assessed up to 6 years

Description: The number of patients experiencing toxicity defined as grade 3 or higher adverse events (using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0) considered at least possibly related to treatment is reported below.

Measure: Number of Patients Experiencing Toxicity

Time: Up to 42 days after treatment discontinuation

Other Outcomes

Description: Agreement of EGFR mutations detected in plasma DNA with those detected in tumor DNA will be evaluated.

Measure: EGFR Mutations Detected in Plasma Deoxyribonucleic Acid (DNA)

Time: Up to 6 years

Description: Agreement of EGFR mutations detected in plasma DNA with those detected in tumor DNA will be evaluated.

Measure: EGFR Mutations Detected in Tumor Deoxyribonucleic Acid (DNA)

Time: Up to 6 years

Description: Tested using Cox proportional hazard model after adjusting for treatment effect. The robustness of treatment effect in different subgroups will be examined in a Forest plot.

Measure: Prevalence of EGFR T790M Resistance Mutations From Pretreatment > Tumor Biopsies Using More Sensitive Mutation Detection Methods

Time: Baseline

Description: Detected from pre-treatment tumor specimen using allele specific quantitative polymerase chain reaction (PCR). The PFS of patients with EGFR T790M mutations will be estimated and the survival difference will be tested using Cox proportional hazard model after adjusting for treatment effect. The robustness of treatment effect in different subgroups will be examined in a Forest plot.

Measure: EGFR T790M Mutations

Time: Up to 6 years

Description: Evaluated using time-dependent receiver operating characteristic curve and area under curve.

Measure: Predictive Value of Plasma VEGF-A Levels on Progression Free Survival in Patients Treated With Erlotinib Hydrochloride Alone or in Combination With Bevacizumab

Time: Baseline

114 Randomized Study of Erlotinib vs Observation in Patients With Completely Resected Epidermal Growth Factor Receptor (EGFR) Mutant Non-Small Cell Lung Cancer (NSCLC)

This phase III ALCHEMIST trial studies how well erlotinib hydrochloride compared to observation works in treating patients with stage IB-IIIA non-small cell lung cancer that has been completely removed by surgery. Erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT02193282
Conditions
  1. Lung Non-Squamous Non-Small Cell Carcinoma
  2. Stage IB Lung Non-Small Cell Carcinoma AJCC v7
  3. Stage II Lung Non-Small Cell Cancer AJCC v7
  4. Stage IIA Lung Non-Small Cell Carcinoma AJCC v7
  5. Stage IIB Lung Non-Small Cell Carcinoma AJCC v7
  6. Stage IIIA Lung Non-Small Cell Cancer AJCC v7
Interventions
  1. Other: Clinical Observation
  2. Drug: Erlotinib Hydrochloride
  3. Other: Laboratory Biomarker Analysis
  4. Other: Placebo Administration
MeSH:Carcinoma Carcinoma, Non-Small-Cell Lung
HPO:Carcinoma Non-small cell lung carcinoma

Analysis of the overall adverse event rates, as well as specific events of interest will involve chi-square tests or Fisher's exact tests.. Inclusion Criteria: - Previously registered to A151216, with the result of lung cancer harboring an EGFR exon 19 deletion or L858R mutation; the testing must have been performed by one of the following criteria: 1. Patient registered to A151216 and the assessment performed centrally by the protocol-specified laboratory 2. By a local Clinical Laboratory Improvement Amendments (CLIA) certified laboratory; the report must indicate the result as well as the CLIA number of the laboratory that performed the assay; these patients will also have been registered to A151216, but can be enrolled on A081105 regardless of the central lab results - Patients with known resistant mutations in the EGFR tyrosine-kinase (TK) domain (T790M) are not eligible - Patients that are both EGFR mutant and anaplastic lymphoma kinase (ALK) rearrangements will be registered to A081105 - Completely resected stage IB (>= 4 cm), II or IIIA non-squamous NSCLC with negative margins; patients may not have received neoadjuvant therapy (chemo- or radio-therapy) for this lung cancer - Complete recovery from surgery and standard post-operative therapy (if required); patients must be completely recovered from surgery at the time of randomization; the minimum time requirement between date of surgery and randomization must be at least 28 days, the maximum time requirement between surgery and randomization must be 90 days if no adjuvant chemotherapy was administered, 240 days if adjuvant chemotherapy was administered, and 300 days if adjuvant chemotherapy and radiation therapy was administered - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - No locally advanced or metastatic cancer requiring systemic therapy within 5 years prior to registration; no secondary primary lung cancer diagnosed concurrently or within 2 years prior to registration - Non-pregnant and non-lactating - No history of cornea abnormalities - Granulocytes >= 1,500/ul - Platelets >= 100,000/ul - Total bilirubin =< 1.5 x upper limit of normal (ULN) - Serum glutamic oxaloacetic transaminase (SGOT) =< 1.5 x ULN - Serum creatinine =< 1.5 x ULN Inclusion Criteria: - Previously registered to A151216, with the result of lung cancer harboring an EGFR exon 19 deletion or L858R mutation; the testing must have been performed by one of the following criteria: 1. Patient registered to A151216 and the assessment performed centrally by the protocol-specified laboratory 2. By a local Clinical Laboratory Improvement Amendments (CLIA) certified laboratory; the report must indicate the result as well as the CLIA number of the laboratory that performed the assay; these patients will also have been registered to A151216, but can be enrolled on A081105 regardless of the central lab results - Patients with known resistant mutations in the EGFR tyrosine-kinase (TK) domain (T790M) are not eligible - Patients that are both EGFR mutant and anaplastic lymphoma kinase (ALK) rearrangements will be registered to A081105 - Completely resected stage IB (>= 4 cm), II or IIIA non-squamous NSCLC with negative margins; patients may not have received neoadjuvant therapy (chemo- or radio-therapy) for this lung cancer - Complete recovery from surgery and standard post-operative therapy (if required); patients must be completely recovered from surgery at the time of randomization; the minimum time requirement between date of surgery and randomization must be at least 28 days, the maximum time requirement between surgery and randomization must be 90 days if no adjuvant chemotherapy was administered, 240 days if adjuvant chemotherapy was administered, and 300 days if adjuvant chemotherapy and radiation therapy was administered - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - No locally advanced or metastatic cancer requiring systemic therapy within 5 years prior to registration; no secondary primary lung cancer diagnosed concurrently or within 2 years prior to registration - Non-pregnant and non-lactating - No history of cornea abnormalities - Granulocytes >= 1,500/ul - Platelets >= 100,000/ul - Total bilirubin =< 1.5 x upper limit of normal (ULN) - Serum glutamic oxaloacetic transaminase (SGOT) =< 1.5 x ULN - Serum creatinine =< 1.5 x ULN Lung Non-Squamous Non-Small Cell Carcinoma Stage IB Lung Non-Small Cell Carcinoma AJCC v7 Stage II Lung Non-Small Cell Cancer AJCC v7 Stage IIA Lung Non-Small Cell Carcinoma AJCC v7 Stage IIB Lung Non-Small Cell Carcinoma AJCC v7 Stage IIIA Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVE: I. To assess whether adjuvant therapy with erlotinib hydrochloride (erlotinib) will result in improved overall survival (OS) over observation for patients with completely resected stage IB (>= 4 cm)-IIIA epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) (confirmed centrally) following complete resection and standard post-operative therapy. --- L858R --- --- T790M ---

Analysis of the overall adverse event rates, as well as specific events of interest will involve chi-square tests or Fisher's exact tests.. Inclusion Criteria: - Previously registered to A151216, with the result of lung cancer harboring an EGFR exon 19 deletion or L858R mutation; the testing must have been performed by one of the following criteria: 1. Patient registered to A151216 and the assessment performed centrally by the protocol-specified laboratory 2. By a local Clinical Laboratory Improvement Amendments (CLIA) certified laboratory; the report must indicate the result as well as the CLIA number of the laboratory that performed the assay; these patients will also have been registered to A151216, but can be enrolled on A081105 regardless of the central lab results - Patients with known resistant mutations in the EGFR tyrosine-kinase (TK) domain (T790M) are not eligible - Patients that are both EGFR mutant and anaplastic lymphoma kinase (ALK) rearrangements will be registered to A081105 - Completely resected stage IB (>= 4 cm), II or IIIA non-squamous NSCLC with negative margins; patients may not have received neoadjuvant therapy (chemo- or radio-therapy) for this lung cancer - Complete recovery from surgery and standard post-operative therapy (if required); patients must be completely recovered from surgery at the time of randomization; the minimum time requirement between date of surgery and randomization must be at least 28 days, the maximum time requirement between surgery and randomization must be 90 days if no adjuvant chemotherapy was administered, 240 days if adjuvant chemotherapy was administered, and 300 days if adjuvant chemotherapy and radiation therapy was administered - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - No locally advanced or metastatic cancer requiring systemic therapy within 5 years prior to registration; no secondary primary lung cancer diagnosed concurrently or within 2 years prior to registration - Non-pregnant and non-lactating - No history of cornea abnormalities - Granulocytes >= 1,500/ul - Platelets >= 100,000/ul - Total bilirubin =< 1.5 x upper limit of normal (ULN) - Serum glutamic oxaloacetic transaminase (SGOT) =< 1.5 x ULN - Serum creatinine =< 1.5 x ULN Inclusion Criteria: - Previously registered to A151216, with the result of lung cancer harboring an EGFR exon 19 deletion or L858R mutation; the testing must have been performed by one of the following criteria: 1. Patient registered to A151216 and the assessment performed centrally by the protocol-specified laboratory 2. By a local Clinical Laboratory Improvement Amendments (CLIA) certified laboratory; the report must indicate the result as well as the CLIA number of the laboratory that performed the assay; these patients will also have been registered to A151216, but can be enrolled on A081105 regardless of the central lab results - Patients with known resistant mutations in the EGFR tyrosine-kinase (TK) domain (T790M) are not eligible - Patients that are both EGFR mutant and anaplastic lymphoma kinase (ALK) rearrangements will be registered to A081105 - Completely resected stage IB (>= 4 cm), II or IIIA non-squamous NSCLC with negative margins; patients may not have received neoadjuvant therapy (chemo- or radio-therapy) for this lung cancer - Complete recovery from surgery and standard post-operative therapy (if required); patients must be completely recovered from surgery at the time of randomization; the minimum time requirement between date of surgery and randomization must be at least 28 days, the maximum time requirement between surgery and randomization must be 90 days if no adjuvant chemotherapy was administered, 240 days if adjuvant chemotherapy was administered, and 300 days if adjuvant chemotherapy and radiation therapy was administered - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - No locally advanced or metastatic cancer requiring systemic therapy within 5 years prior to registration; no secondary primary lung cancer diagnosed concurrently or within 2 years prior to registration - Non-pregnant and non-lactating - No history of cornea abnormalities - Granulocytes >= 1,500/ul - Platelets >= 100,000/ul - Total bilirubin =< 1.5 x upper limit of normal (ULN) - Serum glutamic oxaloacetic transaminase (SGOT) =< 1.5 x ULN - Serum creatinine =< 1.5 x ULN Lung Non-Squamous Non-Small Cell Carcinoma Stage IB Lung Non-Small Cell Carcinoma AJCC v7 Stage II Lung Non-Small Cell Cancer AJCC v7 Stage IIA Lung Non-Small Cell Carcinoma AJCC v7 Stage IIB Lung Non-Small Cell Carcinoma AJCC v7 Stage IIIA Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVE: I. To assess whether adjuvant therapy with erlotinib hydrochloride (erlotinib) will result in improved overall survival (OS) over observation for patients with completely resected stage IB (>= 4 cm)-IIIA epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) (confirmed centrally) following complete resection and standard post-operative therapy. --- L858R --- --- T790M --- --- L858R --- --- T790M ---

Primary Outcomes

Description: Estimated using the method of Kaplan-Meier survival curves and a 1-sided stratified log rank test (accounting for all the stratification factors) will be used to compare OS between the two arms. Cox proportional hazards model (including time varying coefficients as necessary) will be used to assess whether the distribution of OS times differ with respect to treatment regimen after having adjusted for the stratification factors as well as other potential prognostic and treatment covariates.

Measure: Overall survival (OS)

Time: The time from randomization until death, assessed up to 10 years

Secondary Outcomes

Description: DFS will be defined as the proportion of patients alive and disease free at 2 years from the date of randomization. Estimated using the method of Kaplan-Meier survival curves. A 1-sided stratified log rank test (accounting for all the stratification factors) will be used to compare DFS between the arms, as well as to compare DFS and OS between the arms within the stage groups. Cox proportional hazards model (including time varying coefficients as necessary) will be used to assess potential differences in time to event outcomes after adjusting for the stratification factors and other potential prognostic and treatment covariates.

Measure: Disease free survival (DFS) rate

Time: Time from randomization until documented disease-recurrence or death, whichever occurs first, assessed at 2 years

Description: Will be defined as the proportion of patients alive at 5 years from date of randomization. Estimated using the method of Kaplan-Meier survival curves. A 1-sided stratified log rank test (accounting for all the stratification factors) will be used to compare DFS between the arms, as well as to compare DFS and OS between the arms within the stage groups. Cox proportional hazards model (including time varying coefficients as necessary) will be used to assess potential differences in time to event outcomes after adjusting for the stratification factors and other potential prognostic and treatment covariates.

Measure: Overall survival (OS) rate at 5 years

Time: At 5 years

Description: Will be defined as the proportion of patients alive at 10 years from date of randomization. Estimated using the method of Kaplan-Meier survival curves. A 1-sided stratified log rank test [accounting for all the stratification factors] will be used to compare DFS and OS between the arms within the stage groups. Cox proportional hazards model (including time varying coefficients as necessary) will be used to assess potential differences in time to event outcomes after adjusting for the stratification factors and other potential prognostic and treatment covariates.

Measure: Overall survival (OS) rate at 10 years

Time: At 10 years

Description: Estimated using the method of Kaplan-Meier survival curves (21). A 1-sided stratified log rank test [accounting for all the stratification factors] will be used to compare DFS between the arms, as well as to compare DFS and OS between the arms within the stage groups. Cox proportional hazards model (including time varying coefficients as necessary) will be used to assess potential differences in time to event outcomes after adjusting for the stratification factors and other potential prognostic and treatment covariates.

Measure: Overall disease free survival (DFS) between the erlotinib hydrochloride and observation arms

Time: Time from randomization until documented disease-recurrence or death, whichever occurs first, assessed up to 10 years

Description: The maximum grade for each type of adverse event will be recorded for each patient and frequency tables will be reviewed to determine the overall patterns. The number and severity of grade 3 + adverse events will be tabulated and summarized. All adverse events analysis will entail comparisons between the arms within Arms A and B, respectively. Analysis of the overall adverse event rates, as well as specific events of interest will involve chi-square tests or Fisher's exact tests.

Measure: Incidence of adverse events associated with each treatment arm

Time: Up to 10 years

115 A Phase Ib Open-label Clinical Trial of Once Daily Oral Treatment of Afatinib Plus Weekly Intravenous Infusion of Xentuzumab (BI 836845) in Patients With EGFR Mutant Non-small Cell Lung Cancer With Progression Following Prior EGFR Tyrosine Kinase Inhibitors

Part A: To determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of Xentuzumab (BI 836845) in combination with afatinib in patients with non-small cell lung cancer with progression following prior treatment (EGFR TKI or platinum-based chemotherapy). Part B: To evaluate the early anti-tumour activity of Xentuzumab (BI 836845) in combination with afatinib in patients with EGFR mutant non-small cell lung cancer with progression following prior irreversible EGFR TKIs. Part A and B: To evaluate the safety and pharmacokinetics of BI 836845 in combination with afatinib in patients with non-small cell lung cancer

NCT02191891
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Drug: BI 836845
  2. Drug: afatinib
MeSH:Carci Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Inclusion criteria: - Aged 18 years or older - Pathologically confirmed of advanced and/or metastatic stage IIIb/IV non-small cell carcinoma of lung - Activating EGFR mutation (exon 19 deletion, L858R, G719X, L861X) - Presence of EGFR activating mutation and absence of EGFR T790M in the tumour associated with the latest disease progression. --- L858R --- --- T790M ---

AZD9291 or CO-1686) Inclusion criteria: - Aged 18 years or older - Pathologically confirmed of advanced and/or metastatic stage IIIb/IV non-small cell carcinoma of lung - Activating EGFR mutation (exon 19 deletion, L858R, G719X, L861X) - Presence of EGFR activating mutation and absence of EGFR T790M in the tumour associated with the latest disease progression. --- L858R --- --- T790M ---

Primary Outcomes

Measure: Maximum tolerated dose (MTD) of BI 836845 in combination with afatinib - part A

Time: up to 12 months

Measure: Dose limiting toxicity (DLT) during the first treatment course - part A

Time: up to 28 days

Measure: Objective response (OR), defined as complete response (CR) or partial response (PR)

Time: up to 12 months

Secondary Outcomes

Measure: Disease control (DC), defined as complete response (CR), partial response (PR) or stable disease (SD)

Time: up to 12 months

Measure: Time to objective response, defined as the duration of time from the date of first treatment administration until objective response

Time: up to 12 months

Measure: Duration of objective response, defined as the duration of time from first objective response to the date of first objective tumour progression or death due to any cause

Time: up to 12 months

116 An Open-label Study of the Oral Administration of ASP8273 in Patients With Non-small Cell Lung Cancer Harboring Epidermal Growth Factor Receptor (EGFR) Mutations

Purpose of the study is to determine the following in patients with non-small cell lung cancer (NSCLC) harboring EGFR activating mutations. - the safety and tolerability of ASP8273. - the pharmacokinetics (PK) of ASP8273. - the antitumor activity of ASP8273.

NCT02192697
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: ASP8273
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- *Erlotinib, gefitinib, and EGFR-TKIs under clinical investigation (e.g., neratinib, afatinib, dacomitinib) - Expression of the EGFR-T790M mutation as confirmed by a tumor biopsy of the primary or metastatic lesions after confirmation of PD following previous treatment with EGFR-TKIs and before enrollment, or by a tumor tissue sample that had been collected and archived after confirmation of PD following previous treatment with EGFR-TKIs. --- T790M ---

- Previously received treatment with EGFR-TKIs (e.g., CO-1686, AZD9291) that can inhibit EGFR with the T790M mutation. --- T790M ---

Primary Outcomes

Description: A DLT is defined as any pre-determined toxicity that is related to study drug per the investigator and which occurs during Cycle 0 and Cycle 1 using the Japan Clinical Oncology Group (JCOG) Japanese translation of the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE ver 4.0 - JCOG)

Measure: Phase I: Safety and tolerability of ASP8273 as assessed by Dose Limiting Toxicities (DLTs)

Time: Up to Day 23

Description: The overall response rate, which is defined as the proportion of subjects whose best overall response is rated as complete response (CR) or partial response (PR) according to RECIST Version 1.1, will be calculated

Measure: Phase II: Overall response rate (CR+PR) at Week 24

Time: Week 24

Secondary Outcomes

Description: An AE is defined as any untoward medical occurrence in a subject administered a study drug or has undergone study procedures and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product

Measure: Phase I: Safety and tolerability of ASP8273 as assessed by adverse events (AEs)

Time: Up to 18 months

Description: Laboratory tests to be conducted are hematology, biochemistry, urinalysis, coagulation profile, lipid panel and lymphocyte subpopulation

Measure: Phase I: Safety and tolerability of ASP8273 as assessed by laboratory tests

Time: Up to 18 months

Description: Vital signs to be measured includes blood pressure, pulse rate and temperature

Measure: Phase I: Safety and tolerability of ASP8273 as assessed by vital signs

Time: Up to 18 months

Description: including the assessment of QT intervals

Measure: Phase I: Safety and tolerability of ASP8273 as assessed by 12-lead ECG

Time: Up to 18 months

Measure: Phase I: Plasma concentrations of unchanged ASP8273

Time: Up to Day 1 of Cycle 3

Measure: Phase I: Urine concentrations of unchanged ASP8273

Time: Up to Day 1 of Cycle 3

Description: The overall response rate is defined as the proportion of subjects whose best overall response is rated as complete response (CR) or partial response (PR) according to RECIST Version 1.1, will be calculated

Measure: Phase I: Overall response rate (CR+PR)

Time: Up to 18 months

Description: The disease control rate is defined as the proportion of subjects whose best overall response is rated as CR, PR, or stable disease (SD) according to RECIST Version 1.1, will be calculated.

Measure: Phase I: Disease control rate (CR+PR+SD)

Time: Up to 18 months

Measure: Phase II: Plasma concentrations of unchanged ASP8273

Time: Up to Day 1 of Cycle 3

Measure: Phase II: Urine concentrations of unchanged ASP8273

Time: Up to Day 1 of Cycle 3

Description: An AE is defined as any untoward medical occurrence in a subject administered a study drug or has undergone study procedures and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product

Measure: Phase II: Safety and tolerability of ASP8273 as assessed by adverse events (AEs)

Time: Up to 18 months

Description: Laboratory tests to be conducted are hematology, biochemistry, urinalysis, coagulation profile, lipid panel and lymphocyte subpopulation

Measure: Phase II: Safety and tolerability of ASP8273 as assessed by laboratory tests

Time: Up to 18 months

Description: Vital signs to be measured includes blood pressure, pulse rate and temperature

Measure: Phase II: Safety and tolerability of ASP8273 as assessed by vital signs

Time: Up to 18 months

Description: including the assessment of QT intervals

Measure: Phase II: Safety and tolerability of ASP8273 as assessed by 12-lead ECG

Time: Up to 18 months

Description: The disease control rate is defined as the proportion of subjects whose best overall response is rated as CR, PR, or stable disease (SD) according to RECIST Version 1.1, will be calculated.

Measure: Phase II: Disease control rate

Time: Up to 18 months

Measure: Phase II: Progression-free survival (PFS)

Time: Up to 18 months

Measure: Phase II: Overall survival (OS)

Time: Up to 18 months

Description: The overall response rate, which is defined as the proportion of subjects whose best overall response is rated as complete response (CR) or partial response (PR) according to RECIST Version 1.1, will be calculated

Measure: Phase II: Overall response rate (CR+PR)

Time: Up to 18 months

117 TIGER 1: A Randomized, Open-Label, Phase 2/3 Study of CO-1686 or Erlotinib as First-Line Treatment of Patients With EGFR-Mutant Advanced/Metastatic NSCLC

The purpose of this study is to compare the safety and anti-tumor effect of rociletinib with erlotinib in patients whose tumors have specific EGFR mutations and who have not previously received any treatment for advanced/metastatic EGFR mutated NSCLC. This study is a 'Randomized' Study. This means that upon entering the study, patients will be randomly assigned to be dosed with either rociletinib twice a day or erlotinib once a day. Patients will continue to take either rociletinib or erlotinib until it is no longer beneficial.

NCT02186301
Conditions
  1. Non-Small Cell Lung Cancer
Interventions
  1. Drug: Rociletinib Mono-Therapy
  2. Drug: Erlotinib Mono-Therapy
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

In the Phase 2 part only, patients initially randomized to erlotinib may be eligible to participate in an optional crossover phase to receive rociletinib if they demonstrate the T790M resistance mutation after radiographic progression on erlotinib treatment among other eligibility requirements. --- T790M ---

Primary Outcomes

Description: To compare the antitumor efficacy of oral single-agent rociletinib with that of erlotinib as measured by progression-free survival (PFS), when administered as a first-line targeted treatment to patients with EGFR-mutated, advanced NSCLC.Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.The appearance of one or more new lesions is also considered progression.

Measure: Progression Free Survival (PFS) According to RECIST Version 1.1 as Determined by Investigator Review (invPFS)

Time: Cycle 1 Day 1 to End of Treatment, up to approximately 35 months

Secondary Outcomes

Description: Proportion of patients with a best overall confirmed response of partial response (PR) or complete response (CR) recorded from the start of the treatment until disease progression or recurrence. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions, defined by and assessed as: Complete Response (CR), is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR),at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter. Overall Response (OR),is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment was dependent on the achievement of both measurement and confirmation criteria.

Measure: Confirmed Response Rate

Time: Cycle 1 Day 1 to End of Treatment, up to approximately 35 months.

Description: Duration of Response in Patients with Confirmed Response per Investigator

Measure: Duration of Response

Time: Cycle 1 Day 1 to End of Treatment, up to approximately 35 months

118 A Phase 1/2, Open-Label, Safety, Pharmacokinetic and Preliminary Efficacy Study of Oral Rociletinib in Patients With Previously Treated Mutant EGFR Non-Small Cell Lung Cancer (NSCLC)

Rociletinib is a novel, potent, small molecule irreversible tyrosine kinase inhibitor (TKI) that selectively targets mutant forms of the epidermal growth factor receptor (EGFR) while sparing wild-type (WT) EGFR. The purpose of the study is to evaluate the pharmacokinetic (PK) and safety profile of oral rociletinib; to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of oral rociletinib; to assess the safety and efficacy of rociletinib in previously treated NSCLC patients known to have the T790M EGFR mutation.

NCT01526928
Conditions
  1. Locally Advanced or Metastatic Non Small Cell Lung Cancer
Interventions
  1. Drug: Rociletinib
  2. Drug: Rociletinib
  3. Drug: Rociletinib
  4. Drug: Rociletinib
  5. Drug: Rociletinib
  6. Drug: Rociletinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

The purpose of the study is to evaluate the pharmacokinetic (PK) and safety profile of oral rociletinib; to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of oral rociletinib; to assess the safety and efficacy of rociletinib in previously treated NSCLC patients known to have the T790M EGFR mutation. --- T790M ---

Percentage of T790M Positive Patients With Confirmed Response Per Investigator. --- T790M ---

Percentage of patients with a T790M mutation (determined by central lab) with a best overall confirmed response of partial response (PR) or complete response (CR) recorded from the start of the treatment until disease progression or recurrence. --- T790M ---

Partial Response (PR),at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter.. Duration of Response (DOR) in T790M Positive Patients According to RECIST Version 1.1 as Determined by Investigator Assessment. --- T790M ---

Duration of Response in patients with a T790M mutation (determined by central lab) with confirmed response per investigator. --- T790M ---

Adequate hematological and biological function 7. Written consent on an IRB/IEC-approved Informed Consent Form (ICF) prior to any study-specific evaluation Phase 2 Cohorts must also meet the following inclusion criteria: - Disease progression confirmed by radiologic assessment while on treatment with EGFR- TKI Or - Disease progression confirmed by radiologic assessment while on treatment with the first single agent EGFR TKI and - Documented evidence of T790M mutation in EGFR following disease progression on the first single agent EGFR TKI. - Measureable disease according to RECIST Version 1.1 Exclusion Criteria - Any of the following criteria will exclude patients from study participation: 1. Documented evidence of an Exon 20 insertion activating mutation in the EGFR gene 2. Active second malignancy 3. Known pre-existing interstitial lung disease 4. Patients with Leptomeningeal carcinomatosis are excluded. --- T790M ---

Other CNS metastases are only permitted if treated, asymptomatic and stable (not requiring steroids for at least 4 weeks prior to start of study treatment). 5. Treatment with prohibited medications less than or equal to 14 days prior to treatment with rociletinib 6. Patients who are currently receiving treatment with any medications that have the potential to prolong the QT interval and the treatment cannot be either discontinued or switched to a different medication before starting rociletinib 7. Prior treatment with rociletinib or other drugs that target T790M positive mutant EGFR with sparing of wild type EGFR 8. Certain cardiac abnormalities or history 9. Non-study related surgical procedures less than or equal to 7 days prior to administration of rociletinib 10. --- T790M ---

However, patients on TKIs eventually progress, and in approximately 50% of cases, progression is due to development of an additional mutation called T790M. --- T790M ---

Nonclinical data demonstrate that rociletinib inhibits T790M. --- T790M ---

It is anticipated that rociletinib may promote cell death in tumor cells with the T790M mutation, thus providing possible therapeutic benefit in patients who have developed T790M-mediated resistance to first generation TKIs. --- T790M ---

It is anticipated that rociletinib may promote cell death in tumor cells with the T790M mutation, thus providing possible therapeutic benefit in patients who have developed T790M-mediated resistance to first generation TKIs. --- T790M --- --- T790M ---

This study will include 2 parts: Phase 1: Dose-escalation Period with 21-day cycles; optional Treatment Extension Period starting on Day 22 Phase 2: Evaluation of activity and safety in patients with the T790M EGFR mutation who have: Cohort A - Progressed on EGFR directed therapy (irrespective of the number and order of previous lines of NSCLC therapy) or Cohort B - Progression on the first single agent EGFR directed therapy received and also had no more than one previous line of chemotherapy or Cohort C - Patients with discordance between local (T790M positive) and central (T790M negative) T790M results, or had no central test result due to inadequacy of the tissue specimen and known to be T790M positive by local test --- T790M ---

This study will include 2 parts: Phase 1: Dose-escalation Period with 21-day cycles; optional Treatment Extension Period starting on Day 22 Phase 2: Evaluation of activity and safety in patients with the T790M EGFR mutation who have: Cohort A - Progressed on EGFR directed therapy (irrespective of the number and order of previous lines of NSCLC therapy) or Cohort B - Progression on the first single agent EGFR directed therapy received and also had no more than one previous line of chemotherapy or Cohort C - Patients with discordance between local (T790M positive) and central (T790M negative) T790M results, or had no central test result due to inadequacy of the tissue specimen and known to be T790M positive by local test --- T790M --- --- T790M ---

This study will include 2 parts: Phase 1: Dose-escalation Period with 21-day cycles; optional Treatment Extension Period starting on Day 22 Phase 2: Evaluation of activity and safety in patients with the T790M EGFR mutation who have: Cohort A - Progressed on EGFR directed therapy (irrespective of the number and order of previous lines of NSCLC therapy) or Cohort B - Progression on the first single agent EGFR directed therapy received and also had no more than one previous line of chemotherapy or Cohort C - Patients with discordance between local (T790M positive) and central (T790M negative) T790M results, or had no central test result due to inadequacy of the tissue specimen and known to be T790M positive by local test --- T790M --- --- T790M --- --- T790M ---

This study will include 2 parts: Phase 1: Dose-escalation Period with 21-day cycles; optional Treatment Extension Period starting on Day 22 Phase 2: Evaluation of activity and safety in patients with the T790M EGFR mutation who have: Cohort A - Progressed on EGFR directed therapy (irrespective of the number and order of previous lines of NSCLC therapy) or Cohort B - Progression on the first single agent EGFR directed therapy received and also had no more than one previous line of chemotherapy or Cohort C - Patients with discordance between local (T790M positive) and central (T790M negative) T790M results, or had no central test result due to inadequacy of the tissue specimen and known to be T790M positive by local test --- T790M --- --- T790M --- --- T790M --- --- T790M ---

This study will include 2 parts: Phase 1: Dose-escalation Period with 21-day cycles; optional Treatment Extension Period starting on Day 22 Phase 2: Evaluation of activity and safety in patients with the T790M EGFR mutation who have: Cohort A - Progressed on EGFR directed therapy (irrespective of the number and order of previous lines of NSCLC therapy) or Cohort B - Progression on the first single agent EGFR directed therapy received and also had no more than one previous line of chemotherapy or Cohort C - Patients with discordance between local (T790M positive) and central (T790M negative) T790M results, or had no central test result due to inadequacy of the tissue specimen and known to be T790M positive by local test --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M ---

Primary Outcomes

Description: Percentage of patients with a T790M mutation (determined by central lab) with a best overall confirmed response of partial response (PR) or complete response (CR) recorded from the start of the treatment until disease progression or recurrence. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions, defined by and assessed as: Complete Response (CR), is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR),at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter.

Measure: Percentage of T790M Positive Patients With Confirmed Response Per Investigator

Time: Cycle 1 Day 1 to End of Treatment, up to approximately 42 months

Description: Duration of Response in patients with a T790M mutation (determined by central lab) with confirmed response per investigator. The DOR for complete response (CR) and partial response (PR) was measured from the date that any of these best responses is first recorded until the first date that progressive disease (PD) is objectively documented. For patients who continue treatment post-progression, the first date of progression was used for the analysis.

Measure: Duration of Response (DOR) in T790M Positive Patients According to RECIST Version 1.1 as Determined by Investigator Assessment

Time: Cycle 1 Day 1 to End of Treatment, up to approximately 36 months

Description: The number of Phase 1 patients who experienced dose limiting toxicities after one cycle (21 days) of study drug.

Measure: Dose Limiting Toxicity (DLT) Incidence

Time: Cycle 1 Day 1 to Cycle 1 Day 21

Secondary Outcomes

Description: Overall survival was calculated as 1+ the number of days from the first dose of study drug to death due to any cause. Patients without a documented date of death were censored on the date the patient was last known to be alive.

Measure: Overall Survival (OS) Determined by Investigator Assessment

Time: Cycle 1 Day 1 to date of death, assessed up to 42 months

Description: Progression-free survival was calculated as the number of days from the date of the first dose of study drug to the date of disease progression or death due to any cause + 1. Patients without a documented event of disease progression were censored on the date of their last adequate tumor assessment (i.e., radiologic assessment) or date of first dose of study drug if no tumor assessments have been performed. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression.

Measure: Progression Free Survival (PFS) According to RECIST Version 1.1 as Determined by Investigator Review (invPFS)

Time: Cycle 1 Day 1 to End of Treatment, up to approximately 42 months

Description: Cmax = maximum concentration following administration of rociletinib

Measure: PK Profile of Rociletinib - Cmax

Time: Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days

Description: Tmax = time to maximum concentration following administration of rociletinib

Measure: PK Profile of Rociletinib - Tmax

Time: Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days

Description: AUC 0-24 = area under the curve from 0 to 24 hours

Measure: PK Profile of Rociletinib - AUC 0-24

Time: Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days

Description: T 1/2 = elimination half-life following administration of rociletinib

Measure: PK Profile of Rociletinib - T 1/2

Time: Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days

Description: Cmax = maximum concentration following administration of rociletinib. The effect of food on rociletinib PK parameters was assessed over a 24-hour period in blood samples from a subset of 3 patients. These patients were given a single dose of rociletinib 150mg FB 1 week prior (Day -7) to the start of continuous daily dosing after fasting. On Day 1 of Cycle 1, patients consumed a high-fat, high-calorie breakfast at the study site prior to receiving rociletinib. On each day, patients underwent blood sampling for PK at the specified time points.

Measure: Food Effect on PK of Rociletinib - Cmax

Time: Day -7 prior to Cycle 1 Day 1, or approximately 7 days

Description: Tmax = time to maximum concentration following administration of rociletinib. The effect of food on rociletinib PK parameters was assessed over a 24-hour period in blood samples from a subset of 3 patients. These patients were given a single dose of rociletinib 150mg FB 1 week prior (Day -7) to the start of continuous daily dosing after fasting. On Day 1 of Cycle 1, patients consumed a high-fat, high-calorie breakfast at the study site prior to receiving rociletinib. On each day, patients underwent blood sampling for PK at the specified time points.

Measure: Food Effect on PK of Rociletinib - Tmax

Time: Day -7 prior to Cycle 1 Day 1, or approximately 7 days

Description: AUC 0-24 = area under the curve from 0 to 24 hours. The effect of food on rociletinib PK parameters was assessed over a 24-hour period in blood samples from a subset of 3 patients. These patients were given a single dose of rociletinib 150mg FB 1 week prior (Day -7) to the start of continuous daily dosing after fasting. On Day 1 of Cycle 1, patients consumed a high-fat, high-calorie breakfast at the study site prior to receiving rociletinib. On each day, patients underwent blood sampling for PK at the specified time points.

Measure: Food Effect on PK of Rociletinib - AUC 0-24

Time: Day -7 prior to Cycle 1 Day 1, or approximately 7 days

Description: C24 = rociletinib plasma concentration at 24 hours post the morning dose. The effect of food on rociletinib PK parameters was assessed over a 24-hour period in blood samples from a subset of 3 patients. These patients were given a single dose of rociletinib 150mg FB 1 week prior (Day -7) to the start of continuous daily dosing after fasting. On Day 1 of Cycle 1, patients consumed a high-fat, high-calorie breakfast at the study site prior to receiving rociletinib. On each day, patients underwent blood sampling for PK at the specified time points.

Measure: Food Effect on PK of Rociletinib - C24

Time: Day -7 prior to Cycle 1 Day 1, or approximately 7 days

Description: T 1/2 = elimination half-life following administration of rociletinib. The effect of food on rociletinib PK parameters was assessed over a 24-hour period in blood samples from a subset of 3 patients. These patients were given a single dose of rociletinib 150mg FB 1 week prior (Day -7) to the start of continuous daily dosing after fasting. On Day 1 of Cycle 1, patients consumed a high-fat, high-calorie breakfast at the study site prior to receiving rociletinib. On each day, patients underwent blood sampling for PK at the specified time points.

Measure: Food Effect on PK of Rociletinib - T 1/2

Time: Day -7 prior to Cycle 1 Day 1, or approximately 7 days

Description: Frequency of QT interval prolongation by daily dose (corrected using Fridericia's method, QTcF). To evaluate the effects of rociletinib on the QT (interval from Q wave to T wave)/QTc (interval corrected for heart rate) interval, all patients underwent serial ECG monitoring at Baseline, on Cycle 1 Day 1, Cycle 1 Day 15, on Day 1 of all subsequent cycles, at the EOT Visit, and as clinically indicated. Worst post-baseline QTcF value was used to categorize each patient.

Measure: QTcF Values Post Baseline by Daily Dose

Time: Screening to End of Treatment, up to approximately 42 months

Description: QTcF value change from baseline by daily dose (corrected using Fridericia's method, QTcF). To evaluate the effects of rociletinib on the QT (interval from Q wave to T wave)/QTc (interval corrected for heart rate) interval, all patients underwent serial ECG monitoring at Baseline, on Cycle 1 Day 1, Cycle 1 Day 15, on Day 1 of all subsequent cycles, at the EOT Visit, and as clinically indicated. Worst post-baseline QTcF value was used to categorize each patient.

Measure: QTcF Value Change From Baseline

Time: Screening to End of Treatment, up to approximately 42 months

Description: Objective response rate (ORR), duration of response (DOR) and progression-free survival (PFS) per RECIST Version 1.1 as determined by independent radiology review (IRR)

Measure: Objective Response Rate (ORR), Duration of Response (DOR) and Progression-Free Survival (PFS) Per RECIST Version 1.1 as Determined by IRR

Time: Cycle 1 Day 1 to End of Treatment / End of Follow-up

119 Phase 2 Open Label Trial Of Oral Intermittent Dacomitinib In Patients With Advanced Nsclc

This is a Phase 2 study of oral dacomitinib given every 12 hours over days 1-4 of each two-week cycle to patients with Non-small cell lung cancer. The study includes two groups of patients, those whose tumor has a documented T790M mutation, and those without this mutation. All patients will receive repeated cycles of dacomitinib until disease progression, occurrence of unacceptable toxicity, or other withdrawal criteria are met.

NCT01858389
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: Dacomitinib
  2. Drug: Dacomitinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

The study includes two groups of patients, those whose tumor has a documented T790M mutation, and those without this mutation. --- T790M ---

Best Overall Response (BOR) in Participants With T790M Mutation. --- T790M ---

BOR was analyzed only for participants with T790M mutation according to the primary study objective.. Objective Response Rate (ORR) in Participants With T790M Mutation. --- T790M ---

BOR was analyzed only for participants with T790M mutation according to the primary study objective.. Objective Response Rate (ORR) in Participants With T790M Mutation. --- T790M --- --- T790M ---

ORR was analyzed only for participants with T790M mutation according to the primary study objective.. Disease Control Rate (DCR) for Participants With T790M Mutation. --- T790M ---

ORR was analyzed only for participants with T790M mutation according to the primary study objective.. Disease Control Rate (DCR) for Participants With T790M Mutation. --- T790M --- --- T790M ---

DCR was analyzed only for participants with T790M mutation according to the study objective.. Duration of Response in Participants With T790M Mutation. --- T790M ---

DCR was analyzed only for participants with T790M mutation according to the study objective.. Duration of Response in Participants With T790M Mutation. --- T790M --- --- T790M ---

DR was only calculated and summarized for the subgroup of participants with an objective tumor response in the cohort of participants with T790M mutation.. Progression-free Survival. --- T790M ---

- Evidence of T790M mutation to enroll in Cohort A. - Evidence of measurable disease by radiographic technique. --- T790M ---

Exclusion Criteria: - Patients with T790M mutation who stopped any prior EGFR-directed therapy without evidence of disease progression. --- T790M ---

Primary Outcomes

Description: BOR was best response from start of treatment until disease progression, according to the RECIST,v1.1. CR=disappearance of all preexisting lesions except nodal disease, with all nodal lesions decreased to normal size (short axis <10 mm) and no appearance of new unequivocal malignant lesions. PR= ≥30% decrease from baseline of sum of diameters of all target lesions with no unequivocal progression of preexisting non-target lesions or appearance of new lesions. CR and PR were confirmed on a follow-up imaging assessment ≥4 weeks after the initial response documentation. Progression= ≥20% increase in the sum of diameters of target measurable lesions above the smallest sum observed, with a minimum absolute increase of 5 mm or unequivocal progression of pre-existing non-target lesions or appearance of any new unequivocal malignant lesions. Stable disease=not qualify for CR, PR or progression. BOR was analyzed only for participants with T790M mutation according to the primary study objective.

Measure: Best Overall Response (BOR) in Participants With T790M Mutation

Time: From baseline until disease progression, up to 61 weeks.

Description: ORR was calculated as the percentage of participants with a confirmed CR or PR relative to the total number of participants enrolled. Response Evaluation Criteria in Solid Tumors (RECIST), version (v) 1.1 were used to define CR and PR. CR=disappearance of all preexisting lesions except nodal disease, with all nodal lesions decreased to normal size (short axis <10 mm) and no appearance of new unequivocal malignant lesions. PR= ≥30% decrease from baseline of sum of diameters of all target lesions with no unequivocal progression of preexisting non-target lesions or appearance of new lesions. CR and PR were confirmed on a follow-up imaging assessment ≥4 weeks after the initial response documentation. ORR was analyzed only for participants with T790M mutation according to the primary study objective.

Measure: Objective Response Rate (ORR) in Participants With T790M Mutation

Time: From baseline to disease progression, up to 61 weeks.

Secondary Outcomes

Description: DCR was calculated as the percentage of participants with an objective response (CR or PR) or stable disease, based on the RECIST, v1.1, relative to the total number of participants enrolled in the cohort. If baseline tumor assessment was inadequate for a participant, and the participant could not be assessed for RECIST responses and had no objective status of stable disease documented at least 6 weeks after the start date and before the progression, the participant was only counted in the denominator. CR=disappearance of all preexisting lesions except nodal disease, with all nodal lesions decreased to normal size (short axis <10 mm) and no appearance of new unequivocal malignant lesions. PR= ≥30% decrease from baseline of sum of diameters of all target lesions with no unequivocal progression of preexisting non-target lesions or appearance of new lesions. DCR was analyzed only for participants with T790M mutation according to the study objective.

Measure: Disease Control Rate (DCR) for Participants With T790M Mutation

Time: From baseline to baseline to disease progression, up to 61 weeks.

Description: Duration of response was defined as the time from first documentation of response (CR or PR, whichever occurred first) to the date of disease progression or to death due to any cause, whichever occurred first. CR and PR were defined using RECIST, v1.1. CR=disappearance of all preexisting lesions except nodal disease, with all nodal lesions decreased to normal size (short axis <10 mm) and no appearance of new unequivocal malignant lesions. PR= ≥30% decrease from baseline of sum of diameters of all target lesions with no unequivocal progression of preexisting non-target lesions or appearance of new lesions. CR and PR were confirmed on a follow-up imaging assessment ≥4 weeks after the initial response documentation. DR was only calculated and summarized for the subgroup of participants with an objective tumor response in the cohort of participants with T790M mutation.

Measure: Duration of Response in Participants With T790M Mutation

Time: From baseline to date of disease progression or death, up to 61 weeks.

Description: Progression-free survival was defined as the time from the date of first dosing of dacomitinib to the date of disease progression by RECIST v1.1, per the investigators' assessment, or death due to any cause, whichever occurred first. Objective progression= ≥20% increase in the sum of diameters of target measurable lesions above the smallest sum observed, with a minimum absolute increase of 5 mm or unequivocal progression of pre-existing non-target lesions or appearance of any new unequivocal malignant lesions.

Measure: Progression-free Survival

Time: From baseline to disease progression or death, up to 61 weeks.

Description: Progression-free survival at 4 months was defined as the percentage of participants who were alive without disease progression at 4 months relative to all participants enrolled. Disease progression was defined by RECIST v1.1. Objective progression= ≥20% increase in the sum of diameters of target measurable lesions above the smallest sum observed, with a minimum absolute increase of 5 mm or unequivocal progression of pre-existing non-target lesions or appearance of any new unequivocal malignant lesions.

Measure: Progression-free Survival at 4 Months

Time: Month 4

Description: Cmax was observed directly from data. Whole blood for pharmacokinetic analysis was collected immediately after completion of electrocardiograms, blood pressure, and pulse rate.

Measure: Maximum Plasma Concentration (Cmax) for Dacomitinib and PF-05199265

Time: Pre-dose (hour 0), 2, 4, 6, 8, and 10 hours post-dose on Day 4, Cycle 0.

Description: Tmax was observed directly from data as time of first occurrence. Whole blood for pharmacokinetic analysis was collected immediately after completion of electrocardiograms, blood pressure, and pulse rate.

Measure: Time to Maximum Plasma Concentration (Tmax) for Dacomitinib and PF-05199265

Time: Pre-dose (hour 0), 2, 4, 6, 8, and 10 hours post-dose on Day 4, Cycle 0.

Description: ECGs recorded on Day 1 of Cycle 0 were used as baseline. For the ECGs assessments, the following directions were followed by the ECG central laboratory: Blinding of ECG readers to treatment, time, and day identifiers. Review of ECGs from a particular participant was performed by a single reader. Prespecification of the lead for internal measurements. Baseline and on-treatment ECG assessments were based on the same lead.

Measure: Changes From Time-matched Baseline in Adjusted Fridericia Corrected QT Interval (QTcF) on Echocardiogram (ECG)

Time: From Baseline to Cycle 0, Day 4

120 A Phase I/Ib Study of APX005M in Combination With Nivolumab and Cabiralizumab in Patients With Advanced Melanoma, Non-small Cell Lung Cancer or Renal Cell Carcinoma Whose Disease Has Progressed on Anti-PD- 1/PD-L1 Therapy

This trial is a phase 1/1b study to evaluate the safety, efficacy, and tolerability of APX005M in combination with nivolumab and cabiralizumab. The phase 1 dose escalation portion of the study will enroll patients with advanced solid tumors melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC) in 6 cohorts to determine the recommended phase II dose (RP2D) of APX005M. The phase 1b dose expansion portion will study the triple drug combination separately in the three disease cohorts: melanoma, NSCLC, and RCC.

NCT03502330
Conditions
  1. Advanced Melanoma
  2. Non-small Cell Lung Cancer
  3. Renal Cell Carcinoma
Interventions
  1. Drug: APX005M
  2. Drug: Cabiralizumab
  3. Drug: Nivolumab
MeSH:Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung Melanoma Carcinoma, Renal Carcinoma, Renal Cell
HPO:Carcinoma Clear cell renal cell carcinoma Cutaneous melanoma Melanoma Neoplasm of the lung Non-small cell lung carcinoma Papillary renal cell carcinoma Renal cell carcinoma

Patients with TKI-treated EGFR mutant NSCLC harboring the secondary EGFR T790M tumor must have received prior osimertinib. --- T790M ---

Primary Outcomes

Description: AEs and SAEs will be examined with (National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v 4.03

Measure: Safety and Tolerability measured by assessing serious adverse events (SAEs)and adverse events (AEs)

Time: From study enrollment up to 12 months.

Description: This 5-point scale ranges from full functioning (1) to dead (5)

Measure: Safety and Tolerability measured by Eastern Cooperative Oncology Group(ECOG) performance status

Time: From study enrollment up to 12 months.

Secondary Outcomes

Description: ORR will be determined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria v. 1.1.

Measure: Efficacy measured by objective response rate (ORR)

Time: Six months.

Other Outcomes

Description: This outcome will be assessed by blood collection.

Measure: Pharmacokinetics (PK) of APX005M assessed by area under the curve (AUC).

Time: 12 weeks

Description: This outcome will be assessed by blood collection.

Measure: Pharmacokinetics (PK) of APX005M assessed by minimum blood plasma concentration (Cmin).

Time: 12 weeks

Description: This outcome will be assessed by blood collection.

Measure: Pharmacokinetics (PK) of APX005M assessed by clearance (CL).

Time: 12 weeks

Description: This outcome will be assessed by blood collection.

Measure: Pharmacokinetics (PK) of APX005M assessed by volume of distribution (Vss)

Time: 12 weeks

Description: This outcome will be assessed by blood collection.

Measure: Pharmacokinetics (PK) of APX005M assessed by peak plasma concentration (Cmax).

Time: 12 weeks

Description: This outcome will be assessed with tissue biopsies.

Measure: Tissue-based pharmacodynamics (PD) of APX005M, in combination with nivolumab and cabiralizumab assessed by CD8+ T cells .

Time: Change from baseline to 8 weeks.

Description: This outcome will be assessed with tissue biopsies.

Measure: Tissue-based pharmacodynamics (PD) of APX005M, in combination with nivolumab and cabiralizumab assessed by CD163+ macrophages .

Time: Change from baseline to 8 weeks.

Description: This outcome will be assessed via blood collection.

Measure: Blood-based pharmacodynamics (PD) of APX005M, in combination with nivolumab and cabiralizumab assessed by circulating CD163+ macrophages .

Time: Change from baseline to 8 weeks.

Description: This outcome will be assessed via blood collection.

Measure: Blood-based pharmacodynamics (PD) of APX005M, in combination with nivolumab and cabiralizumab assessed by circulating CD8+ T cells.

Time: Change from baseline to 8 weeks.

Description: This outcome will be assessed via blood collection.

Measure: Cytokine-based pharmacodynamic (PD) biomarkers of APX005M, in combination with nivolumab and cabiralizumab assessed by CD40L levels.

Time: Change from baseline to 8 weeks.

Description: This outcome will be assessed via blood collection.

Measure: Cytokine-based pharmacodynamic (PD) biomarkers of APX005M, in combination with nivolumab and cabiralizumab assessed by IL-10 levels.

Time: Change from baseline to 8 weeks.

Description: This outcome will be assessed via blood collection.

Measure: Cytokine-based pharmacodynamic (PD) biomarkers of APX005M, in combination with nivolumab and cabiralizumab assessed by interferon-gamma levels .

Time: Change from baseline to 8 weeks.

Description: PFS will be determined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria v. 1.1.

Measure: Efficacy measured by progression-free survival (PFS)

Time: From study enrollment up to 6 years.

Description: OS will be ascertained by review of the National Death Index, medical records and follow-up phone calls.

Measure: Efficacy measured by overall survival (OS)

Time: From study enrollment up to 6 years.

121 A Phase I/II Study to Assess the Safety,Tolerability, Pharmacokinetics and Anti-tumour Activity of ASK120067 in Patients With Locally Advanced or Metastatic T790M Mutation-positive Non-Small Cell Lung Cancer Who Have Progressed Following Prior Therapy With an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Agent

ASK120067 Tablets is a Epidermal Growth Factor Receptor (EGFR) mutation selective Tyrosine Kinase Inhibitor which can efficient suppress the EGFR T790M drug-resistant mutation tumor cell in Xenograft mouse model. This study aims at local advanced or metastatic non-small cell lung cancer patients with T790M drug-resistant mutation.

NCT03502850
Conditions
  1. Locally Advanced or Metastatic NSCLC
Interventions
  1. Drug: ASK120067
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

A Phase I/II Study to Assess the Safety,Tolerability, Pharmacokinetics and Anti-tumour Activity of ASK120067 in Patients With Locally Advanced or Metastatic T790M Mutation-positive Non-Small Cell Lung Cancer Who Have Progressed Following Prior Therapy With an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Agent. --- T790M ---

Safety, Tolerability, Pharmacokinetics and Anti-tumour Activity of ASK120067 in Locally Advanced and Metastatic Non Small Cell Lung Cancer ASK120067 Tablets is a Epidermal Growth Factor Receptor (EGFR) mutation selective Tyrosine Kinase Inhibitor which can efficient suppress the EGFR T790M drug-resistant mutation tumor cell in Xenograft mouse model. --- T790M ---

This study aims at local advanced or metastatic non-small cell lung cancer patients with T790M drug-resistant mutation. --- T790M ---

Primary Outcomes

Description: Evaluation of objective response rate assessed by RECIST 1.1

Measure: Objective response rate

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression,date of death or withdrawal from study,whichever came first, assessed up to approximately 2 years.

Secondary Outcomes

Description: Assessed by number and severity of adverse events as recorded on the case report form, vital signs, laboratory variables, physical examination, electrocardiogram, ophthalmic examinations and NCI CTCAE v4.03

Measure: Incidence and Severity of Treatment-Emergent Adverse Events

Time: Adverse events will be collected from baseline until 28 days after the last dose

Description: Progression of tumor was assessed by RECIST 1.1 thereby to evaluate progression free survival

Measure: Progression free survival

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression,date of death or withdrawal from study,whichever came first, assessed up to approximately 2 years.

Description: Duration of response assessed by RECIST 1.1

Measure: Duration of response

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression,date of death or withdrawal from study,whichever came first, assessed up to approximately 2 years.

Description: Evaluation of Disease control rate assessed by RECIST 1.1

Measure: Disease control rate

Time: CT or MRI at screening and every 2 Cycles (from first dose of multiple dosing) until disease progression,date of death or withdrawal from study,whichever came first, assessed up to approximately 2 years.

Description: defined as the time from date of first dose until date of death due to any cause

Measure: Overall survival

Time: Time from treatment start to the time of death due to any cause or withdrawal from study,whichever came first, assessed up to approximately 2 years.

Description: Collect plasma concentrations of ASK120067 and 1 metabolites following single dose at designated time points of Day 1 to figure out Cmax

Measure: Maximum Plasma Concentration [Cmax] of single dose ASK120067

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose)

Description: Collect plasma concentrations of ASK120067 and 1 metabolite following single dose at designated time points of Day 1 to figure out tmax

Measure: Peak Plasma Time [tmax] of single dose ASK120067

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose)

Description: Collect plasma concentrations of ASK120067 and 1 metabolite following single dose at designated time points of Day1 to figure out AUC

Measure: Area under the plasma concentration versus time curve (AUC) of single dose ASK120067

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose)

Description: Collect plasma concentrations of ASK120067 and 1 metabolite following single dose at designated time points of Day 1 to figure out terminal rate constant

Measure: Terminal rate constant of single dose single dose ASK120067

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose)

Description: Collect plasma concentrations of ASK120067 and 1 metabolite following single dose at designated time points of Day 1 to figure out clearance

Measure: Clearance of single dose ASK120067

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose)

Description: Collect plasma concentrations of ASK120067 and 1 metabolite following single dose at designated time points of Day 1 to figure out half life

Measure: Half life of single dose ASK120067

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose)

Description: Collect plasma concentrations of f ASK120067 and 1 metabolite following single dose at designated time points of Day 1 to figure out volume of distribution

Measure: Volume of distribution of single dose ASK120067

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose)

Description: Collect plasma concentrations of ASK120067 and 1 metabolite following single dose at designated time points of Day 1 to figure out mean resistance time

Measure: Mean resistance time of single dose ASK120067

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1, (pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24, 48, 72 ,96,144 hours post dose)

Description: Cmax of ASK120067 and 1 metabolite at steady state following multiple doses

Measure: Steady state Cmax of multiple doses ASK120067

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 8, 10,12,15,18,22. Cycle 1 D28- pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24 hours post dose)

Description: Tmax of ASK120067 and 1 metabolite at steady state following multiple doses

Measure: Steady state tmax of multiple doses ASK120067

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 8, 10,12,15,18,22. Cycle 1 D28- pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24 hours post dose)

Description: Cmin of ASK120067 and 1 metabolite at steady state following multiple doses

Measure: Steady state Cmin (Minimum Plasma Concentration) of multiple doses ASK120067

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day8, 10,12,15,18,22. Cycle 1 D28- pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24 hours post dose)

Description: AUC of ASK120067 and 1 metabolite at steady state following multiple doses

Measure: Steady state AUC of multiple doses ASK120067

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 8, 10,12,15,18,22. Cycle 1 D28- pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24 hours post dose)

Description: Clearance of ASK120067 and 1 metabolite at steady state following multiple doses

Measure: Steady state clearance of multiple doses ASK120067

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 8, 10,12,15,18,22. Cycle 1 D28- pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24 hours post dose)

Description: Accumulation ratio of ASK120067 and 1 metabolite following multiple doses

Measure: Accumulation ratio of multiple doses ASK120067

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 8, 10,12,15,18,22. Cycle 1 D28- pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24 hours post dose)

Description: Time dependency of ASK120067 and 1 metabolite following multiple doses

Measure: Time dependency of multiple doses ASK120067

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 8, 10,12,15,18,22. Cycle 1 D28- pre-dose, 1, 2, 3, 4, 5,6, 8, 10, 24 hours post dose)

122 A Phase 1/2 Open Label, Multicenter Study to Assess the Safety, Tolerability, Pharmacokinetics, and Anti-tumor Activity of ZN-e4 (KP-673) in Patients With Advanced Non-Small Cell Lung Cancer With Activating Epidermal Growth Factor Receptor (EGFR) Mutations

This is a Phase 1/2, open-label, multicenter, sequential dose-escalation study to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of ZN-e4 administered orally in subjects with advanced non-small cell lung cancer (NSCLC) with activating EGFR mutations who have progressed while on treatment with an EGFR tyrosine kinase inhibitor (TKI) agent (other lines of treatment are allowed, except for other epidermal growth factor receptor inhibitors [EGFRis]) for Phase 1; and for Phase 2, subjects who have T790M+ and are osimertinib naïve (Cohort 1), and also those who have not been treated with an EGFR Inhibitor (EGFRi) (Cohort2).

NCT03446417
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Drug: ZN-e4
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- Measurable disease meeting the criteria specified by RECIST v1.1 - Phase 2, Cohort 1 only: Subjects must have confirmation of tumor T790M mutation status (confirmed positive) and are osimertinib naïve - Phase 2, Cohort 2 only: EGFR aberrations that are amenable to EGFRi therapy, including but not limited to: G719X, exon 19 deletion, exon 21 L858R, and L861Q, and be EGFRi naïve EXCLUSION CRITERIA - Subjects who have received only neoadjuvant or adjuvant therapy for NSCLC. --- T790M ---

Primary Outcomes

Measure: Observed dose limiting toxicities

Time: 1 Cycle (21 days)

Secondary Outcomes

Measure: Safety and tolerability as measured by incidence of treatment emergent adverse events

Time: Through study completion, approximately 2 years

123 Trastuzumab-emtansine and Osimertinib Combination Treatment to Target HER2 Bypass Track Resistance in EGFR Mutation Positive NSCLC

This is a single arm open-label multi-center phase II study, investigating disease control rate after 3 months of treatment with trastuzumab-emtansine/osimertinib combination therapy in patients with advanced EGFR mutation positive non-small cell lung cancer (NSCLC) with HER2 bypass track resistance.

NCT03784599
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Drug: Trastuzumab emtansine
  2. Drug: Osimertinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

3. A rebiopsy after having acquired resistance to a first, second or third generation TKI-treatment must have been performed and be: 1. Negative for T790M in case of treatment with a first or second generation EGFR TKI. --- T790M ---

After progression on a third generation EGFR TKI patients may either be positive or negative for T790M. --- T790M ---

Primary Outcomes

Description: Safety as indicated by intensity and incidence of adverse events, graded according to NCI CTCAE Version 4.03

Measure: Safety (intensity and incidence of adverse events)

Time: Up to 30 days after last study drug intake

Description: Complete response and partial response after 3 months of treatment

Measure: Objective response rate according to RECIST v1.1 after 3 months of treatment

Time: From date of registration until 3 months.

Secondary Outcomes

Description: PFS, defined as the time from first administration of the study drug combination to disease progression by RECIST v1.1. or lost to follow up or death, whichever comes first

Measure: Progression-free survival

Time: From date of registration until the date of first documented progression up to 100 months

Description: DCR, defined as the percentage of patients with stable disease (SD), partial response (PR) or complete response (CR)

Measure: Disease control rate, after 3 months of treatment

Time: From date of registration until 3 months.

Description: OS, defined as the time from first administration of the study drug combination to lost to follow up or death, whichever comes first

Measure: Overall survival

Time: From date of registration until the date of death from any cause, assessed up to 100 months.

Other Outcomes

Description: cfDNA samples will be collected to assess predictors of response and resistance

Measure: Genetic profiling to assess predictors of response and resistance - circulating free (cf)DNA

Time: At baseline, every 6 weeks and at treatment discontinuation (expected 6 months after start)

124 ALCMI-012 A Prospective Biospecimen Collection Study From Patients With EGFR Mutant Tumors

A biospecimen collection study from individuals with EGFR mutant cancers resistant to EGFR TKIs or those harboring an Exon 20 insertion mutation.

NCT03872440
Conditions
  1. Non Small Cell Lung Cancer
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

1. EGFR T790M patients who have progressed on osimertinib or other third generation (mutant selective) EGFR TKI therapy or 2. Patients must have an EGFR exon 19 deletion or L858R and progressed on first line osimertinib or 3. Patients with an exon EGFR or HER2 20 insertion mutation. --- T790M ---

Osimertinib is an EGFR inhibitor approved for patients newly diagnosed with EGFR exon 19 or L858R mutations and for patients who have been treated with a prior EGFR inhibitor but have developed EGFR T790M as a resistance mechanism. --- L858R --- --- T790M ---

Primary Outcomes

Description: Successful generation of at least fifty (50) PDX models with full characterization including whole exome sequencing (WES) and RNA sequencing. These PDX models will be used to inform the study of EGFR-driven cancers at large.

Measure: The primary objective is to develop a unique cohort of PDX models from EGFR mutant cancers as a resource to the research community.

Time: 48 months

125 Open Label, Multicenter, Real World Treatment Study of Single Agent Tagrisso; KOREA PLUS Study (Korea Osimertinib Real World Evidence Study to Assess Safety and Efficacy - PLUS).

This is a local, prospective, non-interventional, regulatory postmarketing surveillance study. The objectives of this study are to assess the safety and efficacy of single agent Tagrisso (Osimertinib, hereinafter "the study drug") in a real world setting according to the approved label in Korea

NCT03918304
Conditions
  1. Carcinoma, Non-Small-Cell Lung
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- Inclusion Criteria: 1. Eligible for, or on active study drug treatment according to the approved label; The first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumours have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations, Treatment of patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy 2. Provision of signed and dated written informed consent by the patient or legally acceptable representative - Exclusion Criteria: 1. History of hypersensitivity to the active substance or to any of the excipients of this drug 2. Pregnancy and/or breast feeding 3. Current participation in any interventional trial - Inclusion Criteria: 1. Eligible for, or on active study drug treatment according to the approved label; The first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumours have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations, Treatment of patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy 2. Provision of signed and dated written informed consent by the patient or legally acceptable representative - Exclusion Criteria: 1. History of hypersensitivity to the active substance or to any of the excipients of this drug 2. Pregnancy and/or breast feeding 3. Current participation in any interventional trial Carcinoma, Non-Small-Cell Lung Carcinoma, Non-Small-Cell Lung - Primary objective: To assess safety of the study drug for EGFR-tyrosine kinase inhibitor (TKI) naïve patients with locally advanced or metastatic, EGFR exon 19 deletions or exon 21 (L858R) substitution mutation-positive NSCLC, patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy in Korea - Secondary objective: To assess efficacy of the study drug for EGFR-tyrosine kinase inhibitor (TKI) naïve patients with locally advanced or metastatic, EGFR exon 19 deletions or exon 21 (L858R) substitution mutation-positive NSCLC, patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy in Korea --- L858R --- --- T790M ---

- Inclusion Criteria: 1. Eligible for, or on active study drug treatment according to the approved label; The first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumours have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations, Treatment of patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy 2. Provision of signed and dated written informed consent by the patient or legally acceptable representative - Exclusion Criteria: 1. History of hypersensitivity to the active substance or to any of the excipients of this drug 2. Pregnancy and/or breast feeding 3. Current participation in any interventional trial - Inclusion Criteria: 1. Eligible for, or on active study drug treatment according to the approved label; The first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumours have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations, Treatment of patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy 2. Provision of signed and dated written informed consent by the patient or legally acceptable representative - Exclusion Criteria: 1. History of hypersensitivity to the active substance or to any of the excipients of this drug 2. Pregnancy and/or breast feeding 3. Current participation in any interventional trial Carcinoma, Non-Small-Cell Lung Carcinoma, Non-Small-Cell Lung - Primary objective: To assess safety of the study drug for EGFR-tyrosine kinase inhibitor (TKI) naïve patients with locally advanced or metastatic, EGFR exon 19 deletions or exon 21 (L858R) substitution mutation-positive NSCLC, patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy in Korea - Secondary objective: To assess efficacy of the study drug for EGFR-tyrosine kinase inhibitor (TKI) naïve patients with locally advanced or metastatic, EGFR exon 19 deletions or exon 21 (L858R) substitution mutation-positive NSCLC, patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy in Korea --- L858R --- --- T790M --- --- L858R --- --- T790M ---

- Inclusion Criteria: 1. Eligible for, or on active study drug treatment according to the approved label; The first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumours have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations, Treatment of patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy 2. Provision of signed and dated written informed consent by the patient or legally acceptable representative - Exclusion Criteria: 1. History of hypersensitivity to the active substance or to any of the excipients of this drug 2. Pregnancy and/or breast feeding 3. Current participation in any interventional trial - Inclusion Criteria: 1. Eligible for, or on active study drug treatment according to the approved label; The first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumours have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations, Treatment of patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy 2. Provision of signed and dated written informed consent by the patient or legally acceptable representative - Exclusion Criteria: 1. History of hypersensitivity to the active substance or to any of the excipients of this drug 2. Pregnancy and/or breast feeding 3. Current participation in any interventional trial Carcinoma, Non-Small-Cell Lung Carcinoma, Non-Small-Cell Lung - Primary objective: To assess safety of the study drug for EGFR-tyrosine kinase inhibitor (TKI) naïve patients with locally advanced or metastatic, EGFR exon 19 deletions or exon 21 (L858R) substitution mutation-positive NSCLC, patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy in Korea - Secondary objective: To assess efficacy of the study drug for EGFR-tyrosine kinase inhibitor (TKI) naïve patients with locally advanced or metastatic, EGFR exon 19 deletions or exon 21 (L858R) substitution mutation-positive NSCLC, patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy in Korea --- L858R --- --- T790M --- --- L858R --- --- T790M --- --- L858R --- --- T790M ---

- Inclusion Criteria: 1. Eligible for, or on active study drug treatment according to the approved label; The first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumours have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations, Treatment of patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy 2. Provision of signed and dated written informed consent by the patient or legally acceptable representative - Exclusion Criteria: 1. History of hypersensitivity to the active substance or to any of the excipients of this drug 2. Pregnancy and/or breast feeding 3. Current participation in any interventional trial - Inclusion Criteria: 1. Eligible for, or on active study drug treatment according to the approved label; The first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumours have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations, Treatment of patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy 2. Provision of signed and dated written informed consent by the patient or legally acceptable representative - Exclusion Criteria: 1. History of hypersensitivity to the active substance or to any of the excipients of this drug 2. Pregnancy and/or breast feeding 3. Current participation in any interventional trial Carcinoma, Non-Small-Cell Lung Carcinoma, Non-Small-Cell Lung - Primary objective: To assess safety of the study drug for EGFR-tyrosine kinase inhibitor (TKI) naïve patients with locally advanced or metastatic, EGFR exon 19 deletions or exon 21 (L858R) substitution mutation-positive NSCLC, patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy in Korea - Secondary objective: To assess efficacy of the study drug for EGFR-tyrosine kinase inhibitor (TKI) naïve patients with locally advanced or metastatic, EGFR exon 19 deletions or exon 21 (L858R) substitution mutation-positive NSCLC, patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who have been previously treated with EGFR TKI therapy in Korea --- L858R --- --- T790M --- --- L858R --- --- T790M --- --- L858R --- --- T790M --- --- L858R --- --- T790M ---

Primary Outcomes

Measure: Proportion (%) of patients with at least one event of adverse events (AEs), serious adverse events (SAEs) and AEs of special interest (AESI)

Time: for about 1 year since the first dose of the study drug

Measure: Severity of (S)AEs according to CTCAE

Time: for about 1 year since the first dose of the study drug

Secondary Outcomes

Measure: ORR (Objective response rate), if available

Time: for about 1 year since the first dose of the study drug

126 A Prospective, Multicenter, Phase-IV Clinical Trial to Assess Safety of Osimertinib in Indian Adult Patients With Metastatic Epidermal Growth Factor Receptor (EGFR) T790M Mutation-positive Non-small Cell Lung Cancer (NSCLC).

This is a prospective, single-arm, multicenter, phase-IV study investigating the safety of osimertinib in Indian adult patients.

NCT03853551
Conditions
  1. Non Small Cell Lung Cancer (NSCLC)
Interventions
  1. Drug: Osimertinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

A Prospective, Multicenter, Phase-IV Clinical Trial to Assess Safety of Osimertinib in Indian Adult Patients With Metastatic Epidermal Growth Factor Receptor (EGFR) T790M Mutation-positive Non-small Cell Lung Cancer (NSCLC).. Osimertinib Study in Indian Patients This is a prospective, single-arm, multicenter, phase-IV study investigating the safety of osimertinib in Indian adult patients. --- T790M ---

Inclusion Criteria: 1. Patient of either gender and ≥18 years of age 2. Patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by an appropriate test, who have progressed on or after EGFR TKI therapy by an independent clinical judgment of treating physician based on locally approved prescribing information 3. --- T790M ---

2. Pregnant and/or lactating women 3. Patients participating in any current or future interventional trial will not be enrolled in the current study Inclusion Criteria: 1. Patient of either gender and ≥18 years of age 2. Patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by an appropriate test, who have progressed on or after EGFR TKI therapy by an independent clinical judgment of treating physician based on locally approved prescribing information 3. --- T790M ---

2. Pregnant and/or lactating women 3. Patients participating in any current or future interventional trial will not be enrolled in the current study Non Small Cell Lung Cancer (NSCLC) Lung Neoplasms Carcinoma, Non-Small-Cell Lung This is a prospective, single-arm, multicenter, phase-IV trial investigating the safety of osimertinib in Indian adult patients with locally advanced or metastatic EGFR-T790M mutation-positive NSCLC. --- T790M ---

Patients with metastatic EGFR T790M mutation-positive NSCLC, who are eligible to osimertinib treatment as per locally approved prescribing information and ratified by an independent clinical judgment of treating physician will be evaluated for the inclusion into the current phase-IV study based on eligibility criteria. --- T790M ---

EGFR T790M positivity on plasma or tissue biopsy on PCR-based platform will be considered appropriate test. --- T790M ---

EGFR T790M must be performed after progressive disease on last line of therapy (on or after EGFR TKI therapy). --- T790M ---

Primary Outcomes

Description: Patient safety and adverse events will be assessed using the Common Terminology Criteria for Adverse Events (CTCAE)

Measure: To assess the safety of osimertinib

Time: 5 months

127 LUNGMAP: A Master Protocol To Evaluate Biomarker-Driven Therapies And Immunotherapies In Previously-Treated Non-Small Cell Lung Cancer (Lung-Map Screening Study)

This screening and multi-sub-study randomized phase II/III trial will establish a method for genomic screening of similar large cancer populations followed by assigning and accruing simultaneously to a multi-sub-study hybrid Master Protocol (Lung-MAP). The type of cancer trait (biomarker) will determine to which sub-study, within this protocol, a participant will be assigned to compare new targeted cancer therapy, designed to block the growth and spread of cancer, or combinations to standard of care therapy with the ultimate goal of being able to approve new targeted therapies in this setting. In addition, the protocol includes non-match sub-studies which will include all screened patients not eligible for any of the biomarker-driven sub-studies.

NCT03851445
Conditions
  1. Previously Treated Non-Small Cell Lung Cancer
Interventions
  1. Drug: Screening Platform
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Patients must agree to have any tissue that remains after testing retained for the use of sub-study Translational Medicine (TM) studies at the time of consent the patient is enrolled in. 5. Patients with known EGFR sensitizing mutations, EGFR T790M mutation, ALK gene fusion, ROS 1 gene rearrangement, or BRAF V600E mutation are not eligible unless they have progressed following all standard of care targeted therapy. --- T790M ---

Primary Outcomes

Description: The tissue submission will be measured by the proportion of patients who register to this screening study for whom a tissue sample is submitted.

Measure: Screening Success (Tissue Submission)

Time: Up to 3 years

Description: Adequate tissue will be measured by the proportion of patients who submitted a specimen for whom genomic results were successfully obtained, if multiple platforms are being used (e.g. both FMI and IHC), these rates will be summarized by the individual assays and combined. These rates are summarized for the entire screened population and by screening type (screened at progression versus pre-screened prior to progression). The rates are evaluated for both the initial submission success rates and the overall success rate accounting for new tissue submissions following an unsuccessful result.

Measure: Screening Success (Adequate Tissue)

Time: Up to 3 years

Description: Pre-screening-to-sub-study assignment will be measured among pre-screened patients and the proportion of patients assigned to a sub-study (which is triggered by the submission of the notice of progression form, see Section 14.0). Note: Patients screened at progression are notified of their sub-study assignment within 1 day of the biomarker results being reported to SWOG.

Measure: Screening Success (Prescreening-to-sub-study Assignment)

Time: Up to 3 years

Description: Screening success will be measured by the reasons for non-participation collection on the LungMAP Notice of Intention not to Register Form. The proportions of patients with this form submitted are summarized overall and by screening type. The reasons for submission are summarized overall and by screening type.

Measure: Screening Success (Notice of Intention Not to Register Submission)

Time: Up to 3 years

Description: Match to Biomarker-Driven Sub-Study will be measured by successful biomarker screening, the proportion assigned to a biomarker-driven substudy.

Measure: Screening Success (Match to Biomarker-Driven Sub-Study)

Time: Up to 3 years

Description: Assignment Success will be measured by the proportion of patients assigned to a sub-study who are registered to a sub-study, these rates are summarized overall and among biomarker-driven and non-match sub-study assignments, separately. In addition, these rates are summarized by screening type.

Measure: Screening Success (Assignment Success)

Time: Up to 3 years

128 A Phase I Trial of Atezolizumab and Varlilumab in Combination With Radiation in Patients With Metastatic Non-Small Cell Lung Cancer (NSCLC)

This phase I trial studies the side effects of atezolizumab, varlilumab, and radiation therapy in treating patients with non-small cell lung cancer that has spread to other places in the body (advanced) and cannot be removed by surgery (unresectable). Immunotherapy with monoclonal antibodies such as atezolizumab may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Immunotherapy with monoclonal antibodies such as varlilumab may induce changes in body?s immune system and may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving atezolizumab, varlilumab, and radiation therapy may increase the amount of time the disease is not active or does not spread to another part of the body.

NCT04081688
Conditions
  1. Refractory Lung Non-Small Cell Carcinoma
  2. Stage IV Lung Cancer AJCC v8
Interventions
  1. Drug: Atezolizumab 1200 MG in 20 ML Injection
  2. Radiation: Stereotactic Body Radiation Therapy
  3. Drug: Varlilumab 3 mg/kg
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Patients with a EGFR T790M resistant mutation must have failed a 3rd generation TKI such as osimertinib - Must not have received any prior therapy with immune regulatory molecule (such as targeting OX-40, IDO-1, LAG-3) or anti-CD27 monoclonal antibody (including varlilumab) - Must have at least one lesion that has not previously been irradiated (and is not within a previously radiated field) and for which palliative radiation is potentially indicated. --- T790M ---

Primary Outcomes

Description: Will include grade 3 and 4 toxicities as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

Measure: Assess the safety and tolerability of combined therapy in patients with metastatic NSCLC who have progressed on prior PD-1/PD-L1 therapy

Time: Up to 30 days after the last dose of treatment

Secondary Outcomes

Description: Will be defined as the proportion of all subjected confirmed with an immune-related partial response (irPR) or immune-related complete response (irCR) divided by the number of assigned patients according to immune-related Response Evaluation Criteria in Solid Tumors (irRECIST).

Measure: To determine objective response rate (ORR) of therapy

Time: From the start of treatment until disease progression/recurrence, assessed up to 1 year

Description: Will be defined as the percentage of patients who achieve irCR, irPR, and immune-related stable disease.

Measure: To estimate clinical benefit rate of the combination

Time: Up to 1 year

Description: The log-rank test will be used to analyze PFS for comparison of treatment effects, i.e., the only covariate that will be used is the treatment arm. Distributions of PFS times will be estimated using the Kaplan- Meier product-limit method. The median PFS times with two-sided 95% confidence intervals will be estimated for each treatment group.

Measure: To estimate median progression-free survival (PFS) of the combination

Time: From cycle 1, day 1 (each cycle is 21 days) of treatment until the criteria for disease progression is met as defined by irRECIST or death as a result of any cause, assessed up to 1 year

Description: irAE's are defined as any treatment-related AE that is inflammatory in nature, consistent with the mechanism of action of immunotherapy and generally medically manageable with topical and/or systemic immunosuppressants.

Measure: To compare the frequency of immune-related adverse events (irAEs)

Time: Up to 30 days after the last dose of treatment

Other Outcomes

Description: Will be assessed by immunohistochemistry (IHC) and will score the percentage of cells staining positively for PD-L1 incrementally. Scoring will be performed for the percentage of malignant tumor cells and for the percentage of nonmalignant inflammatory cell compartment that express PD-L1, separately.

Measure: To compare pre- and post-treatment tumor PD-L1 expression

Time: Baseline up to cycle 2, day 8 (each cycle is 21 days)

Description: Will be assessed by IHC staining to identify tumor infiltrating lymphocytes at the tumor stroma interface.

Measure: To compare pre- and post-treatment tumor levels of infiltrating CD3+, CD8+ T-cells

Time: Baseline up to cycle 2, day 8 (each cycle is 21 days)

129 Use of the Idylla Platform for the Detection of EGFR Mutations in Liquid- Based Cytology Specimens of Lung Adenocarcinoma

This study will investigate whether liquid based cytology specimens are a feasible alternative to formalin-fixed paraffin embedded histology samples for detection of epidermal growth factor receptor (EGFR) mutations in lung adenocarcinoma using the Biocartis Idylla platform. The Biocartis Idylla is a fully automated, real-time PCR based molecular diagnostics system. The Idylla carries out the entire analytical process from sample to result. This study will be based in the cytology department at Royal Cornwall Hospital as part of a service improvement. It will use residual material from existing samples sent to the laboratory as part of the routine service. It will use existing material from patients diagnosed with lung adenocarcinoma by cytology using the current, validated procedure which uses formalin-fixed paraffin embedded (FFPE) samples over a 10 month period. EGFR mutation results obtained using the validated procedure (formalin fixed paraffin embedded) will be compared to those produced using liquid based cytology samples.

NCT04086680
Conditions
  1. Adenocarcinoma of Lung
MeSH:Adenocarcinoma Adenocarcinoma of Lung

This faster pathway would be beneficial in cases of already confirmed adenocarcinoma for second line EGFR treatment testing (T790M) and in cases where the residual cytology sample, that would normally be discarded, can be utilised for testing, optimising the potential of the sampling. --- T790M ---

Primary Outcomes

Description: The relative sensitivity and specificity will be calculated. Significance of use of liquid based cytology samples will be calculated using McNemars chi-squared test.

Measure: Significance of using liquid based cytology samples for EGFR mutation detection using the Idylla platform (in comparison to the use of FFPE samples)

Time: 10 months

130 A Phase I/Ib Study of Alisertib in Combination With Osimertinib in Metastatic EGFR-mutant Lung Cancer

This is a phase I/Ib, open-label, single-center, single-arm study of alisertib and osimertinib for patients with stage IV EGFR-mutated lung cancer, incorporating both a dose escalation and dose-expansion phase

NCT04085315
Conditions
  1. Lung C
  2. Lung Cancer Metastatic
  3. EGFR Gene Mutation
Interventions
  1. Drug: Osimertinib
  2. Drug: Alisertib
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

2. Male or female patients ≥18 years of age 3. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 (see Appendix 1). 4. Documented activating EGFR mutation (Exon 19 deletion, Exon 19 insertion, E709K, G719X, S768I, V769L, T790M, L833F, L833V, V834L, H835L, L858R, A859S, K860I, L861Q, A871E, V843I, or H870R) on tumor sample or cell-free DNA sample performed in Clinical Laboratory Improvement Amendments (CLIA)-approved laboratory. 5. Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. --- E709K --- --- S768I --- --- V769L --- --- T790M ---

Primary Outcomes

Description: ≤1 out of 6 at highest dose level below the maximal administered dose. If 0 of these 3 additional participants experience a dose limiting toxicity (DLT) (1 of 6), proceed to the next dose level. If 1 or more of the 3 additional participants experience DLT (2 of 6), then dose escalation is stopped, and this dose is declared the maximal administered dose (highest dose administered). Three (3) additional participants will be entered at the next lowest dose level if only 3 participants were treated previously at that dose.

Measure: Maximum Tolerated Dose (MTD)

Time: First 28 days of study treatment

Secondary Outcomes

Description: defined as the best overall response recorded from the start of the treatment until disease progression from the start of treatment. The frequency and percentages of patients with a best overall response rate of complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) will be determined based on RECIST 1.1 criteria. We will compute a 95% confidence interval using a binomial distribution.

Measure: Overall Response Rate (ORR)

Time: Up to 2 years

Description: The DR for CR and PR will be measured from the date that the best response if first recorded until the date that PD is documented over the period of 2 years. For patients who continue treatment post-progression, the date of PD documentation will be used for analysis. The DR will be summarized using descriptive statistics (N, mean, standard deviation, minimum, and maximum)

Measure: Duration of Response (DR)

Time: Up to 2 years

Description: The depth of response will be assessed by RECIST 1.1 criteria. The DOR will be summarized using descriptive statistics (N, mean, standard deviation, minimum, and maximum).

Measure: Depth of response (DOR)

Time: Up to 2 years

Description: Defined as the percentage of patients who have achieved CR, PR, or SD for at least 12 weeks. The DCR will be summarized using descriptive statistics (N, mean, standard deviation, minimum, and maximum).

Measure: Disease Control Rate (DCR)

Time: Up to 2 years

Description: PFS will be calculated as 1+ the number of days from the first dose of alisertib to documented radiographic progression or death due to any cause over a period of 2 years. For patients who continue treatment post-progression, the date of radiographic progression will be used for PFS analysis. The Kaplan-Meier analysis will be used to calculate the mean PFS with 95% confidence interval.

Measure: Progression Free Survival (PFS)

Time: Up to 2 years

Description: OS will be calculated as 1+ the number of days from the first dose of alisertib to death due to any cause over a period of 2 years. The Kaplan-Meier analysis will be used to calculate the mean OS with 95% confidence interval.

Measure: Overall Survival (OS)

Time: Up to 2 years

Description: Defined as the percentage of patients who have achieved CR, PR, or SD in the CNS for at least 12 weeks. The CNS disease control rate will be summarized using descriptive statistics (N, mean, standard deviation, minimum, and maximum).

Measure: Central Nervous System (CNS) disease control rate

Time: Up to 2 years

Description: Pre-treatment tumor biopsy formalin-fixed paraffin-embedded (FFPE) samples will be stained for TPX2 expression by IHC. TPX2 IHC staining will be scored using the following scale: 0, 0-10% of tissue stained positive; 1, 10-20% stained positive; 2, 20-40% stained positive; 3, 40-70% stained positive; and 4, > 70% positive cells. The sum of staining score index (intensity + extent) will be designated as follows: 0-2, negative expression; 3-4, strong expression. The IHC score will be generated from three different areas of the slides and an average score will be calculated for each sample. We will determine whether there is a difference in TPX2 staining between responders and non-responders to alisertib + osimertinib treatment by the Fisher's exact test.

Measure: Intratumoral TPX2 expression by Immunohistochemistry (IHC)

Time: From pretreatment biopsy to time of response, up to 2 years

Description: Plasma will be collected to measure the drug concentrations at the indicated time points and area under curve (AUC) 0-24 hours. The area under the curve (AUC) is the definite integral in a plot of drug concentration in blood plasma vs. time

Measure: Area Under Curve (AUC)

Time: 1, 2, 3, 4, 6, 8, and 24 hours post-dose, up to 2 days

Description: Plasma will be collected to measure the drug concentrations at the indicated time points and Cmax will be calculated. It is a standard measurement in pharmacokinetics

Measure: Maximum (or peak) serum concentration (Cmax)

Time: 1, 2, 3, 4, 6, 8, and 24 hours post-dose, up to 2 days

Description: Plasma will be collected to measure the drug concentrations at the indicated time points and Tmax will be calculated. It is a standard measurement in pharmacokinetics

Measure: Amount of time (maximum) drug concentration in serum (Tmax)

Time: 1, 2, 3, 4, 6, 8, and 24 hours post-dose, up to 2 days

131 A Randomized, Open-label, Phase III Study of Single Agent Nazartinib Versus Investigator's Choice (Erlotinib or Gefitinib) as First-Line Treatment in Patients With Locally Advanced or Metastatic Non-Small Cell Lung Cancer Harboring EGFR Activating Mutations

This is a phase III, open label, randomized controlled multi-center global study designed to evaluate the safety and efficacy of single agent nazartinib (EGF816) compared with investigator's choice (erlotinib or gefitinib) in patients with locally advanced or metastatic NSCLC who are treatment naïve and whose tumors harbor EGFR activating mutations (L858R or ex19del).

NCT03529084
Conditions
  1. Carcinoma, Non-small Cell Lung
Interventions
  1. Drug: EFG816
  2. Drug: erlotinib or gefitinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- Known T790M positive mutation. --- T790M ---

Primary Outcomes

Description: PFS using central BIRC assessment according to RECIST 1.1, is defined as the time from the date of randomization to the date of the first documented progression (as assessed by BIRC per RECIST 1.1) or death due to any cause, whichever occurs first.

Measure: Progression Free Survival (PFS) by Blinded independent review committee (BIRC)

Time: Approximately 3 years

Secondary Outcomes

Description: Overall survival is defined as the time from date of randomization to date of death due to any cause.

Measure: Overall Survival

Time: Approximately 6 years

Description: PFS by Investigator assessment according to RECIST 1.1, is defined as the time from the date of randomization to the date of the first documented progression (as assessed by Investigator per RECIST 1.1) or death due to any cause, whichever occurs first.

Measure: PFS by investigator

Time: Approximately 3 years

Description: PFS after next-line of treatment (PFS2) using investigator assessment according to RECIST 1.1 is defined as time from date of randomization to the first documented disease progression (clinical or radiologic) as per investigator assessment on next-line therapy or death from any cause, whichever occurs first.

Measure: PFS after next-line of treatment (PFS2) using investigator assessment according to RECIST 1.1

Time: Approximately 4 years

Description: Time to progression in CNS, defined as time from date of randomization to the date of first documented progression of brain metastases as assessed by central neuro-radiologist BIRC per modified RECIST 1.1 for patients with at least one non-measurable and/or measurable lesion in the brain at baseline.

Measure: Time to progression in Central Nervous System (CNS) per central neuro-radiologist BIRC

Time: Approximately 3 years

Description: ORR in accordance with RECIST 1.1. ORR is defined as the percentage of participants with best overall response (BOR) of complete response (CR) or partial response (PR)

Measure: Overall response rate (ORR) by central BIRC

Time: Approximately 3 years

Description: DOR is defined as the time from date of first documented response (CR and PR) to the date of the first documented progression or death due to underlying cancer, whichever occurs first.

Measure: Duration of response (DOR) by central BIRC

Time: Approximately 3 years

Description: DCR is defined as the percentage of participants with BOR of CR, PR, or stable disease (SD).

Measure: Disease control rate (DCR) by central BIRC

Time: Approximately 3 years

Description: TTR is defined as the time from the date of randomization to the first documented response CR or PR.

Measure: Time to response (TTR) by central BIRC

Time: Approximately 3 years

Description: CNS ORR in patients with brain metastases who have measurable disease in the brain at baseline review per modified RECIST 1.1

Measure: CNS ORR per central neuro-radiologist BIRC

Time: Approximately 3 years

Description: CNS DoR in patients with brain metastases who have measurable disease in the brain at baseline per modified RECIST 1.1

Measure: CNS DoR per central neuro-radiologist BIRC

Time: Approximately 3 years

Description: Peak plasma concentration (Cmax) of EGF816 and its metabolite (LMI258)

Measure: Charactise Plasma PK (Cmax) of EGF816

Time: Day 1 of Cycles 1 to 6 inclusive (21 day cycle)

Description: Area under the plasma concentration versus time curve (AUC) of EGF816 and its metabolite (LMI258)

Measure: Charactise Plasma PK (AUC) of EGF816

Time: Day 1 of Cycles 1 to 6 inclusive (21 day cycle)

Description: Elimination half life (t1/2) of EGF816 and its metabolite (LMI258)

Measure: Charactise Plasma PK (t1/2) of EGF816

Time: Day 1 of Cycles 1 to 6 inclusive (21 day cycle)

Description: HRQoL as measured by European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 quality of life score

Measure: Patient Reported Outcome: Health Related Quality of Life (HRQoL) as measured by QLQ-C30 Questionnaire

Time: Approximately 4 years

Description: HRQoL as measured by European Organization for Research and Treatment of Cancer (EORTC) QLQ-LC13 quality of life score

Measure: Patient Reported Outcome: Health Related Quality of Life (HRQoL) as measured by QLQ-LC13 Questionnaire

Time: Approximately 4 years

Description: Global health status/quality of life score of the EQ-5D-5L

Measure: Patient Reported Outcome: Health Related Quality of Life (HRQoL) as measured by EuroQoL-5 Dimension-5 (EQ-5D-5L) Questionnaire

Time: Approximately 4 years

132 An Open-label PET Study to Determine Brain Exposure of Osimertinib After IV Microdose Administration of [11C]Osimertinib and Therapeutic Oral Doses of Osimertinib to Patients With EGFR Mutated NSCLC With Brain Metastases

This is an open-label, single centre, Phase I study to determine the brain exposure of [11C]osimertinib in patients with EGFRm NSCLC with brain metastases.

NCT03463525
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: Osimertinib
  2. Drug: [11C]osimertinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

4. Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR-TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) or T790M EGFR resistance mutation as assessed by local laboratory/or central laboratory via tissue/cytology or in plasma. --- L858R --- --- L861Q --- --- T790M ---

Primary Outcomes

Description: Measurement of the brain standard uptake value (SUV) seen on PET scan at baseline.

Measure: Brain Exposure to [11C]osimertinib in Tumour Region of Interest

Time: PET Scan on Day 1

Description: Pharmacokinetics of [11C]osimertinib by assessment of maximum plasma concentration (Cmax), derived from the curve taken at baseline.

Measure: Pharmacokinetics of [11C]osimertinib

Time: Blood samples collected on Day 1 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.

Description: Measurement of the brain to plasma partition coefficient (concentration brain/plasma ratio) by assessment of area under the concentration-time curve, derived from the curve taken at baseline.

Measure: Pharmacokinetics of [11C]osimertinib Brain to Plasma Ratio of Area Under the Concentration Curve (AUC)

Time: Measurement collected on Day 1 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.

Description: Pharmacokinetics of [11C]osimertinib radioactivity by assessment of time to Cmax (Tmax), derived from the curve taken at baseline.

Measure: Pharmacokinetics of [11C]osimertinib Radioactivity by Assessment of Time to Cmax (Tmax)

Time: Blood samples collected on Day 1 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.

Description: Measurement of the brain standard uptake value (SUV) seen on PET scan after a single dose of oral osimertinib.

Measure: Brain Exposure to [11C]osimertinib in Tumour Region of Interest

Time: PET Scan on Day 2

Description: Measurement of the brain standard uptake value (SUV) seen on PET scan after at least 21days of continuous oral osimertinib dosing.

Measure: Brain Exposure to [11C]osimertinib in Tumour Region of Interest

Time: PET Scan on Day 29

Description: Pharmacokinetics of [11C]osimertinib by assessment of maximum plasma concentration (Cmax), derived from the curve taken during the treatment period.

Measure: Pharmacokinetics of [11C]osimertinib

Time: Blood samples collected on Day 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.

Description: Pharmacokinetics of [11C]osimertinib by assessment of maximum plasma concentration (Cmax), derived from the curve taken during the treatment period.

Measure: Pharmacokinetics of [11C]osimertinib

Time: Blood samples collected on Day 29 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.

Description: Pharmacokinetics of [11C]osimertinib radioactivity by assessment of time to Cmax (Tmax), derived from the curve taken during the treatment period.

Measure: Pharmacokinetics of [11C]osimertinib Radioactivity by Assessment of Time to Cmax (Tmax)

Time: Blood samples collected on Day 2 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.

Description: Pharmacokinetics of [11C]osimertinib radioactivity by assessment of time to Cmax (Tmax), derived from the curve taken during the treatment period.

Measure: Pharmacokinetics of [11C]osimertinib Radioactivity by Assessment of Time to Cmax (Tmax)

Time: Blood samples collected on Day 29 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.

Description: Measurement of the brain to plasma partition coefficient (concentration brain/plasma ratio) by assessment of area under the concentration-time curve, derived from the curve taken during the treatment period.

Measure: Pharmacokinetics of [11C]osimertinib Brain to Plasma Ratio of Area Under the Concentration Curve (AUC)

Time: Measurement collected on Day 2 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.

Description: Measurement of the brain to plasma partition coefficient (concentration brain/plasma ratio) by assessment of area under the concentration-time curve, derived from the curve taken during the treatment period.

Measure: Pharmacokinetics of [11C]osimertinib Brain to Plasma Ratio of Area Under the Concentration Curve (AUC)

Time: Measurement collected on Day 29 at 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 75, and 90 minutes post-[11C]osimertinib injection.

Secondary Outcomes

Description: Pharmacokinetics of osimertinib and its metabolite by assessment of AUC metabolite to parent ratio, derived from the curves taken during the treatment period.

Measure: Pharmacokinetics of Osimertinib and its Metabolite by Assessment of AUC Metabolite to Parent Ratio

Time: Blood samples collected on Day 2 at pre-administration, 2, 4 and 7.5 hour(s) post dose (can be modified if necessary).

Description: Pharmacokinetics of osimertinib by assessment of maximum plasma concentration (Cmax), derived from the curve taken during the treatment period.

Measure: Pharmacokinetics of Osimertinib by Assessment of Maximum Plasma Concentration (Cmax)

Time: Blood samples collected on Day 2 at pre-administration, 2, 4 and 7.5 hour(s) post dose (can be modified if necessary).

Description: Pharmacokinetics of osimertinib by assessment of area under the concentration-time curve from time zero to the last measurable time point.

Measure: Pharmacokinetics of Osimertinib by Assessment of Area Under the Concentration-time Curve

Time: Blood samples collected on Day 2 at pre-administration, 2, 4 and 7.5 hour(s) post dose (can be modified if necessary).

Description: Pharmacokinetics of osimertinib by assessment of time to Cmax (Tmax), derived from the curve taken during the treatment period.

Measure: Pharmacokinetics of Osimertinib by Assessment of Time to Cmax (Tmax)

Time: Blood samples collected on Day 2 at pre-administration, 2, 4 and 7.5 hour(s) post dose (can be modified if necessary).

Other Outcomes

Description: Collection and assessment of adverse events graded using CTCAE (version 4.03).

Measure: Incidence of Treatment Emergent Adverse Events [Safety and Tolerability] with IV [11C]osimertinib administration

Time: From study Day 1 and until 30 days after the study drug is discontinued.

Description: Collection and assessment of adverse events using CTCAE (version 4.03)

Measure: Incidence of Treatment Emergent Adverse Events [Safety and Tolerability] with continuous oral osimertinib

Time: From study Day 1 and until 30 days after the study drug is discontinued.

133 A Phase I Trial to Assess the Safety, Pharmacokinetics, and Anti-tumor Activity of SCC244 in Subjects With Advanced Solid Tumors

This study evaluates the Safety, Tolerability, Pharmacokinetics, and Anti-tumor Activity of SCC244 in patients with advanced solid tumors with c-Met Alterations.

NCT03466268
Conditions
  1. Advanced Solid Tumor
Interventions
  1. Drug: Glumetinib for tablet
MeSH:Neoplasms
HPO:Neoplasm

No EGFR T790M mutation for subjects with c-Met gene amplification or c-Met protein overexpression; KRAS/ALK/ROS1 WT or unknown mutation/rearrangement status for subjects with c-Met exon 14 skipping mutation. --- T790M ---

4. Presence of EGFR T790M mutation in NSCLC subjects pretreated with an EGFR-TKI; Known KRAS/ALK/ROS1 mutation/rearrangement in NSCLC subjects with c-Met exon 14 skipping mutation. --- T790M ---

Primary Outcomes

Description: To evaluate the DLT in patients with advanced solid tumor

Measure: DLT(Dose limit toxity)

Time: 35 days

Description: To evaluate the MTD in patients with advanced solid tumor

Measure: MTD(Max tolerance does)

Time: 35 days

Description: To evaluate the BED in patients with advanced solid tumor

Measure: BED(Biological effective dose)

Time: 35 days

Description: To evaluate the ORR in patients with advanced solid tumor in Ib

Measure: ORR(Objective response rate)

Time: 8 weeks

134 MasterKey-01: A Phase 1/2, Open-label, Two-part, Multicenter Study to Assess the Safety, Tolerability, Pharmacokinetics & Antitumor Activity of BDTX-189, an Inhibitor of Allosteric ErbB Mutations, in Patients w/ Advanced Solid Malignancies

This is a clinical study with an orally administered drug, BDTX-189 in participants with advanced solid tumors that have select mutations or alterations in human epidermal growth factor receptor 2 (HER2/ErbB2) genes or epidermal growth factor receptor (EGFR/ErbB1). The main goals of this study are to: - Find the recommended dose of BDTX-189 that can be given safely to participants - Learn more about the side effects of BDTX-189 - Learn what the body does to BDTX-189 after it has been taken (pharmacokinetics or PK) - Determine the antitumor activity of BDTX-189 in participants with select allosteric ErbB gene mutations

NCT04209465
Conditions
  1. Solid Tumor
Interventions
  1. Drug: BDTX-189

Evidence of second- or third-degree atrioventricular block 2. Clinically significant arrhythmia (as determined by the Investigator) 3. QTcF interval of >470 msec - Leptomeningeal or untreated and/or symptomatic CNS malignancies (primary or metastatic) - Women who are pregnant or breast-feeding - Taking or unable to discontinue proton pump inhibitors within 1 week prior to baseline - Known concurrent KRAS mutation - Known tumor-harboring resistance mutations including EGFR T790M or C797S mutations or HER2 C805S mutation Phase 2 Only: - Prior documented treatment response to approved or investigational HER2 or EGFR tyrosine kinase inhibitor therapies Main Inclusion Criteria: - Histologically- or cytologically-confirmed locally advanced or metastatic solid tumor with documented recurrence or disease progression from standard anticancer therapy in the advanced/metastatic setting - No standard therapy available or standard therapy is considered unsuitable or intolerable according to the Investigator and consultation with the Medical Monitor Phase 1 Only: - Solid tumor patients with alterations that may be associated with antitumor activity based on preclinical data for BDTX-189 such as: 1. Allosteric HER2 or HER3 mutation(s) 2. EGFR or HER2 exon 20 insertion mutation(s) 3. HER2 amplified or overexpressing tumors 4. EGFR exon 19 deletion or L858R mutation Phase 2 Only: - Patients with a solid tumor harboring an: 1. Allosteric HER2 mutation (including but not limited to S310F/Y, R678Q, L755S/P, V777L, V842I) 2. EGFR or HER2 exon 20 insertion mutation Eligible mutations must be determined by a validated next-generation sequencing (NGS) test routinely used by each institution and performed in a CLIA-certified or equivalent laboratory. --- T790M ---

Evidence of second- or third-degree atrioventricular block 2. Clinically significant arrhythmia (as determined by the Investigator) 3. QTcF interval of >470 msec - Leptomeningeal or untreated and/or symptomatic CNS malignancies (primary or metastatic) - Women who are pregnant or breast-feeding - Taking or unable to discontinue proton pump inhibitors within 1 week prior to baseline - Known concurrent KRAS mutation - Known tumor-harboring resistance mutations including EGFR T790M or C797S mutations or HER2 C805S mutation Phase 2 Only: - Prior documented treatment response to approved or investigational HER2 or EGFR tyrosine kinase inhibitor therapies Solid Tumor BDTX-189 is an irreversible, small molecular inhibitor that is highly selective versus wild-type EGFR and potent for cancer driver mutations of the ErbB family, including extracellular, transmembrane, and kinase domain allosteric mutations of HER2, as well as EGFR and HER2 exon 20 insertion mutations. --- T790M ---

Primary Outcomes

Description: Certain toxicities will be considered dose-limiting unless clearly attributable to an extraneous cause, such as underlying disease.

Measure: Incidence of dose limiting toxicities as a determinant of the Recommended Phase 2 Dose (RP2D)

Time: After the first dose of treatment for up to 21 days.

Description: Objective response rate is defined as the proportion of participants who achieve a confirmed complete response (CR; disappearance of all target and non-target lesions) or partial response (PR; at least a 30% decrease from baseline in the sum of diameters of target lesions) per RECIST version 1.1.

Measure: Phase 2: Objective response rate as a measure of antitumor activity

Time: Assessed until disease progression or death for up to 12 months

Secondary Outcomes

Description: Adverse events will be assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.

Measure: Phase 1 and Phase 2: Incidence of treatment-emergent adverse events as a measure of safety and tolerability of BDTX-189

Time: From Cycle 1 Day 1 (each cycle is 21 days) until 30 days post last dose

Description: Blood samples will be taken to measure the plasma concentrations of BDTX-189 in both a fed and fasted state.

Measure: Phase 1 and Phase 2: Plasma concentration of BDTX-189 as a measure of pharmacokinetics

Time: Multiple time points during Cycles 1-4 (each cycle is 21 days)

Description: Objective response is defined as the proportion of participants who achieved a complete response (CR; disappearance of all target and non-target lesions) or partial response (PR; at least a 30% decrease from baseline in the sum of diameters of target lesions) per RECIST version 1.1.

Measure: Phase 1: Objective response rate as a preliminary measure of antitumor activity

Time: Assessed until disease progression or death for up to 12 months

Description: Duration of response is the time from first documentation of a response to first evidence of progressive disease per RECIST version 1.1 or death. A response is defined as either a complete response (CR; disappearance of all target lesions and non-target lesions) or partial response (PR; at least a 30% decrease in the sum of diameters of target lesions). Progressive disease is defined by a target lesion increase of 20% and at least 5mm from smallest on-study lesion sum, the appearance of new lesions, or unequivocal progression of non-target lesions.

Measure: Phase 1 and Phase 2: Duration of response as a measure of antitumor activity

Time: Assessed until disease progression or death for up to 12 months

Description: Disease control rate is defined as the proportion of participants achieving: a complete response (CR; disappearance of all target and non-target lesions), partial response (PR; at least a 30% decrease in the sum of diameters of target lesions), or stable disease (SD; neither sufficient shrinkage to qualify for a PR nor sufficient increase in lesions) per RECIST version 1.1.

Measure: Phase 1 and Phase 2: Disease control rate as a measure of antitumor activity

Time: Assessed until disease progression or death for up to 12 months

Description: Progression-free survival is the time from first study dose until disease progression (PD; target lesion increase of 20% and at least 5mm from smallest on-study lesion sum, the appearance of new lesions, or unequivocal progression of non-target lesions) per RECIST v1.1.

Measure: Phase 1 and Phase 2: Progression-free survival as a measure of antitumor activity

Time: Assessed until disease progression or death for up to 12 months

Description: Overall survival is the time from first study dose until death from any cause or study discontinuation.

Measure: Phase 2: Overall survival as a measure of clinical activity

Time: Assessed every 12 weeks after treatment discontinuation for up to 1 year

135 START: Real-world Study on Sequential Therapy With Afatinib as First-line Treatment in Patients With Epidermal Growth Factor Receptor (EGFR) Mutation-positive Advanced Non-small Cell Lung Cancer (NSCLC)

This study aims to observe the sequential strategy with afatinib as first-line treatment and to find the optimal treatment strategy for long-term chemotherapy-free regimens in Chinese patients with EGFR-mutated advanced NSCLC. Furthermore, this study can also assess the effectiveness and safety of afatinib as first-line treatment.

NCT04206787
Conditions
  1. Non-squamous, Non-Small Cell Lung Cancer
Interventions
  1. Drug: Afatinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Time on treatment (TOT) of afatinib as firstline treatment followed by 3rd generation EGFR-TKI in the event of the T790M resistance mutation is developed in patients with EGFR mutation-positive NSCLC. --- T790M ---

Time on treatment (TOT) with afatinib as first-line treatment followed by investigator's choice treatment in event of the T790M negative status in real-world setting. --- T790M ---

Primary Outcomes

Measure: Time on treatment (TOT) of afatinib as firstline treatment followed by 3rd generation EGFR-TKI in the event of the T790M resistance mutation is developed in patients with EGFR mutation-positive NSCLC

Time: 28 months

Secondary Outcomes

Measure: Time on treatment (TOT) with afatinib as first-line treatment followed by investigator's choice treatment in event of the T790M negative status in real-world setting

Time: 28 months

Measure: Overall Survival from the start of afatinib until the date of death

Time: 50 months

Measure: Progression-Free Survival as judged by an investigator with afatinib in first-line treatment

Time: 33 months

Measure: Objective Response Rate [OR is defined as best overall response of CR and PR] according to RECIST 1.1

Time: 33 months

Measure: Disease Control Rate [DC is defined as best overall response of CR, PR, and SD] according to to RECIST 1.1

Time: 33 months

Measure: Proportion of resistance mechanisms after afatinib first-line

Time: 12 months

Measure: Adverse Event(s), Serious Adverse Event (s), afatinib-related AEs (ADRs) as indicated by incidence seriousness and intensity grade according to United States (US) national cancer institute's (NCI) (CTCAE Version 5.0)

Time: 50 months

136 Phase I, Open-label, Single-arm Study to Evaluate the Safety, Tolerance, Pharmacokinetics and Preliminary Efficacy of TY-9591 Tablets in Advanced NSCLC Patients With Epidermal Growth Factor Receptor( EGFR) Positive Mutation

The primary objective of this study is to evaluate the safety and tolerability of TY-9591, with dose-escalation stage and dose-expansion stage.

NCT04204473
Conditions
  1. NSCLC
Interventions
  1. Drug: TY-9591(10mg,40mg) qd. po
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

5. Eastern Cooperative Oncology Group (ECOG) performance score 0 or 1. 6. Documentation of disease progression while on previous continuous treatment with first-line EGFR TKI; patients must have confirmation of tumor EGFR activating mutations (exon 19 del, or exon 21 ) and T790M mutation status 7. Adequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values: a.Neutrophils (absolute value) ≥ 1.5×10^9/L; b.Hemoglobin ≥ 90 g/L; c.Platelet ≥ 80×10^9/L; d.Serum total bilirubin ≤ 1.5× ULN(for Patients with Gilbert Syndrome, total bilirubin ≤ 3×ULN and bilirubin ≤ 1.5×ULN should be permitted) f. --- T790M ---

Exclusion Criteria: 1. Treatment with any of the following: 1. Treatment with an EGFR TKI within 14 days or about 5x half-life, whichever is the longer, of the first dose of study drug; 2. Any cytotoxic chemotherapy, investigational agents or anticancer drugs for the treatment from a previous treatment regimen within 4 weeks of the first dose of study treatment; 3. Major surgery within 4 weeks of the first dose of study treatment; 4. Radiotherapy with a limited field of radiation within 1 week of the first dose of study treatment, with the exception of patients receiving radiation to more than 30% of the bone marrow or with a wide field of radiation that had to be completed within 4 weeks of the first dose of study treatment; 5. Previously treated by other third-generation epidermal growth factor receptor tyrosine kinase inhibitor(EGFR-TKI) for T790M (for example Osimertinib). --- T790M ---

Primary Outcomes

Description: Incidence of Dose Limiting Toxicity (DLT)

Measure: Dose Limiting Toxicity (DLT)

Time: First 29 days of dosing

Description: To determine the Maximum Tolerated Dose (MTD) of TY-9591 in subjects with NSCLC

Measure: Maximum Tolerated Dose (MTD)

Time: 1year

Description: Recommended Phase 2 dose (RP2D) of TY-9591 in subjects with NSCLC

Measure: Recommended Phase 2 dose (RP2D)

Time: through study completion, an average of 2.5 years

Description: ORR is defined as the proportion of patients with a best overall response of complete response (CR) or partial response (PR) assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1)

Measure: Overall Response Rate (ORR)

Time: At least 24 weeks

Secondary Outcomes

Description: Cmax of TY-9591 following single dose

Measure: Cmax

Time: pharmacokinetics(PK) blood samples are collected at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10,12, 24, 48, 72,96,120,144,168 and 192 hours post-dose.

Description: Tmax of TY-9591 following single dose

Measure: Tmax

Time: pharmacokinetics(PK) blood samples are collected at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10,12, 24, 48, 72,96,120,144,168 and 192 hours post-dose.

Description: AUC of TY-9591 following single dose

Measure: Area Under Curve(AUC)

Time: pharmacokinetics(PK) blood samples are collected at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10,12, 24, 48, 72,96,120,144,168 and 192 hours post-dose

Description: Cmax of TY-9591 following multiple dose

Measure: Cmax

Time: The datas should be evaluated multiple times on Cycle 1 day1,8,15, 21 pre-dose; Cycle 2 day1 (at pre-dose, 0.5,1, 2, 3, 4, 6, 8, 10,12, 24 hours post-dose). Each cycle is 21 days

Description: Cmin of TY-9591 following multiple dose

Measure: Cmin

Time: The datas should be evaluated multiple times on Cycle 1 day1,8,15, 21 pre-dose; Cycle 2 day1 (at pre-dose, 0.5,1, 2, 3, 4, 6, 8, 10,12, 24 hours post-dose). Each cycle is 21 days

Description: AUC of TY-9591 following multiple dose

Measure: AUC

Time: The datas should be evaluated multiple times on Cycle 1 day1,8,15, 21 pre-dose; Cycle 2 day1 (at pre-dose, 0.5,1, 2, 3, 4, 6, 8, 10,12, 24 hours post-dose). Each cycle is 21 days

Description: PFS is defined as time from date of first dose of study treatment to date of first documented disease progression or death due to any cause determined by by Investigator assessment in accordance to RECIST 1.1

Measure: Progression-free survival (PFS)

Time: 10.1 months

Description: DOR is defined as the time from first documented response (PR or CR) to the date of first documented disease progression or death due to any cause determined by Investigator assessment in accordance to RECIST 1.1

Measure: Duration of Response (DOR)

Time: 9.7 months

137 A Phase 1/2 Study of the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-Tumor Activity of the Oral ALK/EGFR Inhibitor AP26113

The purpose of this study is 2-fold: initially, in the dose escalation phase, the goal is to determine the safety profile of orally administered brigatinib, including: the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), recommended phase 2 dose (RP2D), and pharmacokinetic (PK) profile. Then, once the RP2D is established, an expansion phase will assess the preliminary anti-tumor activity of brigatinib, both in non-small cell lung cancer (NSCLC) with ALK gene rearrangement (including participants with active brain metastases) or mutated EGFR, and in other cancers with abnormal targets against which brigatinib is active.

NCT01449461
Conditions
  1. Lymphoma, Large-Cell, Anaplastic
  2. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Drug: Brigatinib
MeSH:Lymphoma Carcinoma, Non-Small-Cell Lung Lymphoma, Large-Cell, Anaplastic
HPO:Anaplastic large-cell lymphoma Lymphoma Non-small cell lung carcinoma

Resistant to crizotinib (and have not received any other prior ALK inhibitor therapy); 3. Expansion cohort 3: NSCLC participants whose tumors exhibit an epidermal growth factor receptor EGFR-T790M mutation and who are resistant to 1 prior EGFR TKI: i. Histologically or cytologically confirmed NSCLC ii. --- T790M ---

Documented evidence of an EGFR-T790M mutation following disease progression on the most recent EGFR TKI therapy; iv. --- T790M ---

Primary Outcomes

Description: The RP2D is the maximum tolerated dose (MTD) or less. The MTD is defined as the dose range at which ≤ 1 of 6 evaluable participants experience dose limiting toxicities (DLT) within the first 28 days of treatment (end of cycle 1).

Measure: Recommended Phase 2 Dose of Brigatinib

Time: 28 days

Description: ORR assessed by the investigator, is defined as the proportion of the participants with complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid tumors (RECIST) v1.1 after the initiation of study treatment. CR for target lesion: disappearance of all extranodal lesions and all pathological lymph nodes must have decreased to <10 mm in short axis. CR for non-target lesion: Disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and normalization of tumor marker level. PR: at least a 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline sum diameters. Crzb=Crizotinib.

Measure: Objective Response Rate (ORR)

Time: Screening and at 8-week intervals thereafter up to data cut-off date: 16 November 2015 (approximately up to 50 months)

Secondary Outcomes

Description: An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.

Measure: Number of Participants Who Had at Least One Treatment-Emergent Adverse Event (TEAE)

Time: Any adverse event reported on or after the day of first dose of study drug (approximately up to 50 months)

Description: The MTD is defined as the highest dose at which ≤ 1 of 6 evaluable participants experience a DLT within the first 28 days of treatment (end of cycle 1). Evaluable participants must complete at least 75% of their planned doses, unless missed doses are due to AEs. The cohort may be expanded to better define the safety profile for confirmation of the MTD. The maximum administered dose in the trial will likely exceed the MTD.

Measure: Maximum Tolerated Dose (MTD) Assessed in Dose Escalation Phase of the Study

Time: Up to Cycle 1 (28 days)

Description: DLT include any toxicity that is possibly, probably, or definitely drug-related. Toxicity grades will be defined by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v 4.0. DLTs are defined by the following: A) Non-hematologic toxicities: Any grade ≥3 non-hematologic toxicity, with the exception of self-limiting or medically controllable toxicities (eg, nausea, vomiting, fatigue, electrolyte disturbances, hypersensitivity reactions) lasting < 3 days, and excluding alopecia. B) Hematologic toxicities: Febrile neutropenia not related to underlying disease (fever, > 101°F; ANC<500); Prolonged grade 4 neutropenia (> 7 days); Neutropenic infection: ≥ grade 3 neutropenia with ≥ grade 3 infection; Thrombocytopenia ≥ grade 3 with bleeding or grade 4 lasting ≥ 7 days. C) Missed ≥ 25% of planned doses of brigatinib over 28 days due to treatment-related AEs in the first cycle.

Measure: Number of Participants With Dose Limiting Toxicities (DLTs) Assessed in Dose Escalation Phase of the Study

Time: Up to Cycle 1 (28 days)

Measure: Cmax: Maximum Observed Plasma Concentration for Brigatinib

Time: Cycle 1 Day 1

Measure: Cmax: Maximum Observed Plasma Concentration for Brigatinib

Time: Cycle 2 Day 2

Measure: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Brigatinib

Time: Cycle 1 Day 1

Measure: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Brigatinib

Time: Cycle 2 Day 1

Measure: AUC(0-24): Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours Post-dose for Brigatinib

Time: Cycle 1 Day 1, 8, 15 and 22 pre-dose and Day 1 multiple timepoints (up to 48 hours) post-dose; Cycle 2 Day 1 and 3 pre-dose and Day 1 multiple time points (up to 48 hours) post-dose

Measure: Terminal Phase Elimination Half-life (T1/2) for Brigatinib

Time: Cycle 2 Day 1

Description: Best overall response is defined as proportion of participants with CR, PR, stable disease (SD) or progressive disease (PD) as per of RECIST v1.1 as evaluated by investigator. CR for target lesion: disappearance of all extranodal lesions and all pathological lymph nodes must have decreased to <10 mm in short axis. CR for non-target lesion: disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and normalization of tumor marker level. PR: at least a 30% decrease in the SLD of target lesions, taking as reference the baseline sum diameters. Disease progression for target lesion: SLD increased by at least 20% from smallest value on study and SLD must also demonstrate an absolute increase of at least 5 mm or development of any new lesion. PD for non-target lesion: unequivocal progression of existing non-target lesions. SD for neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

Measure: Best Overall Response

Time: Screening and at 8-week intervals thereafter up to data cut-off date: 16 November 2015 (approximately up to 50 months)

Description: Duration of response is defined as time interval from the time that measurement criteria are first met for CR/PR (whichever is first recorded) until first date that progressive disease is objectively documented or death due to any cause. Participants who did not progress nor die were censored at last valid response assessment. CR for target lesion: disappearance of all extranodal lesions and all pathological lymph nodes must have decreased to <10 mm in short axis. CR for non-target lesion: disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (<10mm short axis) and normalization of tumor marker level. PR: at least a 30% decrease in SLD of target lesions. PD for target lesion: SLD increased by at least 20% from smallest value and must also demonstrate an absolute increase of at least 5 mm or development of any new lesion. PD for non-target lesion: unequivocal progression of existing non-target lesions.

Measure: Duration of Response

Time: Screening and at 8-week intervals thereafter up to data cut-off date: 16 November 2015 (approximately up to 50 months)

Description: PFS is defined as the time interval from the date of the first dose of the study treatment until the first date at which disease progression is objectively documented, or death due to any cause, whichever occurs first. Disease progression for target lesion: SLD increased by at least 20% from the smallest value on study (including baseline, if that is the smallest) and SLD must also demonstrate an absolute increase of at least 5 mm or development of any new lesion. Disease progression for non-target lesion: Unequivocal progression of existing non-target lesions. (Subjective judgment by experienced reader). PFS was calculated by Kaplan-Meier estimation.

Measure: Progression Free Survival (PFS)

Time: Screening and at 8-week intervals thereafter up to data cut-off date: 16 November 2015 (approximately up to 50 months)

Description: OS is defined as the time interval from the date of the first dose of the study treatment until death due to any cause.

Measure: Overall Survival (OS)

Time: Screening and at 8-week intervals thereafter up to data cut-off date: 16 November 2015 (approximately up to 50 months)

Description: Intracranial objective response rate is defined as the proportion of the participants with CR or PR in the intracranial CNS per modification of RECIST v1.1 after the initiation of study drug. CR for target lesion: disappearance of all extranodal lesions. CR for non-target lesion: disappearance of all extranodal non-target lesions and normalization of tumor marker level. PR: at least a 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline sum diameters. Meta.=Metastases.

Measure: Intracranial Objective Response Rate

Time: Screening and at 8-week intervals thereafter up to data cut-off date: 16 November 2015 (approximately up to 50 months)

Description: Intracranial duration of response is defined as the time interval from the time that the measurement criteria are first met for CR/PR in brain metastases (whichever is first recorded) until the first date that progressive disease is objectively documented or death due to any cause. Participants who did not progress nor die were censored at the last valid response assessment. Duration intracranial of response was calculated by Kaplan-Meier estimation.

Measure: Duration of Intracranial Response

Time: Screening and at 8-week intervals thereafter up to data cut-off date: 16 November 2015 (approximately up to 50 months)

Description: PFS is defined as the time interval from the date of the first dose of the study treatment until the first date at which disease progression in brain, or death due to any cause, whichever occurs first. Intracranial PFS was calculated by Kaplan-Meier estimation.

Measure: Intracranial Progression Free Survival (PFS)

Time: Screening and at 8-week intervals thereafter up to data cut-off date: 16 November 2015 (approximately up to 50 months)

138 A Phase 1, Open-Label, Dose Escalation Study to Evaluate Safety, Pharmacokinetics and Pharmacodynamics of Combined Oral C-Met/ALK Inhibitor (PF-02341066) and Pan-Her Inhibitor (PF-0299804) in Patients With Advanced Non-Small Cell Lung Cancer

Background: - PF-02341066 and PF-00299804 are drugs that specifically target certain proteins that may be more active in cancer cells than normal cells, in particular in non-small cell lung cancer. Both drugs seem to be able to stop the growth of or kill cancer cells. Researchers want to combine them to see if they are a safe and effective treatment for advanced non-small cell lung cancer. Objectives: - To test the safety and effectiveness of PF-02341066 and PF-00299804 for advanced non-small cell lung cancer. Eligibility: - Individuals at least 18 years of age with advanced non-small cell lung cancer that has not responded to standard treatments. Design: - Participants will be screened with a medical history and physical exam. They will also have blood and urine tests, and imaging studies. Heart and lung function tests and an eye exam may also be given. - The first cycle of treatment will be 28 days. Every cycle after the first will be 21 days. Participants may have up to 17 cycles of treatment. - Participants will take both study drugs as tablets. Twelve hours after the first dose, participants will take only the PF-02341066. This dose schedule will remain the same throughout the study. - Participants will be monitored with frequent blood and urine tests and imaging studies. Tumor biopsies will be taken as needed. Those in the study will keep a diary to record any symptoms or side effects of taking the study drugs. - After 17 cycles of treatment, or after stopping the study drugs early for any other reason, participants will have a final followup visit.

NCT01441128
Conditions
  1. Carcinoma, Non-Small Cell Lung
  2. Adenocarcinoma
  3. Carcinoma, Squamous Cell
  4. Carcinoma, Large Cell
Interventions
  1. Drug: PF-02341066/PF-00299804
  2. Drug: PF-02341066/PF-00299804
MeSH:Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung Carcinoma, Squamous Cell Carcinoma, Large Cell
HPO:Carcinoma Neoplasm of the lung Non-small cell lung carcinoma Squamous cell carcinoma

Biomarkers in tumor and blood that are potentially predictive for drug activity: for example, KRAS mutations, EGFR mutations (eg, T790M), EGFR and HER2 amplifications, c Met amplification and mutations, ALK, PTEN and PIK3A status in tumor biopsi.... null. --- T790M ---

- Despite the dramatic initial response to gefitinib and erlotinib, about 50% of NSCLC tumors develop resistance due to secondary activating mutations in EGFR itself, including the EGFR T790M gatekeeper mutation, and more than 20% of acquired resistance is due to an increase in mesenchymal-epithelial transition factor (c-Met) signaling. --- T790M ---

- There is evidence from a limited number of tumors from patients with acquired resistance to EGFR-TKIs that both T790M and cMET resistance mechanisms can occur in the same patient at different metastatic sites and even in different fractions of the same lesion. --- T790M ---

- Tumors with acquired resistance to erlotinib and gefitinib might be vulnerable to a combination of PF-00299804 a second generation EGFR TKI which is also an inhibitor of T790M mutation, and PF-02341066 which is an inhibitor of c- Met/Hepatocyte Growth Factor Receptor (HGFR). --- T790M ---

Primary Outcomes

Measure: Overall safety profile of combined PF 02341066 plus PF 00299804 including adverse events (AE), as defined and graded by the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE], and first cycle Dose Limiting Tox...

Time: 18 months

Secondary Outcomes

Measure: Plasma concentrations and pharmacokinetic (PK) parameters of PF 02341066 and PF 00299804 including AUCtau, Cmax, Ctrough, Tmax, and CLss/F

Time: 18 months

Measure: Clinical activity of combined PF 02341066 plus PF 00299804 including objective response (OR) and stable disease (SD) as defined by RECIST version 1.1, duration of response (DR) and progression free survival (PFS).

Time: 18 months

Measure: Biomarkers in tumor and blood that are potentially predictive for drug activity: for example, KRAS mutations, EGFR mutations (eg, T790M), EGFR and HER2 amplifications, c Met amplification and mutations, ALK, PTEN and PIK3A status in tumor biopsi...

Time: 12 months

Measure: Pharmacodynamic biomarkers in tumor biopsies (e.g., phospho c Met, c Met, EGFR, phospho EGFR) and in blood (e.g., HGF and s Met) that are modulated following drug exposure.

Time: 12 months

139 Induction Therapy With Gefitinib Followed by Taxane Platinum Chemotherapy and Intercalated Gefitinib in NSCLC Stages II-IIIB With Activating EGFR Mutation - A Single Arm Phase II Trial.

This study is designed as a single arm, un-controlled, open-label, multi-center hypothesis generating two-stage phase II trial. It is based on the assumption that the proposed treatment scheme doubles the rate of pathologic complete remission in Mutated epidermal growth factor receptor (EGFRmt) + NSCLC patients compared to historical control data from standard treatments. Patients with NSCLC and activating EGFR mutation in stages II, IIIA and IIIB eligible for induction therapy with docetaxel and cisplatin and gefitinib Patients will be treated for 12 days with gefitinib 250 mg/day p.o. (d -12 to -1) and induced with chemotherapy docetaxel 75 mg/m2 and cisplatin 50 mg/m2 d1+2 and intercalated gefitinib 250 mg/day d4-20 (cycle 1 and 2) and d4-17 (for cycle3). Surgery is planned in the 4th week after d1 of the last cycle.

NCT02326285
Conditions
  1. Non-squamous Non-small Cell Lung Cancer Stage II
  2. Non-squamous Non-small Cell Lung Cancer Stage IIIA
  3. Non-squamous Non-small Cell Lung Cancer Stage IIIB
  4. Activating EGFR Mutation
  5. NSCLC
Interventions
  1. Drug: Gefitinib
  2. Drug: docetaxel
  3. Drug: cisplatin
  4. Procedure: Surgery
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

analysis of EGFR ctDNA in patient plasma; screening for EGFR mutation status (activating and resistance mutations especially T790M), monitoring of EGFR mutation status by means of Circulating tumor DNA (ctDNA) detection in patient plasma. --- T790M ---

T790M); 3. Significant cardiovascular disease, such as uncontrolled hypertension, myocardial infarction within the last 6 months, unstable angina pectoris, CHF ≥ NYHA 2, serious arrhythmia, significant peripheral vascular disease; 4. Pre-existing neuropathic ≥ grade 2; 5. Patients with confirmed HIV infection. --- T790M ---

Primary Outcomes

Description: The primary objective of the study is to assess the pathologic complete remission rate after induction therapy with gefitinib d -12 to d-1 followed by docetaxel 75 mg/m2 and cisplatin 50 mg/m2 d1+2 q21 and intercalated gefitinib 250 mg d4 to d20 (cycle 1 and 2) and d4-17 (for cycle3), in order to demonstrate feasibility and efficacy of this treatment scheme. It is expected to achieve a pCR ≥30% regression grade IIB and III (Junker criteria) compared to historical controls in the mediastinal lymph nodes.

Measure: pathologic complete remission rate (pCR rate)

Time: 12 weeks (after 3 cycles and surgery) after enrollment

Secondary Outcomes

Description: AEs/SAEs from 21 patients during induction CTx with docetaxel and cisplatin in combination with intercalated gefitinib

Measure: Adverse Events (AEs) / Serious adverse events (SAEs)

Time: 30 months

Description: R0 resection rate as assessed according to the German S3 guidelines

Measure: Surgical R0 resection rate

Time: 30 month

Measure: Response: radiologic response based on CT

Time: 30 month

Description: Progression-free survival (PFS) will be defined as the time from enrollment to the time of disease progression or relapse or death, or to the date of last assessment without any such event (censored observation).

Measure: progression free survival (PFS)

Time: 30 month

Description: The duration of overall survival (OS) will be determined by measuring the time interval from enrollment to the date of death or last observation (censored).

Measure: Overall survival (OS)

Time: 30 month

Description: After the end of treatment will be performed every 3 month (+/- 14 days) for minimum 12 months in order to collect information on relapse and site of relapse

Measure: relapse pattern

Time: 30 month

Description: Explorative analysis of health related quality of life, QoL at various time points throughout the study, to assess the QoL during and after induction therapy with gefitinib, after three cycles of chemotherapy with intercalated gefitinib including pre- and post surgery

Measure: quality of life

Time: 30 month

Description: To collect and store tumor tissue as well as plasma and serum samples for exploratory analyses of potential predictive markers, monitoring of biomarkers during and after treatment

Measure: translational research

Time: 30 month

Description: analysis of EGFR ctDNA in patient plasma; screening for EGFR mutation status (activating and resistance mutations especially T790M), monitoring of EGFR mutation status by means of Circulating tumor DNA (ctDNA) detection in patient plasma

Measure: monitoring of epidermal growth factor receptor (EGFR) mutation status

Time: 30 month

140 An epidemiOlogy Study to deteRmine the Prevalence of EGFR muTations in RUSsian Patients With Advanced NSCLC (ORTUS)

This is a multicentre, non-interventional, prospective study to be carried out in representative oncology departments / institutions in order to determine the prevalence of EGFR mutations in treatment-naive Russian patients with cytologically verified advanced NSCLC in Russia.

NCT02321046
Conditions
  1. Non-Small Cell Lung Cancer
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

EGFR mutations (EGFR del746-750, EGFR L858R, EGFR T790M) rate in cytology and plasma samples prior to treatment. --- L858R --- --- T790M ---

Primary Outcomes

Measure: EGFR mutations (EGFR del746-750, EGFR L858R, EGFR T790M) rate in cytology and plasma samples prior to treatment

Time: up to 18 months

Secondary Outcomes

Measure: Patient characteristics: Gender. Age. Race, ethnicity. Smoking habits. Family history of NSCLC.

Time: up to 18 months

Description: Date of the cytological verification of the NSCLC diagnosis. Disease stage and TNM classification. Morphological classification. Extent of the disease. Performance Status ECOG, including at diagnosis

Measure: Disease information/diagnostic procedures

Time: up to 18 months

Measure: EGFR mutations profile in cytology and/or histology (depending on the availablility of samples) and plasma samples at the time of every progression or in 1.5 year follow up in case of no progression

Time: up to 18 months

Description: 1st line and subsequent lines of therapy treatment, therapy regimen, medicines used for therapy (drugs by INN), for EGFRm+ patients - number of cycles of antitumor therapy, onset date, end date of each line

Measure: Characteristics of the 1st line and subsequent lines of antitumor therapy

Time: up to 18 months

Description: Treatment response/ progression of disease on every line of antitumor therapy: progressive disease, partial response, stable disease and complete response according to RECIST 1.1 evaluation and/or any other clinical assessment. Death: Disease-related or for other reasons

Measure: Clinical outcome/Patient response (for EGFRm+ patients who entered observation phase)

Time: up to 18 months

141 A Phase II, Multicenter, Open-label Study of EGF816 in Combination With Nivolumab in Adult Patients With EGFR Mutated Non-small Cell Lung Cancer and of INC280 in Combination With Nivolumab in Adult Patients With cMet Positive Non-small Cell Lung Cancer

To determine the efficacy and safety of Nivolumab in combination with EGF816 and of Nivolumab in combination with INC280 in previously treated NSCLC patients

NCT02323126
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: EGF816
  2. Drug: INC280
  3. Drug: Nivolumab
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

EGFR T790M positivity post progression on EGFR TKI for Group 1; cMet status for Group 2) must be provided for analysis Group 1 patients: - Patients with EGFR T790M NSCLC (adenocarcinoma) - Documented progression of disease according to RECIST v1.1 following primary standard of care (e.g. --- T790M ---

EGFR T790M positivity post progression on EGFR TKI for Group 1; cMet status for Group 2) must be provided for analysis Group 1 patients: - Patients with EGFR T790M NSCLC (adenocarcinoma) - Documented progression of disease according to RECIST v1.1 following primary standard of care (e.g. --- T790M --- --- T790M ---

Inhaled or topical steroids, and adrenal replacement steroid doses> 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease - Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) - Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection - Patients with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity - Patients with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity Prior therapy: - Patients who have been treated with prior PD-1 and PD-L1 agents - Patients who previously received agents targeting c-MET and/or EGFR T790M Note: Previous treatment with afatinib may be allowable after discussions between Novartis and Investigator. --- T790M ---

Primary Outcomes

Measure: Progression Free Survival (PFS) rate using RECIST version1.1

Time: 6 month

Secondary Outcomes

Description: Safety of EGF816 and Nivolumab and INC280 and Nivolumab by looking at hematology and chemistry laboratory parameters, vital signs, and electrocardiograms (ECGs)

Measure: Number of participants with Adverse Events (AEs)

Time: Continuously during study until 100 days after post study treatment

Measure: Objective response rate (ORR)

Time: baseline, every 8 weeks up to cycle 12, then every 12 weeks from cycle 13 until disease progression, consent withdrawal or death up to 1 year

Measure: Disease control rate

Time: baseline, every 8 weeks upto cycle 12, then every 12 weeks from cycle 13 until disease progression, consent withdrawal or death up to 1 year

Measure: Progression free survival

Time: baseline, every 8 weeks upto cycle 12, then every 12 weeks from cycle 13 until disease progression, consent withdrawal or death up to 1 year

Measure: Overall Survival

Time: Start of treatment until death, average 1 year

Measure: Plasma pharmacokinetic parameters (AUClast, AUC0-t,AUCtau,Cmax, Tmax)

Time: Cycle 1: Day1, Day 8, Day 15 and Cycle 2: Day 1, Cycle 4: Day 1 Cycle 6: Day 1 and Cycle 8: Day 1 Subsequent cycles (nivolumab only): every 8th cycle until discontinuation of study treatment

142 A Phase Ib/II, Multicenter, Open-label Study of EGF816 in Combination With INC280 in Adult Patients With EGFR Mutated Non-small Cell Lung Cancer.

The study is designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of EGF816 in combination with INC280 and to estimate the preliminary anti-tumor activity of EGF816 in combination with INC280 in patients with advanced non-small cell lung cancer (NSCLC) with documented EGFR mutation.

NCT02335944
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: INC280
  2. Drug: EGF816
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion criteria: - Histologically documented, locally advanced or recurrent (stage IIIB who are not eligible for combined modality treatment) or metastatic (Stage IV) NSCLC - Locally documented EGFR mutation L858R and/or ex19del, or a characterized de novo EGFR T790M mutation (or other rare activating mutations that confer sensitivity to 1st and 2nd generation EGFR inhibitors (e.g. --- L858R --- --- T790M ---

- Phase II Group 1 (EGFRmut, any T790M, any c-MET, 2/4L antineoplastic, EGFR TKI resistant) only: Patients demonstrated a documented clinical benefit (CR (any duration), PR (any duration), or SD for at least 6 months) on prior EGFR TKI (e.g. --- T790M ---

- Phase II Group 2 (EGFRmut, de novo T790M, any c-MET, 1/3L antineoplastic, EGFR TKI naïve) only: Advanced NSCLC patients who have not been previously treated with any therapy known to inhibit EGFR and harbor de novo T790M mutation . --- T790M ---

- Phase II Group 2 (EGFRmut, de novo T790M, any c-MET, 1/3L antineoplastic, EGFR TKI naïve) only: Advanced NSCLC patients who have not been previously treated with any therapy known to inhibit EGFR and harbor de novo T790M mutation . --- T790M --- --- T790M ---

- Phase II Group 3 (EGFRmut, T790M negative, any c-MET, 1L antineoplastic) only: patients must harbor an EGFR activating mutation and must be naïve from any line of systemic antineoplastic therapy in the advanced setting. --- T790M ---

- Phase II Group 4 (EGFRmut, any T790M, any c-MET, 1L (treatment-naïve), 2//3L antineoplastic): All patients must harbor an EGFR activating mutation and 2/3L patients must have failed (defined as intolerance to treatment or documented disease progression) a maximum of 2 prior lines of antineoplastic therapy in the advanced setting Exclusion Criteria: - Phase Ib: - More than one previous treatment line with erlotinib, gefitinib or afatinib - Previous treatment with any investigational agent known to inhibit EGFR (mutant or wild-type) - Patients who have received more than three prior lines of antineoplastic therapies (including EGFR TKI) in advanced setting. --- T790M ---

- Phase II Group 1 (EGFRmut, any T790M, any c-MET, 2/4L antineoplastic, EGFR TKI resistant): - More than 3 prior lines of systemic antineoplastic therapies (including EGFR TKI) in the advanced setting - More than 1 previous treatment line with 1st or 2nd generation EGFR TKI (e.g. --- T790M ---

- Phase II Group 2 (EGFRmut, de novo T790M, any c-MET, 1/3L antineoplastic, EGFR TKI naïve): - More than two previous treatment lines of systemic antineoplastic therapies in the advanced setting - Previous treatment with an investigational or marketed agent that inhibits EGFR. --- T790M ---

- Phase II Group 3 (EGFRmut, T790M negative, any c-MET, 1L antineoplastic): - De novo EGFR T790M mutation identified by central assessment - Previous treatment with any systemic antineoplastic therapy in the advanced setting (NSCLC stage IIIB or IV. --- T790M ---

- Phase II Group 3 (EGFRmut, T790M negative, any c-MET, 1L antineoplastic): - De novo EGFR T790M mutation identified by central assessment - Previous treatment with any systemic antineoplastic therapy in the advanced setting (NSCLC stage IIIB or IV. --- T790M --- --- T790M ---

- Phase II Group 4 (EGFRmut, any T790M, any c-MET, 1/3L antineoplastic): - More than 2 prior lines of systemic antineoplastic therapies in the advanced setting - Previous treatment with an investigational or marketed 3rd generation EGFR TKI (e.g. --- T790M ---

Primary Outcomes

Measure: Phase Ib: Incidence of dose limiting toxicities (DLTs) and Estimation of the Maximum tolerated dose (MTD) or Recommended Phase II dose (RP2D)

Time: First 28 days of treatment

Description: ORR is defined as the proportion of patients with a best overall response of complete response (CR) or partial response (PR) determined by Blinded Independent Review Committee (BIRC) assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1)

Measure: Phase II Groups 1, 2 and 3: Overall Response Rate per RECIST 1.1

Time: At least 24 weeks

Description: Frequency of treatment-emergent adverse events

Measure: Phase II Group 4 Incidence and severity of AEs/SAEs, dose interruptions, reductions and dose intensity

Time: At least 24 weeks

Secondary Outcomes

Description: Assessment of the safety of EGF816 in combination with INC280 will be performed continuously during the treatment phase and 30 days after discontinuation of the study treatment

Measure: Safety of INC280 and EGF816: Incidence and severity of AEs and SAEs, including changes in hematology and chemistry values, vital signs and ECGs (Phase I/II)

Time: At least 24 weeks

Description: Assessment of the tolerability of EGF816 in combination with INC280 will be performed continuously during the treatment phase and 30 days after discontinuation of the study treatment

Measure: Frequency of dose interruption, frequency of reduction and dose intensity (Phase I/II)

Time: At least 24 weeks

Description: ORR is defined as proportion of patients with best overall response of (PR+CR) determined by Investigator assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1)

Measure: Overall Response Rate (Phase Ib and Phase II Group 4)

Time: At least 24 weeks

Description: DCR is defined as the proportion of patients with best overall response of CR, PR, or SD determined by Investigator assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1)

Measure: Disease Control Rate (Phase I/II)

Time: At least 24 weeks

Description: Progression-free survival (PFS). PFS is defined as time from date of first dose of study treatment to date of first documented disease progression or death due to any cause determined by Investigator assessment in accordance to RECIST 1.1

Measure: Progression Free Survival (Phase I/II)

Time: At least 24 weeks

Description: DOR is defined as the time from first documented response (PR or CR) to the date of first documented disease progression or death due to any cause determined by Investigator assessment in accordance to RECIST 1.1

Measure: Duration of Response (Phase I/II)

Time: At least 24 weeks

Description: OS is defined as the time from first dose of the study treatment to the date of death due to any cause.

Measure: Overall Survival (Phase I/II)

Time: At least 24 weeks

Measure: Plasma concentration versus time profiles

Time: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1

Measure: Area under the plasma concentration versus time curve (AUC) of EGF816

Time: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1

Measure: Area under the plasma concentration versus time curve (AUC) of INC280

Time: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1

Measure: Peak plasma concentration (Cmax) of INC280

Time: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1

Measure: Peak plasma concentration (Cmax) of EGF816

Time: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1

Measure: Elimination half life (t1/2) of INC280

Time: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1

Measure: Elimination half life (t1/2) of EGF816

Time: Cycle 1 : Day 1, Day 2, Day 8, Day 15 and Day 16, Cycle 2 : Day 1 and Day 2, Cycle 3 Day 1 and Cycle 4 Day 1

Description: TTR is defined as the time from the date of the first dose to the date of first documented response (CR or PR) determined by Investigator assessment in accordance to Response Evaluation Criteria in Solid Tumors (RECIST 1.1)

Measure: Time to Response (Phase I/II)

Time: At least 24 weeks

143 Safety, Tolerability, Pharmacokinetics and Anti-tumour Activity of AC0010 in Patients With EGFR T790M Positive Advanced Non Small Cell Lung Cancer Who Progressed on Prior Therapy With EGFR TKIs

AC0010 is a novel, potent, small molecule irreversible tyrosine kinase inhibitor (TKI) that selectively targets mutant forms of the epidermal growth factor receptor (EGFR) while sparing wild-type (WT) EGFR. The purpose of the study is to evaluate the pharmacokinetic (PK) and safety profile of oral AC0010; to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of oral AC0010; to assess the safety and efficacy of AC0010 in previously treated mutant EGFR in NSCLC patients with EGFR T790M mutation.

NCT02330367
Conditions
  1. Metastatic Non-small Cell Lung Cancer
Interventions
  1. Drug: AC0010
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Safety, Tolerability, Pharmacokinetics and Anti-tumour Activity of AC0010 in Patients With EGFR T790M Positive Advanced Non Small Cell Lung Cancer Who Progressed on Prior Therapy With EGFR TKIs. --- T790M ---

Safety, Pharmacokinetic and Preliminary Efficacy Study of AC0010 in Patients With EGFR T790M Positive NSCLC AC0010 is a novel, potent, small molecule irreversible tyrosine kinase inhibitor (TKI) that selectively targets mutant forms of the epidermal growth factor receptor (EGFR) while sparing wild-type (WT) EGFR. --- T790M ---

The purpose of the study is to evaluate the pharmacokinetic (PK) and safety profile of oral AC0010; to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of oral AC0010; to assess the safety and efficacy of AC0010 in previously treated mutant EGFR in NSCLC patients with EGFR T790M mutation. --- T790M ---

To assess the overall objective response rate (ORR) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).. DoR (Duration of Response). --- T790M ---

To assess the duration of response (DOR) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).. PFS (Progression-free survival). --- T790M ---

To assess the progression-free survival (PFS) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).. DCR (Disease control rate). --- T790M ---

To assess the disease control rate (DCR) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).. OS (Overall survival). --- T790M ---

To assess the overall survival (OS) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).. EORTC QLQ-C30 and LC-13 questionnaire. --- T790M ---

To assess the safety of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).. Adverse events. --- T790M ---

To assess the safety of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).. Inclusion Criteria - Stage 1: 1. Patients of either gender, aged from 18 years older to 75. 2. Histologically or cytologically confirmed metastatic, or unresectable locally advanced, recurrent NSCLC. --- T790M ---

4. Failed to the treatment of EGFRTKI with definite state of T790M, or harbored T790M mutation without the treatment of EGFRTKI. 5. Offer biopsy sample to central lab if failed or without the treatment of EGFRTKI. --- T790M ---

4. Failed to the treatment of EGFRTKI with definite state of T790M, or harbored T790M mutation without the treatment of EGFRTKI. 5. Offer biopsy sample to central lab if failed or without the treatment of EGFRTKI. --- T790M --- --- T790M ---

4. Failed to the treatment of EGFR-TKI and harbored T790M mutation. --- T790M ---

Patients with arbored T790M mutation should be treated with only one kind of medicine or never be treated. --- T790M ---

However, patients on TKIs eventually progress, and in approximately 50% of cases, progression is due to development of an additional mutation called T790M. --- T790M ---

Pre-clinical data demonstrated that AC0010 inhibits T790M. --- T790M ---

It is anticipated that AC0010 may promote cell death in tumor cells with the T790M mutation, thus providing possible therapeutic benefit in patients who have developed T790M-mediated resistance to previous TKIs. --- T790M ---

It is anticipated that AC0010 may promote cell death in tumor cells with the T790M mutation, thus providing possible therapeutic benefit in patients who have developed T790M-mediated resistance to previous TKIs. --- T790M --- --- T790M ---

This study will include 2 parts: Stage 1 : Dose-escalation Period with 28-day cycles; Optional Treatment Extension Period starting on Day 29 Stage 2 : Evaluation of activity and safety in patients with the EGFR T790M mutation --- T790M ---

Primary Outcomes

Description: To assess the overall objective response rate (ORR) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).

Measure: ORR(Objective Response Rate)

Time: Every 6 weeks from time of first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 11 months

Secondary Outcomes

Description: To assess the duration of response (DOR) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).

Measure: DoR (Duration of Response)

Time: Every 6 weeks from time of first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 11 months

Description: To assess the progression-free survival (PFS) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).

Measure: PFS (Progression-free survival)

Time: Every 6 weeks from time of first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 11 months

Description: To assess the disease control rate (DCR) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).

Measure: DCR (Disease control rate)

Time: Every 6 weeks from time of first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 11 months

Description: To assess the overall survival (OS) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).

Measure: OS (Overall survival)

Time: Every 6 weeks from time of first dose until objective disease progression, then every 3 months until death of lost of follow-up, up to approximately 18 months

Description: To assess the safety of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).

Measure: EORTC QLQ-C30 and LC-13 questionnaire

Time: From screening to the end of survival follow-up, which is assessed though study completion

Description: To assess the safety of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).

Measure: Adverse events

Time: From screening to 30days after end of treatment, which is assessed through study completion

144 A Prospective Study of Plasma Genotyping as a Noninvasive Biomarker for Genotype-directed Cancer Care

Tumor genotyping has become an essential biomarker for the care of advanced lung cancer and melanoma, and is currently used to identify patients for treatment with targeted kinase inhibitors like erlotinib and vemurafenib. However, tumor genotyping can be slow and cumbersome, and is limited by availability of tumor biopsy tissue for testing. The aim of this study is to prospectively evaluate a blood-based genotyping tool that can quantify the presence of oncogenic mutations (EGFR, KRAS, BRAF) in patients with lung cancer and melanoma. This assay is being studied both as a diagnostic tool for classifying patient genotype, and a serial measurement tool for quantification of response and progression on therapy.

NCT02279004
Conditions
  1. NSCLC
  2. Melanoma
MeSH:Melanoma
HPO:Cutaneous melanoma Melanoma

We will determine the accuracy of plasma NGS in performing noninvasive genotyping compared to tumor NGS and paired ddPCR.. Inclusion Criteria To participate in this study a participant must meet the eligibility of one of the following cohorts: Cohort 1: Cancers beginning initial treatment - One of the following diagnoses: - Cohort 1A (CLOSED): ---Advanced non-squamous NSCLC (including adenosquamous) - Cohort 1B: - Stage II-III non-squamous NSCLC (including adenosquamous) - Stage IIIB-IV melanoma - Patient must be planned to begin initial therapy, or completely resected before or after receiving adjuvant therapy - For patients with NSCLC, EGFR and KRAS genotype may be known or unknown - For patients with melanoma, BRAF and NRAS genotype may be known or unknown - For patients without tumor genotyping, there must be a plan for genotyping including either: - Archived tumor tissue available and planned for genotyping - A biopsy at some future time is anticipated and will be available for genotyping Cohort 2: Cancers with acquired resistance to targeted therapy - One of the following diagnoses: - Cohort 2A (CLOSED): ---Advanced NSCLC harboring a known EGFR mutation - Cohort 2B: - Advanced NSCLC harboring a targetable genotype other than EGFR - Advanced melanoma harboring a known tumor genotype - Clinical determination of progression targeted therapy, as evidence by plans to start a new systemic treatment regimen, or obtain a biopsy to plan a new treatment regimen - New systemic treatment regimen planned OR - Re-biopsy for resistance genotyping planned - Note, date of targeted therapy start and clinical progression must be provided Cohort 3: Cancers with a known genotype starting palliative systemic therapy Cohort 3A (CLOSED): - Advanced NSCLC harboring one of the following mutations: - EGFR exon 19 deletion - EGFR L858R - EGFR T790M - KRAS G12X - BRAF V600E - Patients must be initiating palliative systemic therapy, either on or off a clinical trial Cohort 4: Paired plasma NGS and ddPCR - Cohort 4A (CLOSED): - Advanced NSCLC, newly diagnosed or with progression following treatment. --- L858R --- --- T790M ---

T790M, etc) Exclusion Criteria - Participants who are unable to provide informed consent - Participants who are 18 years of age or younger - Participants who are unable to comply with the study procedures Inclusion Criteria To participate in this study a participant must meet the eligibility of one of the following cohorts: Cohort 1: Cancers beginning initial treatment - One of the following diagnoses: - Cohort 1A (CLOSED): ---Advanced non-squamous NSCLC (including adenosquamous) - Cohort 1B: - Stage II-III non-squamous NSCLC (including adenosquamous) - Stage IIIB-IV melanoma - Patient must be planned to begin initial therapy, or completely resected before or after receiving adjuvant therapy - For patients with NSCLC, EGFR and KRAS genotype may be known or unknown - For patients with melanoma, BRAF and NRAS genotype may be known or unknown - For patients without tumor genotyping, there must be a plan for genotyping including either: - Archived tumor tissue available and planned for genotyping - A biopsy at some future time is anticipated and will be available for genotyping Cohort 2: Cancers with acquired resistance to targeted therapy - One of the following diagnoses: - Cohort 2A (CLOSED): ---Advanced NSCLC harboring a known EGFR mutation - Cohort 2B: - Advanced NSCLC harboring a targetable genotype other than EGFR - Advanced melanoma harboring a known tumor genotype - Clinical determination of progression targeted therapy, as evidence by plans to start a new systemic treatment regimen, or obtain a biopsy to plan a new treatment regimen - New systemic treatment regimen planned OR - Re-biopsy for resistance genotyping planned - Note, date of targeted therapy start and clinical progression must be provided Cohort 3: Cancers with a known genotype starting palliative systemic therapy Cohort 3A (CLOSED): - Advanced NSCLC harboring one of the following mutations: - EGFR exon 19 deletion - EGFR L858R - EGFR T790M - KRAS G12X - BRAF V600E - Patients must be initiating palliative systemic therapy, either on or off a clinical trial Cohort 4: Paired plasma NGS and ddPCR - Cohort 4A (CLOSED): - Advanced NSCLC, newly diagnosed or with progression following treatment. --- T790M ---

T790M, etc) Exclusion Criteria - Participants who are unable to provide informed consent - Participants who are 18 years of age or younger - Participants who are unable to comply with the study procedures Inclusion Criteria To participate in this study a participant must meet the eligibility of one of the following cohorts: Cohort 1: Cancers beginning initial treatment - One of the following diagnoses: - Cohort 1A (CLOSED): ---Advanced non-squamous NSCLC (including adenosquamous) - Cohort 1B: - Stage II-III non-squamous NSCLC (including adenosquamous) - Stage IIIB-IV melanoma - Patient must be planned to begin initial therapy, or completely resected before or after receiving adjuvant therapy - For patients with NSCLC, EGFR and KRAS genotype may be known or unknown - For patients with melanoma, BRAF and NRAS genotype may be known or unknown - For patients without tumor genotyping, there must be a plan for genotyping including either: - Archived tumor tissue available and planned for genotyping - A biopsy at some future time is anticipated and will be available for genotyping Cohort 2: Cancers with acquired resistance to targeted therapy - One of the following diagnoses: - Cohort 2A (CLOSED): ---Advanced NSCLC harboring a known EGFR mutation - Cohort 2B: - Advanced NSCLC harboring a targetable genotype other than EGFR - Advanced melanoma harboring a known tumor genotype - Clinical determination of progression targeted therapy, as evidence by plans to start a new systemic treatment regimen, or obtain a biopsy to plan a new treatment regimen - New systemic treatment regimen planned OR - Re-biopsy for resistance genotyping planned - Note, date of targeted therapy start and clinical progression must be provided Cohort 3: Cancers with a known genotype starting palliative systemic therapy Cohort 3A (CLOSED): - Advanced NSCLC harboring one of the following mutations: - EGFR exon 19 deletion - EGFR L858R - EGFR T790M - KRAS G12X - BRAF V600E - Patients must be initiating palliative systemic therapy, either on or off a clinical trial Cohort 4: Paired plasma NGS and ddPCR - Cohort 4A (CLOSED): - Advanced NSCLC, newly diagnosed or with progression following treatment. --- T790M --- --- L858R --- --- T790M ---

T790M, etc) Exclusion Criteria - Participants who are unable to provide informed consent - Participants who are 18 years of age or younger - Participants who are unable to comply with the study procedures NSCLC Melanoma Melanoma null --- T790M ---

Primary Outcomes

Description: We will determine the accuracy of a droplet digital PCR (ddPCR)-based plasma genotyping assay in performing noninvasive tumor genotyping.

Measure: Accuracy of Plasma Genotyping Assay

Time: 2 years

Secondary Outcomes

Description: The amount of time required to perform this noninvasive genotyping assay.

Measure: Turnaround Time of Plasma Genotyping Assay

Time: 2 years

Description: The ability of serial quantitative ddPCR-based plasma genotyping to predict early treatment failure in patients initiating a new line of therapy.

Measure: Early Treatment Failure

Time: 2 years

Description: We will determine the accuracy of plasma NGS in performing noninvasive genotyping compared to tumor NGS and paired ddPCR.

Measure: Accuracy of Plasma NGS

Time: 2 years

145 Safety, Tolerability, Pharmacokinetics and Anti-tumour Activity of AC0010 in Patients With Advanced Non Small Cell Lung Cancer Who Progressed on Prior Therapy With an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Agent

AC0010 Maleate Capsules is a new, irreversible, Epidermal Growth Factor Receptor (EGFR) mutation selective Tyrosine Kinase Inhibitor.Aim at local advanced or metastatic non-small cell lung cancer patients with EGFR mutation or T790M drug-resistant mutation. The molecular mechanism: by irreversible combining the EGFR-RTKs ATP binding site of cell, selectively suppress the activities of EGFR tyrosine kinase phosphorylation, block the sigal signal transduction system of EGFR, and close the function of ras/raf/MAPK downstream. at last block the tumor cell growth by EGFR induction, and promotes apoptosis. AC0010 Maleate Capsules has three characters: 1. Irreversible combination with EGFR; 2.Efficient suppress the EGFR mutant tumor cell and has no suppression to EGFR wild-type cell; 3. Efficient suppress the EGFR T790M drug-resistant mutation tumor cell.

NCT02274337
Conditions
  1. Non-Small Cell Lung Cancer
Interventions
  1. Drug: AC0010
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Safety, Tolerability, Pharmacokinetics and Anti-tumour Activity of AC0010 in Advanced Non Small Cell Lung Cancer AC0010 Maleate Capsules is a new, irreversible, Epidermal Growth Factor Receptor (EGFR) mutation selective Tyrosine Kinase Inhibitor.Aim at local advanced or metastatic non-small cell lung cancer patients with EGFR mutation or T790M drug-resistant mutation. --- T790M ---

AC0010 Maleate Capsules has three characters: 1. Irreversible combination with EGFR; 2.Efficient suppress the EGFR mutant tumor cell and has no suppression to EGFR wild-type cell; 3. Efficient suppress the EGFR T790M drug-resistant mutation tumor cell. --- T790M ---

- Have undergone or are able to undergo a biopsy of either primary or metastatic tumor tissue within 28 days of dosing of Avitinib, and have tissue available to send to central lab for further genetic profiling especially the status of T790M. --- T790M ---

Primary Outcomes

Description: Assessed by number and severity of adverse events as recorded on the case report form, vital signs, laboratory variables, physical examination, electrocardiogram, ophthalmic examinations, RECIST1.1, and NCI CTCAE v4.03

Measure: Safety, tolerability and ORR of AC0010

Time: Adverse events will be collected from baseline until 28 days after the last dose

Secondary Outcomes

Description: Plasma concentrations of AC0010 and 4 metabolites and pharmacokinetic parameters following single dose with fast in D1 and fed in D4 (Cmax, tmax, AUC, terminal rate constant, clearance, half life, volume of distribution and mean resistance time)

Measure: Plasma concentrations and pharmacokinetic parameters of single dose AC0010

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 1 ,4 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48hours post dose)

Description: Plasma concentrations of AC0010 and 4 metabolites and pharmacokinetic parameters following multiple doses (steady state Cmax, tmax, Cmin AUC, clearance, accumulation ratio and time dependency)

Measure: Plasma concentrations and pharmacokinetic parameters of multiple doses AC0010

Time: Blood samples will be collected from each subject at pre-specified times during the multiple dosing cycles (Cycle 1-pre-dose Day 1, 8 ,15 and 22. D28- pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48 hours post dose)

Description: Evaluation of tumour response, duration of response, tumour shrinkage, progression free survival and overall survival as assessed by RECIST 1.1

Measure: Efficacy of AC0010

Time: CT or MRI at screening and every 4-8 weeks (from first dose of multiple dosing) until disease progression or withdrawal from study, expected average 6 months

Measure: Food effect on AC0010's bioavailibility

Time: Blood samples will be collected from each subject at pre-specified times after the first dose of the study on Day 4 (pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48hours post dose)

146 Multicenter, Randomized, Phase Ib/IIb Study to Evaluate the Efficacy and Tolerability of Gefitinib in Combination With Olaparib (AZD2281) Versus Gefitinib Alone, in Patients With EGFR Mutation Positive Advanced Non-small-cell Lung Cancer

This is a study of gefitinib plus olaparib gefitinib in combination with olaparib (AZD2281) versus gefitinib alone, in patients with Epidermal Growth Factor Receptor (EGFR) mutation positive advanced non-small-cell lung cancer.

NCT01513174
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: Gefitinib
  2. Drug: Gefitinib plus olaparib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

4. Tumor tissue available (according to the criterion of the specimen-processing laboratory) for EGFR mutation assessment: to be included in the study patients should present at least one EGFR mutation (exon 19 deletion or L858R with or without T790M). --- L858R --- --- T790M ---

Primary Outcomes

Measure: MTD (Maximum Tolerated Dose) defined as the highest dose level at which < 2 out of 6 patients experience a DLT

Time: 5 weeks

Secondary Outcomes

Measure: Progression-free survival

Time: An expected average of 2 years

Measure: Overall response rate

Time: An expected average of 2 years

Measure: Overall survival

Time: An expected average of 2 years

Measure: Peak Plasma Concentration

Time: Predose, half an hour, 1, 2, 4, 6 and 12 hours post-dose

147 Phase II Trial of XL184 (Cabozantinib) Plus Erlotinib in Patients With Advanced EGFR-Mutant Non-small Cell Lung Cancer (NSCLC) Who Have Progressed on Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor (TKI) Therapy

This phase II trial studies how well cabozantinib-s-malate and erlotinib hydrochloride works in treating patients with previously treated metastatic non-small cell lung cancer. Cabozantinib-s-malate and erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Cabozantinib-s-malate may also stop the growth of non-small cell lung cancer by blocking blood flow to the tumor. Giving cabozantinib-s-malate together with erlotinib hydrochloride may be an effective treatment for non-small cell lung cancer.

NCT01866410
Conditions
  1. Recurrent Non-Small Cell Lung Carcinoma
  2. Stage IV Non-Small Cell Lung Cancer AJCC v7
Interventions
  1. Drug: Cabozantinib S-malate
  2. Drug: Erlotinib Hydrochloride
  3. Other: Laboratory Biomarker Analysis
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Estimated using the product-limit method of Kaplan and Meier.. Progression-free Survival by T790M Mutation Status. --- T790M ---

DNA was analyzed for the presence of the T790M point mutation.. Overall Survival by T790M Mutation Status. --- T790M ---

DNA was analyzed for the presence of the T790M point mutation.. Overall Survival by T790M Mutation Status. --- T790M --- --- T790M ---

V. Correlate outcome with tumor biomarkers such as met proto-oncogene (MET) amplification, T790M mutation, and serum markers of the vascular endothelial growth factor (VEGF) and MET pathways in a preliminary manner. --- T790M ---

Primary Outcomes

Description: Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR

Measure: Objective Response Rate

Time: Up to 2 years

Secondary Outcomes

Description: Tumor doubling time was estimated using an exponential growth model. Specifically, the pre-progression scan, and the baseline scan were used to estimate the doubling time prior to enrollment, td = log(2)∗1time/1log(tumor size) [derivation, S(t) = S(to)∗2∧[(t-to)/td] for a parameterization of exponential growth with a doubling time of td. Taking the logarithm on both sides: log(S(t))-log(S(to)) = log(2)∗(t - to)/td or td = log(2)∗(t - to)/[log(S(t))-log(S(to))] = log(2)∗1time/1log(S)], the baseline scan and first evaluation scan were used to determine the doubling time. Based on pre-planned protocol assessment, we estimated the percent of patients that experienced a slowing of tumor kinetics (a 30% increase in the length of time for tumor doubling) based on RECIST v1.1 measurements. Patients who did not get a scan on study, and patients whose pre-progression scans were missing or whose pre-progression tumor size was zero or whose tumor was decreasing prior to enrollment were excluded.

Measure: Percentage of Patients With a Greater Than 30% Increase in Tumor Doubling Time

Time: Up to 2 years

Description: Grade 3 & 4 adverse events attributed to treatment agents. Events are graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.

Measure: Number of Adverse Events

Time: Up to 2 years

Description: Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD), ≥ 20% increase in the sum of the longest diameter of target lesions compared with the smallest-sum longest diameter recorded or the appearance of one or more new lesions; Stable Disease (SD), Neither CR, PR or PD.

Measure: Best Response Patient Count

Time: Up to 2 years

Description: Estimated using the product-limit method of Kaplan and Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Measure: Progression-free Survival

Time: Until disease progression or death from any cause, up to 2 years

Description: Estimated using the product-limit method of Kaplan and Meier.

Measure: Overall Survival

Time: Until death from any cause, up to 2 years

Other Outcomes

Description: Estimated using the product-limit method of Kaplan and Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. DNA was analyzed for the presence of the T790M point mutation.

Measure: Progression-free Survival by T790M Mutation Status

Time: Until disease progression or death from any cause, up to 2 years

Description: Estimated using the product-limit method of Kaplan and Meier.

Measure: Overall Survival by T790M Mutation Status

Time: Until death from any cause, up to 2 years

Measure: Changes in VEGF Levels

Time: Baseline up to 6 months after last study treatment

Measure: Changes in HGF Levels

Time: Baseline up to 6 months after last study treatment

148 A Randomized Open-Label Phase II Trial of Pemetrexed and a Platinum (Carboplatin or Cisplatin) With or Without Erlotinib in Patients With Non-Small Cell Lung Cancer Harboring Activating Epidermal Growth Factor Receptor Mutations and Acquired Resistance to First-Line EGFR TKIs, Erlotinib or Gefitinib

This randomized phase II trial studies how well pemetrexed disodium and carboplatin or cisplatin with or without erlotinib hydrochloride work in treating patients with epidermal growth factor receptor (EGFR) mutant positive stage IV non-small cell lung cancer and acquired resistance to first-line therapy with erlotinib hydrochloride or gefitinib. In patients that develop resistance to first-line therapy with EGFR tyrosine kinase inhibitors (TKIs) the drug is usually stopped and the patient is switched to chemotherapy. Drugs used in chemotherapy, such as pemetrexed disodium, carboplatin, and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether pemetrexed disodium and carboplatin or cisplatin is more effective with or without erlotinib hydrochloride in treating patients with EGFR mutant non-small cell lung cancer and acquired resistance to EGFR TKIs.

NCT01928160
Conditions
  1. Recurrent Non-small Cell Lung Cancer
  2. Stage IV Non-small Cell Lung Cancer
Interventions
  1. Drug: pemetrexed disodium
  2. Drug: carboplatin
  3. Drug: cisplatin
  4. Drug: erlotinib hydrochloride
  5. Other: laboratory biomarker analysis
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

TERTIARY OBJECTIVES: I. To determine whether presence of the T790M resistance mutation can be used to predict which patients will benefit from the addition of erlotinib to chemotherapy. --- T790M ---

Primary Outcomes

Description: The Kaplan-Meier approach will be used to estimate the time-to-PFS distribution (and median PFS times) for each treatment arm. The stratified log-rank test will be used to compare the PFS distributions between the two treatment arms. The stratified Cox-regression model will be used to estimate the hazard ratio (erlotinib plus chemotherapy vs chemotherapy alone) and corresponding 80% confidence interval (CI).

Measure: Progression free survival using the Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1

Time: From randomization to the first occurrence of disease progression or death from any cause, whichever occurs earlier, assessed up to 1 year

Secondary Outcomes

Description: The Kaplan-Meier approach will be used. The stratified log-rank test will be used to compare the Overall Survival (OS) distributions between the two treatment arms. The stratified Cox-regression model will be used to estimate the hazard ratio (erlotinib plus chemotherapy vs chemotherapy alone) and corresponding 80% confidence interval (CI).

Measure: Overall survival

Time: From the date of randomization to the date of death from any cause, assessed up to 1 year

Description: An estimate of the objective response rate and its 95% CI (Blyth-Still-Casella) will be calculated for each treatment arm. The Mantel-Haenszel chi-squared test stratified according to the factors specified by EGFR activating mutation type (exon 19 deletion vs. exon 21 single point mutation), time to progression on first-line EGFR TKI (≤ 1 year vs. > 1 year), and ECOG performance status (0 vs. 1) will be used to compare the response rates between the two treatment arms. An unadjusted Fisher's exact test result will also be provided.

Measure: Objective response rate defined as partial response (PR) and complete response (CR) using RECIST version 1.1

Time: Up to 1 year

Description: Safety will be assessed through summaries of Adverse Events (AEs), Serious Adverse Events (SAEs), deaths, grade 3 or 4 AEs, AEs with incidence rates greater than 10% (all grades), AE of grade 3 or 4 with incidence rates greater 2%, and changes in laboratory test results. Verbatim descriptions of AEs will be mapped to Medical Dictionary for Regulatory Activities (MedDRA) thesaurus terms

Measure: Number of patients with each worst grade toxicity grades 3-5 based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4

Time: Up to 45 days post-treatment

149 A Multi-center Phase II Study of AUY922 in Patients With Stage IV Non-small Cell Lung Cancer (NSCLC) With Driver Molecular Alterations Other Than Sensitive EGFR Mutation, Who Have Progressed After One Line of Systemic Therapy

This is an open-label, single-arm, multicenter phase II trial in patients with stage IV EGFR T790M, EGFR exon 20 and other uncommon, HER2, or BRAF-mutated; ALK, ROS1, or RET-rearranged NSCLC.

NCT01922583
Conditions
  1. Non-small Cell Lung Cancer (NSCLC)
Interventions
  1. Drug: AUY922
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

AUY922 in Patient With Stage IV NSCLC This is an open-label, single-arm, multicenter phase II trial in patients with stage IV EGFR T790M, EGFR exon 20 and other uncommon, HER2, or BRAF-mutated; ALK, ROS1, or RET-rearranged NSCLC. --- T790M ---

To define the by RECIST 1.1 of AUY922 in patients with stage IV EGFR T790M, EGFR exon 20 and other uncommon, HER2, or BRAF-mutated; ALK, ROS1, or RET-rearranged NSCLC. --- T790M ---

- One of the molecular alterations as follows: - EGFR mutations in exon 20 T790M. --- T790M ---

A767_V769dupASV or H773_V774insH) or point mutations other than T790M; or other uncommon mutations. --- T790M ---

Non-small Cell Lung Cancer (NSCLC) Lung Neoplasms Carcinoma, Non-Small-Cell Lung Study Design: This is an open-label, single-arm, multicenter phase II trial in patients with stage IV EGFR T790M, EGFR exon 20 and other uncommon, HER2, or BRAF-mutated; ALK, ROS1, or RET-rearranged NSCLC (n = 9 x 7) Objectives: Primary objective(s): To define the objective response rate by RECIST 1.1 of AUY922 in patients with stage IV EGFR T790M, EGFR exon 20 and other uncommon, HER2, or BRAF-mutated; ALK, ROS1, or RET-rearranged NSCLC Secondary objective(s): (1) To define the disease control rate (complete response + partial response + stable disease >=24 weeks) of AUY922 in patients with stage IV EGFR T790M, EGFR exon 20 and other uncommon, HER2, or BRAF-mutated; ALK, ROS1, or RET-rearranged NSCLC. --- T790M ---

Non-small Cell Lung Cancer (NSCLC) Lung Neoplasms Carcinoma, Non-Small-Cell Lung Study Design: This is an open-label, single-arm, multicenter phase II trial in patients with stage IV EGFR T790M, EGFR exon 20 and other uncommon, HER2, or BRAF-mutated; ALK, ROS1, or RET-rearranged NSCLC (n = 9 x 7) Objectives: Primary objective(s): To define the objective response rate by RECIST 1.1 of AUY922 in patients with stage IV EGFR T790M, EGFR exon 20 and other uncommon, HER2, or BRAF-mutated; ALK, ROS1, or RET-rearranged NSCLC Secondary objective(s): (1) To define the disease control rate (complete response + partial response + stable disease >=24 weeks) of AUY922 in patients with stage IV EGFR T790M, EGFR exon 20 and other uncommon, HER2, or BRAF-mutated; ALK, ROS1, or RET-rearranged NSCLC. --- T790M --- --- T790M ---

Non-small Cell Lung Cancer (NSCLC) Lung Neoplasms Carcinoma, Non-Small-Cell Lung Study Design: This is an open-label, single-arm, multicenter phase II trial in patients with stage IV EGFR T790M, EGFR exon 20 and other uncommon, HER2, or BRAF-mutated; ALK, ROS1, or RET-rearranged NSCLC (n = 9 x 7) Objectives: Primary objective(s): To define the objective response rate by RECIST 1.1 of AUY922 in patients with stage IV EGFR T790M, EGFR exon 20 and other uncommon, HER2, or BRAF-mutated; ALK, ROS1, or RET-rearranged NSCLC Secondary objective(s): (1) To define the disease control rate (complete response + partial response + stable disease >=24 weeks) of AUY922 in patients with stage IV EGFR T790M, EGFR exon 20 and other uncommon, HER2, or BRAF-mutated; ALK, ROS1, or RET-rearranged NSCLC. --- T790M --- --- T790M --- --- T790M ---

(2) To determine the progression-free survival of AUY922 in patients with stage IV EGFR T790M, EGFR exon 20 and other uncommon, HER2, KRAS, or BRAF-mutated; ALK, ROS1, or RET-rearranged NSCLC. --- T790M ---

(3) To determine the overall survival of AUY922 in patients with stage IV EGFR T790M, EGFR exon 20 and other uncommon, HER2, KRAS, or BRAF-mutated; ALK, ROS1, or RET-rearranged NSCLC. --- T790M ---

2. EGFR T790M mutation; EGFR exon 20 and other uncommon mutation; HER2 mutation; BRAF mutation; ALK translocation; ROS1 translocation; or RET translocation in tumor samples. --- T790M ---

Primary Outcomes

Description: To define the by RECIST 1.1 of AUY922 in patients with stage IV EGFR T790M, EGFR exon 20 and other uncommon, HER2, or BRAF-mutated; ALK, ROS1, or RET-rearranged NSCLC

Measure: Objective response rate

Time: Patients will be followed up for 2 years(post disease progression)

Secondary Outcomes

Description: Patients will be followed for progression-free survival (PFS) and overall survival (OS) which will be analyzed by using a Kaplan-Meier curve. Patients will be followed up for PFS and OS for 2 years.

Measure: Efficacy, progression-free survival (PFS)

Time: Patients will be followed up for PFS and OS for 2 years.(post disease progression)

Description: Patients will be followed for overall survival (OS)

Measure: overall survival (OS)

Time: Patients will be followed up for OS for 2 years.(post disease progression)

150 A Phase III, Randomised, Controlled, Multi-center, 3-Arm Study of Neoadjuvant Osimertinib as Monotherapy or in Combination With Chemotherapy Versus Standard of Care Chemotherapy Alone for the Treatment of Patients With Epidermal Growth Factor Receptor Mutation Positive, Resectable Non-small Cell Lung Cancer

This is a Phase III, randomised, controlled, 3-arm, multi-centre study of neoadjuvant osimertinib as monotherapy or in combination with chemotherapy, versus SoC chemotherapy alone, for the treatment of patients with resectable EGFRm Non-Small Cell Lung Cancer

NCT04351555
Conditions
  1. Non-Small Cell Lung Cancer
Interventions
  1. Drug: Osimertinib
  2. Drug: Cisplatin
  3. Drug: Carboplatin
  4. Drug: Placebo
  5. Drug: Pemetrexed
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Eastern Cooperative Oncology Group (ECOG) PS of 0 or 1 at enrolment, with no deterioration over the previous 2 weeks prior to baseline or day of first dosing - A tumour which harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R), either alone or in combination with other EGFR mutations (ie, T790M, G719X, Exon20 insertions, S7681 and L861Q). --- L858R --- --- T790M ---

Primary Outcomes

Description: Defined as ≤10% residual cancer cells in the main tumour, as assessed per central pathology laboratory post-surgery

Measure: Major Pathological Response (MPR)

Time: From date of randomization to an average of 12 weeks after the first dose

Secondary Outcomes

Description: Defined as absence of any residual cancer cells in the dissected tumour samples, including the main tumour and lymph nodes, assessed post-surgery

Measure: Pathological complete response (pCR)

Time: From date of randomization to an average of 12 weeks after the first dose

Description: An event is defined as documented disease progression that precludes surgery or requires non-protocol therapy; recurrence or a new lesion, local or distant (a new primary malignancy confirmed by pathology is not considered to be an EFS event.); death due to any cause

Measure: Event-free survival (EFS)

Time: Up to approximately 42 months after the last patient is randomized

Description: Patients will be followed up to approximately 5.5 years after they are randomized.

Measure: Overall Survival (OS)

Time: Up to approximately 5.5 years after the last patient is randomized

Description: DFS is defined as the time from the date of surgery until the first date of disease recurrence (local or distant) or date of death due to any cause, whichever occurs first.

Measure: Disease free survival (DFS)

Time: From date of randomization up to approximately 42 months after date of resection

Description: Measured using pathologic mediastinal lymph node evaluation

Measure: Downstaging

Time: From date of randomization to an average of 12 weeks after the first dose

Description: Assess disease-related symptoms, functioning, and global health status/quality-of-life in patients

Measure: Difference between treatment arms in change from baseline in EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 items)

Time: From randomization to 264 weeks post-surgery

Measure: Concordance of EGFRm status between tumour tissue DNA and patient-matched plasma-derived ctDNA

Time: Baseline

Measure: Corcordance of EGFR mutation status between the local and central cobas EGFR mutation test results from baseline tumour samples

Time: Baseline

Measure: PK plasma concentrations of osimertinib

Time: From the pre-dose of Cycle 2 to post-dose of Cycle 3 (each cycle is 21 days)

Description: Assess lung cancer-associated symptoms and side effects from conventional chemotherapy and radiotherapy

Measure: Difference between treatment arms in change from baseline in EORTC QLQ-LC13 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 items)

Time: From randomization to 264 weeks post-surgery

Other Outcomes

Description: The cure rate is defined as the percentage of people in this study who are still alive and disease free for a certain period of time after they finished the surgery. Here 5-year landmark cure rate will be calculated in the same time as OS analysis.

Measure: Cure rate

Time: From the surgery until 5 years after surgery

Description: Other clinical variables include deaths, laboratory data, vital signs (pulse and BP), ECG, LVEF, ECOG performance status, and ophthalmologic assessment

Measure: Number of adverse events as assessed by CTCAE 5.0 and other clinical variables for safety and tolerability profile of neoadjuvant osimertinib as monotherapy or in combination with chemotherapy prior to surgery compared with chemotherapy alone

Time: From the time of enrollment to either 28-days after the last dose of last study treatment for patients who do not undergo surgery, or 90-days post-surgery

Measure: MPR using plasma-derived circulating-free tumour DNA (ctDNA)

Time: From randomization to 5 years post-surgery

151 Prospective Observational Trial to Evaluate the Efficacy of the Combination of Osimertinib and Aspirin in Patients With Disease Progression to 3st Generation Epidermal Growth Factor Receptor-tyrosine Kinase Inhibitor(EGFR-TKI) Osimertinib

The third generation epidermal growth gactor receptor-tyrosine Kinase Inhibitor(EGFR-TKI) osimertinib has obvious curative effect for EGFR sensitive mutation and T790M mutation(PMID 27959700), but acquired drug resistance will occur. Previous studies show that apoptosis escape can lead to EGFR-TKI resistance.Osimertinib resistant cells show abnormal activation of PI3K/AKT/BIM activation(PMID 28765329). The classical drug aspirin can effectively decrease AKT phosphorylation and activate of BIM(PMID 28881293).So Investigators speculate that aspirin may decrease the PI3K/AKT/BIM signaling pathways, then promote osimertinib resistant cells apoptosis. The current study aims to evaluate the combination of aspirin and osimertinib in patients with EGFR/T790M mutations.

NCT03532698
Conditions
  1. Non-Small Cell Lung Cancer Stage IIIB
  2. Non-small Cell Lung Cancer Stage IV
  3. EGFR T790M
Interventions
  1. Drug: Aspirin
  2. Drug: Osimertinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Combination of Osimertinib and Aspirin to Treat Osimertinib Resistance Non-small Cell Lung Cancer ( NSCLC) The third generation epidermal growth gactor receptor-tyrosine Kinase Inhibitor(EGFR-TKI) osimertinib has obvious curative effect for EGFR sensitive mutation and T790M mutation(PMID 27959700), but acquired drug resistance will occur. --- T790M ---

The current study aims to evaluate the combination of aspirin and osimertinib in patients with EGFR/T790M mutations. --- T790M ---

Non-Small Cell Lung Cancer Stage IIIB Non-small Cell Lung Cancer Stage IV EGFR T790M Lung Neoplasms Carcinoma, Non-Small-Cell Lung Reversible small-molecule EGF receptor tyrosine kinase inhibitors (EGFR-TKI) have shown dramatic therapeutic efficacy in non-small cell lung cancer (NSCLC) patients with EGFR-activating mutations, and have been recommended as the standard first-line therapy in these patients. --- T790M ---

Osimertinib is a 3rd-generation EGFR-TKI used to treat NSCLC patients with resistance to 1st generation EGFR-TKI due to T790M mutation. --- T790M ---

Here, investigators'group observed that in clinic, several patients who took osimertinib and aspirin together have shown excellent effect.Investigators therefore conduct this clinical trial to observe whether the combination of Aspirin and Osimertinib could enhance efficacy of Osimertinib in lung cancer patients resistant to 1st generation EGFR-TKI with T790M. --- T790M ---

Primary Outcomes

Description: To evaluate the response to therapy and Objective Response Rate of the combination of Osimertinib and Aspirin in patients who has metastatic pulmonary adenocarcinoma disease progression to 3st generation EGFR-TKI Osimertinib.

Measure: Objective Response Rate(ORR) according to resist 1.1

Time: 2years

Secondary Outcomes

Description: To evaluate the response to therapy and disease control rate of the combination of Osimertinib and Aspirin in patients who has metastatic pulmonary adenocarcinoma disease progression to 3st generation EGFR-TKI Osimertinib.

Measure: disease control rate(DCR) according to resist 1.1

Time: 2years

Description: To evaluate the response to therapy and Time to progression of the combination of Osimertinib and Aspirin in patients who has metastatic pulmonary adenocarcinoma disease progression to 3st generation EGFR-TKI Osimertinib.

Measure: Time to progression(TTP) according to resist 1.1

Time: 2years

Description: To evaluate the response to therapy and duration of Response of the combination of Osimertinib and Aspirin in patients who has metastatic pulmonary adenocarcinoma disease progression to 3st generation EGFR-TKI Osimertinib.

Measure: duration of Response(DOR) according to resist 1.1

Time: 2years

152 A Phase II Study of Rucaparib in Patients With Genomic LOH High and/or Deleterious BRCA1/2 Mutation Stage IV or Recurrent Non-Small Cell Lung Cancer (LUNG-MAP Sub-Study)

This phase II Lung-MAP trial studies how well rucaparib works in treating patients with genomic loss of heterozygosity (LOH) high and/or deleterious BRCA1/2 mutation stage IV non-small cell lung cancer or that has come back. Rucaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT03845296
Conditions
  1. Deleterious BRCA1 Gene Mutation
  2. Deleterious BRCA2 Gene Mutation
  3. Loss of Heterozygosity
  4. Lung Non-Small Cell Squamous Carcinoma
  5. Recurrent Large Cell Lung Carcinoma
  6. Recurrent Lung Adenocarcinoma
  7. Recurrent Lung Non-Small Cell Carcinoma
  8. Recurrent Non-Squamous Non-Small Cell Lung Carcinoma
  9. Stage IV Lung Cancer AJCC v8
  10. Stage IVA Lung Cancer AJCC v8
  11. Stage IVB Lung Cancer AJCC v8
Interventions
  1. Drug: Rucaparib
MeSH:Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung Adenocarcinoma of Lung Carcinoma, Squamous Cell
HPO:Carcinoma Neoplasm of the lung Non-small cell lung carcinoma Squamous cell carcinoma

- Patients must not have EGFR sensitizing mutations, EGFR T790M mutation, ALK gene fusion, ROS 1 gene rearrangement, and BRAF V600E mutation unless they have progressed following all standard of care targeted therapy. --- T790M ---

Primary Outcomes

Description: Will be estimated using the method of Kaplan-Meier. The Brookmeyer-Crowley method will be used to calculate confidence intervals for median times.

Measure: Investigator assessed progression free survival (PFS)

Time: From date of sub-study registration to date of first documentation of progression assessed by local review or symptomatic deterioration, or death due to any cause, assessed up to 3 years

Description: Response will be assessed by Response Evaluation Criteria in Solid Tumors 1.1. Response rates and associated confidence intervals will be calculated. Will be estimated using the method of Kaplan-Meier. The Brookmeyer-Crowley method will be used to calculate confidence intervals for median times. Response rates can be estimated within 16% with 95% confidence.

Measure: Duration of response (DoR)

Time: From date of first documentation of response (complete response [CR] or partial response [PR]) to date of first documentation of progression assessed by local review or symptomatic deterioration, or death due to any cause, assessed up to 3 years

Description: Will be estimated using the method of Kaplan-Meier. The Brookmeyer-Crowley method will be used to calculate confidence intervals for median times.

Measure: Overall survival

Time: From date of sub-study registration to date of death due to any cause, assessed up to 3 years

Measure: Time to death

Time: From date of sub-study registration to date of death due to any cause, assessed up to 3 years

Description: Toxicity will be evaluated among all patients enrolled on the study (combining the squamous and non-squamous cohorts). Toxicity can be estimated to within 11% with 95% confidence.

Measure: Incidence of adverse events

Time: Up to 3 years

153 Achieving Value in Cancer Diagnostics: Blood Versus Tissue Molecular Profiling - a Prospective Canadian Study

Current guidelines in non-small cell lung cancer recommend genomic assessment for mutations in EGFR and BRAF, gene rearrangements in ALK and ROS1, and resistance mutations such as T790M upon progression during EGFR inhibitor therapy. However, obtaining sufficient tumour tissue to test for these molecular alterations, as well as those with emerging targeted therapies, is challenging in lung cancer. A promising method to improve molecular diagnostic testing in lung and other cancers is the use of circulating cell-free DNA (cfDNA) obtained from blood samples or liquid biopsies. This multi-centre prospective study will compare blood-based profiling (using the GUARDANT360 assay) to standard of care tissue-based profiling within the Canadian system.

NCT03576937
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Diagnostic Test: GUARDANT360
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Achieving Value in Cancer Diagnostics: Blood Versus Tissue Molecular Profiling - a Prospective Canadian Study Current guidelines in non-small cell lung cancer recommend genomic assessment for mutations in EGFR and BRAF, gene rearrangements in ALK and ROS1, and resistance mutations such as T790M upon progression during EGFR inhibitor therapy. --- T790M ---

Cohort 2 only: evidence of disease progression on prior targeted tyrosine kinase inhibitor or other targeted therapy for EGFR including T790M, ALK, ROS-1 or BRAF-deranged advanced NSCLC. --- T790M ---

Patients progressing on 1st or 2nd generation EGFR TKI must have undergone SOC testing for EGFR T790M. --- T790M ---

If blood- or tissue-negative for T790M, the patient is eligible for this study. --- T790M ---

If T790M-positive, the patient must have progressed on a T790M inhibitor to be eligible. --- T790M ---

If T790M-positive, the patient must have progressed on a T790M inhibitor to be eligible. --- T790M --- --- T790M ---

Primary Outcomes

Description: Measure best response to first-line therapy using investigator-assessed RECIST 1.1, including progression free survival and time to treatment failure, in patients with advanced lung adenocarcinoma using the cfDNA GUARDANT360 assay versus standard of care tissue genotyping.

Measure: Response rate to first-line therapy

Time: Up to 18 Months

Secondary Outcomes

Description: Compare the proportion of patients receiving targeted therapy using the cfDNA GUARDANT360 assay versus standard of care tissue genotyping.

Measure: Proportion of patients receiving targeted therapy

Time: Up to 18 Months

Description: The time to treatment initiation using both genotyping methods, will be calculated as the number of days from the date of pathologic or clinical stage IV NSCLC diagnosis until initiation of systemic treatment. This will be compared to the turnaround time for GUARDANT360 results.

Measure: Time to Treatment Initiation

Time: Up to 18 Months

Description: Count the number of actionable genomic alterations identified in cfDNA that were not identified in tumour tissue standard of care testing.

Measure: Incremental number of actionable genomic alterations

Time: Up to 18 Months

Description: Calculate the time (in days) from the date of request for testing to the report date for both genotyping methods.

Measure: Turnaround time of cfDNA vs. tissue results

Time: Up to 18 Months

Description: Cost consequence analysis to examine incremental mean direct and indirect costs in Canadian dollars between the two approaches (cfDNA testing vs tumour tissue genotyping).

Measure: Costs of cfDNA vs. tissue testing

Time: Up to 18 Months

Other Outcomes

Description: Assess response rate in patients (Cohort 1) who received single agent or combination immunotherapy.

Measure: Response rate to immunotherapy

Time: Up to 18 Months

Description: Assess response duration in patients (Cohort 1) who received single agent or combination immunotherapy.

Measure: Response duration to immunotherapy

Time: Up to 18 Months

Description: Patient quality of life will be measured using the EQ5D-5L, which will be administered upon entry to the study and 3 months after starting systemic therapy.

Measure: Patient reported quality of life

Time: Upon entry and 3 months following initiation of systemic therapy

Description: Evaluate patient willingness-to-pay for using a next generation sequencing assay, such as the GUARDANT360, using a validated patient survey.

Measure: Patient willingness-to-pay

Time: Within 30 days of study enrollment

154 Efficacy and Safety of Toripalimab (JS001) Combined With Pemetrexed and Anlotinib for Patients With T790M Positive Non-Small Cell Lung Cancer After Osimertinib Resistance:a Phase II,Muti-center, Single Arm Study

This is an open-label, single-arm, multi-center, phase II exploratory study that evaluates the efficacy and safety of Toripalimab injection (JS001) combined with Pemetrexed and Anlotinib as a second-line treatment for patients with T790M positive Non-Small Cell Lung Cancer (IIIb / IV ) after Osimertinib resistance.

NCT04316351
Conditions
  1. IIIb/IV NSCLC With T790M Positive Mutations Failed to Osimertinib Therapy
Interventions
  1. Drug: Toripalimab + Pemetrexed + Anlotinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Efficacy and Safety of Toripalimab (JS001) Combined With Pemetrexed and Anlotinib for Patients With T790M Positive Non-Small Cell Lung Cancer After Osimertinib Resistance:a Phase II,Muti-center, Single Arm Study. --- T790M ---

Efficacy and Safety of Toripalimab (JS001) Combined With Pemetrexed and Anlotinib for Patients With T790M Positive Non-Small Cell Lung Cancer After Osimertinib Resistance This is an open-label, single-arm, multi-center, phase II exploratory study that evaluates the efficacy and safety of Toripalimab injection (JS001) combined with Pemetrexed and Anlotinib as a second-line treatment for patients with T790M positive Non-Small Cell Lung Cancer (IIIb / IV ) after Osimertinib resistance. --- T790M ---

Efficacy and Safety of Toripalimab (JS001) Combined With Pemetrexed and Anlotinib for Patients With T790M Positive Non-Small Cell Lung Cancer After Osimertinib Resistance This is an open-label, single-arm, multi-center, phase II exploratory study that evaluates the efficacy and safety of Toripalimab injection (JS001) combined with Pemetrexed and Anlotinib as a second-line treatment for patients with T790M positive Non-Small Cell Lung Cancer (IIIb / IV ) after Osimertinib resistance. --- T790M --- --- T790M ---

overall incidence of adverse events (AE); incidence of grade 3 or higher AE; incidence of severe adverse events (SAE); incidence of AEs leading to discontinuation of drug use; incidence of AEs leading to suspension of drug use.. Inclusion Criteria: 1. Fully understand this study and voluntarily sign the informed consent form (ICF); 2. Histologically and/or cytologically confirmed Stage IIIb / IV NSCLC (according to the seventh edition of AJCC); patients with T790M-positive mutations who were resistant to Osimertinib treatment; 3. --- T790M ---

Inclusion Criteria: 1. Fully understand this study and voluntarily sign the informed consent form (ICF); 2. Histologically and/or cytologically confirmed Stage IIIb / IV NSCLC (according to the seventh edition of AJCC); patients with T790M-positive mutations who were resistant to Osimertinib treatment; 3. --- T790M ---

IIIb/IV NSCLC With T790M Positive Mutations Failed to Osimertinib Therapy Carcinoma, Non-Small-Cell Lung null --- T790M ---

Primary Outcomes

Description: Defined as percentage of participants achieving complete response (CR) and partial response (PR) assessed by the Independent Review Committee (IRC) according to the RECIST 1.1

Measure: Overall response rate (ORR)

Time: two years

Secondary Outcomes

Description: assessed by IRC and researchers based on RECIST 1.1

Measure: Progression-free survival (PFS)

Time: two years

Description: assessed by IRC and researchers based on RECIST 1.1

Measure: Overall survival (OS)

Time: two years

Description: assessed by IRC and researchers based on RECIST 1.1

Measure: Disease Control Rate (DCR)

Time: two years

Description: assessed by IRC and researchers based on RECIST 1.1

Measure: Duration of disease response (DOR)

Time: two years

Description: overall incidence of adverse events (AE); incidence of grade 3 or higher AE; incidence of severe adverse events (SAE); incidence of AEs leading to discontinuation of drug use; incidence of AEs leading to suspension of drug use.

Measure: overall incidence of adverse events (AE)

Time: two years

155 A Phase Ib Study to Evaluate the Efficacy and Safety of RC48-ADC for Injection in Subjects With Advanced Non-small Cell Lung Cancer With HER2 Overexpression or HER2 Mutation

This study will evaluate the efficacy and safety of RC48-ADC for injection in subjects with advanced non-small cell lung cancer with HER2 overexpression or HER2 mutation.

NCT04311034
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: RC48
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

For EGFR gene mutation-positive patients, one of the following is met: 1) T790M gene mutation negative, c-Met gene amplification negative and HER2 IHC 2+ or 3+ after first-generation EGFR-TKI drug resistance; 2) Third-generation EGFR-TKI treatment failed and HER2 IHC 2+ or 3+. 9. Measurable lesion according to the RECIST 1.1. --- T790M ---

Primary Outcomes

Description: Objective Response Rate was defined as the percentage of participants with a complete response (CR) or partial response (PR).

Measure: Objective Response Rate (ORR)

Time: 15 months

Description: Disease Control Rate (DCR) was defined as the percentage of patients with advanced or metastatic cancer who have achieved complete response, partial response and stable disease to a therapeutic intervention in clinical trials of anticancer agents.

Measure: Disease Control Rate (DCR)

Time: 15 months

Description: Progression-free Survival (PFS) (median) was determined using the number of months measured from the initial date of treatment to the date of documented progression, or the date of death (in the absence of progression) of participants. Progression is defined using Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Measure: Progression Free Survival (PFS)

Time: 15 months

Description: Duration of response is the length of time that a tumor continues to respond to treatment without the cancer growing or spreading.

Measure: Duration of Response (DOR)

Time: 15 months

Description: Overall survival, or OS, measures how long patients, who undergo a certain treatment regimen.

Measure: Overall Survival (OS)

Time: 24 months

Secondary Outcomes

Description: The drug safety was assessed by investigator(s) according to NCI-CTCAE v4.03.

Measure: Adverse events (AEs)

Time: Up to 2 years

156 Tislelizumab Combined With Bevacizumab and Albumin Paclitaxel in the Treatment of Advanced Lung Adenocarcinoma: a Single-arm, Phase Ⅱ Clinical Trial

The single arm clinical study is to evaluate the efficacy and safety of Tislelizumab combined with Bevacizumab and albumin paclitaxel in the treatment of advanced lung adenocarcinoma. All of the patients were received EGFR-TKI therapy for 1 line and disease progression. The primary endpoint is one-year PFS rate and safety, the seconday endpoint is ORR and one-year OS rate.

NCT04310943
Conditions
  1. Lung Adenocarcinoma Stage IV
Interventions
  1. Drug: Tislelizumab
MeSH:Adenocarcinoma Adenocarcinoma of Lung

Inclusion Criteria: - lung adenocarcinoma stage Ⅳ(according AJCC 8) - received EGFR-TKI for 1 line and disease progression - EGFR T790M negative - ECOG PS 0-1 Exclusion Criteria: - histology of mixed NSCLC with squamous cell carcinoma, neuroendocrine carcinoma and small cell carcinoma. --- T790M ---

- uncontrolled pleural effusion, pericardial effusion, or ascites after appropriate intervention - any unstable systemic disease - patients who were treated with systemic glucocorticoids (>10mg/ day prednisone therapeutic dose) or other immunosuppressive drugs within 14 days prior to the initial administration or during the study period Inclusion Criteria: - lung adenocarcinoma stage Ⅳ(according AJCC 8) - received EGFR-TKI for 1 line and disease progression - EGFR T790M negative - ECOG PS 0-1 Exclusion Criteria: - histology of mixed NSCLC with squamous cell carcinoma, neuroendocrine carcinoma and small cell carcinoma. --- T790M ---

Primary Outcomes

Description: rate of progression free survical in one year

Measure: PFS rate

Time: one year

Description: TEAE are adverse events that occur during or after the first administration of the study drug until 30 days after the study drug is discontinued or the new anticancer treatment is initiated or worse than at baseline (before treatment)

Measure: Safety of Tislelizumab

Time: 30 days after the trial finished

Secondary Outcomes

Description: objective response rate

Measure: ORR

Time: one year

Description: rate of oversurvival rate

Measure: OS rate

Time: one year

157 A Single Arm Phase II Study Osimertinib in Patients With Stage 4 Non-small Cell Lung Cancer With Uncommon EGFR Mutations

This is a research study to find out if a drug called, osimertinib, is safe and effective in treating advanced Non-Small Cell Lung Cancer (NSCLC) by targeting the treatment of epidermal growth factor receptor (EGFR) mutation exon 18 G719X, exon 20 S7681, or exon 21 L861Q. Patients on the study will not have had previous tyrosine kinase inhibitor (TKI) treatment.

NCT03434418
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: osimertinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Malabsorption syndrome, refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of osimertinib - Detection of concurrent EGFR mutation with exon 20 T790M, exon 19 deletion, exon 21 L858R mutation or exon 20 insertion. --- T790M ---

Primary Outcomes

Description: RECIST 1.1 will be used to measure confirmed partial or complete responses to the study drug.

Measure: Objective response rate as assessed by the investigator using Response Evaluation Criteria In Solid Tumors RECIST 1.1 (brand name)

Time: Up to 3 years

Secondary Outcomes

Description: Progression will be defined as time from starting study therapy to disease progression or death (whichever occurs first)

Measure: Progression free survival as measured by Response Evaluation Criteria In Solid Tumors RECIST 1.1 (brand name) as assessed by the investigator.

Time: Up to 5 years

Description: Evaluation of safety using the National Cancer Institute (NCI) CTCAE version 4.03

Measure: AEs as measured by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03

Time: Up to 3 years

Description: Overall survival as defined as time from starting study therapy until death from any causes.

Measure: Overall survival as noted by follow-up via composite of telephone or medical record review.

Time: Up to 5 years

158 A Multicenter, Two-Part, Phase 1B Clinical Study of CMP-001 in Combination With Atezolizumab With and Without Radiation Therapy in Subjects With Advanced Non Small Cell Lung Cancer (NSCLC)

This is a multicenter, two part (Part A and Part B) clinical study of CMP-001 administered intratumorally (IT) and subcutaneously (SC) in combination with atezolizumab with or without radiation therapy in participants with NSCLC.

NCT03438318
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: CMP-001
  2. Drug: Atezolizumab
  3. Radiation: Radiation Therapy
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Participants with epidermal growth factor (EGFR) activating mutations, EGFR T790M or anaplastic lymphoma kinase (ALK) gene re-arrangement must have received prior standard of care and have evidence of disease progression. --- T790M ---

Primary Outcomes

Description: TEAEs will be evaluated and assigned a grade using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Measure: Part A and B: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)

Time: From first dose of CMP-001 (Week 1 Day 1) until 30 days after the last CMP-001 injection (up to approximately 2 years 9 months)

Measure: Part A and B: DLT

Time: First 30 days of therapy starting from Week 1 Day 1

Secondary Outcomes

Description: Oral temperature should be measured in supine or seated position, following at least 3 minutes of rest.

Measure: Part A and B: Oral Temperature

Time: From screening up to end of treatment (EOT) (up to approximately 2 years 9 months)

Description: Respiratory rate should be measured in supine or seated position, following at least 3 minutes of rest.

Measure: Part A and B: Respiratory Rate

Time: From screening up to EOT (up to approximately 2 years 9 months)

Description: Blood pressure should be measured in supine or seated position, following at least 3 minutes of rest.

Measure: Part A and B: Systolic and Diastolic Blood Pressure

Time: From screening up to EOT (up to approximately 2 years 9 months)

Description: Physical examination included body weight measurement.

Measure: Part A and B: Body Weight

Time: From screening up to EOT (up to approximately 2 years 9 months)

Description: Physical examination included BMI measurement.

Measure: Part A and B: Body Mass Index (BMI)

Time: From screening up to EOT (up to approximately 2 years 9 months)

Description: ECG parameters will include heart rate and PR, QRS, QT, and QT corrected for heart rate (QTc) intervals. QT will be corrected using Fridericia's (QTcF) formula. ECG will be performed after the participant has been resting in supine or semi-supine position for at least 5 minutes.

Measure: Part A and B: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiogram (ECG) Parameters

Time: From screening up to EOT (up to approximately 2 years 9 months)

Description: Clinical laboratory parameters include serum chemistry, hematology, and urinalysis.

Measure: Part A and B: Number of Participants With Clinically Significant Abnormalities in Clinical Laboratory Parameters

Time: From screening up to EOT (up to approximately 2 years 9 months)

Measure: Part A and B: Concentration of Chemokine IP-10

Time: Day 1 of Weeks 1, 3, 8, and Day 2 of Weeks 3, 8

Description: ORR will be calculated as the number of participants with a confirmed complete response (CR) or partial response (PR) divided by the number of participants dosed.

Measure: Part A and B: Objective Response Rate (ORR) (Percentage of Participants With Objective Response) as per RECIST V1.1 or iRECIST Using CT/PET or MRI Scans

Time: Baseline until confirmed disease progression (CR or PR) or death, whichever occur first (assessment at every 9 weeks throughout the study from Week 1 Day 1, up to approximately 2 years 9 months

Measure: Part A and B: Time to Response (TTR) as per RECIST V1.1 or iRECIST Using CT/PET or MRI Scans

Time: From first dose of CMP-001 until disease progression or death, whichever occur first (assessment at every 9 weeks throughout the study from Week 1 Day 1, up to approximately 2 years 9 months)

Measure: Part A and B: Duration of Response (DOR) as per RECIST V1.1 or iRECIST Using CT/PET or MRI Scans

Time: From the date of first confirmed CR or PR until the first date of recurrent or progressive disease (assessment at every 9 weeks throughout the study from Week 1 Day 1, up to approximately 2 years 9 months)

159 A Phase II Study to Evaluate Neoadjuvant Osimertinib Therapy in Patients With Surgically Resectable, EGFR-Mutant Non-Small Cell Lung Cancer

This phase II trial studies how well osimertinib works in treating participants with stage I-IIIA Epithelial Growth Factor Receptor (EGFR) -mutant non-small cell lung cancer before surgery. Osimertinib may stop the growth of tumor cells by blocking mutant EGFR signaling in cancer cells.

NCT03433469
Conditions
  1. Stage I Non-Small Cell Lung Cancer
  2. Stage IA Non-Small Cell Lung Cancer
  3. Stage IB Non-Small Cell Lung Cancer
  4. Stage II Non-Small Cell Lung Cancer
  5. Stage IIA Non-Small Cell Lung Cancer
  6. Stage IIB Non-Small Cell Lung Cancer
  7. Stage IIIA Non-Small Cell Lung Cancer
Interventions
  1. Drug: Osimertinib
  2. Procedure: Therapeutic Conventional Surgery
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - Males and females >=18 years of age - Histologically or cytologically confirmed non-small cell lung cancer (NSCLC), performed on a biopsy that occurred within the last 90 days - Documented activating EGFR mutation (Exon 19 deletion, T790M, or L858R) on tumor samples by Clinical Laboratory Clinical Laboratory Improvement Amendments (CLIA)-approved test - Positron emission tomography (PET)-computed tomography (CT) within the last 60 days showing radiographic stage I to IIIa lung cancer (mediastinal staging biopsy is allowed but not required) - Brain magnetic resonance imaging (MRI) (or CT if contraindication to MRI) within the last 60 days showing no evidence of metastatic disease - Documentation that the patient is a candidate for surgical resection of their lung cancer by an American Board of Thoracic Surgery certified surgeon - The patient must have a tumor size >=1 centimeter (cm) in its longest diameter. --- T790M ---

malabsorption syndrome, history of biliary tract disease), including refractory nausea or vomiting, or chronic GI disease which may affect absorption or tolerance to oral medications - History of hypersensitivity to active or inactive excipients of osimertinib or drugs with a similar chemical structure or class to osimertinib - Involvement in the planning and/or conduct of the study (applies to both investigator staff and/or staff at the study site) - Participation in another clinical study with an investigational product during the last 2 months or within five half-lives of the compound, whichever is longer - Uncontrolled medical, psychological, familial, sociological, or geographical conditions that interfere with the patient?s safety, ability to provide informed consent, or ability to comply with the protocol Inclusion Criteria: - Males and females >=18 years of age - Histologically or cytologically confirmed non-small cell lung cancer (NSCLC), performed on a biopsy that occurred within the last 90 days - Documented activating EGFR mutation (Exon 19 deletion, T790M, or L858R) on tumor samples by Clinical Laboratory Clinical Laboratory Improvement Amendments (CLIA)-approved test - Positron emission tomography (PET)-computed tomography (CT) within the last 60 days showing radiographic stage I to IIIa lung cancer (mediastinal staging biopsy is allowed but not required) - Brain magnetic resonance imaging (MRI) (or CT if contraindication to MRI) within the last 60 days showing no evidence of metastatic disease - Documentation that the patient is a candidate for surgical resection of their lung cancer by an American Board of Thoracic Surgery certified surgeon - The patient must have a tumor size >=1 centimeter (cm) in its longest diameter. --- T790M ---

Primary Outcomes

Description: Tumors that exhibit =< 10% viable tumor will meet the criteria for a major pathological response. MPR rate will be determined in patients who receive at least one dose of study drug and become ineligible for surgery either because of disease progression or adverse event will be deemed not to have achieved MPR. The major pathological response rate will be reported with 95% confidence intervals.

Measure: Major pathological response rate (MPR)

Time: Up to 1 year

Secondary Outcomes

Description: The frequency and percentages of patients with a best overall response rate of complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) determined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria and by investigator's assessment will be determined from the time of treatment until surgery. The frequency and percentages of patients with a best ORR of CR, PR, SD, or PD will be determined. The ORR will be reported with 95% confidence intervals.

Measure: Objective Response Rate (ORR)

Time: Up to 70 days

Description: DFS will be calculated as 1+ the number of days from date of surgical resection to documented radiographic relapse/progression or death due to any cause over a period of 60 months. The Kaplan-Meier analysis will be used to calculate the median DFS with 95% confidence interval.

Measure: Mean Disease-free survival (DFS)

Time: Up to 5 years

Description: DFS will be calculated as 1+ the number of days from date of surgical resection to documented radiographic relapse/progression or death due to any cause over a period of 60 months. The 5-year DFS rate will be calculated as the percentage of patients who are disease free at 5 years. This will be calculated using the Kaplan-Meier method

Measure: Disease-free survival rate (DFS)

Time: Up to 5 years

Description: 5-year OS rate will be calculated using the Kaplan-Meier method . OS will be defined as the 1+ the number of days from surgical resection to death due to any cause over a period of 60 months. The Kaplan-Meier analysis will be used to calculate the median OS with 95% confidence interval.

Measure: Overall survival (OS)

Time: Up to 5 years

Description: DpR will be defined as the percentage change in tumor burden by RECIST criteria at best response versus baseline imaging. DpR will be summarized using descriptive statistics and correlated with patient outcomes using hazard ratios via the Cox proportional hazards model.

Measure: Depth of response (DpR)

Time: Up to 1 year

Description: The pCR is defined as absence of (0%) viable tumor present histologically in the resected tumor specimen

Measure: Pathologic complete response rate (pCR)

Time: Up to 1 year

Description: Treatment-emergent adverse events will be classified according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

Measure: Number of Treatment-emergent adverse events (AEs)

Time: Up to 1 year

Description: Rate of conversion from operable to non-operative will be recorded as rate of patients initially assessed as surgically resectable, who are subsequently unable to undergo surgical resection due to either treatment-related adverse events (AEs) or disease progression.

Measure: Percentage of participants unable to undergo surgical resection

Time: Up to 70 days

Description: Rate of surgical complications occurring prior to the end of treatment visit will be reported

Measure: Percentage of surgical complications

Time: Up to 1 year

160 A Phase III, Randomized, Double-Blind Study of Bevacizumab, Carboplatin, and Paclitaxel or Pemetrexed With or Without Atezolizumab in Chemotherapy-Naïve Patients With Stage IV Non-Squamous Non-Small Cell Lung Cancer (IMpower151)

This study will evaluate the efficacy and safety of atezolizumab when given in combination with bevacizumab, investigator's choice of either paclitaxel or pemetrexed, and carboplatin compared with placebo given in combination with bevacizumab, paclitaxel or pemetrexed, and carboplatin in patients with chemotherapy-naive, Stage IV non-squamous Non-Small Cell Lung Cancer (NSCLC). The study will be conducted in two phases: Induction Phase and Maintenance Phase.

NCT04194203
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Drug: Atezolizumab
  2. Drug: Placebo
  3. Drug: Bevacizumab
  4. Drug: Paclitaxel
  5. Drug: Pemetrexed
  6. Drug: Carboplatin
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Patients who have progressed on or were intolerant to first- or second-generation EGFR TKIs, such as erlotinib, gefitinib, afatinib, dacomitinib, and who have no evidence of the EGFR T790M mutation in the tumor tissue after TKI therapy are eligible. --- T790M ---

Patients who have progressed on or were intolerant to first- or second-generation EGFR TKIs and who have evidence of the T790M mutation in their tumor tissue must have also progressed on or were intolerant to osimertinib to be eligible. --- T790M ---

Primary Outcomes

Description: PFS after randomization, defined as the time from randomization to the first occurrence of disease progression or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1

Measure: Progression Free Survival (PFS) in the intent to treat (ITT) population, as determined by the investigator

Time: Randomization until the first occurence of disease progression or death from any cause, whichever occures first (up to approximately 33 months)

Secondary Outcomes

Description: OS after randomization, defined as the time from randomization to death from any cause.

Measure: Overall Survival (OS) in the ITT population

Time: Randomization to death from any cause (up to approximately 33 months)

Description: PFS after randomizationdefined as the time from randomization to the first occurrence of disease progression or death from any cause (whichever occurs first), as determined by the an Independent Review Facility (IRF) according to RECIST v1.1

Measure: PFS in the ITT population, as determined by IRF

Time: Randomization until the first occurence of disease progression or death from any cause, whichever occures first (up to approximately 33 months)

Description: PFS after randomization as determined by the investigator according to RECIST v1.1 in the subgroup of patients with PD-L1 expression defined by the SP263 immunohistochemistry (IHC) assay.

Measure: PFS in subgroup of participants with PD-L1 Expression, as determined by the investigator

Time: Randomization until the first occurence of disease progression or death from any cause, whichever occures first (up to approximately 33 months)

Description: PFS after randomization as determined by the investigator according to RECIST v1.1 in the subgroup of patients with genomic alterations in EGFR (i.e., sensitizing EGFR mutations) or ALK gene.

Measure: PFS in the subgroup of participants with genomic alterations in EGFR or ALK gene, as determined by the investigator

Time: Randomization until the first occurence of disease progression or death from any cause, whichever occures first (up to approximately 33 months)

Description: ORR, defined as the proportion of patients with a complete response (CR) or partial response (PR) on two consecutive occasions >=4 weeks apart, as determined by the investigator according to RECIST v1.1.

Measure: Objective Response Rate (ORR) in the ITT population

Time: Randomization until disease progression or death, which ever occurs first (up to approximately 33 months)

Description: DOR defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1.

Measure: Duration of response (DOR) in the ITT population

Time: Randomization until the first occurence of a documented objective response to disease progression or death from any cause, whichever occures first (up to approximately 33 months)

Description: (TTD) in physical functioning, defined as the time from randomization to the first observed >=10-point decrease in the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) for cancer linearly transformed physical functioning scale score that is sustained for two consecutive assessments or followed by death while the patient is on study treatment.

Measure: Time to Deterioration (TTD) in physical functioning in the ITT population

Time: Randomization up until approximately 33 months

Measure: Percentage of Participants With Adverse Events

Time: Randomization up to approximately 33 months

161 Phase I Study to Evaluate Safety, Tolerability, Pharmacokinetics and Anti-Tumor Activity of WSD0922-FUFU

This phase I trial studies the side effects and best dose of WSD0922-FU for the treatment of glioblastoma, anaplastic astrocytoma, or non-small cell lung cancer that has spread to the central nervous system (central nervous system metastases). WSD0922-FU is a targeted treatment which blocks the EGFR protein - a strategy that has led to a lot of benefit in patients with many different cancers. WSD0922-FU may also be able to get into cancers in the brain and spinal cord and help patients with brain and spinal cord cancers.

NCT04197934
Conditions
  1. Anaplastic Astrocytoma, IDH-Wildtype
  2. Glioblastoma, IDH-Wildtype
  3. Lung Non-Small Cell Carcinoma
  4. Metastatic Malignant Neoplasm in the Central Nervous System
  5. Metastatic Malignant Neoplasm in the Leptomeninges
Interventions
  1. Drug: EGFR/EGFRvIII Inhibitor WSD0922-FU
  2. Procedure: Therapeutic Conventional Surgery
MeSH:Neoplasms Glioblastoma Astrocytoma Neoplasms, Second Primary Carcinoma, Non-Small-Cell Lung
HPO:Astrocytoma Glioblastoma multiforme Neoplasm Non-small cell lung carcinoma Subependymal giant-cell astrocytoma

Patients are not considered to have a "currently active" malignancy if they have completed therapy and are free of disease for more than three years prior to registration - Any of the following cardiac criteria: - A marked baseline prolongation of QT/corrected QT (QTc) interval - (e.g., repeated demonstration of a QTc interval > 480 milliseconds (ms) (Common Terminology Criteria for Adverse Events [CTCAE] grade 1) using Fridericia's QT correction formula - A history of additional risk factors for torsade de pointes (TdP) (e.g., heart failure, hypokalemia, family history of long QT syndrome) - The use of concomitant medications that prolong the QT/QTc interval - Patients confirmed to have a cis double mutation (Del19/T790M or L858R/T790M) or cis triple mutation (Del19/T790m/C797S or L858R/T790M/C797S) - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease. --- T790M ---

Primary Outcomes

Description: The RP2D is either the maximum tolerated dose (MTD) or the highest dose tested (in the case that none of the doses are deemed higher than the MTD), whichever is higher.

Measure: Recommended phase 2 dose

Time: Up to 28 days

Secondary Outcomes

Measure: Incidence of adverse events

Time: Up to 4-6 weeks after study completion

Description: The overall response rate will be defined as the number of patients with a partial response (PR) or better that is confirmed in consecutive evaluations (at least 8 weeks apart) divided by the total number of evaluable patients. A 95% confidence interval will also be constructed using the properties of the binomial distribution.

Measure: Overall response rate

Time: Up to 5 years

Description: Duration of response is defined as the number of days between a patient's first occurrence of a PR (or better) and progression. If a patient goes off study prior to progression (for another reason) then they will be censored at that time. A time to event analysis will be performed utilizing the Kaplan-Meier method which will yield a median DOR.

Measure: Duration of response (DOR)

Time: From the first occurrence of a PR (or better) and progression, assessed up to 5 years

Description: A patient's progression free survival time is the number of days between study entry and disease progression. These data will be analyzed utilizing the Kaplan-Meier method which will yield a median PFS time.

Measure: Progression Free Survival (PFS)

Time: From study entry to disease progression, assessed up to 5 years

Other Outcomes

Measure: Maximum plasma Concentration [Cmax] of WSD0922-FU after a single dose of WSD0922-FU

Time: Cycle 1 Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hours

Measure: Area under the plasma concentration versus time curve (AUC) of WSD022-FU after a single dose of WSD0922-FU

Time: Pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours of day 1 of cycles 1 and 2; and pre-dose day 1 of cycles 3 and 4

Measure: Maximum plasma Concentration [Cmax] of WSD0922-FU after multiple doses of WSD0922-FU

Time: Cycle 1 Day 15: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours

Measure: Area under the plasma concentration versus time curve (AUC) of WSD022-FU after multiple doses of WSD0922-FU

Time: Cycle 1 Day 15: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours

Measure: CSF concentration of WSD0922-FU after multiple doses of WSD0922-FU (Dose Expansion - NSCLC leptomeningeal metastases (NSCLC LM) cohort only).

Time: Cycle 2 Day 1

Measure: Brain tumor concentration of WSD0922-FU after a single dose of WSD0922-FU (Dose Expansion - Brain tumor penetration (BTP) cohort only).

Time: Cycle 0 Day 1

Measure: Tumor EGFR inhibition after a single dose of WSD0922-FU (Dose Expansion - Brain tumor penetration (BTP) cohort only).

Time: Cycle 0 Day 1

Measure: Effect of food on Maximum plasma Concentration [Cmax] of WSD0922-FU after a single dose of WSD0922-FU (Dose Expansion - NSCLC LM cohort only).

Time: Cycle 0 Day 1 and Cycle 0 Day 4

Measure: Effect of food on Area under the plasma concentration versus time curve (AUC) of WSD022-FU after a single dose of WSD0922-FU (Dose Expansion - NSCLC LM cohort only).

Time: Cycle 0 Day 1 and Cycle 0 Day 4

162 A Randomized Phase II Study of Individualized Combined Modality Therapy for Stage III Non-small Cell Lung Cancer (NSCLC)

This randomized phase II trial studies how well erlotinib hydrochloride or crizotinib with chemoradiation therapy works in treating patients with stage III non-small cell lung cancer. Radiation therapy uses high energy x rays to kill tumor cells. Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Drugs used in chemotherapy, such as cisplatin, etoposide, paclitaxel, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether giving erlotinib hydrochloride is more effective than crizotinib with chemoradiation therapy in treating patients with non-small cell lung cancer.

NCT01822496
Conditions
  1. Stage III Non-Small Cell Lung Cancer AJCC v7
  2. Stage IIIA Non-Small Cell Lung Cancer AJCC v7
  3. Stage IIIB Non-Small Cell Lung Cancer AJCC v7
Interventions
  1. Radiation: Radiation Therapy
  2. Drug: Carboplatin
  3. Drug: Cisplatin
  4. Drug: Crizotinib
  5. Drug: Erlotinib
  6. Drug: Etoposide
  7. Drug: Paclitaxel
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - Histologically or cytologically confirmed, newly diagnosed non-squamous NSCLC - Unresectable stage IIIA or IIIB disease; patients must be surgically staged to confirm N2 or N3 disease; patients may have invasive mediastinal staging by mediastinoscopy, mediastinotomy, endobronchial ultrasound transbronchial aspiration (EBUS-TBNA), endoscopic ultrasound (EUS), or video-assisted thoracoscopic surgery (VATS) - Patients with any tumor (T) with node (N)2 or N3 are eligible; patients with T3, N1-N3 disease are eligible if deemed unresectable; patients with T4, any N are eligible - Patients must have measurable disease, i.e., lesions that can be accurately measured in at least 1 dimension (longest dimension in the plane of measurement is to be recorded) with a minimum size of 10 mm by computed tomography (CT) scan (CT scan slice thickness no greater than 5 mm) - Patients with a pleural effusion, which is a transudate, cytologically negative and non-bloody, are eligible if the radiation oncologist feels the tumor can be encompassed within a reasonable field of radiotherapy - If a pleural effusion can be seen on the chest CT but not on chest x-ray and is too small to tap, the patient will be eligible; patients who develop a new pleural effusion after thoracotomy or other invasive thoracic procedure will be eligible - The institution's pre-enrollment biomarker screening at a Clinical Laboratory Improvement Amendments (CLIA) certified lab documents presence of known "sensitive" mutations in epidermal growth factor receptor tyrosine kinase (EGFR TK) domain (exon 19 deletion, L858) and/or EML4-anaplastic lymphoma kinase (ALK) fusion arrangement; either the primary tumor or the metastatic lymph node tissue may be used for testing of mutations - The institution's pre-enrollment biomarker screening at a CLIA certified lab documents absence of T790M mutation in the EGFR TK domain - Appropriate stage for protocol entry, including no distant metastases, based upon the following minimum diagnostic workup: - History/physical examination, including recording of pulse, blood pressure (BP), weight, and body surface area, within 45 days prior to registration - Whole body fludeoxyglucose-positron emission tomography (FDG-PET)/CT (orbits to mid-thighs) within 30 days prior to registration; PET/CT must be negative for distant metastasis - CT scan with contrast of the chest and upper abdomen to include liver and adrenals (unless medically contraindicated) within 30 days prior to registration - Magnetic resonance imaging (MRI) of the brain with contrast (or CT scan with contrast, if MRI medically contraindicated) within 30 days prior to registration - Zubrod performance status 0-1 within 14 days prior to registration - Absolute neutrophil count (ANC) >= 1,000 cells/mm^3 - Platelets >= 100,000 cells/mm^3 - Hemoglobin >= 8.0 g/dl (Note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 8.0 g/dl is acceptable) - Serum creatinine < 1.5 mg/dL or calculated creatinine clearance >= 50 ml/min (by Cockcroft-Gault formula) within 14 days prior to registration - Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN) within 14 days prior to registration - Bilirubin within normal institutional limits within 14 days prior to registration - Negative serum pregnancy test within 14 days prior to registration for women of childbearing potential - Patient must provide study specific informed consent prior to study entry, including consent for mandatory screening of tissue Exclusion Criteria: - Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 730 days (2 years) (for example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible) - Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable - Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields - Atelectasis of the entire lung - Contralateral hilar node involvement - Exudative, bloody, or cytologically malignant effusions - Severe, active co-morbidity, defined as follows: - Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months - Transmural myocardial infarction within the last 6 months - Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration - Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration; hepatic insufficiency resulting in clinical jaundice and/or coagulation defects - Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; note, however, that human immunodeficiency virus (HIV) testing is not required for entry into this protocol; protocol-specific requirements may also exclude immuno-compromised patients - Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception - Prior allergic reaction to the study drug(s) involved in this protocol Inclusion Criteria: - Histologically or cytologically confirmed, newly diagnosed non-squamous NSCLC - Unresectable stage IIIA or IIIB disease; patients must be surgically staged to confirm N2 or N3 disease; patients may have invasive mediastinal staging by mediastinoscopy, mediastinotomy, endobronchial ultrasound transbronchial aspiration (EBUS-TBNA), endoscopic ultrasound (EUS), or video-assisted thoracoscopic surgery (VATS) - Patients with any tumor (T) with node (N)2 or N3 are eligible; patients with T3, N1-N3 disease are eligible if deemed unresectable; patients with T4, any N are eligible - Patients must have measurable disease, i.e., lesions that can be accurately measured in at least 1 dimension (longest dimension in the plane of measurement is to be recorded) with a minimum size of 10 mm by computed tomography (CT) scan (CT scan slice thickness no greater than 5 mm) - Patients with a pleural effusion, which is a transudate, cytologically negative and non-bloody, are eligible if the radiation oncologist feels the tumor can be encompassed within a reasonable field of radiotherapy - If a pleural effusion can be seen on the chest CT but not on chest x-ray and is too small to tap, the patient will be eligible; patients who develop a new pleural effusion after thoracotomy or other invasive thoracic procedure will be eligible - The institution's pre-enrollment biomarker screening at a Clinical Laboratory Improvement Amendments (CLIA) certified lab documents presence of known "sensitive" mutations in epidermal growth factor receptor tyrosine kinase (EGFR TK) domain (exon 19 deletion, L858) and/or EML4-anaplastic lymphoma kinase (ALK) fusion arrangement; either the primary tumor or the metastatic lymph node tissue may be used for testing of mutations - The institution's pre-enrollment biomarker screening at a CLIA certified lab documents absence of T790M mutation in the EGFR TK domain - Appropriate stage for protocol entry, including no distant metastases, based upon the following minimum diagnostic workup: - History/physical examination, including recording of pulse, blood pressure (BP), weight, and body surface area, within 45 days prior to registration - Whole body fludeoxyglucose-positron emission tomography (FDG-PET)/CT (orbits to mid-thighs) within 30 days prior to registration; PET/CT must be negative for distant metastasis - CT scan with contrast of the chest and upper abdomen to include liver and adrenals (unless medically contraindicated) within 30 days prior to registration - Magnetic resonance imaging (MRI) of the brain with contrast (or CT scan with contrast, if MRI medically contraindicated) within 30 days prior to registration - Zubrod performance status 0-1 within 14 days prior to registration - Absolute neutrophil count (ANC) >= 1,000 cells/mm^3 - Platelets >= 100,000 cells/mm^3 - Hemoglobin >= 8.0 g/dl (Note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 8.0 g/dl is acceptable) - Serum creatinine < 1.5 mg/dL or calculated creatinine clearance >= 50 ml/min (by Cockcroft-Gault formula) within 14 days prior to registration - Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN) within 14 days prior to registration - Bilirubin within normal institutional limits within 14 days prior to registration - Negative serum pregnancy test within 14 days prior to registration for women of childbearing potential - Patient must provide study specific informed consent prior to study entry, including consent for mandatory screening of tissue Exclusion Criteria: - Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 730 days (2 years) (for example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible) - Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable - Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields - Atelectasis of the entire lung - Contralateral hilar node involvement - Exudative, bloody, or cytologically malignant effusions - Severe, active co-morbidity, defined as follows: - Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months - Transmural myocardial infarction within the last 6 months - Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration - Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration; hepatic insufficiency resulting in clinical jaundice and/or coagulation defects - Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; note, however, that human immunodeficiency virus (HIV) testing is not required for entry into this protocol; protocol-specific requirements may also exclude immuno-compromised patients - Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception - Prior allergic reaction to the study drug(s) involved in this protocol Stage III Non-Small Cell Lung Cancer AJCC v7 Stage IIIA Non-Small Cell Lung Cancer AJCC v7 Stage IIIB Non-Small Cell Lung Cancer AJCC v7 Lung Neoplasms Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVES: I. To assess whether patients with unresectable local-regionally advanced non-small cell lung cancer (NSCLC) treated with targeted agents based on molecular characteristics have a longer progression-free survival than those treated with standard care therapy alone. --- T790M ---

Inclusion Criteria: - Histologically or cytologically confirmed, newly diagnosed non-squamous NSCLC - Unresectable stage IIIA or IIIB disease; patients must be surgically staged to confirm N2 or N3 disease; patients may have invasive mediastinal staging by mediastinoscopy, mediastinotomy, endobronchial ultrasound transbronchial aspiration (EBUS-TBNA), endoscopic ultrasound (EUS), or video-assisted thoracoscopic surgery (VATS) - Patients with any tumor (T) with node (N)2 or N3 are eligible; patients with T3, N1-N3 disease are eligible if deemed unresectable; patients with T4, any N are eligible - Patients must have measurable disease, i.e., lesions that can be accurately measured in at least 1 dimension (longest dimension in the plane of measurement is to be recorded) with a minimum size of 10 mm by computed tomography (CT) scan (CT scan slice thickness no greater than 5 mm) - Patients with a pleural effusion, which is a transudate, cytologically negative and non-bloody, are eligible if the radiation oncologist feels the tumor can be encompassed within a reasonable field of radiotherapy - If a pleural effusion can be seen on the chest CT but not on chest x-ray and is too small to tap, the patient will be eligible; patients who develop a new pleural effusion after thoracotomy or other invasive thoracic procedure will be eligible - The institution's pre-enrollment biomarker screening at a Clinical Laboratory Improvement Amendments (CLIA) certified lab documents presence of known "sensitive" mutations in epidermal growth factor receptor tyrosine kinase (EGFR TK) domain (exon 19 deletion, L858) and/or EML4-anaplastic lymphoma kinase (ALK) fusion arrangement; either the primary tumor or the metastatic lymph node tissue may be used for testing of mutations - The institution's pre-enrollment biomarker screening at a CLIA certified lab documents absence of T790M mutation in the EGFR TK domain - Appropriate stage for protocol entry, including no distant metastases, based upon the following minimum diagnostic workup: - History/physical examination, including recording of pulse, blood pressure (BP), weight, and body surface area, within 45 days prior to registration - Whole body fludeoxyglucose-positron emission tomography (FDG-PET)/CT (orbits to mid-thighs) within 30 days prior to registration; PET/CT must be negative for distant metastasis - CT scan with contrast of the chest and upper abdomen to include liver and adrenals (unless medically contraindicated) within 30 days prior to registration - Magnetic resonance imaging (MRI) of the brain with contrast (or CT scan with contrast, if MRI medically contraindicated) within 30 days prior to registration - Zubrod performance status 0-1 within 14 days prior to registration - Absolute neutrophil count (ANC) >= 1,000 cells/mm^3 - Platelets >= 100,000 cells/mm^3 - Hemoglobin >= 8.0 g/dl (Note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 8.0 g/dl is acceptable) - Serum creatinine < 1.5 mg/dL or calculated creatinine clearance >= 50 ml/min (by Cockcroft-Gault formula) within 14 days prior to registration - Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN) within 14 days prior to registration - Bilirubin within normal institutional limits within 14 days prior to registration - Negative serum pregnancy test within 14 days prior to registration for women of childbearing potential - Patient must provide study specific informed consent prior to study entry, including consent for mandatory screening of tissue Exclusion Criteria: - Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 730 days (2 years) (for example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible) - Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable - Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields - Atelectasis of the entire lung - Contralateral hilar node involvement - Exudative, bloody, or cytologically malignant effusions - Severe, active co-morbidity, defined as follows: - Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months - Transmural myocardial infarction within the last 6 months - Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration - Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration; hepatic insufficiency resulting in clinical jaundice and/or coagulation defects - Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; note, however, that human immunodeficiency virus (HIV) testing is not required for entry into this protocol; protocol-specific requirements may also exclude immuno-compromised patients - Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception - Prior allergic reaction to the study drug(s) involved in this protocol Inclusion Criteria: - Histologically or cytologically confirmed, newly diagnosed non-squamous NSCLC - Unresectable stage IIIA or IIIB disease; patients must be surgically staged to confirm N2 or N3 disease; patients may have invasive mediastinal staging by mediastinoscopy, mediastinotomy, endobronchial ultrasound transbronchial aspiration (EBUS-TBNA), endoscopic ultrasound (EUS), or video-assisted thoracoscopic surgery (VATS) - Patients with any tumor (T) with node (N)2 or N3 are eligible; patients with T3, N1-N3 disease are eligible if deemed unresectable; patients with T4, any N are eligible - Patients must have measurable disease, i.e., lesions that can be accurately measured in at least 1 dimension (longest dimension in the plane of measurement is to be recorded) with a minimum size of 10 mm by computed tomography (CT) scan (CT scan slice thickness no greater than 5 mm) - Patients with a pleural effusion, which is a transudate, cytologically negative and non-bloody, are eligible if the radiation oncologist feels the tumor can be encompassed within a reasonable field of radiotherapy - If a pleural effusion can be seen on the chest CT but not on chest x-ray and is too small to tap, the patient will be eligible; patients who develop a new pleural effusion after thoracotomy or other invasive thoracic procedure will be eligible - The institution's pre-enrollment biomarker screening at a Clinical Laboratory Improvement Amendments (CLIA) certified lab documents presence of known "sensitive" mutations in epidermal growth factor receptor tyrosine kinase (EGFR TK) domain (exon 19 deletion, L858) and/or EML4-anaplastic lymphoma kinase (ALK) fusion arrangement; either the primary tumor or the metastatic lymph node tissue may be used for testing of mutations - The institution's pre-enrollment biomarker screening at a CLIA certified lab documents absence of T790M mutation in the EGFR TK domain - Appropriate stage for protocol entry, including no distant metastases, based upon the following minimum diagnostic workup: - History/physical examination, including recording of pulse, blood pressure (BP), weight, and body surface area, within 45 days prior to registration - Whole body fludeoxyglucose-positron emission tomography (FDG-PET)/CT (orbits to mid-thighs) within 30 days prior to registration; PET/CT must be negative for distant metastasis - CT scan with contrast of the chest and upper abdomen to include liver and adrenals (unless medically contraindicated) within 30 days prior to registration - Magnetic resonance imaging (MRI) of the brain with contrast (or CT scan with contrast, if MRI medically contraindicated) within 30 days prior to registration - Zubrod performance status 0-1 within 14 days prior to registration - Absolute neutrophil count (ANC) >= 1,000 cells/mm^3 - Platelets >= 100,000 cells/mm^3 - Hemoglobin >= 8.0 g/dl (Note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 8.0 g/dl is acceptable) - Serum creatinine < 1.5 mg/dL or calculated creatinine clearance >= 50 ml/min (by Cockcroft-Gault formula) within 14 days prior to registration - Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN) within 14 days prior to registration - Bilirubin within normal institutional limits within 14 days prior to registration - Negative serum pregnancy test within 14 days prior to registration for women of childbearing potential - Patient must provide study specific informed consent prior to study entry, including consent for mandatory screening of tissue Exclusion Criteria: - Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 730 days (2 years) (for example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible) - Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable - Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields - Atelectasis of the entire lung - Contralateral hilar node involvement - Exudative, bloody, or cytologically malignant effusions - Severe, active co-morbidity, defined as follows: - Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months - Transmural myocardial infarction within the last 6 months - Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration - Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration; hepatic insufficiency resulting in clinical jaundice and/or coagulation defects - Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; note, however, that human immunodeficiency virus (HIV) testing is not required for entry into this protocol; protocol-specific requirements may also exclude immuno-compromised patients - Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception - Prior allergic reaction to the study drug(s) involved in this protocol Stage III Non-Small Cell Lung Cancer AJCC v7 Stage IIIA Non-Small Cell Lung Cancer AJCC v7 Stage IIIB Non-Small Cell Lung Cancer AJCC v7 Lung Neoplasms Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVES: I. To assess whether patients with unresectable local-regionally advanced non-small cell lung cancer (NSCLC) treated with targeted agents based on molecular characteristics have a longer progression-free survival than those treated with standard care therapy alone. --- T790M --- --- T790M ---

Primary Outcomes

Description: Progression is defined using the Response Evaluation Criteria In Solid Tumors Criteria (RECIST) guideline v1.1 as a 20% increase in the sum of the longest diameter of target lesions, a measurable increase in a non-target lesion, or the appearance of new lesions at any location. Progression-free survival time is measured from the date of randomization to the date of first progression, death, or last known follow-up (censored). No statistical testing was done due to early study termination.

Measure: Progression-free Survival

Time: From randomization to study termination. Maximum follow-up was 39.0 months

Secondary Outcomes

Description: Per the RECIST guideline v1.1 complete response is defined as the disappearance of all target lesions; any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial response is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. No statistical testing was done due to early study termination.

Measure: Percentage of Patients With Complete or Partial Response

Time: From randomization to study termination. Maximum follow-up was 39.0 months

Description: Adverse events (AE) are graded using the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE.

Measure: Number of Patients With Grade 3-5 Adverse Events

Time: From randomization to study termination. Maximum follow-up was 39.0 months

Description: Overall survival time is defined as time from randomization to the date of death from any cause. Overall survival rates are estimated by the Kaplan-Meier method. Patients last known to be alive are censored at the date of last contact.

Measure: Overall Survival

Time: From randomization to study termination. Maximum follow-up was 39.0 months

Description: Progression is defined using the RECIST guideline v1.1 as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new regional lesions. Local progression is defined as progression within the planning target volume (PTV). Regional progression is defined as progression outside of the PTV but within the same lobe of the lung as the primary tumor or in regional lymph nodes as defined by the American Joint Committee on Cancer (AJCC) 7th edition nodal stations. Local-regional progression-free survival time is measured from the date of randomization to the date of first local-regional progression, death, or last known follow-up (censored). Local-regional progression-free survival rates are estimated using the Kaplan-Meier method. No testing was done due to early study termination.

Measure: Local-regional Progression-free Survival

Time: From randomization to study termination. Maximum follow-up was 39.0 months

Description: Distant progression is defined as the first occurrence of distant metastasis. Distant progression-free survival time is measured from the date of randomization to the date of first distant progression, death, or last known follow-up (censored). Distant progression-free survival rates are estimated using the Kaplan-Meier method. No testing was done due to early study termination.

Measure: Distant Progression-free Survival

Time: From randomization to study termination. Maximum follow-up was 39.0 months

Measure: Correlation Between Clinical Outcomes and Tumor Molecular Aberrations

Time: Baseline

163 Trial of Afatinib (BIBW 2992) in Suspected or Confirmed Mutant EGFR Lung Cancer Patients Unfit for Chemotherapy

The purpose of this study is to examine the efficacy and safety of using afatinib (BIBW 2992) to treat non-small cell lung cancer patients considered unfit for chemotherapy and have either suspected or confirmed Epidermal Growth Factor Receptor (EGFR) mutation.

NCT01415011
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Drug: Afatinib (BIBW 2992)
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

L858R, exon 19 deletions, exon 20 insertions, T790M, list is not exhaustive), and WHO PS 0-3 Or No tissue suitable for EGFR genotyping, failed genotype, or EGFR genotyping unavailable, and NSCLC Adenocarcinoma sub-type, and Eligible smoking history: Never smoker (<100 cigarettes in lifetime), or Former smoker (stopped >1year ago and ≤10 pack-years) and WHO PS 0-2 - Unsuitable for or patient declining chemotherapy due to significant co-morbidity - Measurable disease according to RECIST version 1.1 - Adequate haematopoietic, hepatic and renal function defined as follows: Absolute neutrophil count (ANC) ≤1.5 x 109/L and platelet count ≤100 x 109/L - Bilirubin ≤1.5 x ULN, ALT (SGPT) ≤3 x ULN (or ≤ 5 x ULN in cases of liver metastases) - Serum creatinine clearance ≥45 ml/min - Palliative radiotherapy allowed unless to a solitary target lesion - Age 18 or over (no upper age limit) - Written informed consent that is consistent with ICH-GCP guidelines Exclusion Criteria: - Previous treatment with afatinib (BIBW 2992), or any EGFR-directed inhibitor - Any concurrent anticancer systemic therapy - Prior chemotherapy for relapsed and/or metastatic NSCLC - Neoadjuvant/adjuvant chemotherapy is permitted if at least 12 months has elapsed between the end of chemotherapy and registration - Suitable for radical radiotherapy - Palliative radiotherapy within 2 weeks prior to registration - Palliative radiotherapy to a solitary target lesion - Surgery (other than biopsy) within 4 weeks prior to registration - Inability to take oral medication, requirement for intravenous feeding, active peptic ulcer, prior surgical procedures affecting absorption, any medical co- morbidity affecting gastrointestinal absorption - Patients with current or pre-existing interstitial lung disease - Active or uncontrolled infections or serious illnesses or medical conditions that could interfere with the patient's participation in the trial - Significant or recent acute gastrointestinal abnormalities with diarrhoea as a major symptom e.g., Crohn's disease, mal-absorption, or CTCAE version 4.0 Grade ≥3 diarrhoea of any etiology at baseline - Active brain metastases (defined as stable for <4 weeks and/or symptomatic and/or requiring treatment with anticonvulsants and/or leptomeningeal disease). --- L858R --- --- T790M ---

In ~50% of cases this is due to the gefitinib/erlotinib-resistant T790M genotype acquired through either secondary somatic mutation or clonal expansion. --- T790M ---

Primary Outcomes

Description: Progression free survival will be determined by measurement of tumour size using RECIST version 1.1 at progression or date of patient death.

Measure: Progression free survival

Time: At 6 months

Secondary Outcomes

Measure: Overall response

Time: CT scan of chest & abdomen 4 weeks after registartion, then every 8 calender weeks until disease progression. CT scans every 12 weeks if patient is still on BIBW 2992 after 1 year of treatment.

Measure: Overall survival

Time: This will be measured in days, from the first day of treatment to the day of death.

Measure: Change in performance status

Time: At 1 month

Description: For each type of adverse event, the maximum toxicity grade will be obtained for each patient using CTCAE version 4.0 to closely monitor tolerability to BIBW 2992. Focus will be on those with a grade 3 or 4 BIBW 2992 related toxicities. The proportion of patients with any grade 3 or 4 event will also be examined.

Measure: Safety

Time: To be assessed at every timepoint i.e. baseline, fortnightly for the first 2 cycles and then monthly for 12 months and 2 monthly thereafter

Measure: Progression free survival in patients aged 70 and over

Time: At progression or patient death

Measure: Treatment compliance

Time: Compliance will be examined based on the time between starting treatment and stopping it completely

164 T-STAR - T790M Mutation Positive 2nd Line STandard of cAre Registry

The aim of the study is to collect real world information on patients with locally advanced or metastatic non small cell lung cancer (NSCLC) who progressed after first line treatment with an approved Tyrosine-Kinase Inhibitor (TKI), who are known to be T790M positive and have been prescribed second line platinum-based chemotherapy (Pemetrexed + Cisplatin /Carboplatin).

NCT02368990
Conditions
  1. Non Small Cell Lung Cancer
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

T-STAR - T790M Mutation Positive 2nd Line STandard of cAre Registry. --- T790M ---

T790M Mutation Positive 2nd Line STandard of cAre Registry The aim of the study is to collect real world information on patients with locally advanced or metastatic non small cell lung cancer (NSCLC) who progressed after first line treatment with an approved Tyrosine-Kinase Inhibitor (TKI), who are known to be T790M positive and have been prescribed second line platinum-based chemotherapy (Pemetrexed + Cisplatin /Carboplatin). --- T790M ---

T790M Mutation Positive 2nd Line STandard of cAre Registry The aim of the study is to collect real world information on patients with locally advanced or metastatic non small cell lung cancer (NSCLC) who progressed after first line treatment with an approved Tyrosine-Kinase Inhibitor (TKI), who are known to be T790M positive and have been prescribed second line platinum-based chemotherapy (Pemetrexed + Cisplatin /Carboplatin). --- T790M --- --- T790M ---

- Patients must have had confirmation that tumour is T790M mutation positive from a biopsy or cytology sample taken after confirmed disease progression on 1st line treatment with an approved EGFR-targeted TKI. - WHO performance status 0-1 with no deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks. --- T790M ---

Further tests on biopsied tissue or cytology at progression after treatment with an approved EGFR targeted TKI are used to determine positivity to T790M mutation. --- T790M ---

Primary Outcomes

Description: This will be assessed as the time from the start date of 2nd line chemotherapy until death due to any cause or censoring (at end of 24 months).To assess efficacy of permetrexed + cisplatinum/carboplatin as the 2nd line of treatment of NSCLC.

Measure: Overall Survival

Time: 24 months from last subject in

Secondary Outcomes

Description: This will be assessed as the time from start of 2nd line therapy until the date of disease progression or death (by any cause in the absence of progression). To assess efficacy of 2nd line treatment and beyond.

Measure: Response to Therapy as assessed by the physician

Time: 24 months from last subject in

Description: This will be assessed as the time from start date of line of therapy to end date of line of therapy or death date. To describe treatment patterns for 2nd line and beyond.

Measure: Time on treatment by line of therapy and between therapies

Time: 24 months from last subject in

Description: This will be assessed as the number and Time from the dates of admission and exit of attendance. To describe Healthcare resource utilization for 2nd line treatment and beyond.

Measure: Admission of planned/unplanned hospitalizations, emergency department visits and outpatient/physician visits

Time: 24 months from last subject in

Description: For each of the symptoms in EORTC QLQ-LC13 and EORTC QLQ-C30, Time from inclusion until the date of first clinically meaningful symptom deterioration or death by any cause in the absence of a clinically meaningful symptom deterioration. To assess the impact of 2nd and subsequent lines of therapy on patients' disease-related symptoms and health related quality of life.

Measure: Time to symptom deterioration

Time: 24 months from last subject in

Description: This will be assessed as the number of patients with two consecutive assessments, which showed a clinically meaningful improvement in that symptom from baseline. To assess the impact of 2nd and subsequent lines of therapies on patients' disease-related symptoms and health related quality of life.

Measure: Symptom Improvement Rate

Time: 24 months from last subject in

Description: This will be assessed as the time from the date of complete or partial response until the first date of recurrence or progression. To assess the efficacy of 2nd line treatment and beyond.

Measure: Duration of Response as defined by the physician

Time: 24 months from last subject in

Description: This will be assessed as the time from start of 2nd line therapy until the date of disease progression or death by any cause. This will be done to assess efficacy of pemetrexed + cisplatin/carboplatin as the 2nd line treatment of NSCLC.

Measure: Progression Free Survival

Time: 24 months from last subject in

165 A Randomized, Open-label Trial of Gefitinib Versus Combination of Vinorelbine Plus Platinum as Adjuvant Treatment in Pathological Stage II-IIIA(N1-N2) Non-small Cell Lung Cancer With EGFR Mutation

Activating somatic mutations of the tyrosine kinase domain of epidermal growth factor receptor (EGFR) have been characterized in a subset of patients with advanced NSCLC.The EGFR mutation rate was 30% in Chinese Non-small Cell Lung Cancer(NSCLC). Patients harboring these mutations in their tumors show excellent response to EGFR tyrosine kinase inhibitors (EGFR-TKIs). This randomized phase III trial is studying gefitinib to see how well it works compared to cisplatin-based chemotherapy in treating patients who have undergone surgery for stage II-IIIA(N1-N2) NSCLC with EGFR activating mutation in Asian population.

NCT01405079
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: Gefitinib
  2. Drug: Vinorelbine+Cisplatin
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

pyrexia of or 38.0℃ over) - Patients who harbouring exon 20 T790M mutation. --- T790M ---

Primary Outcomes

Description: To evaluate the disease free survival of gefitinib versus combination of vinorelbine plus platinum as adjuvant treatment for pathological stage II-IIIA(N1-N2) NSCLC with EGFR mutation.Disease free survival (DFS)- defined as the time from randomization to the first documented disease progression or death, whichever occurs first.

Measure: Disease free survival

Time: Pts after surgery will receive long-term follow-up including chest CT scan, abdominal ultrasound every 3 months, brain MRI every 6 months, bone scan every 12 months for up to 3 years. The survival after 3 years will be followed up with telephone.

Secondary Outcomes

Description: To evaluate the overall survival of gefitinib versus combination of vinorelbine plus platinum as adjuvant treatment for stage II-IIIA(N1-N2) NSCLC with EGFR mutation.

Measure: Overall survival

Time: Pts after surgery will receive long-term follow-up including chest CT scan, abdominal ultrasound every 3 months, brain MRI every 6 months, bone scan every 12 months for up to 3 years. The survival after 3 years will be followed up with telephone.

Description: To compare the randomized treatment arms in terms of 3 yeas DFS rate, 5 years DFS rate, 5 years OS rate.

Measure: 3 yeas DFS rate, 5 years DFS rate, 5 years OS rate

Time: Pts after surgery will receive long-term follow-up including chest CT scan, abdominal ultrasound every 3 months, brain MRI every 6 months, bone scan every 12 months for up to 3 years. The survival after 3 years will be followed up with telephone.

Description: The safety and tolerability profile of gefitinib at a 250 mg daily dose relative to that of Chemotherapy.

Measure: Number of Participants with Adverse Events

Time: In the period of Gefitinib 250 mg/day oral daily for 24 months.Vinorelbine 25 mg/m2 intravenous infusion on day 1 and day 8, Cisplatin 75 mg/m2 on day 1 for 4 cycles.

Description: Quality of life as measured by the total score and Trial Outcome Index (TOI) of the Functional Assessment of Cancer Therapy - Lung Cancer (FACT-L) questionnaire.

Measure: The Total Score and TOI of FACT-L to Measure Quality of life

Time: In the period of Gefitinib 250 mg/day oral daily for 24 months.Vinorelbine 25 mg/m2 intravenous infusion on day 1 and day 8, Cisplatin 75 mg/m2 on day 1 for 4 cycles.

166 A Single-arm, Phase II Study of Preoperative Gefitinib for Stage II-IIIa NSCLC With Activating EGFR Mutation

This is an open-label, single-arm, phase II interventional clinical trial. The investigators hypothesize that the application of EGFR-TKI, like gefitinib will be efficient and safe in a neo-adjuvant setting. 42 resectable stage II-IIIa NSCLC patients with EGFR activating (19/21) mutations will be eligible to be enrolled. EGFR mutation will be prospectively tested in all the participants' biopsy samples and confirmed in surgical resected samples. Eligible patients will be given gefitinib 250mg for 42days followed with surgical resection of tumor. Efficacy of preoperative gefitinib is based on radiographic (CT response/ORR), pathologic (pathologic response), surgical (complete resection) evaluations, and safety is based on adverse effect evaluations.

NCT01833572
Conditions
  1. Non-small-cell Lung Cancer
Interventions
  1. Drug: Gefitinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Patients who harbouring exon 20 T790M mutation. --- T790M ---

Primary Outcomes

Measure: Objective response rate (ORR)

Time: at day 42 of gefitinib treatment

Secondary Outcomes

Measure: Pathologic response rate

Time: Pathologic response rate is depended on the pathology dignosis after surgery, an expected average of 8 weeks from enrollment.

Measure: Complete resection rate

Time: Complete resection rate is depended on the pathology dignosis after surgery, an expected average of 8 weeks from enrollment.

Measure: Number of participants with adverse events

Time: During the neoadjuvant and perioperative period, an expected average of 10 weeks from enrollment

Measure: Quality of life (QoL)

Time: During the neoadjuvant period, an expected average of 6 weeks from enrollment

Measure: Disease free survival (DFS)

Time: Participants after surgery will receive long-term follow-up for up to 5 years

Measure: Overall survival (OS)

Time: Participants after surgery will receive long-term follow-up for up to 5 years

167 Prospective Observational Trial to Evaluate the Efficacy of the Combination of Osimertinib and Aspirin in Patients With Epidermal Growth Factor Receptor(EGFR)-Mutation

The third generation epidermal growth factor receptor-tyrosine Kinase Inhibitor(EGFR-TKI) osimertinib has obvious curative effect for EGFR sensitive mutation and T790M mutation(PMID 27959700), but acquired drug resistance will occur. Previous studies show that apoptosis escape can lead to EGFR-TKI resistance.Osimertinib resistant cells show abnormal activation of PI3K/AKT/BIM activation(PMID 28765329). The classical drug aspirin can effectively decrease AKT phosphorylation and activate of BIM(PMID 28881293).So Investigators speculate that aspirin may decrease the PI3K/AKT/BIM signaling pathways, then promote osimertinib resistant cells apoptosis. The current study aims to evaluate the combination of aspirin and osimertinib in patients with EGFR/T790M mutations.

NCT04184921
Conditions
  1. Lung Cancer Non-small Cell Stage IV
Interventions
  1. Drug: Aspirin 100mg
  2. Drug: Osimertinib 80 MG
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Prospective Observational Trial to Evaluate the Efficacy of the Combination of Osimertinib and Aspirin in Patients With Epidermal Growth Factor Receptor(EGFR)-Mutation. Combination of Osimertinib and Aspirin to Treat EGFR Mutation NSCLC Patients The third generation epidermal growth factor receptor-tyrosine Kinase Inhibitor(EGFR-TKI) osimertinib has obvious curative effect for EGFR sensitive mutation and T790M mutation(PMID 27959700), but acquired drug resistance will occur. --- T790M ---

The current study aims to evaluate the combination of aspirin and osimertinib in patients with EGFR/T790M mutations. --- T790M ---

Osimertinib is a 3rd-generation EGFR-TKI used to treat NSCLC patients with resistance to 1st generation EGFR-TKI due to T790M mutation. --- T790M ---

Primary Outcomes

Description: To evaluate the response to therapy and progression-free survival rate of the combination of Osimertinib and Aspirin in advanced lung cancer patients who has EGFR-mutation.

Measure: progression-free survival rate according to resist 1.1

Time: 2 years

Secondary Outcomes

Description: To evaluate the overall survival of the combination of Osimertinib and Aspirin in advanced lung cancer patients who has EGFR-mutation.

Measure: overall survival(OS)

Time: 5 years

Description: To evaluate the response to therapy and Objective Response Rate of the combination of Osimertinib and Aspirin in patients who has EGFR-mutation.

Measure: Objective Response Rate(ORR) according to resist 1.1

Time: 2 years

Description: To evaluate the response to therapy and Time to progression of the combination of Osimertinib and Aspirin in patients who has EGFR-mutation.

Measure: Time to progression(TTP) according to resist 1.1

Time: 2 years

168 A Randomised Non-comparative Open Label Phase II Trial of Atezolizumab Plus Bevacizumab, With Carboplatin-paclitaxel or Pemetrexed, in EGFR-mutant Non-small Cell Lung Carcinoma With Acquired Resistance

ETOP 15-19 ABC-lung is an international, multi-centre open-label, randomized phase II trial with two non-comparative parallel arms of atezolizumab plus bevacizumab with carboplatin-paclitaxel (Arm A) or atezolizumab, bevacizumab and pemetrexed (Arm B) in patients with stage IIIB-IV non-squamous non-small cell lung cancer (NSCLC) harbouring EGFR mutations after failure of standard EGFR tyrosine kinase inhibitors (TKIs).

NCT04245085
Conditions
  1. EGFRmutant Stage IIIB/C or IV Non-squamous NSCLC
Interventions
  1. Drug: Atezolizumab
  2. Drug: Bevacizumab
  3. Drug: Carboplatin
  4. Drug: Paclitaxel
  5. Drug: Pemetrexed
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- T790M genotype is allowed If most recent line of treatment (1st or 2nd line) was a first- or second-generation EGFR TKI (e.g. --- T790M ---

afatinib, dacomitinib, erlotinib, gefitinib): - Patient must be known to be tissue EGFR T790M wild type (local test) on most recent line of EGFR TKI or if no tissue re-biopsy, no evidence of T790M on ctDNA but identified L858R, del19, S768I or G719X genotypes (informative ctDNA test, local test) 6. Treatment with an EGFR TKI therapy for at least 10 days 7. Adequate haematological function: - Haemoglobin greater or equal 90 g/L - Absolute neutrophils count (ANC) greater or equal 1.5× 109/L - Platelet count greater or equal 100× 109/L 8. Adequate renal function: - Creatinine less or equal 1.5× ULN OR - Creatinine clearance greater or equal 45 mL/min (using the Cockcroft-Gault formula) 9. Adequate liver function: - ALT and AST less or equal 2.5× ULN. --- T790M ---

afatinib, dacomitinib, erlotinib, gefitinib): - Patient must be known to be tissue EGFR T790M wild type (local test) on most recent line of EGFR TKI or if no tissue re-biopsy, no evidence of T790M on ctDNA but identified L858R, del19, S768I or G719X genotypes (informative ctDNA test, local test) 6. Treatment with an EGFR TKI therapy for at least 10 days 7. Adequate haematological function: - Haemoglobin greater or equal 90 g/L - Absolute neutrophils count (ANC) greater or equal 1.5× 109/L - Platelet count greater or equal 100× 109/L 8. Adequate renal function: - Creatinine less or equal 1.5× ULN OR - Creatinine clearance greater or equal 45 mL/min (using the Cockcroft-Gault formula) 9. Adequate liver function: - ALT and AST less or equal 2.5× ULN. --- T790M --- --- T790M ---

6. Squamous cell histologic subtype 7. Known EGFR T790M positive genotype by tissue on most recent EGFR TKI progression or ctDNA and have not received an approved EGFR TKI targeting T790M (e.g. a third-generation EGFR TKI such as osimertinib). --- T790M ---

6. Squamous cell histologic subtype 7. Known EGFR T790M positive genotype by tissue on most recent EGFR TKI progression or ctDNA and have not received an approved EGFR TKI targeting T790M (e.g. a third-generation EGFR TKI such as osimertinib). --- T790M --- --- T790M ---

Primary Outcomes

Description: The primary objective of this study is to explore the clinical efficacy of atezolizumab and bevacizumab combined with chemotherapy in patients with EGFR-mutant advanced NSCLC after failure of standard EGFR TKIs.

Measure: Progression-free survival (PFS) rate at 12 months according to RECIST v1.1

Time: 12 months from randomisation

Secondary Outcomes

Description: To assess the safety and tolerability of the treatment.

Measure: Adverse events according to CTCAE v5.0

Time: from the date of randomisation until 90 days after the last dose of protocol treatment

Description: OS is defined as the time from the date of randomisation until death from any cause. Censoring will occur at the last follow-up date.

Measure: Overall survival

Time: through study completion, from the date of randomisation until death, including OS rate at 12 months.

Description: Objective response is defined as best overall response (CR or PR) across all assessment time-points according to RECIST criteria v1.1, from randomisation until the end of protocol treatment.

Measure: Objective response

Time: From date of randomisation until date of treatment completion (until documented disease progression, death or any other causes), assessed up to 2 years.

Description: Quality of life will be assessed by the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30). The key QoL outcome is the time to deterioration (TTD) in the QLQ-C30 global health status/global QoL.

Measure: Quality of Life Core Questionnaire (EORTC QLQ-C30)

Time: from baseline up to 12 months or until disease progression, whatever is first.

Description: Lung cancer associated symptoms will be measured by the lung cancer-specific module (QLQ-LC13).

Measure: Quality of Life lung cancer-specific module (QLQ-LC13)

Time: from baseline up to 12 months or until disease progression, whatever is first.

Description: Extra-cranial progression-free-survival is the time from randomisation to documentation of disease progression outside the central nervous system (CNS) as per RECIST criteria or death, whichever occurred first.

Measure: Extra-cranial PFS

Time: through study completion, from date of randomisation to documentation of PD outside the CNS, assessed up to 2 years

Description: Intracranial progression-free-survival is defined as the time from randomisation to first documented radiographic evidence of CNS progression. CNS progression is defined as progression due to newly developed CNS lesions and/or progression of pre-existing baseline CNS lesions.

Measure: Intracranial PFS

Time: through study completion, from date of randomisation to first documented radiographic evidence of CNS progression, assessed up to 2 years.

169 A Phase III, Randomized, Double-blind Study to Assess the Efficacy and Safety of Lazertinib Versus Gefitinib as the First-line Treatment in Patients With Epidermal Growth Factor Receptor Sensitizing Mutation Positive, Locally Advanced or Metastatic Non-Small Cell Lung Cancer

This Phase III study will be conducted to evaluate the efficacy and safety of YH25448 as first-line treatment in locally advanced or metastatic Non-small Cell Lung Cancer (NSCLC) patients with EGFR mutations

NCT04248829
Conditions
  1. Non-Small Cell Lung Cancer
Interventions
  1. Drug: Lazertinib 240 mg/160 mg
  2. Drug: Gefitinib 250 mg
  3. Drug: Lazertinib-matching placebo 240 mg/160 mg
  4. Drug: Gefitinib-matching placebo 250 mg
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - Pathologically confirmed adenocarcinoma of the lung - Locally advanced or metastatic NSCLC, not amenable to curative surgery or radiotherapy - At least 1 of the 2 common EGFR mutations known to be associated with EGFR TKI sensitivity (Ex19del or L858R), either alone or in combination with other EGFR mutations - Treatment-naïve for locally advanced or metastatic NSCLC - WHO performance status score of 0 to 1 with no clinically significant deterioration over the previous 2 weeks before randomization - At least 1 measurable lesion, not previously irradiated and not chosen for biopsy during the study Screening period Exclusion Criteria: - Symptomatic and unstable brain metastases - Leptomeningeal metastases - Symptomatic spinal cord compression - History of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD - Any medical conditions requiring chronic continuous oxygen therapy - History of any malignancy other than the disease under study within 3 years before randomization - Any cardiovascular disease as follows: - History of symptomatic chronic heart failure or serious cardiac arrhythmia requiring active treatment - History of myocardial infarction or unstable angina within 24 weeks of randomization Inclusion Criteria: - Pathologically confirmed adenocarcinoma of the lung - Locally advanced or metastatic NSCLC, not amenable to curative surgery or radiotherapy - At least 1 of the 2 common EGFR mutations known to be associated with EGFR TKI sensitivity (Ex19del or L858R), either alone or in combination with other EGFR mutations - Treatment-naïve for locally advanced or metastatic NSCLC - WHO performance status score of 0 to 1 with no clinically significant deterioration over the previous 2 weeks before randomization - At least 1 measurable lesion, not previously irradiated and not chosen for biopsy during the study Screening period Exclusion Criteria: - Symptomatic and unstable brain metastases - Leptomeningeal metastases - Symptomatic spinal cord compression - History of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD - Any medical conditions requiring chronic continuous oxygen therapy - History of any malignancy other than the disease under study within 3 years before randomization - Any cardiovascular disease as follows: - History of symptomatic chronic heart failure or serious cardiac arrhythmia requiring active treatment - History of myocardial infarction or unstable angina within 24 weeks of randomization Non-Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung YH25448 is an oral, highly potent, mutant-selective and irreversible EGFR Tyrosine-kinase inhibitors (TKIs) that targets both the T790M mutation and activating EGFR mutations while sparing wild type EGFR. --- L858R --- --- L858R --- --- T790M ---

Primary Outcomes

Description: To assess the efficacy of lazertinib compared with gefitinib as measured by PFS

Measure: Progression-Free Survival (PFS) according to RECIST v1.1 by Investigator assessment

Time: The primary analysis of PFS based on investigator assessment will occur when PFS maturity is observed at approximately 27 months after the first patient is randomized

Secondary Outcomes

Description: To further assess the efficacy of lazertinib compared with gefitinib

Measure: Objective Response Rate (ORR) according to RECIST v1.1 by Investigator assessments

Time: ORR analysis will occur when PFS maturity is observed at approximately 27 months from the first patient being randomized

Description: To further assess the efficacy of lazertinib compared with gefitinib

Measure: Duration of Response (DoR) according to RECIST v1.1 by Investigator assessments

Time: DoR analysis will occur when PFS maturity is observed at approximately 27 months from the first patient being randomized

Description: To further assess the efficacy of lazertinib compared with gefitinib

Measure: Disease Control Rate (DCR) according to RECIST v1.1 by Investigator assessments

Time: DCR analysis will occur when PFS maturity is observed at approximately 27 months from the first patient being randomized

Description: To further assess the efficacy of lazertinib compared with gefitinib

Measure: Depth of Response according to RECIST v1.1 by Investigator assessments

Time: Depth of Response analysis will occur when PFS maturity is observed at approximately 27 months from the first patient being randomized

Description: To further assess the efficacy of lazertinib compared with gefitinib

Measure: Time to Response according to RECIST v1.1 by Investigator assessments

Time: Time to Response analysis will occur when PFS maturity is observed at approximately 27 months from the first patient being randomized

Description: To assess OS of lazertinib compared with gefitinib

Measure: Overall survival (OS)

Time: OS will be analyzed at 2 time points: when PFS maturity is observed at approximately 27 months after the first patient is randomized, and when OS maturity is observed at approximately 45 months after the first patient is randomized

Description: To characterize the pharmacokinetics (PK) of lazertinib

Measure: Plasma concentrations of lazertinib

Time: Plasma concentration analysis will occur when PFS maturity is observed at approximately 27 months from the first patient being randomized

Description: To characterize the PK of lazertinib metabolite YH26334

Measure: Plasma concentrations of Metabolite YH26334

Time: Plasma concentration analysis will occur when PFS maturity is observed at approximately 27 months from the first patient being randomized

Description: To characterize the PK of lazertinib and YH26334

Measure: Ratio of YH26334 to lazertinib plasma concentration

Time: Ratio of YH26334 to lazertinib plasma concentration analysis will occur when PFS maturity is observed at approximately 27 months from the first patient being randomized

Description: To characterize the PK of lazertinib

Measure: Cerebrospinal fluid (CSF) concentrations of lazertinib

Time: CSF concentration analysis will occur when PFS maturity is observed at approximately 27 months from the first patient being randomized

Description: To characterize the PK of lazertinib metabolite YH26334

Measure: CSF concentrations of Metabolite YH26334

Time: CSF concentration analysis will occur when PFS maturity is observed at approximately 27 months from the first patient being randomized

Description: To characterize the PK of lazertinib and YH26334

Measure: Ratio of CSF to plasma concentration of lazertinib and YH26334

Time: Ratio of CSF to plasma concentration analysis will occur when PFS maturity is observed at approximately 27 months from the first patient being randomized

Description: The EORTC QLQ-C30 consists of 30 items and measures cancer patients' functioning (health related quality of life (HRQoL)) and symptoms for all cancer types. Questions can be grouped into 5 multi item functional scales (physical, role, emotional, cognitive, and social); 3 multi item symptom scales (fatigue, pain, nausea/vomiting); a 2 item global HRQoL scale; 5 single items assessing additional symptoms commonly reported by cancer patients (dyspnea, loss of appetite, insomnia, constipation, diarrhea) and 1 item on the financial impact of the disease. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. a high score for a functional scale represents a high / healthy level of functioning a high score for the global health status / QoL represents a high QoL but a high score for a symptom scale / item represents a high level of symptomatology / problems

Measure: Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core 30 items (QLQ-C30)

Time: EORTC-QLQ-C30 analysis will occur when OS maturity is observed at approximately 45 months from the first patient being randomized

Description: The EORTC QLQ-LC13 includes questions assessing cough, hemoptysis, dyspnea, site specific pain (symptoms), sore mouth, dysphagia, peripheral neuropathy, and alopecia (treatment related side effects), and pain medication. The items on both measures were scaled and scored using the recommended EORTC procedures. Raw scores were transformed to a linear scale ranging from 0 to 100, with a higher score representing a higher level of functioning or higher level of symptoms. Provided at least half of the items in the scale were completed, the scale score was calculated using only those items for which values existed.

Measure: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaires Lung Cancer 13 items (EORTC QLQ-LC13)

Time: EORTC QLQ-LC13 analysis will occur when OS maturity is observed at approximately 45 months from the first patient being randomized

Description: The EQ-5D comprises the following two questionnaires: The EQ-5D comprises 5 dimensions of health (mobility, self-care, usual activities, pain/discomfort, anxiety/depression). Each dimension comprises five levels (no problems, slight problems, moderate problem, severe problem, unable/extreme problems). The EQ VAS records the patients self-rated health status on a vertical graduated (0-100) visual analogue scale. The patient's self-rated health is assessed on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state) by the EQ-VAS.

Measure: Change From Baseline in Euro-Quality of Life-5 Dimension-5 level (EQ-5D-5L)

Time: EQ-5D-5L analysis will occur when OS maturity is observed at approximately 45 months from the first patient being randomized

Other Outcomes

Description: To assess the intracranial efficacy of lazertinib compared with gefitinib in only patients with brain metastases (BM) at baseline

Measure: Intracranial PFS according to RECIST v1.1 by Investigator assessment and blinded independent central review (BICR)

Time: Intracranial PFS based on Investigator assessment and BICR analysis will occur when PFS maturity is observed at approximately 27 months from the first patient being randomized

Description: To assess the intracranial efficacy of lazertinib compared with gefitinib in only patients with BM at baseline

Measure: Intracranial ORR according to RECIST v1.1 by Investigator assessments and BICR

Time: Intracranial ORR based on Investigator assessment and BICR analysis will occur when PFS maturity is observed at approximately 27 months from the first patient being randomized

Description: To assess the intracranial efficacy of lazertinib compared with gefitinib in only patients with BM at baseline

Measure: Intracranial DoR according to RECIST v1.1 by Investigator assessment and BICR

Time: Intracranial DoR based on Investigator assessment and BICR analysis will occur when PFS maturity is observed at approximately 27 months from the first patient being randomized

Description: To assess the intracranial efficacy of lazertinib compared with gefitinib in only patients with BM at baseline

Measure: Intracranial DCR according to RECIST v1.1 by Investigator assessment and BICR

Time: Intracranial DCR based on Investigator assessment and BICR analysis will occur when PFS maturity is observed at approximately 27 months from the first patient being randomized

Description: To assess the intracranial efficacy of lazertinib compared with gefitinib in only patients with BM at baseline

Measure: Depth of intracranial response according to RECIST v1.1 by Investigator assessment and BICR

Time: Depth of intracranial response based on Investigator assessment and BICR analysis will occur when PFS maturity is observed at approximately 27 months from the first patient being randomized

Description: To assess the intracranial efficacy of lazertinib compared with gefitinib in only patients with BM at baseline

Measure: Time to intracranial response according to RECIST v1.1 by Investigator assessment and BICR

Time: Time to intracranial response analysis based on Investigator assessment and BICR will occur when PFS maturity is observed at approximately 27 months from the first patient being randomized

Description: To assess the efficacy of lazertinib in the cross-over arm

Measure: PFS according to RECIST v1.1 by Investigator assessment

Time: PFS analysis will occur when OS maturity is observed at approximately 45 months from the first dosing date of lazertinib

Description: To assess the efficacy of lazertinib in the cross-over arm

Measure: ORR according to RECIST v1.1 by Investigator assessments

Time: ORR analysis will occur when OS maturity is observed at approximately 45 months from the first patient being randomized

Description: To assess the efficacy of lazertinib in the cross-over arm

Measure: DoR according to RECIST v1.1 by Investigator assessments

Time: DoR analysis will occur when OS maturity is observed at approximately 45 months from the first patient being randomized

Description: To assess the efficacy of lazertinib in the cross-over arm

Measure: DCR according to RECIST v1.1 by Investigator assessments

Time: DCR analysis will occur when OS maturity is observed at approximately 45 months from the first patient being randomized

Description: To assess the efficacy of lazertinib in the cross-over arm

Measure: Depth of Response according to RECIST v1.1 by Investigator assessments

Time: Depth of Response analysis will occur when OS maturity is observed at approximately 45 months from the first patient being randomized

Description: To assess the efficacy of lazertinib in the cross-over arm

Measure: Time to Response according to RECIST v1.1 by Investigator assessments

Time: Time to Response analysis will occur when OS maturity is observed at approximately 45 months from the first patient being randomized

Description: To compare plasma-derived cfDNA EGFR mutation status at baseline and at progression

Measure: Change from baseline for EGFR mutation status in plasma samples

Time: EGFR mutation status in plasma samples analysis will occur when OS maturity is observed at approximately 45 months from the first patient being randomized

Description: To compare the tumor sample EGFR mutation status at baseline and from an optional tumor sample taken at progression

Measure: Change from baseline for EGFR mutation status in tumor samples

Time: EGFR mutation status in tumor samples analysis will occur when OS maturity is observed at approximately 45 months from the first patient being randomized

170 A Phase I, Multi-center, Open-label, Single-arm, Dose-escalation and Dose-expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetics (PK) and Anti-tumor Activities of FCN-411 Monotherapy in Advanced Non-small Cell Lung Cancer

This phase I trial with dose-escalation stage and dose-expansion stage is the first-in-human study of FCN-411, a drug being developed for treatment of advanced cancers. The initial purpose of the study is to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) of FCN-411 monotherapy in EGFR-positive mutation non-small cell lung cancer chinese patients. The study will also provide early information on how the body handles the drug (pharmacokinetics) and on the anti-tumor activities of FCN-411.

NCT03420079
Conditions
  1. Lung Cancer
Interventions
  1. Drug: FCN-411 Dose-escalation
  2. Drug: FCN-411 Dose-expansion
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

3. Documentation of disease progression while on previous continuous treatment with first-line EGFR TKI; patients must have confirmation of tumor EGFR activating mutations (exon 19 del, or exon 21 ins) and T790M status by biopsy sample or optical microscopy. --- T790M ---

Exclusion Criteria: 1. Treatment with any of the following: 1. Treatment with an EGFR TKI within 14 days or about 5 half-lives, whichever is the longer, of the first dose of study drug; 2. Any cytotoxic chemotherapy, investigational agents or anticancer drugs for the treatment from a previous treatment regimen within 14 days of the first dose of study treatment; 3. Major surgery within 4 weeks of the first dose of study treatment; 4. Systemic irradiation including whole brain irradiation; 5. Previously treated by EGFR-TKI for T790M (for example Osimertinib). --- T790M ---

Primary Outcomes

Description: Cmax of FCN-411 following single dose.

Measure: Cmax of FCN-411 following single dose.

Time: PK blood samples are collected at pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72 and 120 hours post-dose.

Description: AUC of FCN-411 After Single Dosing.

Measure: AUC of FCN-411 following single dose.

Time: PK blood samples are collected at pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72 and 120 hours post-dose.

Description: Cmax of FCN-411 After multiple dosing.

Measure: Cmax of FCN-411 following multiple dosing.

Time: The datas should be evaluated multiple times on the eighth day、fifteenth day of Cycle 1, first day、second day of Cycle 2. Each cycle is 21 days.

Description: AUC of FCN-411 After Multiple Dosing.

Measure: AUC of FCN-411 following multiple dosing.

Time: The datas should be evaluated multiple times on the eighth day、fifteenth day of Cycle 1, first day、second day of Cycle 2. Each cycle is 21 days.

Description: Tmax of FCN-411 following single dose.

Measure: Tmax of FCN-411 following single dose.

Time: PK blood samples are collected at pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72 and 120 hours post-dose.

Description: Tmax of FCN-411 following multiple dosing.

Measure: Tmax of FCN-411 following multiple dosing.

Time: The datas should be evaluated multiple times on the eighth day、fifteenth day of Cycle 1, first day、second day of Cycle 2. Each cycle is 21 days.

Description: t1/2 of FCN-411 following single dose.

Measure: t1/2 of FCN-411 following single dose.

Time: PK blood samples are collected at pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72 and 120 hours post-dose.

Description: t1/2 of FCN-411 following multiple dosing

Measure: t1/2 of FCN-411 following multiple dosing

Time: The datas should be evaluated multiple times on the eighth day、fifteenth day of Cycle 1, first day、second day of Cycle 2. Each cycle is 21 days.

171 An Open Label, Multicenter, Phase II Single-arm Trial of AZD9291 in Non-small Cell Lung Cancer (NSCLC) Patients With Uncommon Epidermal Growth Factor Receptor Mutations

EGFR (ErbB1) mutations define a lung cancer subtype with exquisite sensitivity to EGFR tyrosine kinase inhibitors (TKIs). While in-frame deletion in exon 19 (Del19) and a point mutation (L858R) in exon 21 are the two most common sensitizing EGFR mutations in NSCLC, approximately 10% of EGFR mutation-positive tumors harbor uncommon mutations. These mutations represent a heterogeneous group of rare molecular alterations (or combinations) within exons 18-21, whose oncogenicity and sensitivity to EGFR TKIs may vary and has not been prospectively studied. Recently, a retrospective analysis reported that overall response rate of EGFR TKI (gefitinib or erlotinib) treatment was about 10% or less in Korean NSCLC patients with uncommon EGFR mutation other than del19, L858R and T790M [11]. In preclinical data, the potency of AZD9291 against uncommon EGFR mutants other than exon 20 insertion mutation was fairly good. Based on the result, in this study, we try to evaluate the efficacy of AZD9291, the potent irreversible inhibitor, in NSCLC patients with harboring uncommon EGFR mutations.

NCT03424759
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: AZD9291
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Recently, a retrospective analysis reported that overall response rate of EGFR TKI (gefitinib or erlotinib) treatment was about 10% or less in Korean NSCLC patients with uncommon EGFR mutation other than del19, L858R and T790M [11]. --- L858R --- --- T790M ---

Inclusion Criteria: - Histologically confirmed metastatic or recurrent stage IV NSCLC with activating EGFR mutation other than deletion in exon 19, L858R, T790M and insertion in exon 20 - metastatic or recurrent NSCLC - Be 19years of age on day of signing informed consent - ECOG performance status of 0 to 2 - At least one measurable lesion by RECIST 1.1(The part of radiation treatment in the palliative setting is excluded.) --- L858R --- --- T790M ---

- Untreated asymptomatic brain metastasis or symptomatic brain metastasis treated with local treatment such as operation, whole brain radiotherapy, or gamma-knife surgery - At least 2 weeks later after whole brain radiotherapy or at least 4 weeks later after palliative thoracic radiotherapy - Adequate organ function as evidenced by the following; Absolute neutrophil count > 1.5 x 109/L; Hb > 9.0g/dL; platelets > 100 x 109/L; total bilirubin ≤1.5 UNL; AST and/or ALT < 2.5 ULN if no demonstrable liver metastases or < 5 UNL in the presence of liver metastases, CCr ≥ 50mL/min - Written informed consent form Exclusion Criteria: - Prior treatment with EGFR TKI - Major surgery undertaken less than 4 weeks before the study - Localized palliative radiotherapy unless completed more than 2 weeks before the study - Uncontrolled systemic illness such as DM, CHF, unstable angina, hypertension or arrhythmia - Pregnant or nursing women (Women of reproductive potential have to agree to use an adequate contraceptive method) - Uncontrolled symptomatic brain metastasis - Prior history of malignancy within 5 years from study entry except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer, or well-treated thyroid cancer - Concomitant use of CYP3A4 inducers/inhibitors - Prolonged QT interval in ECG (QTc >450 msec) - Prior history of interstitial lung disease Inclusion Criteria: - Histologically confirmed metastatic or recurrent stage IV NSCLC with activating EGFR mutation other than deletion in exon 19, L858R, T790M and insertion in exon 20 - metastatic or recurrent NSCLC - Be 19years of age on day of signing informed consent - ECOG performance status of 0 to 2 - At least one measurable lesion by RECIST 1.1(The part of radiation treatment in the palliative setting is excluded.) --- L858R --- --- T790M ---

Recently, a retrospective analysis reported that overall response rate of EGFR TKI (gefitinib or erlotinib) treatment was about 10% or less in Korean NSCLC patients with uncommon EGFR mutation other than del19, L858R and T790M (9). --- L858R --- --- T790M ---

Primary Outcomes

Description: 30%

Measure: Objective response rate

Time: through study completion, an average of 2 years

172 An Observational, Multicentre, Prospective Study to Evaluate Concordance of Detecting EGFR (Epidermal Growth Factor Receptor) Mutation by Circulating Tumour Free DNA Versus Tissues Biopsy in NSCLC (Non-small Cell Lung Cancer).

This is a multicentre, prospective, study of EGFR )Epidermal Growth Factor Receptor) mutation status in advanced NSCLC (Non-small cell lung cancer)patients (locally advanced and/or metastatic disease) with adenocarcinoma histology proposed to be conducted at 15 sites from different geographical regions across India. The study targets to enrol 268 patients over a period of 6 months.

NCT03562819
Conditions
  1. NSCLC (Non-small Cell Lung Cancer)
MeSH:Lu Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

by tissue and plasma based testing in terms of Overall Concordance, Sensitivity, specificity, Positive predictive value & negative predictive value.. Assess the frequency of T790M mutation among study patients.. Frequency and percentage of TKI treatment naïve NSCLC patients with T790M mutation will be provided.. Inclusion Criteria: 1. Patients who provide written informed consent 2. Patients aged 18 years and older 3. Newly diagnosed patients with Metastatic (stage IV) NSCLC. --- T790M ---

by tissue and plasma based testing in terms of Overall Concordance, Sensitivity, specificity, Positive predictive value & negative predictive value.. Assess the frequency of T790M mutation among study patients.. Frequency and percentage of TKI treatment naïve NSCLC patients with T790M mutation will be provided.. Inclusion Criteria: 1. Patients who provide written informed consent 2. Patients aged 18 years and older 3. Newly diagnosed patients with Metastatic (stage IV) NSCLC. --- T790M --- --- T790M ---

Primary Outcomes

Description: by tissue and plasma based testing in terms of Overall Concordance, Sensitivity, specificity, Positive predictive value & negative predictive value.

Measure: Determine the level of concordance between EGFR mutation status

Time: 1 Day

Secondary Outcomes

Description: Frequency and percentage of TKI treatment naïve NSCLC patients with T790M mutation will be provided.

Measure: Assess the frequency of T790M mutation among study patients.

Time: 1 Day

173 A Open-label, Single-arm, Phase II Study of TQB2450 Injection Combined With Stereotactic Body Radiation Therapy (SBRT) in Subjects With Advanced Oligometastatic Non-Small Cell Lung Cancer

TQB2450 is a humanized monoclonal antibody targeting programmed death ligand-1 (PD-L1), which prevents PD-L1 from binding to PD-1 and B7.1 receptors on T cell surface, restores T cell activity, thus enhancing immune response and has potential to treat various types of tumors.

NCT04306926
Conditions
  1. Advanced Oligometastatic Non-small Cell Lung Cancer
Interventions
  1. Drug: TQB2450
  2. Radiation: SBRT
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

2.Has mutations in (epidermal growth factor receptor)EGFR, (anaplastic lymphoma kinase)ALK, (c-ros oncogene 1 receptor kinase)ROS1 or T790M and not resistant to targeted drug. --- T790M ---

Primary Outcomes

Description: PFS was defined as the time from the date of study enrollment to the date of the first of the following events, objective disease progression or death due to any cause.

Measure: Progression-Free Survival (PFS)

Time: Baseline up to 96 weeks

Secondary Outcomes

Description: Percentage of subjects achieving complete response (CR) and partial response (PR).

Measure: Objective response rate (ORR)

Time: Baseline up to 96 weeks

Description: OS defined as the time from the first dose to death from any cause. Survival time was censored at the date of last contact for patients who were still alive or lost to follow-up.

Measure: Overall survival (OS)

Time: Baseline up to 96 weeks

Description: Percentage of subjects achieving complete response (CR) and partial response (PR) and stable disease (SD).

Measure: Disease control rate(DCR)

Time: Baseline up to 96 weeks

174 A Phase IIb, Open-label, Single-arm Study to Assess the Safety and Efficacy of BPI-7711 Capsule in Patients With Metastatic or Recurrent Non-small Cell Lung Cancer With EGFR Mutation and T790M Mutation Positive.

A phase IIb, open-label, single-arm study to assess the safety and efficacy of BPI-7711 capsule in patients with metastatic or recurrent non-small cell lung cancer with EGFR mutation and T790M mutation positive.

NCT03812809
Conditions
  1. NSCLC
Interventions
  1. Drug: BPI-7711
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

A Phase IIb, Open-label, Single-arm Study to Assess the Safety and Efficacy of BPI-7711 Capsule in Patients With Metastatic or Recurrent Non-small Cell Lung Cancer With EGFR Mutation and T790M Mutation Positive.. --- T790M ---

A Phase IIb Study of BPI-7711 Capsule in Non-small Cell Lung Cancer Patients With T790M Mutation Positive A phase IIb, open-label, single-arm study to assess the safety and efficacy of BPI-7711 capsule in patients with metastatic or recurrent non-small cell lung cancer with EGFR mutation and T790M mutation positive. --- T790M ---

A Phase IIb Study of BPI-7711 Capsule in Non-small Cell Lung Cancer Patients With T790M Mutation Positive A phase IIb, open-label, single-arm study to assess the safety and efficacy of BPI-7711 capsule in patients with metastatic or recurrent non-small cell lung cancer with EGFR mutation and T790M mutation positive. --- T790M --- --- T790M ---

- Patients must have central confirmation of tumor T790M mutation+ status from a biopsy sample or a plasma sample taken after confirmation of disease progression on the most recent EGFR-TKI treatment. --- T790M ---

Primary T790M mutation positive patients should provide prior written evidence before ICF signature and have not received any EGFR-TKI. --- T790M ---

- Treatment with any 3rd generation EGFR TKIs target on T790M mutation. --- T790M ---

NSCLC Carcinoma, Non-Small-Cell Lung This is a phase IIb, open-label, single arm study assessing the safety and efficacy of BPI-7711 (180 mg, orally, once daily) in China with a confirmed diagnosis of EGFR sensitizing mutation positive and T790M mutation+ unresectable, locally advanced or metastatic NSCLC, who have progressed on prior EGFR-TKIs treatment. --- T790M ---

Primary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) assessed by MRI or CT. ORR is the percentage of patients with at least 1 visit response of CR or PR (according to independent review) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.

Measure: ORR according to RECIST 1.1 by an Independent Central Review (ICR)

Time: up to 52 weeks

Secondary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) assessed by MRI or CT. ORR is the percentage of patients with at least 1 visit response of CR or PR (according to independent review) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.

Measure: ORR according to RECIST 1.1 by investigators

Time: up to 52 weeks

Description: DCR is the percentage of patients with best response of CR, PR or SD (according to independent review), prior to progression (PD) or further anti-cancer therapy.

Measure: Disease control rate (DCR) according to RECIST 1.1

Time: up to 104 weeks

Description: PFS is the time from date of first dose until the date of PD (by independent review) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from BPI-7711 therapy or received another anti-cancer therapy prior to progression. Patients who had not progressed or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 assessment.

Measure: Progression free survival(PFS) according to RECIST 1.1

Time: up to 104 weeks

175 Exploring the Theragnostic Value of Osimertinib in EGFR-mutated Lung Cancer (THEROS) - A Multicentric Phase II Study in Patients With TKI-resistant EGFR-mutated Lung Cancer Exhibiting Early Metabolic Response to Osimertinib

This is a single arm, open label, multicentric proof-of-concept, phase II study in patients with EGFR-mutated non-small-cell lung cancer (NSCLC) with acquired TKI resistance who are "unknown" for EGFR T790M status due to non-informative or unfeasible tumor rebiopsy, and a negative finding for EGFR T790M in a standard plasma genotyping assay. All patients will receive osimertinib as continuous oral treatment for one cycle (28 days). Patients who demonstrate a metabolic response by FDG-PET scanning (to be conducted between day 15 and day 28 of cycle 1) will continue treatment until clinical or radiological progression. Osimertinib treatment will be terminated in patients not experiencing a metabolic response. Primary objective: To study the rate of early metabolic responses to osimertinib in patients with EGFR-mutated NSCLC and acquired TKI resistance who are "unknown" for EGFR T790M status due to non-informative or unfeasible tumor rebiopsy, and a negative finding for EGFR T790M in a standard plasma genotyping assay.

NCT03810066
Conditions
  1. NSCLC
  2. EGFR T790M
  3. FDG-PET
Interventions
  1. Drug: Osimertinib
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

Exploring the Theragnostic Value of Osimertinib in EGFR-mutated Lung Cancer (THEROS) This is a single arm, open label, multicentric proof-of-concept, phase II study in patients with EGFR-mutated non-small-cell lung cancer (NSCLC) with acquired TKI resistance who are "unknown" for EGFR T790M status due to non-informative or unfeasible tumor rebiopsy, and a negative finding for EGFR T790M in a standard plasma genotyping assay. --- T790M ---

Exploring the Theragnostic Value of Osimertinib in EGFR-mutated Lung Cancer (THEROS) This is a single arm, open label, multicentric proof-of-concept, phase II study in patients with EGFR-mutated non-small-cell lung cancer (NSCLC) with acquired TKI resistance who are "unknown" for EGFR T790M status due to non-informative or unfeasible tumor rebiopsy, and a negative finding for EGFR T790M in a standard plasma genotyping assay. --- T790M --- --- T790M ---

Primary objective: To study the rate of early metabolic responses to osimertinib in patients with EGFR-mutated NSCLC and acquired TKI resistance who are "unknown" for EGFR T790M status due to non-informative or unfeasible tumor rebiopsy, and a negative finding for EGFR T790M in a standard plasma genotyping assay. --- T790M ---

Primary objective: To study the rate of early metabolic responses to osimertinib in patients with EGFR-mutated NSCLC and acquired TKI resistance who are "unknown" for EGFR T790M status due to non-informative or unfeasible tumor rebiopsy, and a negative finding for EGFR T790M in a standard plasma genotyping assay. --- T790M --- --- T790M ---

No tumor rebiopsy available or negative result for EGFR T790M mutation status by a SoC molecular pathology test (e.g. --- T790M ---

Sanger sequencing, PCRbased genotyping, deep sequencing) of a rebiopsy of a progressive tumor lesion 6. Negative finding from EGFR T790M mutation testing in plasma-derived DNA using a SoC assay (e.g. --- T790M ---

Exclusion Criteria: 1. EGFR-mutated NSCLC and demonstration of the T790M resistance mutation by standard assay technology in tumor-derived or plasma-derived DNA 2. Absence of a tumor lesion with significant FDG uptake at PET/CT scanning prior to study treatment 3. Involvement in the planning and/or conduct of the study (applies to both sponsor staff and/or staff at the study site) 4. Previous treatment with osimertinib or any experimental or approved mutationspecific EGFR-TKI with clinical activity against the EGFR T790M resistance mutation 5. Treatment with an investigational drug within one week or five drug half-lives (whichever is longer) of the compound (3 weeks for antibodies) 6. Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 week prior) (Appendix A - Guidance regarding Potential Interactions With Concomitant Medications). --- T790M ---

Exclusion Criteria: 1. EGFR-mutated NSCLC and demonstration of the T790M resistance mutation by standard assay technology in tumor-derived or plasma-derived DNA 2. Absence of a tumor lesion with significant FDG uptake at PET/CT scanning prior to study treatment 3. Involvement in the planning and/or conduct of the study (applies to both sponsor staff and/or staff at the study site) 4. Previous treatment with osimertinib or any experimental or approved mutationspecific EGFR-TKI with clinical activity against the EGFR T790M resistance mutation 5. Treatment with an investigational drug within one week or five drug half-lives (whichever is longer) of the compound (3 weeks for antibodies) 6. Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 week prior) (Appendix A - Guidance regarding Potential Interactions With Concomitant Medications). --- T790M --- --- T790M ---

Judgment by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements NSCLC EGFR T790M FDG-PET Lung Neoplasms null --- T790M ---

Primary Outcomes

Description: Rate of metabolic responses as detected by FDG-PET before end of cycle 1. One cycle is defined as 28 days continuous treatment.

Measure: Rate of metabolic responses

Time: 28 days

176 A Phase I/II Study of AZD9291 (Osimertinib) and CB-839 HCl in Patients With EGFR Mutant Non-Small Cell Lung Cancer

This phase I/II trial studies the side effects and best dose of telaglenastat hydrochloride, and to see how well it works when given together with osimertinib in treating patients with stage IV non-small cell lung cancer and a mutation in the EGFR gene. Telaglenastat hydrochloride and osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT03831932
Conditions
  1. Advanced Lung Non-Small Cell Carcinoma
  2. Metastatic Lung Non-Small Cell Carcinoma
  3. Stage IV Lung Cancer AJCC v8
  4. Stage IVA Lung Cancer AJCC v8
  5. Stage IVB Lung Cancer AJCC v8
Interventions
  1. Drug: Osimertinib
  2. Drug: Telaglenastat Hydrochloride
MeSH:Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Carcinoma Neoplasm of the lung Non-small cell lung carcinoma

Screening for chronic conditions is not required - Patients with symptomatic CNS metastases who are neurologically unstable - Patients who are at risk for impaired absorption of oral medication including, but not limited to, refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of CB-839 HCl (telaglenastat) and AZD9291 - Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements - Involvement in the planning and/or conduct of the study (applies to both investigator staff and/or staff at the study site) - PHASE 2: Prior chemotherapy for NSCLC is not permitted - PHASE 2: Must be T790M mutation negative as determined by local Clinical Laboratory Improvement Amendments (CLIA)-certified assessment of a tissue biopsy obtained after progression on front-line therapy Inclusion Criteria: - Histologically confirmed, stage IV NSCLC, with advanced or metastatic disease - Activating mutation present in the EGFR gene (L858R or exon 19 deletion, alone or in combination with other EGFR mutations) as per local assessment of a tissue biopsy/cytology specimen. --- T790M ---

Screening for chronic conditions is not required - Patients with symptomatic CNS metastases who are neurologically unstable - Patients who are at risk for impaired absorption of oral medication including, but not limited to, refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of CB-839 HCl (telaglenastat) and AZD9291 - Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements - Involvement in the planning and/or conduct of the study (applies to both investigator staff and/or staff at the study site) - PHASE 2: Prior chemotherapy for NSCLC is not permitted - PHASE 2: Must be T790M mutation negative as determined by local Clinical Laboratory Improvement Amendments (CLIA)-certified assessment of a tissue biopsy obtained after progression on front-line therapy Advanced Lung Non-Small Cell Carcinoma Metastatic Lung Non-Small Cell Carcinoma Stage IV Lung Cancer AJCC v8 Stage IVA Lung Cancer AJCC v8 Stage IVB Lung Cancer AJCC v8 Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVES: I. To assess the safety and tolerability of osimertinib (AZD9291) and CB-839 hydrochloride (HCl) (telaglenastat) and determine the recommended phase II dose (RP2D) in patients with metastatic, EGFR activating mutation-positive non-small cell lung cancer (NSCLC). --- T790M ---

To determine the efficacy of AZD9291 and CB-839 HCl (telaglenastat) in patients with metastatic, EGFR activating mutation-positive, T790M mutation-negative NSCLC who have developed progressive disease (PD) on front-line EGFR inhibitor therapy, as defined by response rate (RR) per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. --- T790M ---

To determine the progression free survival (PFS) of AZD9291 and CB-839 HCl (telaglenastat) in patients with EGFR mutation positive, T790M mutation negative NSCLC who have developed progressive disease (PD) on front-line EGFR inhibitor therapy. --- T790M ---

To determine the overall survival (OS) of AZD9291 and CB-839 HCl (telaglenastat) in patients with EGFR mutation positive, T790M mutation negative NSCLC who have developed PD on front-line EGFR inhibitor therapy. --- T790M ---

(Phase II) EXPLORATORY/CORRELATIVE OBJECTIVES: I. To assess cell-free deoxyribonucleic acid (DNA) (cfDNA) and measure changes with response to treatment as well as disease progression (EGFR sensitizing mutations, T790M resistance mutation, recognized bypass mechanisms). --- T790M ---

Primary Outcomes

Measure: Recommended phase II dose (RP2D) (Phase I)

Time: Up to 28 days

Description: Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. Will be calculated as the proportion of patients who achieve a response to therapy divided by the total number of evaluable patients. An evaluable patient is defined as an eligible patient who has received at least one dose of therapy. All evaluable patients will be included in calculating the ORR for the study along with corresponding 95% binomial confidence intervals (CIs) (assuming that the number of patients who respond is binomially distributed).

Measure: Objective response rate (ORR) (Phase II)

Time: Up to 30 days after completion of therapy

Secondary Outcomes

Description: Will be assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Frequency and severity of adverse events and tolerability of the regimen will be collected and summarized by descriptive statistics. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns.

Measure: Dose limiting toxicities (DLT) (Phase I)

Time: Up to 28 days

Description: Survival will initially be modeled using Kaplan-Meier methods, resulting in median survival times with 95% CI, assuming sufficient events have occurred.

Measure: Progression-free survival (PFS) (Phase II)

Time: From initiation of therapy to documented progression or death without progression, assessed up to 30 days after completion of therapy

Description: Survival will initially be modeled using Kaplan-Meier methods, resulting in median survival times with 95% CI, assuming sufficient events have occurred.

Measure: Overall survival (OS) (Phase II)

Time: From initiation of therapy to death from any cause, assessed up to 30 days after completion of therapy

Other Outcomes

Description: Will be assessed by CB-839 HCl drug levels following both single agent therapy as well as combination therapy with CB-839 HCl and osimertinib (AZD9291). Will explore PK endpoints such as concentration steady state (Css), area under the curve (AUC), clearance (CL), volume of distribution (Vd), and half-life (t1/2) computed using non-compartmental and compartmental methods. Will use graphical analyses as well as repeated measure models (linear or nonlinear mixed models, generalized estimating equations [GEE]) to assess the PK and pharmacodynamics (PD) markers described above in relation to clinical treatment outcomes, recognizing some inherent limitations due to sample size.

Measure: Post-glutaminase inhibitor CB-839 hydrochloride pharmacokinetics (PK) (CB-839 HCl) (Phase I)

Time: Day 15 of cycle 1, day 2 of cycle 2 and day 1 of each subsequent cycle (each cycle = 28 days)

Description: Will be assessed by AZD9291 drug levels following combination therapy with CB-839 HCl and AZD9291. Will be assessed by CB-839 HCl drug levels following both single agent therapy as well as combination therapy with CB-839 HCl and AZD9291. Will explore PK endpoints such as Css, AUC, CL, Vd, and t1/2 computed using non-compartmental and compartmental methods. Will use graphical analyses as well as repeated measure models (linear or nonlinear mixed models, GEE) to assess the PK and PD markers described above in relation to clinical treatment outcomes, recognizing some inherent limitations due to sample size.

Measure: Post-AZD9291 PK (Phase I)

Time: Day 2 of cycle 2 and day 1 of each subsequent cycle (each cycle = 28 days)

Description: Will be assessed by cell-free deoxyribonucleic acid (cfDNA). All continuous measurements will be summarized using mean +/- standard error of mean (SEM), range, and median at each time point. Changes in these measurements from baseline to after treatment, or baseline to progression will be assessed using paired Wilcoxon tests. Adjustments for multiple comparisons or multiple outcomes will be performed using Bonferroni correction.

Measure: Change in EGFR mutational status (Phase II)

Time: Baseline up to disease progression, assessed up to 30 days after completion of therapy

Description: Will be assessed by plasma concentrations of these compounds. All continuous measurements will be summarized using mean +/- SEM, range, and median at each time point. Changes in these measurements from baseline to after treatment, or baseline to progression will be assessed using paired Wilcoxon tests. Adjustments for multiple comparisons or multiple outcomes will be performed using Bonferroni correction.

Measure: Change in circulating levels of glutamine, glutamate, aspartate, and asparagine (Phase II)

Time: Baseline up to time of disease progression, assessed up to 30 days after completion of therapy

Description: Will be assessed by static (standard uptake value [SUV]max, average SUV, tumor-to-background ratio, metabolic tumor volume, total lesion glycolysis) and dynamic (net influx rate constant and glucose metabolic rate at 30 and 60 minutes) parameters. Will be summarized using mean +/- SEM, range, and median. The changes in the FDG-PET/computed tomography (CT) parameter measurements from baseline to after treatment will be compared between responders and non-responders using two sample t-test or Wilcoxon test, whichever is appropriate.

Measure: Change in 18F-fluorodeoxyglucose (18F-FDG)-positron emission tomography (PET) imaging (Phase II)

Time: Baseline up to 2 cycles of treatment (each cycle = 28 days)

177 A Phase Ib Clinical Study With Extension Phase to Evaluate Safety and Efficacy of Genolimzumab (GB226) in Combination With Fruquintinib in the Treatment of Relapsed or Metastatic NSCLC Patients

This study is a multi-center, open-label, dose-finding phase Ib clinical study with extension phase, which is aimed at evaluating the efficacy and safety of GB226 combined with fruquintinib in treatment of relapsed or metastatic NSCLC patients with EGFR-sensitive mutations who have failed to respond to EGFR-TKI treatment,evaluating the pharmacokinetic characteristics of GB226 and fruquintinib, and the immunogenicity of GB226, and preliminarily evaluating the antitumor activity of GB226 and fruquintinib.

NCT03976856
Conditions
  1. Metastatic Non-small Cell Lung Cancer
Interventions
  1. Drug: GB226
  2. Drug: Fruquintinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

No T790M mutation after failure of EGFR-TKI treatment; 2. T790M mutation after EGFR-TKI treatment failure, and failed to respond to third-generation EGFR-TKI treatment; primary T790M mutation, progressed after third-generation EGFR-TKI treatment or no other available effective therapies; 3. The above patients failed to respond to chemotherapy or are unwilling to or intolerable to chemotherapy; 5. --- T790M ---

No T790M mutation after failure of EGFR-TKI treatment; 2. T790M mutation after EGFR-TKI treatment failure, and failed to respond to third-generation EGFR-TKI treatment; primary T790M mutation, progressed after third-generation EGFR-TKI treatment or no other available effective therapies; 3. The above patients failed to respond to chemotherapy or are unwilling to or intolerable to chemotherapy; 5. --- T790M --- --- T790M ---

No T790M mutation after failure of EGFR-TKI treatment; 2. T790M mutation after EGFR-TKI treatment failure, and failed to respond to third-generation EGFR-TKI treatment; primary T790M mutation, progressed after third-generation EGFR-TKI treatment or no other available effective therapies; 3. The above patients failed to respond to chemotherapy or are unwilling to or intolerable to chemotherapy; 5. --- T790M --- --- T790M --- --- T790M ---

Primary Outcomes

Description: Assessment of adverse events (AEs) graded by Common Terminology Criteria for Adverse Events (CTCAE) v4.03

Measure: Incidence of Adverse Event

Time: all adverse events will be recorded from the time the consent form is signed through 90 days following cessation of treatment.

Description: Assessment of serious adverse events (SAEs) graded by Common Terminology Criteria for Adverse Events (CTCAE) v4.03

Measure: Incidence of Serious Adverse Event

Time: all adverse events will be recorded from the time the consent form is signed through 90 days following cessation of treatment.

Description: Incidence of Dose Limited Toxicity

Measure: Dose Limited Toxicity

Time: Day 1 to Day 28 after first dose

Description: Defined as the highest dose tested in which only 0 or 1 out of 6 evaluable patients experience a dose limiting toxicity, as graded by the National Cancer Institute (NCI) Common terminology Criteria for Adverse Events (CTCAE) version 4.03

Measure: Maximum Tolerated Dose

Time: Day 1 to Day 28 after first dose

Secondary Outcomes

Description: Cmax

Measure: Cmax

Time: up to 90 days after the last administration

Description: Tmax

Measure: Tmax

Time: up to 90 days after the last administration

Description: AUC0-t

Measure: AUC0-t

Time: up to 90 days after the last administration

Description: AUC0-∞

Measure: AUC0-∞

Time: up to 90 days after the last administration

Description: MRT

Measure: MRT

Time: up to 90 days after the last administration

Description: Vd

Measure: Vd

Time: up to 90 days after the last administration

Description: CL

Measure: CL

Time: up to 90 days after the last administration

Description: AUC 0-τ

Measure: AUC 0-τ

Time: up to 90 days after the last administration

Description: C avg

Measure: C avg

Time: up to 90 days after the last administration

Description: C min

Measure: C min

Time: up to 90 days after the last administration

Description: CL ss

Measure: CL ss

Time: up to 90 days after the last administration

Description: To evaluate the efficacy of GB226 as defined by objective response rate in patients with lung cancer.

Measure: Objective Response Rate, ORR

Time: up to 90 days after the last administration

Description: To evaluate the efficacy of GB226 as defined by disease control rate in patients with lung cancer.

Measure: Disease control rate,DCR

Time: up to 90 days after the last administration

Description: To evaluate the duration of response (DOR) of GB226 in patients with lung cancer

Measure: Duration of response, DOR

Time: up to 90 days after the last administration

Description: To evaluate the efficacy of GB226 as defined by progression-free survival in patients with lung cancer

Measure: Progression-free survival, PFS

Time: up to 90 days after the last administration

Description: To evaluate the efficacy of GB226 as defined by overall survival in patients with lung cancer.

Measure: Overall survival, OS

Time: up to 90 days after the last administration

Description: To evaluate the immunogenicity of GB226 in Chinese patients with lung cancer.

Measure: Concentration of AntiDrug Antibody, ADA

Time: up to 90 days after the last administration

178 A Phase I/II, Open-Label, Multicenter Study to Assess the Safety, Tolerability, Pharmacokinetics and Anti-tumor Efficacy of DZD9008 in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC) With EGFR or HER2 Mutation

This study will treat patients with advanced NSCLC with EGFR or HER2 mutation who have progressed following prior therapy. This is the first time this drug is tested in patients, and so it will help to understand what type of side effects may occur with the drug treatment. It will also measure the levels of drug in the body and preliminarily assess its anti-cancer activity as monotherapy.

NCT03974022
Conditions
  1. NonSmall Cell Lung Cancer
Interventions
  1. Drug: DZD9008
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Prior treatment with currently approved EGFR TKIs for sensitizing or T790M resistance mutations, such as gefitinib, erlotinib, osimertinib, afatinib and dacomitinb, are allowed. --- T790M ---

Primary Outcomes

Description: To investigate the safety and tolerability of DZD9008 when given orally to patients with advanced NSCLC with EGFR or HER2 mutations; To establish Maximum Tolerated Dose (MTD) (if possible) and Recommended Phase 2 Dose (PR2D) of DZD9008 when given orally in patients with advanced NSCLC with EGFR or HER2 mutations.

Measure: Part A: Safety and tolerability of DZD9008.

Time: 28 days after the first multiple dose

Description: To evaluate anti-tumor activity of DZD9008 in advanced NSCLC patients with EGFR Exon20 insertion, HER2 Exon20 insertion or EGFR uncommon mutations at defined dose(s) (Part B)

Measure: Part B: Objective Response Rate (ORR) according to RECIST 1.1.

Time: through the study completion, an average of around 1 year

Secondary Outcomes

Description: To characterize the pharmacokinetics (PK) of DZD9008 following a single oral dosing and at steady state after multiple oral dosing, and renal excretion of DZD9008

Measure: Plasma DZD9008 concentration

Time: Through cycle 3 day 1 (8 days for Cycle 0, 28 days for Cycle 1, then 21 days for each subsequent cycle)

179 A Phase II Randomized Study of Ramucirumab Plus MK3475 (Pembrolizumab) Versus Standard of Care for Patients Previously Treated With Immunotherapy for Stage IV or Recurrent Non-Small Cell Lung Cancer (Lung-MAP Non-Matched Sub-Study)

This phase II Lung-MAP non-Match treatment trial studies how well ramucirumab and pembrolizumab work versus standard of care in treating patients with non-small cell lung cancer that is stage IV or has come back. Immunotherapy with monoclonal antibodies, such as ramucirumab and pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in standard of care chemotherapy for non-small cell lung cancer, such as docetaxel, gemcitabine hydrochloride, and pemetrexed, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ramucirumab and pembrolizumab together may work better in treating patients with non-small lung cancer compared to standard of care.

NCT03971474
Conditions
  1. Recurrent Lung Non-Small Cell Carcinoma
  2. Stage IV Lung Cancer AJCC v8
  3. Stage IVA Lung Cancer AJCC v8
  4. Stage IVB Lung Cancer AJCC v8
Interventions
  1. Drug: Docetaxel
  2. Drug: Gemcitabine
  3. Drug: Gemcitabine Hydrochloride
  4. Biological: Pembrolizumab
  5. Drug: Pemetrexed
  6. Drug: Pemetrexed Disodium
  7. Biological: Ramucirumab
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Patients who were screened under S1400 (legacy screening/pre-screening study) must have had prior PD-L1 testing by the Dako 22C3 PharmDx immunohistochemistry (IHC) assay, and must have results available for stratification purposes - Patients must not have EGFR sensitizing mutations, EGFR T790M mutation, ALK gene fusion, ROS 1 gene rearrangement, and BRAF V600E mutation unless they have progressed following all standard of care targeted therapy - Patients must not have an active autoimmune disease that has required systemic treatment in past two years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). --- T790M ---

Primary Outcomes

Description: Will be compared between patients previously treated with platinum-based chemotherapy and immunotherapy for stage IV or recurrent non-small cell lung cancer randomized to ramucirumab and MK-3475 (pembrolizumab) versus standard of care (SoC). Will be estimated using the method of Kaplan-Meier.

Measure: Overall survival (OS)

Time: Up to 3 years

Secondary Outcomes

Description: Will be estimated using the method of Kaplan-Meier. Median and landmark time-point estimates will be based on the Kaplan-Meier estimates. The average hazard ratio (HR) will be estimated using a Cox proportional hazards model. An assessment of the proportional hazards assumption will be performed and an assessment of the time-dependent HR will be done.

Measure: Investigator assessed-progression-free survival (IA-PFS)

Time: From date of sub-study registration to date of first documentation of progression assessed by central review or symptomatic deterioration, or death due to any cause, assessed up to 3 years

Description: Will be estimated using the method of Kaplan-Meier. Median and landmark time-point estimates will be based on the Kaplan-Meier estimates. The average HR will be estimated using a Cox proportional hazards model. An assessment of the proportional hazards assumption will be performed and an assessment of the time-dependent HR will be done.

Measure: Duration of response (DOR)

Time: From date of first documentation of response (CR or PR), or death due to any cause among patients who achieve a response (CR or PR), assessed up to 3 years

Description: Binary proportions will be summarized with associated confidence intervals. Will be compared with toxicities using a chi-squared test at the 1-sided 0.05 level.

Measure: Response rates (RR)

Time: Up to 3 years

Description: Will be assessed using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Binary proportions will be summarized with associated confidence intervals. Will be compared with RR using a chi-squared test at the 1-sided 0.05 level.

Measure: Incidence of adverse events

Time: Up to 3 years

180 Randomized Phase III Multicenter Trial of Customized Chemotherapy Versus Standard of Care for1st Line Treatment of Elderly Patients With Advanced Non-Small-Cell Lung Cancer

This is a randomized phase III trial that will randomize elderly patients(70 years of age and older) who are not considered eligible for standard doublet or triplet regimens. In a 2:1 fashion, patients will be randomized to the customization arm or the standard arm, respectively. This trial will be offered to patients who are previously untreated for stage IV NSCLC. The primary objective is to evaluate if chemotherapy selection based on histology and tumoral molecular determinants ERCC1, RRM1 and TS (arm A, the experimental arm) results in superior outcome in elderly patients with untreated, advanced NSCLC compared to standard of care treatments (arm B, the standard arm).

NCT03402048
Conditions
  1. Stage IV, NSCLC
  2. Lung Neoplasms
  3. Bronchial Neoplasms
  4. Carcinoma, Bronchogenic
  5. Lung Diseases
  6. Neoplasms
  7. Respiratory Tract Diseases
  8. Respiratory Tract Neoplasms
  9. Thoracic Neoplasms
Interventions
  1. Drug: Carboplatin
  2. Drug: Gemcitabine
  3. Drug: Pemetrexed
  4. Drug: Docetaxel
  5. Drug: Vinorelbine
MeSH:Neoplasms Lung Neoplasms Thoracic Neoplasms Respiratory Tract Neoplasms Carcinoma, Bronchogenic Bronchial Neoplasms Lung Diseases Respiratory Tract Diseases
HPO:Abnormal lung morphology Bronchial neoplasm Neoplasm Neoplasm of the lung Neoplasm of the respiratory system

T790M and D770. --- T790M ---

Primary Outcomes

Description: primary endpoint is OS (determined from the date of randomization).Assuming an exponential survival distribution for both treatment arms and a median survival time of 8 months in the control arm we anticipate to detect an improvement of three months in OS.

Measure: Overall Survival

Time: from the date of randomization

Secondary Outcomes

Description: PFS at 6 months (determined from the date of randomization). The anticipated 6-month PFS in arm B is approximately 25% and the goal in the experimental arm is to achieve a 32% improvement to 33%.

Measure: Progression Free survival

Time: at six months determined from the date of randomization

Other Outcomes

Description: adverse events and serious adverse events as a measure of safety and tolerability

Measure: AE and SAE (according to CTCAE version 4.0)

Time: every week from the day 1 treatment until the end of treatment (up to 18 weeks)

Description: Rate of successfully conducted gene expression analysis in patients that have signed the informed consent document

Measure: Rate of successfully conducted gene expression analysis in patients that have signed the informed consent document

Time: up to10 business days of submission of the tumor specimen

181 A Randomized Phase II Study of TAK228 (MLN0128, Sapanisertib) Plus Docetaxel Versus Standard of Care in Patients With Previously - Treated NFE2L2 or KEAP1-Positive Stage IV or Recurrent Squamous Cell Lung Cancer (ECOG-ACRIN LUNG-MAP Sub-Study)

This phase II LUNG-MAP treatment trial studies how well sapanisertib and docetaxel work for the treatment for squamous cell lung cancer that is stage IV or has come back (recurrent). Sapanisertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as docetaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving sapanisertib and docetaxel may work better in treating patients with squamous cell lung cancer compared to standard chemotherapy.

NCT04267913
Conditions
  1. Lung Squamous Cell Carcinoma
  2. Recurrent Lung Carcinoma
  3. Stage IV Lung Cancer AJCC v8
  4. Stage IVA Lung Cancer AJCC v8
  5. Stage IVB Lung Cancer AJCC v8
Interventions
  1. Drug: Dexamethasone
  2. Drug: Docetaxel
  3. Biological: Ramucirumab
  4. Drug: Sapanisertib
MeSH:Carcinoma Lung Neoplasms
HPO:Carcinoma Neoplasm of the lung

These cases should be discussed with a study chair prior to enrollment - Patients must agree to have blood specimens submitted for circulating tumor DNA (ctDNA) - Patients must also be offered participation in banking and in the correlative studies for collection and future use of specimens - Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines - As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system - Patients with impaired decision-making capacity are eligible as long as their neurological or psychological condition does not preclude their safe participation in the study (e.g., tracking pill consumption and reporting adverse events to the investigator) Exclusion Criteria: - Patients must not have EGFR sensitizing mutations, EGFR T790M mutation, ALK gene fusion, ROS 1 gene rearrangement, and BRAF V600E mutation unless they have progressed following all standard of care targeted therapy - Patient must not have leptomeningeal disease, spinal cord compression or brain metastases unless: (1) metastases have been locally treated and have remained clinically controlled and asymptomatic for at least 14 days following treatment, and prior to sub-study randomization, AND (2) patient has no residual neurological dysfunction and has been off corticosteroids for at least 14 days prior to sub-study randomization. --- T790M ---

Primary Outcomes

Description: IA-PFS will be compared between the arms using a stratified log-rank test.

Measure: Investigator-assessed progression-free survival (IA-PFS)

Time: Up to 3 years

Secondary Outcomes

Description: Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

Measure: Overall response rate (ORR)

Time: Up to 3 years

Description: Will be estimated using the Kaplan-Meier method. The Brookmeyer-Crowley method will be used to estimate 95% confidence intervals for the median. For point estimates at landmark times, the associated 95% confidence interval (CI) will be calculated using Greenwood's formula and based on a log-log transformation applied on the survival function. Hazard ratios for these outcomes will be estimated using a Cox Proportional Hazards regression model adjusting for the stratification factors.

Measure: Duration of response

Time: Up to 3 years

Description: Will be estimated using the Kaplan-Meier method. The Brookmeyer-Crowley method will be used to estimate 95% confidence intervals for the median. For point estimates at landmark times, the associated 95% CI will be calculated using Greenwood's formula and based on a log-log transformation applied on the survival function. Hazard ratios for these outcomes will be estimated using a Cox Proportional Hazards regression model adjusting for the stratification factors.

Measure: Progression free survival

Time: Up to 3 years

Description: Will be estimated using the Kaplan-Meier method. The Brookmeyer-Crowley method will be used to estimate 95% confidence intervals for the median. For point estimates at landmark times, the associated 95% CI will be calculated using Greenwood's formula and based on a log-log transformation applied on the survival function. Hazard ratios for these outcomes will be estimated using a Cox Proportional Hazards regression model adjusting for the stratification factors.

Measure: Overall survival

Time: Up to 3 years

182 A Phase II Study of LOXO-292 in Patients With RET Fusion-Positive Stage IV or Recurrent Non-Small Cell Lung Cancer (LUNG-MAP Sub-Study)

This phase II LUNG-MAP treatment trial studies how well selpercatinib works in treating patients with RET fusion-positive non-small cell lung cancer that is stage IV or has come back (recurrent). Selpercatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT04268550
Conditions
  1. Recurrent Lung Non-Small Cell Carcinoma
  2. Stage IV Lung Cancer AJCC v8
  3. Stage IVA Lung Cancer AJCC v8
  4. Stage IVB Lung Cancer AJCC v8
Interventions
  1. Drug: Selpercatinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

This includes EGFR sensitizing mutations, EGFR T790M, ALK gene fusion, ROS1 gene fusion, KRAS activating mutation, BRAF V600E mutation and MET exon 14 skipping mutation or high-level amplification and expression - Note: EGFR, ALK, ROS, KRAS, and BRAF testing is performed as part of the LUNGMAP screening/pre-screening FoundationOne test. --- T790M ---

Primary Outcomes

Description: A response will be confirmed by a complete response (CR) or partial response (PR). Proportions and associated confidence intervals will be calculated.

Measure: Response rate by blinded independent centralized review (BICR)

Time: Up to 3 years from date of sub-study registration

Secondary Outcomes

Description: Will be assessed using Common Terminology Criteria for Adverse Event version 5.0.

Measure: Incidence of adverse events

Time: Up to 3 years from date of sub-study registration

Description: Will be estimated using the method of Kaplan-Meier. The Brookmeyer-Crowley method will be used to estimate confidence intervals for the median using Greenwood's formula and based on a log-log transformation applied on the survival function for landmark times

Measure: BICR-progression-free survival (PFS)

Time: From date of sub-study registration to date of first documentation of progression assessed by BICR or symptomatic deterioration, or death due to any cause, assessed up to 3 years from date of sub-study registration

Description: Will be estimated using the method of Kaplan-Meier. The Brookmeyer-Crowley method will be used to estimate confidence intervals for the median using Greenwood's formula and based on a log-log transformation applied on the survival function for landmark times

Measure: Investigator-assessed (IA) PFS

Time: From date of sub-study registration to date of first documentation of progression assessed by local review or symptomatic deterioration, or death due to any cause, assessed up to 3 years from date of sub-study registration

Description: Will be estimated using the method of Kaplan-Meier. The Brookmeyer-Crowley method will be used to estimate confidence intervals for the median using Greenwood's formula and based on a log-log transformation applied on the survival function for landmark times

Measure: Overall survival

Time: Up to 3 years from date of sub-study registration

Description: Will be evaluated among patients who achieve a confirmed response. Will be estimated using the method of Kaplan-Meier. The Brookmeyer-Crowley method will be used to estimate confidence intervals for the median using Greenwood's formula and based on a log-log transformation applied on the survival function for landmark times. The median DOR and percentage with DOR at landmark times at 6 and 12 months after documentation of confirmed response will be estimated.

Measure: BICR-duration of response (DOR)

Time: From date of first documentation of confirmed response (CR or PR) to date of first documentation of progression assessed by BICR or symptomatic deterioration, or death due to any cause among patients who achieve, assessed at 6 and 12 months

Description: Will be assessed among patients with brain metastases. Will be estimated using the method of Kaplan-Meier. The Brookmeyer-Crowley method will be used to estimate confidence intervals for the median using Greenwood's formula and based on a log-log transformation applied on the survival function for landmark times

Measure: Central nervous system (CNS) response rate

Time: Baseline

Description: Will be assessed among patients with brain metastases. Will be estimated using the method of Kaplan-Meier. The Brookmeyer-Crowley method will be used to estimate confidence intervals for the median using Greenwood's formula and based on a log-log transformation applied on the survival function for landmark times

Measure: Duration of intracranial response among patients with a CNS response

Time: Baseline

183 Prospective Observational Trial to Evaluate the Efficacy of the Combination of Osimertinib and Aspirin in Patients With Disease Progression to 1st Generation EGFR-TKI Due to Acquisition of EGFR T790M

The third generation epidermal growth gactor receptor-tyrosine Kinase Inhibitor(EGFR-TKI) osimertinib has obvious curative effect for EGFR sensitive mutation and T790M mutation(PMID 27959700), but acquired drug resistance will occur. Previous studies show that apoptosis escape can lead to EGFR-TKI resistance.Osimertinib resistant cells show abnormal activation of PI3K/AKT/BIM activation(PMID 28765329). The classical drug aspirin can effectively decrease AKT phosphorylation and activate of BIM(PMID 28881293).So Investigators speculate that aspirin may decrease the PI3K/AKT/BIM signaling pathways, then promote osimertinib resistant cells apoptosis. The current study aims to evaluate the combination of aspirin and osimertinib in patients with EGFR/T790M mutations.

NCT03543683
Conditions
  1. Non-Small Cell Lung Cancer Stage IIIB
  2. Non-small Cell Lung Cancer Stage IV
  3. EGFR T790M
Interventions
  1. Drug: Osimertinib
  2. Drug: Aspirin
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Prospective Observational Trial to Evaluate the Efficacy of the Combination of Osimertinib and Aspirin in Patients With Disease Progression to 1st Generation EGFR-TKI Due to Acquisition of EGFR T790M. --- T790M ---

Combination of Osimertinib and Aspirin to Treat 1st Generation EGFR-TKI Resistance in NSCLC The third generation epidermal growth gactor receptor-tyrosine Kinase Inhibitor(EGFR-TKI) osimertinib has obvious curative effect for EGFR sensitive mutation and T790M mutation(PMID 27959700), but acquired drug resistance will occur. --- T790M ---

The current study aims to evaluate the combination of aspirin and osimertinib in patients with EGFR/T790M mutations. --- T790M ---

To evaluate the response to therapy and 1 year median progression-free survival(PFS) rates of the combination of Osimertinib and Aspirin in patients who harbors T790M EGFR-mutant with metastatic pulmonary adenocarcinoma disease progression to 1st generation EGFR-TKI .. median PFS according to resist 1.1. --- T790M ---

To evaluate the response to therapy and 1 year progression-free survival (PFS) of the combination of Osimertinib and Aspirin in patients who harbors T790M EGFR-mutant with metastatic pulmonary adenocarcinoma disease progression to 1st generation EGFR-TKI .. median overall survival(OS) according to resist 1.1. --- T790M ---

To evaluate the response to therapy and overall survival(OS) of the combination of Osimertinib and Aspirin in patients who harbors T790M EGFR-mutant with metastatic pulmonary adenocarcinoma disease progression to 1st generation EGFR-TKI. --- T790M ---

Non-Small Cell Lung Cancer Stage IIIB Non-small Cell Lung Cancer Stage IV EGFR T790M Lung Neoplasms Carcinoma, Non-Small-Cell Lung Reversible small-molecule EGF receptor tyrosine kinase inhibitors (EGFR-TKI) have shown dramatic therapeutic efficacy in non-small cell lung cancer (NSCLC) patients with EGFR-activating mutations, and have been recommended as the standard first-line therapy in these patients. --- T790M ---

Osimertinib is a 3rd-generation EGFR-TKI used to treat NSCLC patients with resistance to 1st generation EGFR-TKI due to T790M mutation. --- T790M ---

Here, investigators'group observed that in clinic, several patients who took osimertinib and aspirin together have shown excellent effect.Investigators therefore conduct this clinical trial to observe whether the combination of Aspirin and Osimertinib could enhance efficacy of Osimertinib in lung cancer patients resistant to 1st generation EGFR-TKI with T790M. --- T790M ---

Primary Outcomes

Description: To evaluate the response to therapy and 1 year median progression-free survival(PFS) rates of the combination of Osimertinib and Aspirin in patients who harbors T790M EGFR-mutant with metastatic pulmonary adenocarcinoma disease progression to 1st generation EGFR-TKI .

Measure: 1-year median progression-free survival(PFS) rates according to resist 1.1

Time: 3years

Secondary Outcomes

Description: To evaluate the response to therapy and 1 year progression-free survival (PFS) of the combination of Osimertinib and Aspirin in patients who harbors T790M EGFR-mutant with metastatic pulmonary adenocarcinoma disease progression to 1st generation EGFR-TKI .

Measure: median PFS according to resist 1.1

Time: 3years

Description: To evaluate the response to therapy and overall survival(OS) of the combination of Osimertinib and Aspirin in patients who harbors T790M EGFR-mutant with metastatic pulmonary adenocarcinoma disease progression to 1st generation EGFR-TKI

Measure: median overall survival(OS) according to resist 1.1

Time: 3years

184 EGFR Tyrosine Kinase Inhibitor Combined With Concurrent or Sequential Chemotherapy for Advanced Lung Cancer Patients of Gradual Progression After First-line EGFR-TKI Therapy: a Randomized Controlled Study

To compare the efficacy of simultaneous EGFR-TKI and chemotherapy with that of sequential treatment after patients gradually progressed from first-line EGFR-TKI treatment. Patients who had gradual progression and EGFR-T790M mutation-negative were randomly divided into two groups: in concurrent group, patients were treated with pemetrexed plus cisplatin along with the same EGFR-TKI; in sequential group, patients continued with EGFR-TKI until the disease progressed again according to the RECIST criteria, and then switched to chemotherapy. We evaluated progression-free survival (PFS) and overall survival (OS) time of patients. For sequential group, PFS was PFS1 (gradual progression to discontinue EGFR-TKI) plus PFS2 (chemotherapy alone).

NCT03544814
Conditions
  1. Lung Adenocarcinoma
  2. EGFR Activating Mutation
Interventions
  1. Drug: icotinib combined with pemetrexed plus cisplatin
  2. Drug: first icotinib and then pemetrexed plus cisplatin
MeSH:Adenocarcinoma of Lung

Patients who had gradual progression and EGFR-T790M mutation-negative were randomly divided into two groups: in concurrent group, patients were treated with pemetrexed plus cisplatin along with the same EGFR-TKI; in sequential group, patients continued with EGFR-TKI until the disease progressed again according to the RECIST criteria, and then switched to chemotherapy. --- T790M ---

7) Patients did not achieve acquired EGFR-T790M mutation assessed by ARMS, next-generation sequencing (NGS) or droplet digital PCR (ddPCR) after first-line EGFR-TKI therapy 8) Patients did not receive any chemotherapy previously 9) Able to comply with study and follow-up procedures 10) Age >=18 years, ECOG PS: 0~2, estimated survival duration more than 3 months; 11) Major organ function Exclusion criteria: 1. --- T790M ---

The criteria of local progression 6. Patients achieved acquired EGFR-T790M mutation assessed by ARMS, next-generation sequencing (NGS) or droplet digital PCR (ddPCR) after first-line EGFR-TKI therapy 7. Previously (within 5 years) or presently suffering from other malignancies 8. --- T790M ---

Primary Outcomes

Description: Radiographic assessments were performed when enrolled and every 8 weeks until disease progression after chemotherapy according to RECIST version 1.1. After PD, collect the survival information every 16 weeks until death or withdrawal of study consent.

Measure: Progression-free survival (PFS)

Time: 16 months

Secondary Outcomes

Description: Radiographic assessments were performed when enrolled and every 8 weeks until disease progression after chemotherapy according to RECIST version 1.1. After PD, collect the survival information every 16 weeks until death or withdrawal of study consent.

Measure: overall survival (OS)

Time: 32 months

185 A Prospective, Open-label, Single Arm, Multi-center, Phase II Exploratory Trial to Evaluate the Efficacy and Safety of NOV120101 (Poziotinib) as the First-line Treatment Medication in Patients With Harboring EGFR Mutations

The purpose of this open-label, single-arm, multi-center phase II trial is to evaluate the efficacy and safety of novel pan-HER inhibitor, NOV120101 (Poziotinib), as a first-line monotherapeutic agent in patients with lung adenocarcinoma harboring EGFR mutation.

NCT01819428
Conditions
  1. Adenocarcinoma of Lung Stage IIIB
  2. Adenocarcinoma of Lung Stage IV
Interventions
  1. Drug: NOV120101 (Poziotinib)
MeSH:Adenocarcinoma Adenocarcinoma of Lung

to observe HGF expression status in plasma and T790M mutation induction status from plasma DNA. --- T790M ---

Primary Outcomes

Description: the proportion of patients with complete response (CR) and/or partial response (PR)

Measure: Objective response rate (ORR)

Time: about 3 years

Secondary Outcomes

Description: the proportion of patients with complete response (CR) and/or partial response (PR) at 12 months following start of study drug administration.

Measure: Progression free survival (PFS) rate at 12 months

Time: 12 months after enrollment of the last subject

Description: the proportion of patients with CR, PR and/or stable disease (SD)

Measure: Disease control rate (DCR)

Time: 3 years

Description: The length of time during and after medication or treatment during which the disease being treated (usually cnacer) does not get worse.

Measure: Progression free survival (PFS)

Time: 3 years

Description: the time from study drug administration until death from any cause

Measure: Overall survival (OS)

Time: 3 years

Description: Change means the end of treatment minus baseline in each patient

Measure: Change of quality of life (QoL) measured by EQ-5D questionnaire

Time: 3 years

Other Outcomes

Description: to observe pharmacokinetic parameter, inter-individual variability and intra-individual variability considering covariates, demographic factors, influencing PK profile.

Measure: Population pharmacokinetics (PK) of NOV120101 (Poziotinib)

Time: 3 months after enrollment of the last subject

Description: to observe HGF expression status in plasma and T790M mutation induction status from plasma DNA

Measure: Subgroup analyses according to the genetic information

Time: 3 years

186 A Retrospective, Non-interventional Study to Evaluate EGFR-Tyrosine Kinase Inhibitor Retreatment in Patients With Locally Advanced or Metastatic EGFR Mutated NSCLC Who Previously Treated With EGFR-TKI as First-line Therapy and Chemotherapy as Second-line Therapy - SEQUENCE Study

This is a retrospective, non-interventional, multicenter, observational chart review study to explore the clinical benefits of retreatment with TKI in the real world.

NCT01955681
Conditions
  1. Locally Advanced or Metastatic EGFR Mutated NSCLC.

Exclusion Criteria: 1. Patients with EGFR mutation status of positive exon 20 T790M mutation only. --- T790M ---

Primary Outcomes

Description: The median duration of re-administration of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor will be summarized by days or months, if applicable. The range of this treatment duration will also be presented. All analyses will be performed on all eligible patients in this study.

Measure: The treatment duration of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor re-administration

Time: From the start of re-administration of EGFR-TKI to data cut-off date, assessed approximately up to 6 months.

Secondary Outcomes

Description: The outcome of progression-free survival will be presented with median values and associated 95% CIs by Kaplan-Meier curve. PFS is defined as the time interval (in weeks) from the start date of a given treatment to the date of disease progression or death, respectively, which one is observed first. Subjects who did not progress or die without a reported progression will be censored on the date of their last tumor assessment.

Measure: Assessment of progression-free survival for initial, second EGFR-TKI treatment and chemotherapy between two Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor treatments.

Time: From the start of administration of EGFR-TKI to data cut-off date, assessed approximately up to 6 months.

Description: The outcome of overall survival will be presented with median values and associated 95% CIs by Kaplan-Meier curve. OS is defined as the time interval (in weeks) from the beginning of treatment until the date when death or lost to follow up is observed. For those subjects who have not died or lost to follow-up, survival duration will be censored at the last date the subject was known to be alive.

Measure: Assessment of overall survival for initial, second EGFR-TKI treatment and chemotherapy between two Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor treatments.

Time: From the start of administration of EGFR-TKI to data cut-off date, assessed approximately up to 6 months.

Description: The outcome about response rate and the proportion of response rate are estimated by all evaluable patients. The 95% exact confidence interval will be constructed around the rates. The best response during treatment sequences is determined in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines.

Measure: Assessment of response rate for initial, second EGFR-TKI treatment and chemotherapy between two Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor treatments.

Time: From the start of administration of EGFR-TKI to data cut-off date, assessed approximately up to 6 months.

Description: The outcome of disease control rate are estimated by all evaluable patients. The 95% exact confidence interval will be constructed around the rates. Disease Control Rate is defined as patients who are respond to treatment (including CR-complete respond, PR-partial respond or SD- Stable Disease).

Measure: Assessment of disease control rate for initial, second EGFR-TKI treatment and chemotherapy between two Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor treatments.

Time: From the start of administration of EGFR-TKI to data cut-off date, assessed approximately up to 6 months.

Description: Treatment duration in the initial EGFR-TKI therapy and first time chemotherapy.

Measure: Record treatment duration in the initial EGFR-TKI therapy and first time chemotherapy.

Time: Between the initial EGFR-TKI therapy and first time chemotherapy.

Description: Record the reason(s) for treatment change for initial and re-administration of EGFR-TKI therapy and first time chemotherapy (second-line treatment).

Measure: Record the reason(s) for treatment change for initial and re-administration of EGFR-TKI therapy and first time chemotherapy (second-line treatment).

Time: From the start of administration of EGFR-TKI to data cut-off date, assessed approximately up to 6 months.

Description: Explore relationships between efficacy of EGFR-TKI initial and re-administration and patient characteristics (including demographics, histology, disease stage, sites of metastasis, ECOG PS) or EGFR TKI treatment characteristics (including EGFR mutation pattern, response to initial EGFR TKI or not, length of duration between first and second EGFR-TKI treatment)

Measure: Explore relationships between efficacy of EGFR-TKI initial and re-administration and patient characteristics or EGFR TKI treatment characteristics.

Time: EGFR-TKI initial and re-administration

Description: Explore overall survival (OS), plasma CEA level and chemotherapy regimens ever used between first time chemotherapy and EGFR-TKI re-administration (including the types and number of chemotherapy regimens, and treatment duration) for those patients who have the above data available.

Measure: overall survival (OS), plasma CEA level and chemotherapy regimens ever used.

Time: between first time chemotherapy and EGFR-TKI re-administration

Description: If the images are available, conduct image peer review to evaluate tumour size retrospectively in different sequences of treatment: (1) initial and re-administration of EGFR-TKI therapy, (2) first time chemotherapy ever used (second-line treatment) after initial EGFR-TKI treatment. Peer review time point includes baseline, best response and progression of last image while stopping treatment at each treatment mentioned above.

Measure: image peer review to evaluate tumour size retrospectively in different sequences of treatment

Time: (1) initial and re-administration of EGFR-TKI therapy, (2) first time chemotherapy ever used (second-line treatment) after initial EGFR-TKI treatment.

Description: Evaluate the reason(s) for the treatment change for initial and re-administration of EGFR-TKI therapy and first time chemotherapy (second-line treatment) after peer review and compare the difference of reason(s) for the treatment change between initiatial evaluation and after peer review.

Measure: The reason(s) for the treatment change for initial and re-administration of EGFR-TKI therapy and first time chemotherapy (second-line treatment) after peer review

Time: Initial and re-administration of EGFR-TKI therapy and first time chemotherapy (second-line treatment) after peer review.

187 An Open-label Phase II Trial of Erlotinib and Bevacizumab in Patients With Advanced Non-small Cell Lung Cancer and Activating EGFR Mutations

Rationale: Advanced non-small-cell lung cancer (NSCLC) patients harbouring epidermal growth factor receptor (EGFR) mutations (del19 or L858R) show an impressive progression-free survival between 9 and 14 months when treated with erlotinib. However, the presence of EGFR mutations can only imperfectly predict outcome. The investigators hypothesize that progression-free survival could be influenced both by the pretreatment EGFR T790M mutation and by components of DNA repair pathways. The investigators propose a model of treatment whereby patients with EGFR mutations (single or with T790M) can attain a benefit with longer overall PFS when treated with erlotinib plus bevacizumab. When the patients are grouped by BRCA1 mRNA levels and T790M the hypothesis is that the combination of erlotinib plus bevacizumab can improve the PFS in all subgroups.

NCT01562028
Conditions
  1. Lung Cancer
Interventions
  1. Drug: Erlotinib
  2. Drug: Bevacizumab
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

The investigators hypothesize that progression-free survival could be influenced both by the pretreatment EGFR T790M mutation and by components of DNA repair pathways. --- T790M ---

The investigators propose a model of treatment whereby patients with EGFR mutations (single or with T790M) can attain a benefit with longer overall PFS when treated with erlotinib plus bevacizumab. --- T790M ---

When the patients are grouped by BRCA1 mRNA levels and T790M the hypothesis is that the combination of erlotinib plus bevacizumab can improve the PFS in all subgroups. --- T790M ---

To determine long-term outcome of patients with advanced non-squamous NSCLC harbouring EGFR mutations with or without T790M mutation at diagnosis and treated with the combination of erlotinib and bevacizumab. --- T790M ---

Primary endpoint: progression-free survival 2. To evaluate the efficacy and tolerability of the combination 3. To evaluate the correlation of BRCA1 mRNA and AEG-1 mRNA expression and T790M with progression-free survival 4. To monitor EGFR mutations (including T790M) in serum and plasma longitudinally 5. To evaluate molecular biomarkers related to EGFR TKI and bevacizumab Design: This is a multinational, multi-center phase II trial of erlotinib plus bevacizumab in patients with advanced non-squamous NSCLC harbouring EGFR mutations confirmed by central re-assessment. --- T790M ---

Primary endpoint: progression-free survival 2. To evaluate the efficacy and tolerability of the combination 3. To evaluate the correlation of BRCA1 mRNA and AEG-1 mRNA expression and T790M with progression-free survival 4. To monitor EGFR mutations (including T790M) in serum and plasma longitudinally 5. To evaluate molecular biomarkers related to EGFR TKI and bevacizumab Design: This is a multinational, multi-center phase II trial of erlotinib plus bevacizumab in patients with advanced non-squamous NSCLC harbouring EGFR mutations confirmed by central re-assessment. --- T790M --- --- T790M ---

Patients will be stratified into two subgroups, with and without EGFR T790M mutation. --- T790M ---

Primary Outcomes

Description: Time from the date of enrollment until an investigator-documented progression or death, whichever occurs first. Assessment of Progressive Disease (PD) is based on Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1): at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum recorded on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

Measure: Progression Free Survival

Time: From the date of enrollment until documented progression or death, whichever occurs first, assessed up to 48 months.

Secondary Outcomes

Description: Time from the date of enrollment until death from any cause.

Measure: Overall Survival

Time: From the date of enrollment until death, assessed up to 48 months.

Description: Time from the date of enrollment to discontinuation of treatment for any reason including progression of disease (based on RECIST v1.1), treatment toxicity (adverse events classified according to NCI CTCAE version 4.), refusal and death.

Measure: Time to Treatment Failure

Time: From the date of enrollment until discontinuation of treatment, assessed up to 48 months.

Description: Objective response is defined as best overall response (CR or PR) across all assessment time-points during the period from enrollment to termination of trial treatment. Objective response, along with progressive and stable disease, will be determined using RECIST 1.1 criteria: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters. Progression (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum recorded on the trial. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum of diameters recorded on the trial.

Measure: Objective Response

Time: Assessed across all time-points from enrollment to termination of trial treatment (max 48 months).

Description: Disease control is defined as achieving objective response (CR or PR, across all time-points from enrollment to termination of trial treatment) or stable disease for at least 6 weeks. Objective response, along with SD (disease control) and PD (no disease control), will be determined using RECIST 1.1 criteria: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters.Progression (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum recorded on the trial. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum of diameters recorded on the trial.

Measure: Disease Control

Time: Assessed across all time-points from enrollment to termination of trial treatment (max 48 months).

Description: Interval from the date of first documentation of objective response (CR or PR) to the date of first documented progression or relapse. Assessment of Objective response and Progressive Disease (PD) is based on the RECIST 1.1 criteria: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters. Progression (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum recorded on the trial. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum of diameters recorded on the trial.

Measure: Duration of Response

Time: Assessed across all time-points from enrollment to to the date of first documented progression or relapse (max 48 months).

Description: Adverse events graded according to NCI CTCAE V4.

Measure: Adverse Events

Time: Assessed across all time-points until end of treatment (30 +/-5 days following the last dose of study drug) (max 48 months).

188 PHASE 1/2 OPEN-LABEL STUDY OF PF-06747775 (EPIDERMAL GROWTH FACTOR RECEPTOR T790M INHIBITOR) IN PATIENTS WITH ADVANCED EPIDERMAL GROWTH FACTOR RECEPTOR MUTANT (DEL 19 OR L858R ± T790M) NON-SMALL CELL LUNG CANCER

This is a Phase 1/2 study of PF-06747775 as a single agent and in combination with other cancer treatments in patients with advanced EGFRm NSCLC. The overall clinical study consists of a Phase 1 single agent dose-escalation and expansion part to determine the RP2D of PF-06747775 single agent in patients with previously-treated EGFRm NSCLC followed by sequential evaluations of PF-06747775 at the RP2D in 3 different clinical scenarios as detailed below: - Cohort 1: Phase 2 evaluation of PF-06747775 as a single agent in previously untreated patients with advanced EGFRm NSCLC, - Cohort 2: Phase 1b single arm evaluation of PF-06747775 in combination with palbociclib (Cohort 2A) followed by Phase 2 randomized evaluation of PF 06747775 in combination with palbociclib vs PF-06747775 single agent (Cohort 2B) in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M), and - Cohort 3: Phase 1b evaluation of PF-06747775 in combination with avelumab in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M).

NCT02349633
Conditions
  1. Non-Small Cell Lung Cancer
Interventions
  1. Drug: PF-06747775
  2. Drug: Palbociclib
  3. Drug: Avelumab
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

PHASE 1/2 OPEN-LABEL STUDY OF PF-06747775 (EPIDERMAL GROWTH FACTOR RECEPTOR T790M INHIBITOR) IN PATIENTS WITH ADVANCED EPIDERMAL GROWTH FACTOR RECEPTOR MUTANT (DEL 19 OR L858R ± T790M) NON-SMALL CELL LUNG CANCER. --- T790M ---

PHASE 1/2 OPEN-LABEL STUDY OF PF-06747775 (EPIDERMAL GROWTH FACTOR RECEPTOR T790M INHIBITOR) IN PATIENTS WITH ADVANCED EPIDERMAL GROWTH FACTOR RECEPTOR MUTANT (DEL 19 OR L858R ± T790M) NON-SMALL CELL LUNG CANCER. --- T790M --- --- L858R --- --- T790M ---

Study For Patients With NSCLC EGFR Mutations (Del 19 or L858R +/- T790M) This is a Phase 1/2 study of PF-06747775 as a single agent and in combination with other cancer treatments in patients with advanced EGFRm NSCLC. --- L858R --- --- T790M ---

The overall clinical study consists of a Phase 1 single agent dose-escalation and expansion part to determine the RP2D of PF-06747775 single agent in patients with previously-treated EGFRm NSCLC followed by sequential evaluations of PF-06747775 at the RP2D in 3 different clinical scenarios as detailed below: - Cohort 1: Phase 2 evaluation of PF-06747775 as a single agent in previously untreated patients with advanced EGFRm NSCLC, - Cohort 2: Phase 1b single arm evaluation of PF-06747775 in combination with palbociclib (Cohort 2A) followed by Phase 2 randomized evaluation of PF 06747775 in combination with palbociclib vs PF-06747775 single agent (Cohort 2B) in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M), and - Cohort 3: Phase 1b evaluation of PF-06747775 in combination with avelumab in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M). --- T790M ---

The overall clinical study consists of a Phase 1 single agent dose-escalation and expansion part to determine the RP2D of PF-06747775 single agent in patients with previously-treated EGFRm NSCLC followed by sequential evaluations of PF-06747775 at the RP2D in 3 different clinical scenarios as detailed below: - Cohort 1: Phase 2 evaluation of PF-06747775 as a single agent in previously untreated patients with advanced EGFRm NSCLC, - Cohort 2: Phase 1b single arm evaluation of PF-06747775 in combination with palbociclib (Cohort 2A) followed by Phase 2 randomized evaluation of PF 06747775 in combination with palbociclib vs PF-06747775 single agent (Cohort 2B) in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M), and - Cohort 3: Phase 1b evaluation of PF-06747775 in combination with avelumab in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M). --- T790M --- --- T790M ---

The overall clinical study consists of a Phase 1 single agent dose-escalation and expansion part to determine the RP2D of PF-06747775 single agent in patients with previously-treated EGFRm NSCLC followed by sequential evaluations of PF-06747775 at the RP2D in 3 different clinical scenarios as detailed below: - Cohort 1: Phase 2 evaluation of PF-06747775 as a single agent in previously untreated patients with advanced EGFRm NSCLC, - Cohort 2: Phase 1b single arm evaluation of PF-06747775 in combination with palbociclib (Cohort 2A) followed by Phase 2 randomized evaluation of PF 06747775 in combination with palbociclib vs PF-06747775 single agent (Cohort 2B) in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M), and - Cohort 3: Phase 1b evaluation of PF-06747775 in combination with avelumab in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M). --- T790M --- --- T790M --- --- L858R --- --- T790M ---

The overall clinical study consists of a Phase 1 single agent dose-escalation and expansion part to determine the RP2D of PF-06747775 single agent in patients with previously-treated EGFRm NSCLC followed by sequential evaluations of PF-06747775 at the RP2D in 3 different clinical scenarios as detailed below: - Cohort 1: Phase 2 evaluation of PF-06747775 as a single agent in previously untreated patients with advanced EGFRm NSCLC, - Cohort 2: Phase 1b single arm evaluation of PF-06747775 in combination with palbociclib (Cohort 2A) followed by Phase 2 randomized evaluation of PF 06747775 in combination with palbociclib vs PF-06747775 single agent (Cohort 2B) in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M), and - Cohort 3: Phase 1b evaluation of PF-06747775 in combination with avelumab in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M). --- T790M --- --- T790M --- --- L858R --- --- T790M --- --- T790M ---

The overall clinical study consists of a Phase 1 single agent dose-escalation and expansion part to determine the RP2D of PF-06747775 single agent in patients with previously-treated EGFRm NSCLC followed by sequential evaluations of PF-06747775 at the RP2D in 3 different clinical scenarios as detailed below: - Cohort 1: Phase 2 evaluation of PF-06747775 as a single agent in previously untreated patients with advanced EGFRm NSCLC, - Cohort 2: Phase 1b single arm evaluation of PF-06747775 in combination with palbociclib (Cohort 2A) followed by Phase 2 randomized evaluation of PF 06747775 in combination with palbociclib vs PF-06747775 single agent (Cohort 2B) in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M), and - Cohort 3: Phase 1b evaluation of PF-06747775 in combination with avelumab in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M). --- T790M --- --- T790M --- --- L858R --- --- T790M --- --- T790M --- --- T790M ---

The overall clinical study consists of a Phase 1 single agent dose-escalation and expansion part to determine the RP2D of PF-06747775 single agent in patients with previously-treated EGFRm NSCLC followed by sequential evaluations of PF-06747775 at the RP2D in 3 different clinical scenarios as detailed below: - Cohort 1: Phase 2 evaluation of PF-06747775 as a single agent in previously untreated patients with advanced EGFRm NSCLC, - Cohort 2: Phase 1b single arm evaluation of PF-06747775 in combination with palbociclib (Cohort 2A) followed by Phase 2 randomized evaluation of PF 06747775 in combination with palbociclib vs PF-06747775 single agent (Cohort 2B) in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M), and - Cohort 3: Phase 1b evaluation of PF-06747775 in combination with avelumab in previously-treated patients with EGFRm NSCLC with a secondary T790M mutation (del 19 and T790M or L858R and T790M). --- T790M --- --- T790M --- --- L858R --- --- T790M --- --- T790M --- --- T790M --- --- L858R --- --- T790M ---

2. T790M disease as follows: Phase 1 If a repeat biopsy was performed on the tumor following prior EGFR TKI therapy, then T790M positive disease must be present. --- T790M ---

2. T790M disease as follows: Phase 1 If a repeat biopsy was performed on the tumor following prior EGFR TKI therapy, then T790M positive disease must be present. --- T790M --- --- T790M ---

Patients of unknown T790M status following EGFR TKI progression (ie, no post EGFR TKI progression biopsy was performed) are eligible. --- T790M ---

In the PK sub-studies involving food/antacid and CYP3A4 effects, patients with EGFRm (del 19 or L858R) with any T790M status are eligible to enroll. --- L858R --- --- T790M ---

Studies at RP2D Cohort 1: Patients may have de novo T790M mutation, but it is not required. --- T790M ---

Cohort 2 and Cohort 3: Patients must have EGRFm (del 19 AND T790M or L858R AND T790M) NSCLC tumors as detected by local EGFR mutation test that includes QIAGEN Therascreen EGFR RGQ PCR kit, Roche cobas® EGFR Mutation Test or a sponsor-approved laboratory developed test that is validated in a CLIA laboratory, which will then be retrospectively confirmed by the central validated Thermo Fisher Scientific Oncomine Next Generation Sequencing (NGS) cancer panel test. --- T790M ---

Cohort 2 and Cohort 3: Patients must have EGRFm (del 19 AND T790M or L858R AND T790M) NSCLC tumors as detected by local EGFR mutation test that includes QIAGEN Therascreen EGFR RGQ PCR kit, Roche cobas® EGFR Mutation Test or a sponsor-approved laboratory developed test that is validated in a CLIA laboratory, which will then be retrospectively confirmed by the central validated Thermo Fisher Scientific Oncomine Next Generation Sequencing (NGS) cancer panel test. --- T790M --- --- L858R --- --- T790M ---

Patients will also be enrolled if they solely test positive for EGFR (del 19 AND T790M or L858R AND T790M) NSCLC in plasma detected by local EGFR mutation test that includes QIAGEN Therascreen EGFR Plasma RGQ kit, Roche cobas® EGFR mutation test v2 (US-IVD) or Sysmex Inostic's OncoBEAMTM EGFR test or a sponsor-approved laboratory developed test that is validated in a CLIA laboratory, which will then be retrospectively confirmed by a validated cfDNA test as determined by the Sponsor. --- T790M ---

Patients will also be enrolled if they solely test positive for EGFR (del 19 AND T790M or L858R AND T790M) NSCLC in plasma detected by local EGFR mutation test that includes QIAGEN Therascreen EGFR Plasma RGQ kit, Roche cobas® EGFR mutation test v2 (US-IVD) or Sysmex Inostic's OncoBEAMTM EGFR test or a sponsor-approved laboratory developed test that is validated in a CLIA laboratory, which will then be retrospectively confirmed by a validated cfDNA test as determined by the Sponsor. --- T790M --- --- L858R --- --- T790M ---

An archival specimen is acceptable for Phase 1; a de novo specimen is required for Cohorts 2, and 3 if the T790M status was confirmed by tissue biopsy. --- T790M ---

Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible Use of immunosuppressive medication at time of randomization Non-Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung There remains an unmet medical need to develop EGFR TKI agents that effectively target both the single activating mutations of del 19 and L858R, and the secondary resistance mutation T790M, while sparing WT EGFR. --- L858R --- --- T790M ---

Primary Outcomes

Description: The target probability of DLT at MTD will be 30%

Measure: Phase 1 Primary Endpoint - Number of patients with dose limiting toxicities during Phase 1

Time: 21 days

Description: Cohort 1 is an evaluation of PF 06747775 single agent at RP2D Cohorts 2A and 3 will determine the RP2D of PF-06747775 in combination with either palbociclib or avelumab, respectively, based on safety and tolerability. Determination of the RP2D will be performed using the mTPI design. For Cohort 2A, after determination of the RP2D for the PF-06747775 and palbociclib combination, a randomized evaluation of the combination vs PF-06747775 single agent (2:1 ratio) will be initiated (Cohort 2B). For Cohort 3, after determination of the RP2D for the PF-06747775 and avelumab combination, the dose level will be expanded to enroll an overall total of approximately 20 patients to further explore the safety, PK, and antitumor activity of the combination.

Measure: Phase 1b/2 - Cohort 1 = confirmed OR per RECIST; Cohort 2A = Cycle 2 DLT; Cohort 2B = PFS and Cohort 3 = Cycle 1 DLT

Time: Cohorts 1, 2A and 2B = 21 day cycles and Cohort 3 = 28 day cycles

Secondary Outcomes

Description: Number of patients with OR based assessment of confirmed CR or PR according to RECIST. CR are those that persist on repeat imaging at least 4 weeks after the initial documentation of response. PR are those that are greater or equal to a 30% decrease ( per RECIST) under the baseline of the sum of diameters of all target measurable disease

Measure: Phase 1: Secondary Endpoint - Number of patients with Objective Response (OR)

Time: Time from first dose of study drug until OR of CR or PR up to 24 months

Description: PFS (cohort 1, 2A and 3) ORR (cohort 2A, 2B and 3) DOR (All cohorts)

Measure: Phase 1b/2

Time: Time from first dose of study drug until Disease Progression or death (whichever first) up to 24 months

189 A Phase I/II Study of Pacritinib in Patients With EGFR Mutant NSCLC After EGFR TKI

The goal of the study is to find the best dose of pacritinib when given in combination with erlotinib.

NCT02342353
Conditions
  1. Non-Small Cell Lung Cancer
  2. Nonsmall Cell Lung Cancer
  3. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Drug: Pacritinib
  2. Drug: Erlotinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Patients with mutations in T790M are eligible if they have progressed after treatment with a third generation EGFR tyrosine kinase inhibitor (osimertinib), but otherwise patients must have EGFR T790M negative or unknown status. --- T790M ---

Patients with mutations in T790M are eligible if they have progressed after treatment with a third generation EGFR tyrosine kinase inhibitor (osimertinib), but otherwise patients must have EGFR T790M negative or unknown status. --- T790M --- --- T790M ---

Primary Outcomes

Description: The maximum tolerated dose (MTD) is defined as the dose level immediately below the dose level at which 2 patients of a cohort (of 2 to 6 patients) experience dose-limiting toxicity during the first cycle. Dose escalations will proceed until the MTD has been reached. A patient is evaluable for DLT assessment only during Cycle 1 of treatment. If the patient is not able to be treated on Day 1 of Cycle 2, then s/he is still considered in Cycle 1 active treatment and can experience a DLT. Once the patient has been treated in Cycle 2, s/he will no longer be evaluated for DLTs in all subsequent cycles.

Measure: Dose-limiting toxicities and maximum tolerated dose (MTD) - Phase I only

Time: Completion of cycle 1 of all Phase I patients (estimated to be 1 year)

Description: Partial response + complete response per RECIST 1.1 criteria Study terminated prior to enrolling any phase II participants Complete response (CR) = disappearance of all target lesions, non-target lesions, and normalization of tumor marker level Partial response (PR) = at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline of sum diameters

Measure: Response rate - Phase II only

Time: Up to 5 years

Secondary Outcomes

Description: The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting.

Measure: Adverse events (toxicities)

Time: 30 days post completion of treatment (estimated to be 9 months)

Description: Percentage of patients who achieve complete response, partial response, or stable disease per RECIST 1.1 criteria. Complete response (CR) = disappearance of all target lesions, non-target lesions, and normalization of tumor marker level Partial response (PR) = at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline of sum diameters Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

Measure: Disease control rate (DCR)

Time: Up to 5 years

Description: PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. Progressive disease (PD) = at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study, appearance of one or more non-target lesion(s) and/or unequivocal progression of existing non-target lesions

Measure: Progression-free survival (PFS)

Time: Up to 5 years

Description: Overall survival is defined as the time interval from date of diagnosis to date of death from any cause.

Measure: Overall survival (OS)

Time: Up to 5 years

190 Feasibility of New Biological and Histological Samples at Progression for Patients With Advanced or Metastatic Non Small Cell Lung Cancer (NSCLC)

Feasibility of new biological and histological samples at progression in patients with advanced or metastatic Non Small Cell Lung Cancer (NSCLC). A recent paper from Professor Sequist and coll. has depicted the resistance mechanisms as Thréonine790Methionine (T890M) mutation oncogene cMet (CMet) amplification. Re-biopsies showed in 14% of cases the transition between NSCLC to Small Cells Lung Cancer (SCLC). In 3 patients, resistance mechanisms have disappeared and they became again sensitive to Tyrosine Kinase Inhibitors (TKIs). It is mandatory to have a better description to natural history of the disease. This study will be conducted by the French Group of Pneumology-Oncology (Groupe Français de Pneumo Cancérologie (GFPC)) up to 100 patients during 18 Months. Each center will have to define if re-biopsies are possible or not and explain why not.

NCT02086071
Conditions
  1. Lung Cancer
Interventions
  1. Procedure: re biopsy
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

One of the major resistance mechanisms is the onset of T790M mutation, which induces a non sensitivity to TKIs. --- T790M ---

has depicted the resistance mechanisms as mutation T790M or oncogene cMet (CMet) amplification. --- T790M ---

Primary Outcomes

Description: Feasibility of re-biopsies in patients with advanced or metastatic NSCLC after progression of disease under treatment. If the re-biopsy could not be performed : reason of no re-biopsy. If the biopsy could be performed : site and method of rebiopsy.

Measure: Feasibility of re-biopsies

Time: 18 months / 100 patients

Secondary Outcomes

Description: Comparison of types and numbers of resistances before treatment (on the first biopsy) and after treatment (on the re-biopsy). Appearance and/or disappearance of some resistances.

Measure: Type of resistance

Time: 18 months/100 patients

Description: Description of population: age, performance status, smoking status, sex (number, medium, maximum, minimum). Description of treatment: chemotherapy (type and products), radiotherapy (site), surgery (site)

Measure: Disease management

Time: 18 months / 100 patients

Description: Description and comparison of histology on the first biopsy and on the rebiopsy

Measure: Biological history of the disease

Time: 18 months / 100 patients

191 Phase II, Open Label, Single-arm Study to Assess Safety and Efficacy of AZD9291 in Patients With Locally Advanced/Metastatic NSCLC Whose Disease Has Progressed With Previous EGFR TKI and Whose Tumours Are EGFR and T790M Mutation Positive

A Phase II, Open Label, Single-arm Study to Assess the Safety and Efficacy of AZD9291 in Patients with Locally Advanced/Metastatic Non Small Cell Lung Cancer whose Disease has Progressed with Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and whose Tumours are Epidermal Growth Factor Receptor Mutation and T790M Mutation Positive

NCT02094261
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: AZD9291
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Phase II, Open Label, Single-arm Study to Assess Safety and Efficacy of AZD9291 in Patients With Locally Advanced/Metastatic NSCLC Whose Disease Has Progressed With Previous EGFR TKI and Whose Tumours Are EGFR and T790M Mutation Positive. --- T790M ---

Phase II AZD9291 Open Label Study in NSCLC After Previous EGFR TKI Therapy in EGFR and T790M Mutation Positive Tumours A Phase II, Open Label, Single-arm Study to Assess the Safety and Efficacy of AZD9291 in Patients with Locally Advanced/Metastatic Non Small Cell Lung Cancer whose Disease has Progressed with Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and whose Tumours are Epidermal Growth Factor Receptor Mutation and T790M Mutation Positive Objective Response Rate (ORR). --- T790M ---

Phase II AZD9291 Open Label Study in NSCLC After Previous EGFR TKI Therapy in EGFR and T790M Mutation Positive Tumours A Phase II, Open Label, Single-arm Study to Assess the Safety and Efficacy of AZD9291 in Patients with Locally Advanced/Metastatic Non Small Cell Lung Cancer whose Disease has Progressed with Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and whose Tumours are Epidermal Growth Factor Receptor Mutation and T790M Mutation Positive Objective Response Rate (ORR). --- T790M --- --- T790M ---

Patients must have central confirmation of tumour T790M mutation positive status from a biopsy sample taken after confirmation of disease progression on the most recent treatment regimen. --- T790M ---

Non Small Cell Lung Cancer Carcinoma, Non-Small-Cell Lung This is a phase II, open label, single arm study assessing the safety and efficacy of AZD9291 (80 mg, orally, once daily) in patients with a confirmed diagnosis of Epidermal Growth Factor Receptor mutation positive and T790M mutation positive NSCLC,who have progressed following prior therapy with an approved Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI) agent. --- T790M ---

Patients must agree to provide a biopsy for central confirmation of T790M mutation status following confirmed disease progression on the most recent treatment regimen. --- T790M ---

Primary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR (according to independent review) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.

Measure: Objective Response Rate (ORR)

Time: RECIST tumour assessments every 6 weeks from first dose until objective disease progression, up to approximately 11 months (at the time of analysis)

Secondary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. DoR was defined as the time from the date of first documented response (CR or PR that was subsequently confirmed) until the date of documented progression (PD) or death in the absence of disease progression (by investigator assessment).

Measure: Duration of Response (DoR)

Time: RECIST tumour assessments every 6 weeks from first dose until objective disease progression, up to approximately 11 months (at the time of analysis)

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions; Stable disease (SD): Neither sufficient shrinkage to qualify as a response nor sufficient growth to qualify as progression; Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. DCR is the percentage of patients with best response of CR, PR or SD (according to independent review), prior to progression (PD) or further anti-cancer therapy.

Measure: Disease Control Rate (DCR)

Time: RECIST tumour assessments every 6 weeks from first dose until objective disease progression, up to approximately 11 months (at the time of analysis)

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. PFS is the time from date of first dose until the date of PD (by independent review) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from AZD9291 therapy or received another anti-cancer therapy prior to progression. Patients who had not progressed or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 assessment.

Measure: Progression-Free Survival (PFS)

Time: RECIST tumour assessments every 6 weeks from first dose until objective disease progression, up to approximately 11 months (at the time of analysis)

192 A Multicenter, Phase 1/1b, Open-Label, Dose-Escalation Study of ABBV-399, an Antibody Drug Conjugate, in Subjects With Advanced Solid Tumors

This is a Phase 1/1b open-label study evaluating the safety, pharmacokinetics (PK), and preliminary efficacy of ABBV-399 as monotherapy and in combination with osimertinib, erlotinib, and nivolumab in participants with advanced solid tumors likely to express c-Met. Enrollment is closed for the monotherapy arms, Arm A, and Arm D.

NCT02099058
Conditions
  1. Advanced Solid Tumors Cancer
Interventions
  1. Drug: Osimertinib
  2. Drug: Nivolumab
  3. Drug: Telisotuzumab vedotin
  4. Drug: Telisotuzumab vedotin
  5. Drug: Erlotinib
MeSH:Neoplasms
HPO:Neoplasm

- Participant must have metastatic/locally advanced nonsquamous NSCLC with documented Epidermal Growth Factor Receptor (EGFR) mutation(s) del19 or L858R, with or without T790M mutation, and none of the EGFR mutations known to be resistant to osimertinib. --- L858R --- --- T790M ---

Primary Outcomes

Description: An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment.

Measure: Number of Participants with Adverse Events

Time: Up to 24 Months

Description: The RPTD of ABBV-399 when administered as monotherapy and in combination with osimertinib, erlotinib or nivolumab will be determined during the dose escalation phase of the study. RPTD will be determined using available safety and pharmacokinetics data.

Measure: Recommended Phase 2 Dose (RPTD) of ABBV-399 when Administered as Monotherapy and in Combination with Osimertinib, Erlotinib or Nivolumab

Time: Up to 24 Months

Description: AUC (0-t) = Area under the serum concentration versus time curve from time zero (pre-dose) to the time of the last measurable concentration.

Measure: Area under the curve (AUC) from time zero to the last measurable concentration AUC (0-t)

Time: Up to 24 months

Description: Maximum observed plasma concentration (Cmax).

Measure: Maximum observed plasma concentration (Cmax)

Time: Up to 24 months

Description: Time to Cmax (Tmax).

Measure: Time to Cmax (Tmax)

Time: Up to 24 months

Description: Terminal elimination half life.

Measure: Terminal elimination half life

Time: Up to 24 months

193 A Randomized, Double-blind Phase 2 Study of Itacitinib in Combination With Erlotinib Versus Erlotinib Alone in Subjects With Stage IIIB/ IV or Recurrent Non-Small Cell Lung Cancer (NSCLC) Whose Tumors Have Epidermal Growth Factor Receptor (EGFR) Activating Mutations

The purpose of this study is to determine if Itacitinib in combination with erlotinib is safe and effective in the treatment of nonsquamous non-small cell lung cancer (NSCLC) that is Stage IIIB/Stage IV or recurrent whose tumors have EGFR activating mutations.

NCT02355431
Conditions
  1. Solid Tumors and Hematologic Malignancy
  2. NSCLC (Non-small Cell Lung Carcinoma)
Interventions
  1. Drug: Itacitinib
  2. Drug: erlotinib
  3. Drug: placebo
MeSH:Carcinoma, Non-Small-Cell Lung Hematologic Neoplasms
HPO:Hematological neoplasm Leukemia Non-small cell lung carcinoma

Exclusion Criteria: - Known presence of the T790M mutation in EGFR in tumor samples - Candidates for curative radiation therapy or surgery. --- T790M ---

Primary Outcomes

Description: Subjects will take erlotinib daily and begin dosing with itacitinib once daily (QD) on Cycle 1, Day 1. The safety and tolerability of the regimen will be assessed during the first 21 days of therapy

Measure: Part 1: Determination of the dose of itacitinib that is safe and tolerable in combination with erlotinib as measured by the number of dose-limiting toxicities (DLTs) observed in the evaluation cohort.

Time: Baseline through Day 21

Measure: Part 2: Overall Survival (OS)

Time: Randomization until death. Approximately 31 months.

Description: PFS is defined as the time from randomization until the earliest date of disease progression determined by investigator assessment of objective radiographic disease assessments per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, or death due to any cause if sooner.

Measure: Part 2: Progression-free survival (PFS)

Time: Randomization to disease progression, or death due to any cause if sooner. Approximately 23 months.

Secondary Outcomes

Description: Objective response determined by radiographic disease assessments per RECIST (v1.1), by investigator assessment

Measure: Part 2: Objective Response

Time: Baseline through end of study. Approximately 31 months.

Description: Duration of response determined by radiographic disease assessments per RECIST (v1.1), by investigator assessment Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

Measure: Part 2: Duration of Response

Time: Baseline through end of study. Approximately 31 months.

Measure: Part 2: Safety and tolerability of the treatment regimens assessed by a summary of adverse events and clinical laboratory assessments.

Time: Baseline through approximately 30 days post treatment discontinuation. Assessed after approximately 31 months.

194 An Open Label, Randomized, Multicenter, Phase II Study to Compare Efficacy and Safety of Gefitinib/ Pemetrexed With Pemetrexed Alone as Maintenance Therapy in Patients With Advanced (Stage IV) EGFR Mutation Negative or T790M Single Mutation Nonsquamous NSCLC Who Respond to 4 Cycles of Pemetrexed/ Platinum as First-line Therapy

The study aims to randomize 52 patients with advanced (Stage IV) EGFR mutation negative nonsquamous non-small cell lung cancer (NSCLC) who respond (CR/PR/SD) to 4 cycles of pemetrexed / cisplatin or pemetrexed/carboplatin as first-line therapy. In order to achieve that, approximately 144 treatment naïve patients with advanced nonsquamous NSCLC need to be enrolled from around 6 investigational sites in Taiwan that have expertise in lung cancer diagnosis.

NCT01579630
Conditions
  1. NSCLC
Interventions
  1. Drug: Pemetrexed 500mg/m2 iv
  2. Drug: Pemetrexed 500mg/m2 iv and Gefitinib 250 mg

An Open Label, Randomized, Multicenter, Phase II Study to Compare Efficacy and Safety of Gefitinib/ Pemetrexed With Pemetrexed Alone as Maintenance Therapy in Patients With Advanced (Stage IV) EGFR Mutation Negative or T790M Single Mutation Nonsquamous NSCLC Who Respond to 4 Cycles of Pemetrexed/ Platinum as First-line Therapy. --- T790M ---

Genius Study Study to Compare Efficacy and Safety of Gefitinib/ Pemetrexed With Pemetrexed Alone as Maintenance Therapy in Patients With Stage IV EGFR Mutation Negative or T790M Single Mutation Who Respond to Pemetrexed/ Platinum as First-line Therapy The study aims to randomize 52 patients with advanced (Stage IV) EGFR mutation negative nonsquamous non-small cell lung cancer (NSCLC) who respond (CR/PR/SD) to 4 cycles of pemetrexed / cisplatin or pemetrexed/carboplatin as first-line therapy. --- T790M ---

5. Measurable disease according to RECIST (Version 1.1) criteria 6. World Health Organization (WHO) performance status (PS) of 0 to 1 7. Provision of cancer tissue sample for mutation testing or the result of EGFR mutation test is negative (single T790M mutation positive patients can also be enrolled) Exclusion Criteria summary 1. Newly diagnosed Central Nervous System (CNS) metastases that have not yet been definitively treated with surgery and/or radiation. --- T790M ---

Primary Outcomes

Description: Progression of disease will be calculated from the tumour measurements collected at each tumour assessment per the RECIST (V1.1) criteria and/or the date of patient death.

Measure: Progression free survival

Time: up to 4 months

Secondary Outcomes

Description: The RECIST (V1.1) criteria will be used to assess objective tumour response. Details of target and non-target lesions will be collected on the appropriate CRF pages and used to calculate tumour response. Post-baseline tumour evaluations should use the same modality (CT scan or magnetic resonance imaging [MRI]) as used at baseline and should preferably be undertaken at the same institution.

Measure: Overall objective tumour response

Time: up to 1 year

195 Safety, Tolerability, Pharmacokinetics and Anti-tumour Activity of AZD9291 in Patients With Advanced Non Small Cell Lung Cancer Who Progressed on Prior Therapy With an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Agent

This study will treat patients with advanced NSCLC who have already received at least one course of specific anti-cancer treatment but the tumour has started to re-grow following that treatment. This is the first time this drug has ever been tested in patients, and so it will help to understand what type of side effects may occur with the drug treatment, it will measure the levels of drug in the body, it will also measure the anti-cancer activity. By using these pieces of information together the best dose of this drug to use in further clinical trials will be selected.

NCT01802632
Conditions
  1. Advanced Non Small Cell Lung Cancer
  2. Advanced (Inoperable) Non Small Cell Lung Cancer
Interventions
  1. Drug: AZD9291
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- For dose expansion and extension cohorts, patients must also have confirmation of tumour T790M mutation status (confirmed positive or negative) from a biopsy sample taken after disease progression on the most recent treatment regimen (irrespective of whether this is EGFR TKI or chemotherapy). --- T790M ---

Prior to entry a result from the central analysis of the patient's T790M mutation status must be obtained. --- T790M ---

Primary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR (by investigator assessment) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.

Measure: Objective Response Rate (ORR) for Dose Expansion Population

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 21 months (at time of analysis)

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions; Stable disease (SD): Neither sufficient shrinkage to qualify as a response nor sufficient growth to qualify as progression; Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. Not evaluable (NE): TL response is missing and there is no evidence of progression of NTLs and no new lesions. BOR is the best response (by investigator assessment) a patient has achieved where the order of best to worst is CR, PR, SD, PD, NE prior to or at progression and prior to further anti-cancer therapy.

Measure: Best Objective Response (BOR) for Dose Escalation Population

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 25 months (at time of analysis)

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR (by independent central review) that was confirmed at least 4 weeks later, prior to progression or further anti-cancer therapy.

Measure: Objective Response Rate (ORR) for Extension Population

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 12 months (at the time of analysis)

Secondary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. DoR was defined as the time from the date of first documented response (CR or PR that was subsequently confirmed) until the date of documented progression (PD) or death in the absence of disease progression (by investigator assessment).

Measure: Duration of Response (DoR) for Dose Expansion Population

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 21 months (at time of analysis)

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. PFS is the time from date of first dose until the date of PD (by independent central review) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from AZD9291 therapy or received another anti-cancer therapy prior to progression. Patients who had not progressed or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 assessment.

Measure: Progression-Free Survival (PFS) for Dose Expansion Population

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 21 months (at time of analysis)

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions; Stable disease (SD): Neither sufficient shrinkage to qualify as a response nor sufficient growth to qualify as progression; Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. Not evaluable (NE): TL response is missing and there is no evidence of progression of NTLs and no new lesions. BOR is the best response (by investigator assessment) a patient has achieved where the order of best to worst is CR, PR, SD, PD, NE prior to or at progression and prior to further anti-cancer therapy.

Measure: Best Objective Response (BOR) for 80mg AZD9291 Extension Population

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression, up to approximately 12 months (at the time of analysis)

196 Open Label, Multicenter Phase Ib / II Study of Glumetinib Combined With Osimertinib in the Treatment of Relapsed and Metastatic Non-small Cell Lung Cancer Patients Who Failed to Receive EGFR Inhibitors

To explore the safety and efficacy of Glumetinib combined with Osimertinib in the treatment of relapsed and metastatic non-small cell lung cancer (NSCLC) with failed first-generation or second-generation EGFR inhibitors, negative T790M mutation and met amplification.

NCT04338243
Conditions
  1. Negative T790M Mutation and Met Amplification
Interventions
  1. Drug: Glumetinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Glumetinib Combined With Osimertinib in the Treatment of Relapsed and Metastatic Non-small Cell Lung Cancer Patients Who Failed to Receive EGFR Inhibitors To explore the safety and efficacy of Glumetinib combined with Osimertinib in the treatment of relapsed and metastatic non-small cell lung cancer (NSCLC) with failed first-generation or second-generation EGFR inhibitors, negative T790M mutation and met amplification. --- T790M ---

- Prior exposure to MET-directed or third generation EGFR inhibitors therapy Anticancer therapy (including chemotherapy, targeted therapy, biotherapy, hormone therapy or other investigational agents) within 4 weeks or 5 times of half-lives (whichever is shorter) prior to the first dose of the study drug or who have not recovered from the side effect of such therapy - Major surgery or had significant traumatic injury within 28 days prior to the first dose of the investigational product Negative T790M Mutation and Met Amplification Carcinoma, Non-Small-Cell Lung To explore the safety and efficacy of Glumetinib combined with Osimertinib in the treatment of relapsed and metastatic non-small cell lung cancer (NSCLC) with failed first-generation or second-generation EGFR inhibitors, negative T790M mutation and met amplification. --- T790M ---

- Prior exposure to MET-directed or third generation EGFR inhibitors therapy Anticancer therapy (including chemotherapy, targeted therapy, biotherapy, hormone therapy or other investigational agents) within 4 weeks or 5 times of half-lives (whichever is shorter) prior to the first dose of the study drug or who have not recovered from the side effect of such therapy - Major surgery or had significant traumatic injury within 28 days prior to the first dose of the investigational product Negative T790M Mutation and Met Amplification Carcinoma, Non-Small-Cell Lung To explore the safety and efficacy of Glumetinib combined with Osimertinib in the treatment of relapsed and metastatic non-small cell lung cancer (NSCLC) with failed first-generation or second-generation EGFR inhibitors, negative T790M mutation and met amplification. --- T790M --- --- T790M ---

Primary Outcomes

Description: the sum ratio of partial response and complete response(determined by an Independent Radiology Review Committee (IRRC) according to RECIST Version 1.1)

Measure: ORR(Objective response rate)

Time: through study completion, an average of 1 year

Secondary Outcomes

Description: the sum ratio of partial response and complete response(assessed as per investigators)

Measure: ORR(Objective response rate, assessed as per investigators)

Time: through study completion, an average of 1 year

Description: The time from the partial response and complete response of patient to patient progressive disease or death

Measure: DOR(Duration of response)

Time: The time from the date of first documented partial response or complete response to progressive disease or death, an average of 6 months

Description: The time from the patient first dose to death

Measure: OS(Overall survival)

Time: Through study completion, an average of 1 year

197 An Open Label, Multicenter, Phase II Study of Dacomitinib for EGFR Mutated Non-Small Cell Lung Cancer (NSCLC) With Brain Metastases

This is a multi-center, single-arm, open-label, Phase 2 clinical study of Dacomitinib for EGFR Mutated Non-Small Cell Lung Cancer (NSCLC) With Brain Metastases.

NCT04339829
Conditions
  1. Dacomitinib for EGFR Mutated Non-Small Cell Lung Cancer (NSCLC) With Brain Metastases
Interventions
  1. Drug: Dacomitinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung Neoplasm Metastasis Brain Neoplasms
HPO:Brain neoplasm Neoplasm of the lung Non-small cell lung carcinoma

It is acceptable for subjects with the presence of the exon 20 T790M mutation together with either EGFR activating mutation (exon 19 deletion or the L858R mutation in exon 21) to be included in this study; - Evidence of newly diagnosed stage IIIB/IV (based on Union for International Cancer Control (UICC) staging system version 7) or recurrent (minimum of 12 months disease free interval between completion of systemic therapy and recurrence of NSCLC required) NSCLC of adenocarcinoma histo- and/or cytopathology or its pathologically accepted variants using tumor specimen (assessed according to accepted standards by a local laboratory). --- T790M ---

Variations of adenocarcinoma are allowed, however no squamous element can be present; - Any other mutation other than exon 19 deletion or L858R in exon 21, with or without the presence of the exon 20 T790M mutation. --- L858R --- --- T790M ---

Primary Outcomes

Description: Progression Free Survival (PFS)is defined as the time from start of treatment to the date of disease progression as defined by RECIST v1.1 per investigator review or death due to any cause, whichever occurred first.

Measure: Progression Free Survival (PFS)

Time: 20 months

Secondary Outcomes

Description: Intracranial Objective Response Rate is defined as the proportion of subjects with a BOR of either CR or PR of intracranial disease, where BOR is the best response recorded from the start of treatment until disease progression or start of other anticancer therapy. As per RECIST v1.1 guidelines, PR and CR do not need to be confirmed following initial response documentation.

Measure: Intracranial Objective Response Rate

Time: 20 months

Description: Objective Response Rate is defined as the proportion of subjects with a BOR of either CR or PR, where BOR is the best response recorded from the start of treatment until disease progression or start of other anticancer therapy. As per RECIST v1.1 guidelines, PR and CR do not need to be confirmed following initial response documentation.

Measure: Objective Response Rate

Time: 20 months

Description: Disease control rate is defined as the proportion of patients with complete response (CR) or partial response (PR) or subjects with stable disease (SD) as per investigator assessment according to RECIST 1.1 criteria.

Measure: Disease control rate

Time: 20 months

Description: Duration of response is defined as the time from first documented response of CR or PR to date of first documented progression or death due to any cause, according to RECIST 1.1 criteria

Measure: Duration of response

Time: 20 months

Description: Intracranial Progression Free Survival is defined as confirmed by investigator with morphologically proven intracranial PD [presence of at least one key symptom in combination with radiologic evidence including CT or MRI of PD in the brain on follow-up or death due to any cause, whichever occurred first.

Measure: Intracranial Progression Free Survival

Time: 20 months

Description: Overall Survival is defined as the time from start of treatment to the date of death for any cause. In the absence of confirmation of death, survival time will be censored at the last date the subject is known to be alive.

Measure: Overall Survival

Time: 48 months

198 Randomized Phase II Trial of Local Consolidation Therapy (LCT) After Osimertinib for Patients With EGFR Mutant Metastatic Non-Small Cell Lung Cancer (NSCLC)

This phase II trial studies how well osimertinib, surgery, and radiation therapy work in treating patients with stage IIIB or IV non-small cell lung cancer with EGFR mutations. Osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving osimertinib, surgery, and radiation therapy may work better at treating non-small cell lung cancer with EGFR mutations.

NCT03410043
Conditions
  1. EGFR Exon 19 Deletion Mutation
  2. EGFR NP_005219.2:p.L858R
  3. EGFR NP_005219.2:p.T790M
  4. Lung Non-Small Cell Carcinoma
  5. Recurrent Lung Non-Small Cell Carcinoma
  6. Stage IIIB Lung Cancer AJCC v8
  7. Stage IV Lung Cancer AJCC v8
  8. Stage IVA Lung Cancer AJCC v8
  9. Stage IVB Lung Cancer AJCC v8
Interventions
  1. Drug: Osimertinib
  2. Radiation: Radiation Therapy
  3. Procedure: Therapeutic Conventional Surgery
MeSH:Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Carcinoma Neoplasm of the lung Non-small cell lung carcinoma

This subset of patients must be TKI naive; OR - NSCLC which harbors an EGFR T790M mutation that was acquired following progression on erlotinib, gefitinib or afatinib. --- T790M ---

In addition, these lesions will be counted towards the total number of metastases, and will also be counted as target lesions EGFR Exon 19 Deletion Mutation EGFR NP_005219.2:p.L858R EGFR NP_005219.2:p.T790M Lung Non-Small Cell Carcinoma Recurrent Lung Non-Small Cell Carcinoma Stage IIIB Lung Cancer AJCC v8 Stage IV Lung Cancer AJCC v8 Stage IVA Lung Cancer AJCC v8 Stage IVB Lung Cancer AJCC v8 Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVES: I. To determine whether, in patients with tyrosine kinase inhibitor (TKI) naive or TKI resistant (acquired T790M) metastatic EGFR mutant non-small cell lung cancer (NSCLC) who do not progress after 6-12 weeks of induction osimertinib, local consolidative therapy (LCT; radiotherapy +/- surgical resection) followed by osimertinib prolongs progression-free survival (PFS) compared with osimertinib alone. --- T790M ---

To determine whether osimertinib plus LCT improves progression-free survival compared with osimertinib alone in TKI resistant (acquired T790M) EGFR mutant NSCLC. --- T790M ---

Primary Outcomes

Description: Will be estimated using Kaplan-Meier method. The stratified log-rank test will be performed to test the difference in time-to-event distributions between treatment groups. Stratified Cox proportional hazards model will be utilized to include multiple covariates in the time-to-event analysis and to estimate hazard ratios.

Measure: Progression free survival (PFS)

Time: From the start date of osimertinib assessed up to 4 years

Secondary Outcomes

Description: Will be estimated using Kaplan-Meier method. The stratified log-rank test will be performed to test the difference in time-to-event distributions between treatment groups. Stratified Cox proportional hazards model will be utilized to include multiple covariates in the time-to-event analysis and to estimate hazard ratios.

Measure: Overall survival

Time: From the treatment start date assessed up to 4 years

Description: Will be estimated using Kaplan-Meier method. The stratified log-rank test will be performed to test the difference in time-to-event distributions between treatment groups. Stratified Cox proportional hazards model will be utilized to include multiple covariates in the time-to-event analysis and to estimate hazard ratios.

Measure: Time to progression of target lesions

Time: Up to 4 years

Description: Will be estimated using Kaplan-Meier method. The stratified log-rank test will be performed to test the difference in time-to-event distributions between treatment groups. Stratified Cox proportional hazards model will be utilized to include multiple covariates in the time-to-event analysis and to estimate hazard ratios.

Measure: Time to appearance of new metastases

Time: Up to 4 years

Description: Will be estimated using Kaplan-Meier method. The stratified log-rank test will be performed to test the difference in time-to-event distributions between treatment groups. Stratified Cox proportional hazards model will be utilized to include multiple covariates in the time-to-event analysis and to estimate hazard ratios.

Measure: PFS in oligometastatic subgroup

Time: Up to 4 years

Description: Toxicity data related to the treatments will be summarized by frequency tables. The association between the types and severity of toxicity and the treatment groups will be evaluated.

Measure: Incidence of adverse events

Time: Up to 30 days post treatment

199 Phase II Study of Osimertinib in NSCLC Patients With EGFR Exon 20 Insertion Mutation

This is a single-arm, non-randomized multicentre phase 2 study in NSCLC patients with EGFR exon 20 insertion mutation, whose disease has progressed on standard chemotherapy.

NCT03414814
Conditions
  1. Locally Advanced or Metastatic NSCLC
Interventions
  1. Drug: Osimertinib 80 MG [Tagrisso]
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Osimertinib is an oral, potent, irreversible EGFR-TKI selective for sensitizing EGFR and EGFR T790M resistance mutations with a significant selectivity margin against wild-type EGFR. --- T790M ---

Primary Outcomes

Description: Investigator-assessed, confirmed objective response by RECIST version 1.1

Measure: Objective response rate

Time: Through study completion, an average of 1 year

Secondary Outcomes

Description: AEs/SAEs as defined by NCI CTCAE version 4.0

Measure: Incidence of Treatment-Emergent Adverse Events

Time: Through study completion, an average of 1 year

Description: PFS as defined by RECIST version 1.1

Measure: Progression-free survival

Time: From date of initiation until the date of first documented progression, whichever came first, assessed up to 2 years

Description: OS as defined by RECIST version 1.1

Measure: Overall survival

Time: Through study completion, an average of 2 years

Description: Duration of response as defined by RECIST version 1.1

Measure: Duration of response

Time: Through study completion, an average of 1 year

200 A Phase Ia/Ib, Open Label, Dose-escalation Study of the Combination of BI 907828 With BI 754091 and BI 754111, Followed by Expansion Cohorts, in Patients With Advanced Solid Tumors

Phase Ia - Dose Escalation The main objective of the dose-escalation part is to determine the maximum tolerated dose (MTD) of BI 907828 in combination with BI 754091 and BI 754111, based on the frequency of patients experiencing dose-limiting toxicities (DLTs), and/or the recommended dose for further development of BI 907828 in combination with BI 754091 and BI 754111, and to evaluate safety and tolerability of BI 907828 in combination with BI 754091 and BI 754111 by monitoring the occurrence and severity of adverse events (AEs). The secondary objectives are the determination of the pharmacokinetic (PK) profile of BI 907828, BI 754091 and BI 754111 based on Cmax and AUC0-tz, and the preliminary assessment of anti-tumor activity. Phase Ib - Dose Expansion The main objective of the dose-expansion part is to assess the preliminary efficacy of the combination of BI 907828, BI 754091, and BI 754111. The secondary and further objectives are to further assess the safety, the PK profiles at the recommended dose for expansion (RDE), and to determine the Recommended Phase II Dose (RP2D).

NCT03964233
Conditions
  1. Neoplasms
Interventions
  1. Drug: BI 907828
  2. Drug: BI 754091
  3. Drug: BI 754111

Patients with NSCLC harboring genomic aberrations for which FDA approved targeted therapy is available such as non-resistant EGFR mutations, EGFR T790M mutation, ALK rearrangement, ROS re-arrangement, and BRAF V600E mutation, must have received prior treatment with FDA-approved targeted therapy. --- T790M ---

Primary Outcomes

Measure: Phase Ia - maximum tolerated dose (MTD) of BI 907828 in combination with BI 754091 and BI 754111 based on the number of patients with DLTs during the first treatment cycle

Time: Up to 35 Days

Measure: Phase Ib - Objective response (OR)

Time: Up to 24 months

Secondary Outcomes

Measure: Phase Ia - Cmax : Maximum measured plasma concentration of BI 907828, BI 754091, and BI 754111 (during the first cycle)

Time: Up to 21 Days

Measure: Phase Ia - AUC0-tz: Area under the concentration-time curve in plasma for BI 907828, BI 754091 and BI 754111 over the time interval from 0 to the last quantifiable time point (during the first cycle)

Time: Up to 21 Days

Measure: Phase Ia - Number of patients with DLTs observed during the entire treatment period

Time: Up to 24 months

Measure: Phase Ib - Objective Response (OR)

Time: Up to 24 months

Measure: Phase Ib - Disease control (DC)

Time: Up to 24 months

Measure: Phase Ib - Progression-Free Survival (PFS)

Time: Up to 24 months

Measure: Phase Ib - In cohort 3 (liposarcoma and undifferentiated pleomorphic sarcoma): PFS rate at 12 and 24 weeks

Time: 12 and 24 weeks

Measure: Phase Ib - Number of patients with DLTs

Time: Up to 2 years

201 A Multicenter, Open-label, Phase II Study to Evaluate the Safety and Efficacy of SH-1028 in Locally Advanced or Metastatic NSCLC

A Phase II, Open Label, Single-arm Study to Assess the Safety and Efficacy of SH-1028 with Locally Advanced/Metastatic Non-Small Cell Lung Cancer whose Disease has Progressed with Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and whose Tumours harbour a T790M mutation within the Epidermal Growth Factor Receptor Gene.

NCT03823807
Conditions
  1. Non-Small Cell Lung Cancer
Interventions
  1. Drug: SH-1028
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

A Study to Evaluate the Safety and Efficacy of SH-1028 in Locally Advanced or Metastatic NSCLC A Phase II, Open Label, Single-arm Study to Assess the Safety and Efficacy of SH-1028 with Locally Advanced/Metastatic Non-Small Cell Lung Cancer whose Disease has Progressed with Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and whose Tumours harbour a T790M mutation within the Epidermal Growth Factor Receptor Gene. --- T790M ---

Non-Small Cell Lung Cancer Carcinoma, Non-Small-Cell Lung This is a multicenter, open-label, phase II study to evaluate the safety and efficacy of SH-1028 in locally advanced or metastatic NSCLC.The trail is divided into two parts:part A is dose extension phase,and Part B is expand sample size phase to confirm the efficacy of SH-1028.Patients must agree to provide a biopsy for central confirmation of T790M mutation status following confirmed disease progression on the most recent treatment regimen. --- T790M ---

Primary Outcomes

Measure: Objective Response Rate (ORR)

Time: Every 2 cycles (21 days for 1 cycle) until end of treatment, an average of 1 year.

Secondary Outcomes

Measure: Number of participants with treatment-related adverse events as assessed by CTCAE v5.0

Time: From Baseline up to 30 days after the last dose, an average of 1 year.

Measure: Maximum Plasma Concentration (Cmax)

Time: Part A: Day 1 of Cycle 1 and 2 (21 days for 1 cycle).

Measure: Area Under the Curve [AUC]

Time: Part A: Day 1 of Cycle 1 and 2 (21 days for 1 cycle).

Measure: Progression-free survival (PFS)

Time: Every 2 cycles (21 days for 1 cycle) until end of follow-up, an average of 1 year.

Measure: Duration of Response(DOR)

Time: Every 2 cycles (21 days for 1 cycle) until end of treatment, an average of 1 year.

Measure: Disease Control Rates(DCR)

Time: Every 2 cycles (21 days for 1 cycle) until end of treatment, an average of 1 year.

Measure: Overall survival(OS)

Time: Every 2 cycles (21 days for 1 cycle) until end of treatment; Every 12 weeks until end of follow-up, an average of 2 years.

Other Outcomes

Description: optional,use NGS to analyse the gene associated with NSCLC and to determine the reason of SH-1028-resistance.

Measure: Biomakers (eg. AF value of KRAS,MET mutation or other gene mutations ) of drug-resistance measured by next-generation sequencing (NGS).

Time: at end of treatment,an average of 1 years.

Measure: Minimum Plasma Concentration (Cmin)

Time: Before administration in Day 1 of cycle 2, 3 and 5 (21 days for 1 cycle).

202 A Phase II Study of Osimertinib With On-study and Post-progression Biopsy in the First Line Treatment of EGFR Inhibitor naïve Advanced EGFR Mutant Lung Cancer

This research study is studying a targeted therapy as a possible treatment for Non-Small Cell Lung Cancer (NSCLC) with an EGFR mutation. The names of the study drug involved in this study is: - Osimertinib (Tagrisso)

NCT03586453
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Drug: Osimertinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- cardiac ejection fraction of < 45% - Any evidence of severe or uncontrolled systemic diseases, including active bleeding diatheses, which in the investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol - Known to be T790M+ (on pre-treatment tumor or plasma) or known germline T790M. --- T790M ---

Primary Outcomes

Description: Evaluated by comparing the genomic changes using targeted next generation sequencing in the post-osimertinib tumor to the pre-treatment tumor specimen.

Measure: Mechanisms of resistance to Osimertinib

Time: 4 Months

Secondary Outcomes

Description: Best objective response will be evaluated via RECIST 1.1 criteria. RECIST1.1 measurements of CT scans will be measured every 2 cycles on treatment to determine the objective response rate for patients being treated with osimertinib.

Measure: Best objective response

Time: 6 months

Description: Defined as the proportion of patients with best response of CR or PR per investigator assessment using RECIST 1.1. start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started.

Measure: Overall Response Rate

Time: 3 years

Description: Time from registration to documented disease progression or death from any cause, whichever occurs first. The Kaplan-Meier method will be used to determine the progression-free survival of patients enrolled on protocol and treated with combination osimertinib and selumetinib.

Measure: Progression-free survival (PFS)

Time: 2 years

Description: Survival follow-up with clinic visits or phone calls will be used to monitor for overall survival from time of study randomization to death from any cause. The Kaplan-Meier method will be used to calculate overall survival.

Measure: Overall survival

Time: 2 years

203 A Multi-center, One-arm, Phase II Trial of Anlotinib Combined With Osimertinib as the Second-line Treatment in Stage IIIb-IV NSCLC With Confirmed EGFRm and T790M.

Evaluate the efficacy and safety of Anlotinib combined with Icotinib as the second-line treatment in stage IIIb-IV NSCLC patients with sensitive EGFR and T790M mutations.

NCT04029350
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: Anlotinib Combined With Osimertinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

A Multi-center, One-arm, Phase II Trial of Anlotinib Combined With Osimertinib as the Second-line Treatment in Stage IIIb-IV NSCLC With Confirmed EGFRm and T790M.. Study of Anlotinib Combined With Osimertinib as Second-line Treatment in Stage IIIb-IV NSCLC With Confirmed EGFRm and T790M Evaluate the efficacy and safety of Anlotinib combined with Icotinib as the second-line treatment in stage IIIb-IV NSCLC patients with sensitive EGFR and T790M mutations. --- T790M ---

A Multi-center, One-arm, Phase II Trial of Anlotinib Combined With Osimertinib as the Second-line Treatment in Stage IIIb-IV NSCLC With Confirmed EGFRm and T790M.. Study of Anlotinib Combined With Osimertinib as Second-line Treatment in Stage IIIb-IV NSCLC With Confirmed EGFRm and T790M Evaluate the efficacy and safety of Anlotinib combined with Icotinib as the second-line treatment in stage IIIb-IV NSCLC patients with sensitive EGFR and T790M mutations. --- T790M --- --- T790M ---

A Multi-center, One-arm, Phase II Trial of Anlotinib Combined With Osimertinib as the Second-line Treatment in Stage IIIb-IV NSCLC With Confirmed EGFRm and T790M.. Study of Anlotinib Combined With Osimertinib as Second-line Treatment in Stage IIIb-IV NSCLC With Confirmed EGFRm and T790M Evaluate the efficacy and safety of Anlotinib combined with Icotinib as the second-line treatment in stage IIIb-IV NSCLC patients with sensitive EGFR and T790M mutations. --- T790M --- --- T790M --- --- T790M ---

3. Locally confirmed T790M mutation determined from biopsy (preferred) or on circulating tumour DNA, documented in tissue, plasma or serum after disease progression on the most recent first- or second-generation EGFR TK treatment regimen. --- T790M ---

Primary Outcomes

Description: The PFS time is defined as time from enrollment to locoregional or systemic recurrence, second malignancy or death due to any cause; censored observations will be the last date of : "death", "last tumor assessment", "last follow up date" or "last date in drug log"

Measure: Progression-free survival (PFS)

Time: each 42 days up to PD or death (up to 24 months)

Secondary Outcomes

Description: OS was defined as time from date of enrollment to date of death due to any cause. For participants still alive at the time of analysis, OS time was censored on last date that participants were known to be alive.

Measure: OS(Overall Survival)

Time: up to 24 months

Description: To evaluate the effectiveness of Anlotinib Hydrochloric Capsule Plus Icotinib Hydrochloric Tablet by enhanced CT/MRI scan every two cycles. Objective Response Rate (ORR) is defined as participants who had complete response (CR) or partial response(PR) divided by the total number of patients.

Measure: ORR(Objective Response Rate)

Time: each 42 days up to intolerance the toxicity or PD (up to 24 months)

Description: To evaluate the effectiveness of Anlotinib Hydrochloric Capsule Plus Icotinib Hydrochloric Tablet by enhanced CT/MRI scan every two cycles. Disease Control Rate (DCR) defined as the percentage of participants with Disease Control best overall response (complete response, partial response or stable disease).

Measure: DCR(Disease Control Rate)

Time: each 42 days up to intolerance the toxicity or PD (up to 24 months)

Description: Number of Participants with Adverse Events as a Measure of Safety and Tolerability

Measure: Adverse Events

Time: Until 30 day safety follow-up visit

204 A Single-arm, Open-label, Phase 2 Study of Dacomitinib With or Without Dose Titration for the First-line Treatment of Locally Advanced or Metastatic Non-small Cell Lung Cancer in Subjects With an Epidermal Growth Factor Receptor (EGFR) Activation Mutation

This is a multi-national, multi-centre, single-arm, open-label, Phase 2 clinical study of the efficacy and safety of first-line treatment with dacomitinib, with or without dose titration, in subjects with newly diagnosed stage IIIB/IV or recurrent EGFR-mutation-positive non-small cell lung cancer (NSCLC). National Cancer Centre Singapore will be the lead sponsor acting in a coordinating capacity and the rest of the participating sites are sponsors of their own individual sites.

NCT04027647
Conditions
  1. NSCLC Stage IIIB
  2. NSCLC Stage IV
  3. Recurrent NSCLC
  4. EGFR Positive Non-Small Cell Lung Cancer
Interventions
  1. Drug: Dacomitinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Variations of adenocarcinoma are allowed, however no squamous element can be present; - An EGFR exon 20 T790M or exon 20 insertion mutation; - Symptomatic brain or leptomeningeal metastases, who are neurologically unstable or require increasing doses of steroids and/or anti-seizure medications to manage CNS symptoms within two weeks prior to starting dacomitinib; - Any previous anti-cancer systemic treatment of locally advanced, or metastatic NSCLC including but not limited to chemotherapy, targeted therapies, small molecules, EGFR-TKIs and other TKIs, monoclonal antibodies, anti-cancer vaccines, immunotherapy, radiotherapy (other than palliative radiotherapy to lesions that will not be followed for tumor assessment on this study, i.e., non-target lesions). --- T790M ---

Primary Outcomes

Description: Percentage of subjects with PFS at 12 months

Measure: Progression-Free Survival (PFS)

Time: From the start of treatment to the date of disease progression or death due to any cause at 12 months

Secondary Outcomes

Measure: Overall Survival

Time: From the start of treatment to the date of death for any cause, up to 3 years

Description: Proportion of subjects with a best overall response of either complete response (CR) or partial response (PR)

Measure: Objective Response Rate

Time: From the start of treatment until disease progression, up to 3 years

Measure: Time to Treatment Failure

Time: From the start of treatment to the last dose of treatment, up to 3 years

Description: Proportion of subjects with a best overall response of either CR or PR of intracranial disease

Measure: Intracranial Objective Response Rate

Time: From the start of treatment until disease progression, up to 3 years

Measure: Intracranial Progression-Free Survival

Time: From the start of treatment to the date of intracranial progression or death due to any cause, up to 3 years

Measure: Number of incidences of adverse events

Time: From start of treatment to 28 days after end of treatment

205 A Multicenter, Randomized, Double-Blind Study of Gefitinib in Combination With Anlotinib or Placebo in Previously Untreated Patients With EGFR Mutation-Positive Advanced Non-Small-Cell Lung Cancer

Gefitinib is currently the standard-of-care for patients with activating-EGFR mutant advanced non-small cell lung cancer (NSCLC). However, ~30-40% patients are still nonresponsive, and experience significantly varying duration of response and survival rate. Anlotinib is an efficient multi-target tyrosine kinase inhibitor (TKI) that effectively block the migration and proliferation of endothelial cells and reduce tumor microvascular density by targeting VEGFRs, FGFRs, PDGFRs. It has been proved to be safe and effective in advanced lung cancer after second-line standard chemotherapy failure, which can significantly extend the survival of patients and approves as a third-line treatment for advanced NSCLC. Here, we prepared to evaluate whether the combination of gefitinb and anlotinib can preferably improved survival of untreated NSCLC with EGFR activating mutation.

NCT04028778
Conditions
  1. Lung Cancer, Nonsmall Cell
Interventions
  1. Drug: Gefitinib
  2. Drug: Anlotinib Hydrochloride
  3. Other: Placebo
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- 5.patients with positive T790M mutation by Gene detection. --- T790M ---

Primary Outcomes

Description: Progression-Free Survival (PFS) as Assessed by Investigator Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v1.1)

Measure: Progress-free survival (PFS)

Time: Approximately 2 Years

Secondary Outcomes

Description: OS was defined as the time from the date of randomization to the date of death due to any cause.

Measure: Overall Survival (OS)

Time: Approximately 5 Years

Description: PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. CR was defined as disappearance of all target and non-target lesions and normalization of tumor marker levels (as applicable to non-target lesions).

Measure: Percentage of Participants With Objective Response (Partial Response [PR] Plus Complete Response [CR]), as Assessed Using RECIST v.1.1

Time: Approximately 2 Years

Description: Clinical benefit was defined as objective response (PR+CR), or no disease progression lasting for more than or equal to (>/=) 24 weeks since randomization. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. CR was defined as disappearance of all target and non-target lesions and normalization of tumor marker levels (as applicable to non-target lesions). Disease progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. For non-target lesions, disease progression was defined as unequivocal progression of existing lesions. The appearance of one or more new lesions was also considered progression.

Measure: Percentage of Participants With Clinical Benefit, as Assessed According to RECIST v1.1

Time: Approximately 2 Years

Description: Duration of objective response: the time from the first tumor assessment that supported the participant's objective response (CR or PR, whichever was first recorded) to first documented disease progression or death due to any cause, whichever occurred first. CR was defined as disappearance of all target and non-target lesions and normalization of tumor marker levels (as applicable to non-target lesions). PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. Disease progression: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. For non-target lesions, disease progression was defined as unequivocal progression of existing lesions. The appearance of one or more new lesions was also considered progression.

Measure: Duration of Objective Response, as Assessed by Investigator Using RECIST v1.1

Time: Approximately 2 Years

Other Outcomes

Description: The EORTC QLQ-C30 consists of 30 questions that comprise aspects of participant's functioning assessment (physical, emotional, role, cognitive, and social); symptom scales (fatigue; nausea, vomiting, and pain; the global health/quality of life [QoL]); and single items (dyspnoea, insomnia, appetite loss, constipation, diarrhoea, and financial difficulties), within a recall period of "the past week." Most questions used a 4-point scale (1=Not at all to 4=Very much; two questions used a 7-point scale (1=Very poor to 7=Excellent). Scores were averaged and transformed to a 0-100 scale; a higher score for Global Qol/functional scales=better level of functioning; a higher score for symptom scale=greater degree of symptoms.

Measure: Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) Score

Time: Approximately 2 Years

206 Atezolizumab in Combination With Bevacizumab, Carboplatin and Pemetrexed for EGFR-mutant Metastatic Non-small Cell Lung Cancer Patients After Failure of EGFR Tyrosine Kinase Inhibitors: a Single Arm Phase 2 Study

This project will recruit 40 EGFR-mutant metastatic non-small cell lung cancer patients who failed any EGFR tyrosine kinase inhibitors. All recruited patients will receive 1200mg Azetolizumab administered over 60 minutes (1st cycle) and 30 minutes (2nd cycle onwards) intravenously, as well as 7.5mg/kg bevacizumab administered over 90 minutes (1st cycle), 60 minutes (2nd cycle) and 30 minutes (3rd cycle onwards) for every 3 weeks, until radiographically documented disease progression, unacceptable toxicity as judged by investigators or patient withdrawal. The primary objective is to assess the progression-free survival of this treatment population, and to identify potential genomic and immunologic biomarkers for treatment response. Objective response rate (ORR) will be the primary efficacy endpoint.

NCT03647956
Conditions
  1. NSCLC Stage IIIB
  2. NSCLC Stage IV
  3. EGFR Activating Mutation
Interventions
  1. Drug: Atezolizumab
  2. Drug: Bevacizumab
  3. Drug: Carboplatin
  4. Drug: Pemetrexed
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

The use of neoadjuvant or adjuvant platinum-based chemotherapy more than 6 months before study enrollment is allowed - Previous exposure to VEGF inhibitor for anti-cancer treatment - Prior treatment with any other anti-programmed cell death protein-1 (anti-PD-1), or PD Ligand-1 (PD-L1) or PD Ligand-2 (PDL2) agent or an antibody targeting other immuno-regulatory receptors or mechanisms - Patients carries EGFR genotype T790M but have not received 3rd generation EGFR TKI Osimertinib - Currently participating or has participated in a study of an investigational agent or using an investigational device within 4 weeks of administration of atezolizumab - Expected to require any other form of antineoplastic therapy while on study - Patients with untreated symptomatic brain metastases. --- T790M ---

Primary Outcomes

Description: The percentage of patients with radiologically complete or partial response as determined by the investigator according to RECIST version 1.1.

Measure: Objective response rate (ORR)

Time: 3 years

Secondary Outcomes

Description: PFS is measured from the date of study enrollment to radiographically documented progression according to RECIST 1.1 or death from any cause (whichever occurs first). Participants alive and without disease progression or lost to follow-up will be censored at the date of their last radiographic assessment.

Measure: Progression-free Survival (PFS)

Time: 3 years

Description: TTP is measured from the date of study enrollment to radiographically documented progression according to RECIST 1.1. This does not include death from any cause.

Measure: Time to progression (TTP)

Time: 3 years

Measure: Duration of response (DoR)

Time: 3 years

207 Efficacy and Safety of Anlotinib Combined With Platinum Plus Pemetrexed in T790M Mutation Negative Metastastic Non-squamous Non-small-cell Lung Cancer After Progression on First-line EGFR TKI: a Phase II, Muti-center, Single Arm Study

This study is conducted to explore the safety and efficacy of anlotinib, a tyrosine kinase inhibitors of vascular endothelial growth factor receptor 2(VEGFR)、FGFR(fibroblast growth factor receptor), platelet-derived growth factor receptor(PDGFR) and tumor cell proliferation related kinase c-Kit, combined with platinum plus pemetrexed in T790M mutation negative metastatic non-squamous non-small cell lung cancer(NSCLC) after the failure of EGFR-TKI.

NCT03706287
Conditions
  1. Lung Cancer Metastatic
Interventions
  1. Drug: anlotinib 8mg + AP/PC
  2. Drug: anlotinib 10mg + AP/PC
  3. Drug: anlotinib 12mg + AP/PC
  4. Drug: anlotinib + AP/PC
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

Efficacy and Safety of Anlotinib Combined With Platinum Plus Pemetrexed in T790M Mutation Negative Metastastic Non-squamous Non-small-cell Lung Cancer After Progression on First-line EGFR TKI: a Phase II, Muti-center, Single Arm Study. --- T790M ---

Efficacy and Safety of Anlotinib Plus Platinum Plus Pemetrexed in T790M-negative NSCLC This study is conducted to explore the safety and efficacy of anlotinib, a tyrosine kinase inhibitors of vascular endothelial growth factor receptor 2(VEGFR), FGFR(fibroblast growth factor receptor), platelet-derived growth factor receptor(PDGFR) and tumor cell proliferation related kinase c-Kit, combined with platinum plus pemetrexed in T790M mutation negative metastatic non-squamous non-small cell lung cancer(NSCLC) after the failure of EGFR-TKI. --- T790M ---

Efficacy and Safety of Anlotinib Plus Platinum Plus Pemetrexed in T790M-negative NSCLC This study is conducted to explore the safety and efficacy of anlotinib, a tyrosine kinase inhibitors of vascular endothelial growth factor receptor 2(VEGFR), FGFR(fibroblast growth factor receptor), platelet-derived growth factor receptor(PDGFR) and tumor cell proliferation related kinase c-Kit, combined with platinum plus pemetrexed in T790M mutation negative metastatic non-squamous non-small cell lung cancer(NSCLC) after the failure of EGFR-TKI. --- T790M --- --- T790M ---

To determine ORR of Anlotinib Anlotinib combined with Platinum-based Pemetrexed in T790M mutation negative Advanced NSCLC. --- T790M ---

- Epidermal Growth Factor Receptor(EGFR)mutations confirmed by molecular detection (including, but not limited to 19 exon deletion and L858R) external pathological examination was accepted (including pathological or blood test results) - Patients have only be treated with EGFR -TKIs(Tyrosine kinase inhibitors)including gefitinib, elotinib or icotinib, and received a best response of PR for ≥4months or SD for 6 months; disease has progressed recently according to RECIST 1.1 and negative for T790M detection(detection methods including ddPCR, ARMS or NGS) (For recurrent patients, adjuvant chemotherapy, neoadjuvant chemotherapy or neoadjuvant chemotherapy plus adjuvant were assessed for eligibility, and the last treatment time must be more than 6 months before enrollment) - Must have at least one measurable lesion as per RECIST 1.1 defined as a lesion that is 10mm in longest diameter imaged by CT scan or MRI;prior topical treatment, such as radiotherapy cryosurgery to the lesions is not allowed in less than 3 months; - Life expectancy ≥3 months. --- L858R --- --- T790M ---

Phase II is to designed to explore the anti-tumor activity of anlotinib combined with platinum plus pemetrexed in T790M mutation negative metastatic non-squamous non-small cell lung cancer(NSCLC) after the failure of EGFR-TKI. --- T790M ---

Primary Outcomes

Description: PFS defined as the time from first dose of study treatment until the first date of either objective disease progression or death due to any cause.

Measure: Progression-free survival (PFS)

Time: Up to 24 months

Description: Dose Limiting Toxicity (DLT) is referred to grade 3 non-hematological toxicity or grade 4 hematological toxicity according to NCI CTCAE 4.03 criteria

Measure: Dose limiting toxicity (DLT)

Time: Estimated about 6 months

Description: Maximum Tolerance Dose (MTD) is the dose of treatment in the cohort where there are 2 cases of DLT reported.

Measure: Maximum tolerance dose (MTD)

Time: Estimated about 6 months

Secondary Outcomes

Description: To determine ORR of Anlotinib Anlotinib combined with Platinum-based Pemetrexed in T790M mutation negative Advanced NSCLC. ORR is defined as the percentage of subjects with evidence of a confirmed complete response (CR) or partial response (PR) as per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1.

Measure: Objective response rate(ORR)

Time: Up to 24months

Description: Defined as the proportion of patients with a documented complete response, partial response, and stable disease (CR + PR + SD) based on RECIST 1.1.

Measure: Disease Control Rate (DCR)

Time: Up to 24months

Description: Defined as the the time from first confirmed CR or PR until the first date of either objective disease progression or death due to any cause.

Measure: Duration of Response (DOR)

Time: Up to 24months

Description: Number of Participants with Adverse Events as a Measure of Safety and Tolerability

Measure: Safety (Number of Participants with Adverse Events as a Measure of Safety and Tolerability)

Time: Until 21 day safety follow-up visit

208 Phase I Trial Evaluating Safety and Tolerability of the Irreversible Epidermal Growth Factor Receptor Inhibitor Afatinib (BIBW 2992) in Combination With the SRC Kinase Inhibitor Dasatinib for Patients With Non-small Cell Lung Cancer (NSCLC)

The purpose of this study is to: - Find out if the study drugs Afatinib and Dasatinib can be safely given together to patients with lung cancer - Learn how these two drugs work in cancer cells when they are combined - Learn more about the side effects of these two drugs when combined - Find the highest doses of the study drugs Afatinib and Dasatinib that can be given safely without causing serious side effects

NCT01999985
Conditions
  1. Lung Cancer
  2. Non-small Cell Lung Cancer (NSCLC)
Interventions
  1. Drug: Dasatinib - 1A
  2. Drug: Afatinib - 1A
  3. Drug: Dasatinib - 1B
  4. Drug: Afatinib - 1B
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Either or both of the following: Progression or recurrence of disease after receiving prior continuous gefitinib, afatinib, or erlotinib; A tumor known to harbor a de novo T790M mutation, which is known to confer EGFR TKI resistance. --- T790M ---

Primary Outcomes

Description: The MTD for this combined treatment will be defined as either: The highest dosage cohort in which six patients had been treated and there were less than two dose limiting toxicities (DLTs) or, Afatinib at the highest tolerated dose investigated (40 mg by mouth [PO] daily) plus dasatinib at the highest tolerated dose investigated (cohort 3, 140 mg PO daily).

Measure: Maximum Tolerated Dose (MTD) of Afatinib (BIBW 2992) in Combination With Dasatinib

Time: Up to 6 Months

Secondary Outcomes

Description: Estimates objective response rate (complete response [CR] and partial response [PR]) in participants with acquired EGFR resistance

Measure: Number of Participants With Objective Response

Time: Up to 6 Months

Description: Estimate the 6-month progression free survival (PFS) rate in participants with acquired EGFR resistance. Response Criteria for Phase 1B will follow RECIST v.1.1: Progressive Disease (PD) is defined as at least a 20% increase in the sum of LD of target lesions taking as references the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.

Measure: Median Progression Free Survival

Time: Up to 6 Months

209 An Open-label, Phase 1 Dose Escalation Study of Oral ASP8273 in Subjects With Non-Small-Cell Lung Cancer (NSCLC) Who Have Epidermal Growth Factor Receptor (EGFR) Mutations

The purpose of this study is to assess the safety and tolerability of ASP8273 and to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D). This study will also determine the pharmacokinetics (PK) of ASP8273, evaluate the potential inhibition of CYP3A4 by ASP8273 and the antitumor activity of ASP8273 as well as determine the effect of food on the bioavailability of ASP8273.

NCT02113813
Conditions
  1. Non-Small-Cell Lung Cancer (NSCLC)
  2. Epidermal Growth Factor Receptor Mutations
Interventions
  1. Drug: naquotinib
  2. Drug: midazolam
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Defined as the time from the start of the study treatment until death from any cause or radiographic disease progression assessed according to RECIST 1.1, whichever occurs first.. Inclusion Criteria: - Non-child bearing potential or able to follow birth control requirements - Eastern Cooperative Oncology Group (ECOG) ≤ 1 - Life expectancy ≥ 12 weeks - Laboratory criteria as: - Neutrophil count ≥ 1,500/mm3 - Platelet count ≥ 7.5 x 104 /mm3 - Hemoglobin ≥ 9.0 g/dL - Lymphocyte count ≥ 500/mm3 - Serum creatinine < 1.5 x institutional Upper Limit of Normal (ULN) or an estimated glomerular filtration rate (eGFR) of > 50 ml/min as calculated by the Modification of Diet in Renal Disease (MDRD) equation - Total bilirubin < 1.5 x ULN (except for subjects with documented Gilbert's syndrome) - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3.0 x ULN - Dose escalation subjects: Epidermal Growth Factor Receptor (EGFR) activating mutation by local testing: exon 18 G719X, exon 19 deletion, exon 21 L861Q, exon 21 L858R or exon 20 insertion; and received prior treatment with EGFR Tyrosine Kinase Inhibitor (TKI) - Response expansion/RP2D expansion/ FE Cohort subjects: disease progression on or was intolerant to prior EGFR TKI; activating mutation as above AND T790M mutation; tumor sample subsequent to EGFR TKI is available for central testing; at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Inclusion Criteria for Exon 20 cohort: - Subject on any line of treatment and has an EGFR exon 20 insertion mutation on examination of an NSCLC tissue or cellular specimen. --- L861Q --- --- L858R --- --- T790M ---

Exclusion Criteria: - Any ongoing toxicity ≥ Grade 2 attributable to prior Non-Small-Cell Lung Cancer (NSCLC) treatment - Prior EGFR inhibitor within 6 days; received prior treatment with any other agent with antitumor activity chemotherapy, radiotherapy, or immunotherapy within 14 days; any investigational therapy within 28 days or 5 half-lives, whichever is shorter; blood transfusion or hemopoietic factor within 14 days; major surgery within 14 days; any strong CYP3A4 inhibitors within 7 days - Positive hepatitis B surface antigen (HBsAg) or hepatitis C antibody (anti-HCV) or Human Immunodeficiency Virus (HIV) - Symptomatic Central Nervous System (CNS) metastasis - Active infection requiring systemic therapy within 14 days - Severe or uncontrolled systemic diseases including uncontrolled hypertension - History of or active interstitial lung disease - Screening QTcF >450 msec or current medication known to prolong QT - ≥ Grade 2 cardiac arrhythmia or uncontrolled atrial fib of any grade; Class 3 or 4 New York Heart Association congestive heart failure; history of severe/unstable angina, myocardial infarction or cerebrovascular accident within 6 months - History of gastrointestinal ulcer or bleeding within 3 months; any digestive tract dysfunction - Concurrent corneal disorder or ophthalmologic condition making subject unsuitable - RP2D cohort subjects: contraindications to midazolam, any other midazolam within 7 days, or any medications or supplements known to be strong CYP3A inhibitors within 7 days or inducers within 12 days - Any other malignancy requiring treatment Inclusion Criteria: - Non-child bearing potential or able to follow birth control requirements - Eastern Cooperative Oncology Group (ECOG) ≤ 1 - Life expectancy ≥ 12 weeks - Laboratory criteria as: - Neutrophil count ≥ 1,500/mm3 - Platelet count ≥ 7.5 x 104 /mm3 - Hemoglobin ≥ 9.0 g/dL - Lymphocyte count ≥ 500/mm3 - Serum creatinine < 1.5 x institutional Upper Limit of Normal (ULN) or an estimated glomerular filtration rate (eGFR) of > 50 ml/min as calculated by the Modification of Diet in Renal Disease (MDRD) equation - Total bilirubin < 1.5 x ULN (except for subjects with documented Gilbert's syndrome) - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3.0 x ULN - Dose escalation subjects: Epidermal Growth Factor Receptor (EGFR) activating mutation by local testing: exon 18 G719X, exon 19 deletion, exon 21 L861Q, exon 21 L858R or exon 20 insertion; and received prior treatment with EGFR Tyrosine Kinase Inhibitor (TKI) - Response expansion/RP2D expansion/ FE Cohort subjects: disease progression on or was intolerant to prior EGFR TKI; activating mutation as above AND T790M mutation; tumor sample subsequent to EGFR TKI is available for central testing; at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Inclusion Criteria for Exon 20 cohort: - Subject on any line of treatment and has an EGFR exon 20 insertion mutation on examination of an NSCLC tissue or cellular specimen. --- L861Q --- --- L858R --- --- T790M ---

Primary Outcomes

Description: A DLT is defined as any pre-determined toxicity that is related to study drug per the investigator and which occurs during Cycle 0 and Cycle 1 using NCI CTCAE v4.03.

Measure: Safety and tolerability as assessed by Dose Limiting Toxicities (DLTs)

Time: up to 18 months

Description: An AE is defined as any untoward medical occurrence in a subject administered a study drug or has undergone study procedures and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.

Measure: Safety and tolerability as assessed by adverse events (AEs)

Time: up to 18 months

Description: Laboratory tests to be conducted are hematology, biochemistry, urinalysis, coagulation profile, lipid panel and lymphocyte subpopulation.

Measure: Safety and tolerability as assessed by laboratory tests

Time: up to 18 months

Description: Vital signs to be measured includes blood pressure, pulse rate and temperature.

Measure: Safety and tolerability as assessed by vital signs

Time: up to 18 months

Measure: Safety and tolerability as assessed by 12-lead electrocardiograms (ECGs)

Time: up to 18 months

Secondary Outcomes

Description: Maximum concentration (Cmax), the time after dosing when Cmax occurs (tmax), area under the concentration - time curve from time 0 up to the last quantifiable concentration (AUClast), area under the concentration - time curve from time 0 extrapolated to infinity (AUCinf), apparent terminal elimination half-life (t1/2), apparent oral systemic clearance (CL/F), Apparent volume of distribution (Vz/F)

Measure: Composite of pharmacokinetics of ASP8273 concentration and its metabolites (plasma): Cmax, tmax, AUClast, AUCinf, t1/2, CL/F, and Vz/F

Time: Cycle 0: Dose Escalation Days 1-2, FE Days 1-6; Cycle 1: Dose Escalation/Response Expansion/RP2D/FE Days 1,8,15, RP2D Day 21, Exon 20 Days 8,15; Cycle 2 & 3: Dose Escalation/Response Expansion/RP2D Days 1,2, FE Day 1; Exon 20 days 1, 2 & Cycle 3

Measure: Composite of pharmacokinetics of midazolam concentration and its metabolites (plasma): Cmax, tmax, AUClast, AUCinf, t1/2, CL/F, and Vz/F

Time: Day -1 and Day 1 of cycle 1; Day 1 and Day 2 of cycle 2

Description: Defined as proportion of subjects whose best overall response is Complete Response (CR) or Partial Response (PR) among all analyzed subjects.

Measure: Best overall response rate

Time: Up to 18 months

Description: Defined as the proportion of subjects whose best overall response is rated as CR, PR or Stable Disease (SD) among all analyzed subjects.

Measure: Disease control rate

Time: Up to 18 months

Description: Defined as the time from the start of the study treatment until death from any cause or radiographic disease progression assessed according to RECIST 1.1, whichever occurs first.

Measure: Progression free survival

Time: Up to 18 months

210 Detecting EGFR T790M Mutations From Circulating Tumor Cells

The purpose of this research study is to determine if the EGFR mutation can be detected in CTCs. CTCs are cancer cells that are shed from solid tumors and float freely in the bloodstream. A device called the CTC-chip has been developed to find CTCs in the blood of patients with cancer. This is an experimental device. Using this device, the investigators will test participants' blood to try and find CTCs with the EGFR mutation and compare them with the results from the biopsy your doctor has recommended. The long-term goal of this research is to develop a way to test for the EGFR mutation that is less invasive than a tumor biopsy.

NCT01734915
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Device: Circulating tumor cell chip
MeSH:Neoplastic Cells, Circulating

Detecting EGFR T790M Mutations From Circulating Tumor Cells. --- T790M ---

Detecting EGFR T790M Mutations From Circulating Tumor Cells The purpose of this research study is to determine if the EGFR mutation can be detected in CTCs. --- T790M ---

Primary Outcomes

Description: Calculate the number of patients in the study population with detectable EGFR mutations in the CTCs in order to demonstrate the feasibility of testing for EGFR mutations from captured CTCs

Measure: Number of patients with detectable EGFR mutations in their CTCs

Time: 2 years

Description: Determine the concordance of EGFR genotyping from CTCs compared to tumor tissue

Measure: Number of patients with CTC-derived EGFR genotyping matching their tumor-derived EGFR genotyping

Time: 2 yearss

Secondary Outcomes

Description: Explore the feasibility of EGFR genotyping from plasma circulating free DNA (cfDNA)

Measure: Number of patients with EGFR gentoype results detectable from plasma cfDNA

Time: 2 years

211 A Phase Ib/II Multicenter, Randomized, Open Label Trial to Compare Tepotinib (MSC2156119J) Combined With Gefitinib Versus Chemotherapy as Second-Line Treatment in Subjects With MET Positive, Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) Harboring EGFR Mutation and Having Acquired Resistance to Prior EGFR-Tyrosine Kinase Inhibitor (EGFR-TKI) Therapy

This is a multi-center, open-label, randomized, Phase 1b/2 study to determine the recommended phase 2 dose (RP2D) and to evaluate the efficacy in terms of progression free survival (PFS) of Tepotinib when used in combination with gefitinib in partcipants with T790M negative, MET positive locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation and having acquired resistance to Prior EGFR-Tyrosine Kinase Inhibitor (EGFR-TKI) Therapy. This study has 2:1 randomization (Tepotinib/Gefitinib arm versus Chemotherapy arm).

NCT01982955
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: Tepotinib
  2. Drug: Gefitinib
  3. Drug: Pemetrexed
  4. Drug: Cisplatin
  5. Drug: Carboplatin
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Tepotinib With Gefitinib in Participants With Locally Advanced or Metastatic Non-small Cell Lung Cancer (NSCLC) This is a multi-center, open-label, randomized, Phase 1b/2 study to determine the recommended phase 2 dose (RP2D) and to evaluate the efficacy in terms of progression free survival (PFS) of Tepotinib when used in combination with gefitinib in partcipants with T790M negative, MET positive locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation and having acquired resistance to Prior EGFR-Tyrosine Kinase Inhibitor (EGFR-TKI) Therapy. --- T790M ---

Phase II Inclusion criteria: - Locally advanced or metastatic NSCLC other than predominantly squamous histology (confirmed by either histology or cytology); - Activating mutation of the epidermal growth factor (EGFR) receptor (documented, or as determined by the central laboratory) - Acquired resistance on first-line EGFR-Tyrosine Kinase Inhibitors (EGFR-TKI) therapy including gefitinib, erlotinib, icotinib, or afatinib - EGFR T790M status after acquired resistance to first line EGFR-TKI therapy including gefitinib, erlotinib, icotinib, or afatinib treatment (as determined by the central laboratory, using a validated PCR test); - T790M negative status for the randomized part - T790M positive status for the single-arm cohort (mainland China sites only) - Availability of a fresh or archived tumor tissue (excluding fine needle aspiration and cytology samples) obtained between documentation of acquired resistance to gefitinib, erlotinib, icotinib, or afatinib and enrollment is mandatory - MET+ status, as determined by the central laboratory i.e. c-Met overexpression as determined by IHC (i.e., IHC 2+ or IHC 3+) and/or c-Met amplification and/or increased c-Met gene copy number (GCN), both determined by ISH; - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 - Other protocol defined inclusion criteria could apply Exclusion Criteria (Phase I and II): - Estimated life expectancy less than (<) 3 months - Inadequate bone marrow, liver or renal functions - Prior chemotherapy, biological therapy, radiation therapy, or other investigational anticancer therapy (not including palliative radiotherapy at focal sites) within 21 days prior to the first dose of study treatment (Phase 1b only) - Prior systemic anticancer treatment with chemotherapy or other agents targeting the EGFR pathway excluding gefitinib, erlotinib, icotinib, and afatinib for advanced NSCLC (one course of chemotherapy regimen for [neo] adjuvant purpose, or one course of chemoradiation for Stage IIIa disease is allowed) (Phase 2 only) - Other protocol defined exclusion criteria could apply. --- T790M ---

Phase II Inclusion criteria: - Locally advanced or metastatic NSCLC other than predominantly squamous histology (confirmed by either histology or cytology); - Activating mutation of the epidermal growth factor (EGFR) receptor (documented, or as determined by the central laboratory) - Acquired resistance on first-line EGFR-Tyrosine Kinase Inhibitors (EGFR-TKI) therapy including gefitinib, erlotinib, icotinib, or afatinib - EGFR T790M status after acquired resistance to first line EGFR-TKI therapy including gefitinib, erlotinib, icotinib, or afatinib treatment (as determined by the central laboratory, using a validated PCR test); - T790M negative status for the randomized part - T790M positive status for the single-arm cohort (mainland China sites only) - Availability of a fresh or archived tumor tissue (excluding fine needle aspiration and cytology samples) obtained between documentation of acquired resistance to gefitinib, erlotinib, icotinib, or afatinib and enrollment is mandatory - MET+ status, as determined by the central laboratory i.e. c-Met overexpression as determined by IHC (i.e., IHC 2+ or IHC 3+) and/or c-Met amplification and/or increased c-Met gene copy number (GCN), both determined by ISH; - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 - Other protocol defined inclusion criteria could apply Exclusion Criteria (Phase I and II): - Estimated life expectancy less than (<) 3 months - Inadequate bone marrow, liver or renal functions - Prior chemotherapy, biological therapy, radiation therapy, or other investigational anticancer therapy (not including palliative radiotherapy at focal sites) within 21 days prior to the first dose of study treatment (Phase 1b only) - Prior systemic anticancer treatment with chemotherapy or other agents targeting the EGFR pathway excluding gefitinib, erlotinib, icotinib, and afatinib for advanced NSCLC (one course of chemotherapy regimen for [neo] adjuvant purpose, or one course of chemoradiation for Stage IIIa disease is allowed) (Phase 2 only) - Other protocol defined exclusion criteria could apply. --- T790M --- --- T790M ---

Phase II Inclusion criteria: - Locally advanced or metastatic NSCLC other than predominantly squamous histology (confirmed by either histology or cytology); - Activating mutation of the epidermal growth factor (EGFR) receptor (documented, or as determined by the central laboratory) - Acquired resistance on first-line EGFR-Tyrosine Kinase Inhibitors (EGFR-TKI) therapy including gefitinib, erlotinib, icotinib, or afatinib - EGFR T790M status after acquired resistance to first line EGFR-TKI therapy including gefitinib, erlotinib, icotinib, or afatinib treatment (as determined by the central laboratory, using a validated PCR test); - T790M negative status for the randomized part - T790M positive status for the single-arm cohort (mainland China sites only) - Availability of a fresh or archived tumor tissue (excluding fine needle aspiration and cytology samples) obtained between documentation of acquired resistance to gefitinib, erlotinib, icotinib, or afatinib and enrollment is mandatory - MET+ status, as determined by the central laboratory i.e. c-Met overexpression as determined by IHC (i.e., IHC 2+ or IHC 3+) and/or c-Met amplification and/or increased c-Met gene copy number (GCN), both determined by ISH; - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 - Other protocol defined inclusion criteria could apply Exclusion Criteria (Phase I and II): - Estimated life expectancy less than (<) 3 months - Inadequate bone marrow, liver or renal functions - Prior chemotherapy, biological therapy, radiation therapy, or other investigational anticancer therapy (not including palliative radiotherapy at focal sites) within 21 days prior to the first dose of study treatment (Phase 1b only) - Prior systemic anticancer treatment with chemotherapy or other agents targeting the EGFR pathway excluding gefitinib, erlotinib, icotinib, and afatinib for advanced NSCLC (one course of chemotherapy regimen for [neo] adjuvant purpose, or one course of chemoradiation for Stage IIIa disease is allowed) (Phase 2 only) - Other protocol defined exclusion criteria could apply. --- T790M --- --- T790M --- --- T790M ---

Primary Outcomes

Description: Dose limiting toxicity (DLT) using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.0 was defined as toxicities at any dose level and judged to be related to the study treatment by investigator and/or the sponsor. DLTs included Grade 4 neutropenia for more than 7 days; Grade greater than or equal to (>=) 3 febrile neutropenia for more than 1 day; Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with non-traumatic bleeding; Grade >= 3 uncontrolled nausea/vomiting and/or diarrhea despite adequate and optimal treatment and Grade >= 3 any non-hematological adverse event (AE), except the aforementioned gastrointestinal events and alopecia. Number of participants who experienced DLT during Phase 1b were reported.

Measure: Phase 1b: Number of Participants Experiencing at Least One Dose Limiting Toxicity (DLT)

Time: Day 1 to Day 21 of Cycle 1 (each cycle is 21 days)

Description: An AE was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A serious AE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. The term TEAE is defined as AEs starting or worsening after the first intake of the study drug. TEAEs include both Serious TEAEs and non-serious TEAEs. Number of Participants with TEAEs and serious TEAEs were reported.

Measure: Phase 1b: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs

Time: Up to 259 Weeks

Description: Progression-free survival (assessed by the Investigator) time was defined as the time in months from randomization to either first observation of radiologically confirmed progression disease (PD) by the investigator or occurrence of death due to any cause within 84 days of either randomization or the last tumor assessment. PD is defined as at least a 20 percent (%) increase in the sum of diameters of target lesions, taking as reference the smallest sum on study; and/or unequivocal progression of existing non-target lesions and/or the presence of new lesions. The sum must also demonstrate an absolute increase of at least 5 millimeter (mm). PFS was measured using Kaplan-Meier (KM) estimates.

Measure: Phase 2 (Randomized Part Only): Progression-free Survival (PFS) Based on Tumor Assessment by the Investigator

Time: Up to 187 weeks

Secondary Outcomes

Description: Area under the plasma concentration versus time curve from time zero to the last sampling time t at which the concentration is at or above the lower limit of quantification (LLLQ). AUC(0-t) was calculated according to the mixed log-linear trapezoidal rule.

Measure: Phase 1b: Area Under the Plasma Concentration Versus Time Curve From Time Zero to the Last Sampling Time AUC (0-t) of Tepotinib, Its Metabolites and Gefitinib

Time: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1 (each Cycle is 21 days)

Description: AUC (0-tau) is the area under the plasma concentration time curve within 1 dosing interval.

Measure: Phase 1b: Area Under the Plasma Concentration-Time Curve Within 1 Dosing Interval (AUC 0-tau) of Tepotinib, Its Metabolites and Gefitinib

Time: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1 (each Cycle is 21 days)

Description: Cmax is the maximum observed plasma concentration obtained directly from the concentration versus time curve.

Measure: Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib, Its Metabolites and Gefitinib

Time: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1 (each Cycle is 21 days)

Description: Cavg is the average plasma concentration within 1 dosing interval obtained directly from the concentration versus time curve.

Measure: Phase 1b: Average Observed Plasma Concentration (Cavg) of Tepotinib, Its Metabolites and Gefitinib

Time: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 15 of Cycle 1 (each Cycle is 21 days)

Description: Cmin is minimum observed plasma concentration obtained directly from the concentration versus time curve.

Measure: Phase 1b: Minimum Observed Plasma Concentration (Cmin) of Tepotinib, Its Metabolites and Gefitinib

Time: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 15 of Cycle 1 (each Cycle is 21 days)

Description: Tmax is time to reach maximum observed plasma concentration obtained directly from the concentration versus time curve.

Measure: Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib, Its Metabolites and Gefitinib

Time: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1 (each Cycle is 21 days)

Description: The AUC(0-inf) was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity.

Measure: Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC 0-infinity) of Tepotinib, Its Metabolites and Gefitinib

Time: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1 (each Cycle is 21 days)

Description: The CL/f is a measure of the rate at which it was metabolized or eliminated by normal biological processes. Clearance obtained after oral dose was influenced by the fraction of the dose absorbed. The CL/F from plasma was calculated using the formula: Dose divided by area under the concentration time curve from time zero to infinity (AUC0-inf).

Measure: Phase 1b: Apparent Total Body Clearance From Plasma (CL/F) of Tepotinib and Gefitinib

Time: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 15 of Cycle 1 (each Cycle is 21 days)

Description: The Vz/f was defined as the theoretical volume in which the total amount of required to uniformly distribute to produce the desired plasma concentration. Apparent volume of distribution after oral dose (Vz/F) was influenced by the fraction absorbed. The Vz/f was calculated by dividing the dose with area under the concentration time curve from time zero to infinity multiplied with terminal elimination rate constant Lambda(z). Vz/f=Dose/AUC(0-inf) multiply Lambda(z).

Measure: Phase 1b: Apparent Volume of Distribution (Vz/F) During the Terminal Phase of Tepotinib, Its Metabolites and Gefitinib

Time: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1 (each Cycle is 21 days)

Description: Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss/f after oral dose was influenced by the fraction absorbed.

Measure: Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/F) of Tepotinib, Its Metabolites and Gefitinib

Time: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1 (each Cycle is 21 days)

Description: Lambda(z) was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.

Measure: Phase 1b: Apparent Terminal Elimination Rate Constant Lambda(z) of Tepotinib, Its Metabolites and Gefitinib

Time: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1 (each Cycle is 21 days)

Description: Apparent terminal half-life was defined as the time required for the plasma concentration of drug to decrease 50 percent in the final stage of its elimination.

Measure: Phase 1b: Apparent Terminal Half-Life (t1/2) of Tepotinib, Its Metabolites and Gefitinib

Time: Pre dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours post dose on Day 1 and 15 of Cycle 1 (each Cycle is 21 days)

Description: Objective response (OR) was defined as the percentage of participants who had achieved complete response (CR) or partial response (PR) as the best overall response according to local radiological assessments from randomization/the first administration of the study treatment to the first observation of disease progression (PD). CR: defined as disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR: defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. PD defined as an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started and/or unequivocal progression of existing non-target lesions and/or the presence of new lesions. The sum must also demonstrate an absolute increase of at least 5 mm.

Measure: Phase 1b: Percentage of Participants With Objective Response Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria

Time: Up to 259 weeks

Description: Disease control defined as CR, PR, or stable disease(SD) as the best overall response according to local radiological assessments from the date of randomization/the first administration of the study treatment to the first observation of PD. CR:disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR:at least 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. PD:an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started and/or unequivocal progression of existing non-target lesions and/or the presence of new lesions. The sum must also demonstrate an absolute increase of at least 5mm. SD:as any cases that do not qualify for either PR or PD at minimum interval of 42 days after randomization/start of study treatment

Measure: Phase 1b: Percentage of Participants With Disease Control Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria

Time: Up to 259 weeks

Description: An adverse event (AE) was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A serious AE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Term TEAE was defined as AEs starting/worsening after first intake of the study drug. TEAEs included both Serious TEAEs and non-serious TEAEs. Treatment-related AE was defined as having a "Possible" or "Related" relationship to study treatment, as assessed by the Investigator.

Measure: Phase 1b: Number of Participants With Treatment-Related Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Serious TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03

Time: Up to 259 weeks

Description: An adverse event (AE) was defined as any untoward medical occurrence in participant which does not necessarily have casual relationship with treatment was any unfavorable and unintended sign(including abnormal laboratory finding), symptom/disease temporally associated with use of medicinal product, whether/not considered related to medicinal product. Term TEAE was defined as AEs starting/worsening after first intake of the study drug. TEAEs included both Serious TEAEs and non-serious TEAEs. Treatment-related TEAE was defined as having a "Possible" or "Related" relationship to study treatment, as assessed by the Investigator. As per NCI-CTCAE, Grade 3 is Severe, Grade 4 is Life-threatening and Grade 5 or Death. Number of participants with Grade 3/4 TEAEs and Grade 3/4 treatment-related TEAEs were reported.

Measure: Phase 1b: Number of Participants With Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) and Grade 3/4 Treatment-Related TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) Version 4.03

Time: Up to 259 weeks

Description: An adverse event (AE) was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A serious AE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Term TEAE is defined as AEs starting/worsening after first intake of the study drug. TEAEs included both Serious TEAEs and non-serious TEAEs. Number of participants with TEAEs leading to permanent treatment discontinuation were reported.

Measure: Phase 1b: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Leading to Permanent Treatment Discontinuation

Time: Up to 259 weeks

Description: Number of participants with death due to progressive disease (PD), adverse event (AE) related to study treatment, AE not related to study treatment were reported. An AE was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. PD defined as an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started and/or unequivocal progression of existing non-target lesions and/or the presence of new lesions. The sum must also demonstrate an absolute increase of at least 5 mm. Number of participants with deaths due to PD, AE related to study treatment, AE not related to study treatment were reported.

Measure: Phase 1b: Number of Participants With Death and Reasons

Time: Up to 259 weeks

Description: The laboratory measurements included hematology and coagulation, biochemistry and urinalysis.

Measure: Phase 1b: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs)

Time: Up to 259 weeks

Description: Vital signs assessment included blood pressure, heart rate, respiratory rate and body temperature. Number of Participants with any clinically significant abnormalities in vital signs were reported. Clinical significance was determined by the investigator.

Measure: Phase 1b: Number of Participants With Clinically Significant Abnormalities in Vital Signs

Time: Up to 259 weeks

Description: ECG parameters included heart rhythm, pulse rate intervals, QRS, QT intervals, RR intervals and corrected QT(QTc) intervals. Clinical significance was determined by the investigator. Number of participants with clinically significant abnormalities in 12-lead ECG were reported.

Measure: Phase 1b: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiograms (ECG) Findings

Time: Up to 259 weeks

Description: ECOG PS score is widely used by doctors and researchers to assess how a participants' disease is progressing, and is used to assess how the disease affects the daily living abilities of the participant, and determine appropriate treatment and prognosis. The score ranges from Grade 0 to Grade 5, where Grade 0 = Fully active, able to carry on all pre-disease performance without restriction, Grade 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (like light house work, office work), Grade 2 = Ambulatory and capable of all self-care but unable to carry out any work activities, Grade 3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours and Grade 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair, Grade 5 = Death. Number of participants with ECOG performance status score of 2 or higher than 2 were reported.

Measure: Phase 1b: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 2 or Higher Than 2

Time: Up to 259 weeks

Description: An AE was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A serious AE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs was defined as AEs that started or worsened in severity within the first dosing day of study treatment after the last dose of study treatment. TEAEs include both Serious TEAEs and non-serious TEAEs Treatment related AE was defined as having a "Possible" or "Related" relationship to study treatment, as assessed by the Investigator.

Measure: Phase 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Treatment-Related TEAEs and Treatment-Related Serious TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03

Time: Up to 187 weeks

Description: An adverse event (AE) was defined as any untoward medical occurrence in participant which does not necessarily have casual relationship with treatment was any unfavorable and unintended sign(including abnormal laboratory finding), symptom/disease temporally associated with use of medicinal product, whether/not considered related to medicinal product. Term TEAE is defined as AEs starting/worsening after first intake of the study drug. TEAEs included both Serious TEAEs and non-serious TEAEs. Treatment-related AE was defined as having a "Possible" or "Related" relationship to study treatment, as assessed by the Investigator. As per NCI-CTCAE, Grade 3 is Severe, Grade 4 is Life-threatening and Grade 5 or Death. Number of Participants With >= Grade 3 TEAEs and >= Grade 3 treatment-related TEAEs were reported.

Measure: Phase 2: Number of Participants With Greater Than or Equal to (>=) Grade 3 Treatment-Emergent Adverse Events (TEAEs) and >= Grade 3 Treatment-Related TEAEs According to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4.03

Time: Up to 187 weeks

Description: An adverse event (AE) was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. A serious AE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. Term TEAE is defined as AEs starting/worsening after first intake of the study drug. TEAEs included both Serious TEAEs and non-serious TEAEs. Number of participants with TEAEs leading to permanent treatment discontinuation were reported.

Measure: Phase 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Leading to Permanent Treatment Discontinuation

Time: Up to 187 weeks

Description: Number of participants with death due to progressive disease (PD), adverse event (AE) related to study treatment, AE not related to study treatment were reported. An AE was defined as any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. PD defined as an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started and/or unequivocal progression of existing non-target lesions and/or the presence of new lesions. The sum must also demonstrate an absolute increase of at least 5 mm. Number of participants with deaths due to PD, AE related to study treatment, AE not related to study treatment were reported.

Measure: Phase 2: Number of Participants With Death and Reasons

Time: Up to 187 weeks

Description: The laboratory measurements included hematology and coagulation, biochemistry and urinalysis.

Measure: Phase 2: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI-CTCAE Version 4.03 Reported as Treatment-Emergent Adverse Events (TEAEs)

Time: Up to 187 weeks

Description: Vital signs assessment included blood pressure, heart rate, respiratory rate and body temperature. Number of Participants with any clinically significant abnormalities in vital signs were reported. Clinical significance was determined by the investigator.

Measure: Phase 2: Number of Participants With Clinically Significant Abnormalities in Vital Signs

Time: Up to 187 weeks

Description: ECG parameters included heart rhythm, pulse rate intervals, QRS, QT intervals, RR intervals and corrected QT(QTc) intervals. Clinical significance was determined by the investigator. Number of participants with clinically significant abnormalities in 12-lead ECG were reported.

Measure: Phase 2: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiograms (ECG) Findings

Time: Up to 187 weeks

Description: ECOG PS score is widely used by doctors and researchers to assess how a participants' disease is progressing, and is used to assess how the disease affects the daily living abilities of the participant, and determine appropriate treatment and prognosis. The score ranges from Grade 0 to Grade 5, where Grade 0 = Fully active, able to carry on all pre-disease performance without restriction, Grade 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (like light house work, office work), Grade 2 = Ambulatory and capable of all self-care but unable to carry out any work activities, Grade 3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours and Grade 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair, Grade 5 = Death. Number of participants with ECOG performance status score of 2 or higher than 2 were reported.

Measure: Phase 2: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 2 or Higher Than 2

Time: Up to 187 weeks

Description: Progression-free survival (assessed by Independent Review Committee) time was defined as the time in months from randomization to either first observation of radiologically confirmed progression disease (PD) by the IRC or occurrence of death due to any cause within 84 days of either randomization or the last tumor assessment. PD is defined as at least a 20 percent (%) increase in the sum of diameters of target lesions, taking as reference the smallest sum on study; and/or unequivocal progression of existing non-target lesions and/or the presence of new lesions. The sum must also demonstrate an absolute increase of at least 5 mm. PFS was measured using Kaplan-Meier (KM) estimates.

Measure: Phase 2 (Randomized Part Only): Progression-free Survival (PFS) Based on Tumor Assessment by Independent Review Committee (IRC)

Time: Up to 187 weeks

Description: Overall survival time was measured as time in months between the date of randomization and the date of death.

Measure: Phase 2: (Randomized Part Only): Overall Survival (OS) Time

Time: Up to 187 weeks

Description: Objective response (OR) was defined as the percentage of participants who had achieved complete response (CR) or partial response (PR) as the best overall response according to local radiological assessments from randomization/the first administration of the study treatment to the first observation of disease progression (PD). CR: defined as disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR: defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. PD defined as an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started and/or unequivocal progression of existing non-target lesions and/or the presence of new lesions. The sum must also demonstrate an absolute increase of at least 5 mm.

Measure: Phase 2 (Randomized Part Only): Percentage of Participants With Objective Response Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria

Time: Up to 187 weeks

Description: Disease control defined as CR, PR, or stable disease(SD) as the best overall response according to local radiological assessments from the date of randomization/the first administration of the study treatment to the first observation of PD. CR:disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR:at least 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. PD:an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started and/or unequivocal progression of existing non-target lesions and/or the presence of new lesions. The sum must also demonstrate an absolute increase of at least 5mm. SD:as any cases that do not qualify for either PR/PD at minimum interval of 42 days after randomization/start of study treatment.

Measure: Phase 2 (Randomized Part Only): Percentage of Participants With Disease Control Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria

Time: Up to 187 weeks

Description: Progression-free survival (assessed by Investigator) time was defined as the time in months from randomization to either first observation of radiologically confirmed progression disease by the Investigator or occurrence of death due to any cause within 84 days of either randomization or the last tumor assessment. PD is defined as at least a 20 percent (%) increase in the sum of diameters of target lesions, taking as reference the smallest sum on study; and/or unequivocal progression of existing non-target lesions and/or the presence of new lesions. The sum must also demonstrate an absolute increase of at least 5 mm. PFS was measured using Kaplan-Meier (KM) estimates.

Measure: Phase 2 (Non-Randomized Part Only): Progression-free Survival (PFS) Based on Tumor Assessment by Investigator

Time: Up to 117 weeks

Description: Progression-free survival (assessed by Independent Review Committee) time was defined as the time in months from randomization to either first observation of radiologically confirmed progression disease by the IRC or occurrence of death due to any cause within 84 days of either randomization or the last tumor assessment. PD is defined as at least a 20 percent (%) increase in the sum of diameters of target lesions, taking as reference the smallest sum on study; and/or unequivocal progression of existing non-target lesions and/or the presence of new lesions. The sum must also demonstrate an absolute increase of at least 5 mm. PFS was measured using Kaplan-Meier (KM) estimates.

Measure: Phase 2 (Non-Randomized Part Only): Progression-free Survival (PFS) Based on Tumor Assessment by Independent Review Committee (IRC)

Time: Up to 117 weeks

Description: Overall survival time was measured as time in months between the date of randomization and the date of death.

Measure: Phase 2: (Non-Randomized Part Only): Overall Survival (OS) Time

Time: Up to 117 weeks

Description: Objective response (OR) was defined as the percentage of participants who had achieved complete response (CR) or partial response (PR) as the best overall response according to local radiological assessments from randomization/the first administration of the study treatment to the first observation of disease progression (PD). CR: defined as disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR: defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. PD defined as an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started and/or unequivocal progression of existing non-target lesions and/or the presence of new lesions. The sum must also demonstrate an absolute increase of at least 5 mm.

Measure: Phase 2 (Non-Randomized Part Only): Percentage of Participants With Objective Response Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria

Time: Up to 117 weeks

Description: Disease control defined as CR, PR, or stable disease(SD) as the best overall response according to local radiological assessments from the date of randomization/the first administration of the study treatment to the first observation of PD. CR:disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR:at least 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. PD:an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started and/or unequivocal progression of existing non-target lesions and/or the presence of new lesions. The sum must also demonstrate an absolute increase of at least 5mm. SD:as any cases that do not qualify for either PR/PD at minimum interval of 42 days after randomization/start of study treatment.

Measure: Phase 2 (Non-Randomized Part Only): Percentage of Participants With Disease Control Based on Tumor Response Assessment According to Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) Criteria

Time: Up to 117 weeks

Description: EORTC QLQ-C30 is a 30-question tool used to assess the overall quality of life (QoL) in cancer participants. It consisted of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, role, cognitive, emotional, social), and 9 symptom scales/items (Fatigue, nausea and vomiting, pain, dyspnoea, sleep disturbance, appetite loss, constipation, diarrhea, financial impact. The EORTC QLQ-C30 GHS/QoL score ranges from 0 to 100; High score indicates better GHS/QoL. Score 0 represents: very poor physical condition and QoL. Score 100 represents: excellent overall physical condition and QoL.

Measure: Phase 2: Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life (EORTC QLQ-C30) Global Health Status Scale Score at End of Treatment (EOT)

Time: Baseline and EOT (up to 110 weeks)

Description: TTSP was measured from randomization to symptomatic progression by lung cancer symptom scale (LCSS) used to measure symptom changes relevant to quality of life (QoL).It consisted of 9 items focused on cancer symptoms (loss of appetite, fatigue, cough, shortness of breath, blood in sputum, pain, symptoms of cancer, illness affecting normal activity, QoL).For each symptom score distance from left boundary to point where participant has marked line was measured in millimeters (mm).Total scale length was 100 mm. Symptomatic progression was defined as increase/worsening of average symptomatic burden index (ASBI) (mean of 6 major lung cancer specific symptom scores);Worsening defined as 10% increase of scale breadth from baseline. Score 0 indicate no/minimum symptoms;100 indicates maximum level of symptoms.

Measure: Phase 2: Time-to-Symptom Progression (TTSP)

Time: Up to 110 weeks

212 A Dose Finding Study of Continuous and Intermittent High-dose (HDI) Afatinib (EGFR TKI) on CNS Metastases and Leptomeningeal Disease (LMD) in Patients With Advanced Refractory EGFR Mutation Positive Non-small Cell Lung Cancer

Brain metastases occurs in up to 50% of patients with EGFR mutant NSCLC. Leptomeningeal disease is a subset of patients with brain metastases for which there remains an unmet need. This trial aims to evaluate the role of two dosing schedules of afatinib in management of leptomeningeal disease in EGFR mutant NSCLC, specifically to determine Central Nervous System (CNS) penetration of afatinib, as well as clinical activity. Patients will start on daily dosing initially followed by pulsed intermittent dosing should we observe no clinical activity. A secondary objective is to identify the resistance spectrum in leptomeningeal disease. It is anticipated that optimal dosing schedule of afatinib e.g. pulsed dosing may improve CNS disease control.

NCT03711422
Conditions
  1. Non-small Cell Lung Cancer
  2. Leptomeningeal Disease
  3. Central Nervous System Metastases
Interventions
  1. Drug: Afatinib
  2. Drug: Afatinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung Neoplasm Metastasis Meningeal Neoplasms
HPO:Neoplasm of the lung Non-small cell lung carcinoma

To detect EGFR T790M and activating mutation status. --- T790M ---

Primary Outcomes

Description: To assess the difference in drug ratio from two difference dosing of afatinib

Measure: Afatinib concentration in plasma using standard dosing and high intermittent dosing

Time: Day 1 to Day 29 of drug treatment

Description: To assess the difference in drug ratio from two difference dosing of afatinib

Measure: Afatinib concentration in Cerebral Spinal Fluid (CSF) using standard dosing and high intermittent dosing

Time: Part A: Day 15; Part B: Day 17 and 31

Measure: Neurological Progression Free Survival

Time: From time of first study drug administration until first occurrence of disease progression, or death from any cause, up to 2 years

Measure: Neurological Response Rate

Time: From time of first study drug administration until first occurrence of disease progression, up to 2 years

Measure: Overall Survival

Time: From time of first study drug administration to death from any cause, up to 2 years

Secondary Outcomes

Description: To detect EGFR T790M and activating mutation status

Measure: Cell-free DNA sequencing of Cerebrospinal Fluid

Time: From time of first study drug administration to end of study treatment, up to 2 years

Description: To assess the physical, physiological and social functions. The scale ranges from 1="not all all" to 4-"very much"

Measure: European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30

Time: From time of first study drug administration through to end of study treatment or disease progression, up to 2 years

Description: To assess future uncertainty, visual disorder, motor dysfunction, and communication deficit. The scale ranges from 1="not all all" to 4-"very much"

Measure: EORTC Quality of Life Questionnaire Brain Cancer Module

Time: From time of first study drug administration through to end of study treatment or disease progression, up to 2 years

Description: AEs will be graded according to CTCAE, Version 4.0

Measure: Incidences of treatment-emergent adverse events (AE)

Time: From time of first study drug administration to 28 days after last treatment administration

213 A Phase 2 Study of Poziotinib in Patients With EGFR or HER2 Activating Mutations in Advanced Malignancies

This is a Phase 2, open-label, multicenter study to evaluate the efficacy and the safety/tolerability of poziotinib in five patient cohorts for up to 150 previously treated patients with any systemic therapy (Cohort 1: 30 Patients that have HER2-positive or HER2-negative breast cancer with HER2 activating mutations, Cohort 2: 30 Patients that have colorectal cancer with HER2 activating mutations, Cohort 3: Patients that have solid tumors (except NSCLC, breast cancer, or colorectal cancer) with HER2 activating mutations, Cohort 4: 30 Patients that have high-grade glioma with EGFR activating mutations, and Cohort 5: 30 Patients that have solid tumors (except NSCLC or high-grade glioma) with EGFR activating mutations.

NCT04172597
Conditions
  1. Breast Cancer
  2. Colorectal Cancer
  3. Solid Tumor
  4. High Grade Glioma
Interventions
  1. Drug: Poziotinib Hydrochloride
MeSH:Breast Neoplasms
HPO:Breast carcinoma Neoplasm of the breast

7. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 8. Patient has recovered from prior systemic therapy for metastatic disease to Grade ≤1 for non-hematologic toxicities (except for Grade ≤2 peripheral neuropathy) and has adequate hematologic, hepatic, and renal function at Baseline, as defined by: - Absolute neutrophil count (ANC) must be ≥1.0×109/L - Platelet count ≥ 75 × 109/L - Hemoglobin ≥ 9.0 g/dL - Aspartate aminotransferase/serum glutamic-oxaloacetic transaminase (AST/SGOT), alanine aminotransferase/serum glutamic-pyruvic transaminase (ALT/SGPT) ≤2.5 ×upper limit of normal (ULN); if hepatic metastases are present, ≤5.0×ULN - Creatinine clearance ≥ 50 mL/min (calculated according to Cockcroft and Gault formula) Exclusion Criteria: 1. Patient has primary tumors in central nervous system (CNS) or in brain, including glioblastoma multiforme (GBM), meningeal carcinomatosis, leptomeningeal carcinomatosis, spinal cord compression, or unstable brain metastasis except if qualified under inclusion criteria for Cohort 4. 2. Patient with T798M or T798I mutations in HER2, or patients with the T790M mutation in EGFR. --- T798M --- --- T798I --- --- T790M ---

Primary Outcomes

Description: Proportion of patients whose best overall response is confirmed CR or PR

Measure: Objective Response Rate (ORR)

Time: 24 months

Secondary Outcomes

Description: Time from the first CR or PR until progressive disease or death

Measure: Duration of Response (DoR)

Time: 24 months

Description: Proportion of patients whose best overall response is CR, PR, or SD

Measure: Disease Control Rate (DCR)

Time: 24 months

214 UpSwinG: Real World Study on TKI Activity in Uncommon Mutations and Sequencing Giotrif®

Non-interventional, multi-country, multi-centre cohort study based on existing data from medical records (paper or electronic) or electronic health records of patients with advanced NSCLC harbouring EGFR mutations and treated with an EGFR-TKI

NCT04179890
Conditions
  1. Non-squamous, Non-Small Cell Lung Cancer
Interventions
  1. Drug: Epidermal Growth Factor Tyrosine Kinase Inhibitor
  2. Drug: Afatinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Sequencing cohort: 5. Patients with common EGFR mutations (Del19, L858R) 6. Patients were treated with afatinib (Gi(l)otrif®) in the first-line setting and for acquired T790M mutation with osimertinib in the second line; 7. Patients must have started osimertinib treatment at least 10 months prior to data entry. --- L858R --- --- T790M ---

For uncommon mutation cohort: Patients treated with osimertinib with no further uncommon mutation than acquired T790M Further exclusion criteria apply Inclusion Criteria: 1. Adult patients 2. Diagnosed with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFRTKI) naïve advanced EGFR mutated non-small cell lung cancer (NSCLC), 3. treated for Epidermal Growth Factor Receptor (EGFR) mutated NSCLC within regular clinical practice. --- T790M ---

For uncommon mutation cohort: Patients treated with osimertinib with no further uncommon mutation than acquired T790M Further exclusion criteria apply Non-squamous, Non-Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- T790M ---

Primary Outcomes

Description: assessed as the time from start of EGFR-TKI treatment until the end of treatment or death date by any cause.

Measure: Time on treatment with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor

Time: Up to 30 months

Secondary Outcomes

Measure: Rate of overall response

Time: Up to 30 months

Measure: Rate of overall survival

Time: Up to 30 months

Description: uncommon mutation cohort only

Measure: Time on treatment until failure of second-line (TTF2)

Time: Up to 30 months

215 Real World Treatment Patterns, Clinical Outcomes and EGFR / T790M Testing Practices in EGFR-Mutated Advanced Non-Small Cell Lung Cancer Patients Receiving First-Line TKI Therapy

Multinational, multi-center medical record review to describe the treatment patterns, clinical outcomes, and EGFR / T790M testing practices in EGFR-mutated advanced NSCLC patients receiving first-line EGFR TKI therapy in Europe.

NCT04031898
Conditions
  1. Lung Cancer
Interventions
  1. Other: Non Interventional
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

Real World Treatment Patterns, Clinical Outcomes and EGFR / T790M Testing Practices in EGFR-Mutated Advanced Non-Small Cell Lung Cancer Patients Receiving First-Line TKI Therapy. --- T790M ---

Treatment Patterns, Outcomes and Testing in EGFRm NSCLC Patients With EGFR TKI 1L Across Europe (REFLECT) Multinational, multi-center medical record review to describe the treatment patterns, clinical outcomes, and EGFR / T790M testing practices in EGFR-mutated advanced NSCLC patients receiving first-line EGFR TKI therapy in Europe. --- T790M ---

Proportion of patients prescribed other systemic treatments (chemotherapy, osimertinib, other EGFR TKI, I/O therapy, or other therapy) in combination with first-line EGFR TKI therapy.. Proportion of patients tested for T790M mutation and the proportion of patients with positive mutation among patients progressing on first-line EGFR TKI therapy. --- T790M ---

Proportion of patients tested for T790M mutation and among those tested, the proportion who were positive for the mutation, including: Binary distribution of T790M mutation testing and, among those tested, the proportion with a positive result, Type of test used to assess the T790M mutation (tissue/cytology or blood sample). --- T790M ---

Proportion of patients tested for T790M mutation and among those tested, the proportion who were positive for the mutation, including: Binary distribution of T790M mutation testing and, among those tested, the proportion with a positive result, Type of test used to assess the T790M mutation (tissue/cytology or blood sample). --- T790M --- --- T790M ---

Proportion of patients tested for T790M mutation and among those tested, the proportion who were positive for the mutation, including: Binary distribution of T790M mutation testing and, among those tested, the proportion with a positive result, Type of test used to assess the T790M mutation (tissue/cytology or blood sample). --- T790M --- --- T790M --- --- T790M ---

Among patients tested and positive for T790M mutation, what proportion receives treatment with osimertinib - applicable study measures include binary distribution of osimertinib treatment initiation, and requency distribution of the line of therapy (second- or later-line in the metastatic setting) in which osimertinib was initiated.. Proportion of patients receiving second-line therapy and type of second line therapy received among patients progressing on first-line EGFR TKI therapy and tested for T790M mutation. --- T790M ---

Among patients tested and positive for T790M mutation, what proportion receives treatment with osimertinib - applicable study measures include binary distribution of osimertinib treatment initiation, and requency distribution of the line of therapy (second- or later-line in the metastatic setting) in which osimertinib was initiated.. Proportion of patients receiving second-line therapy and type of second line therapy received among patients progressing on first-line EGFR TKI therapy and tested for T790M mutation. --- T790M --- --- T790M ---

Among patients progressing on first-line EGFR TKI therapy and tested for T790M, proportion who receive (or not) second-line therapy and the second-line therapy selection (chemotherapy, osimertinib, other EGFR TKI, I/O therapy, or other therapy), including: Proportion of patients prescribed second-line therapy, as well as time to second-line therapy initiation, as defined by time from first-line EGFR TKI discontinuation until the earliest of second-line initiation, death, or end of available follow-up, Among patients initiating second-line therapy, frequency distribution of the second-line therapy regimen observed (chemotherapy, osimertinib, other EGFR TKI, I/O therapy, or other therapy).. Proportion of patients receiving second-line therapy and type of second line therapy received among patients progressing on first-line EGFR TKI therapy and not tested for T790M. --- T790M ---

Among patients progressing on first-line EGFR TKI therapy and tested for T790M, proportion who receive (or not) second-line therapy and the second-line therapy selection (chemotherapy, osimertinib, other EGFR TKI, I/O therapy, or other therapy), including: Proportion of patients prescribed second-line therapy, as well as time to second-line therapy initiation, as defined by time from first-line EGFR TKI discontinuation until the earliest of second-line initiation, death, or end of available follow-up, Among patients initiating second-line therapy, frequency distribution of the second-line therapy regimen observed (chemotherapy, osimertinib, other EGFR TKI, I/O therapy, or other therapy).. Proportion of patients receiving second-line therapy and type of second line therapy received among patients progressing on first-line EGFR TKI therapy and not tested for T790M. --- T790M --- --- T790M ---

Among patients progressing on first-line EGFR TKI therapy and not tested for T790M, proportion who receive (or not) second-line therapy and the second-line therapy selection (chemotherapy, osimertinib, other EGFR TKI, I/O therapy, or other therapy), including: Proportion of patients prescribed second-line therapy, as well as time to second-line therapy initiation, as defined by time from first-line EGFR TKI discontinuation until the earliest of second-line initiation, death, or end of available follow-up, Among patients initiating second-line therapy, frequency distribution of the second-line therapy regimen observed (chemotherapy, osimertinib, other EGFR TKI, I/O therapy, or other therapy).. How the proportion of patients receiving second-line therapy differs between patients tested for T790M mutation and patients not tested for T790M mutations. --- T790M ---

Among patients progressing on first-line EGFR TKI therapy and not tested for T790M, proportion who receive (or not) second-line therapy and the second-line therapy selection (chemotherapy, osimertinib, other EGFR TKI, I/O therapy, or other therapy), including: Proportion of patients prescribed second-line therapy, as well as time to second-line therapy initiation, as defined by time from first-line EGFR TKI discontinuation until the earliest of second-line initiation, death, or end of available follow-up, Among patients initiating second-line therapy, frequency distribution of the second-line therapy regimen observed (chemotherapy, osimertinib, other EGFR TKI, I/O therapy, or other therapy).. How the proportion of patients receiving second-line therapy differs between patients tested for T790M mutation and patients not tested for T790M mutations. --- T790M --- --- T790M ---

Among patients progressing on first-line EGFR TKI therapy and not tested for T790M, proportion who receive (or not) second-line therapy and the second-line therapy selection (chemotherapy, osimertinib, other EGFR TKI, I/O therapy, or other therapy), including: Proportion of patients prescribed second-line therapy, as well as time to second-line therapy initiation, as defined by time from first-line EGFR TKI discontinuation until the earliest of second-line initiation, death, or end of available follow-up, Among patients initiating second-line therapy, frequency distribution of the second-line therapy regimen observed (chemotherapy, osimertinib, other EGFR TKI, I/O therapy, or other therapy).. How the proportion of patients receiving second-line therapy differs between patients tested for T790M mutation and patients not tested for T790M mutations. --- T790M --- --- T790M --- --- T790M ---

Proportion of patients prescribed second-line therapy, as well as time to second-line therapy initiation, as defined by time from first-line EGFR TKI discontinuation until the earliest of second-line initiation, death, or end of available follow-up among patients tested and not tested for T790M mutation.. Proportion of patients receiving third- or later-line therapy and type of this therapy and to explore whether the proportion receiving third-/later-line therapies varies by the second-line therapy category received. --- T790M ---

OS (in months) measured overall from first diagnosis of or progression to locally advanced or metastatic disease, OS from start of first-line EGFR TKI therapy to the date of death from any cause, with patients last known to be alive censored at the date of last available follow-up.. Incidence of other mutations, in case additional molecular testing was performed either at the time of initial EGFR testing or at the time of T790M testing. --- T790M ---

Proportion of patients with other positive mutations, in case additional molecular testing were performed at the time of initial EGFR testing or at the time of T790M testing (e.g., KRAS, BRAF, ROS1 translocation, PD-L1 expression, MET amplification, ALK rearrangement, RET rearrangement, HER2 exon 20 insertion, TP53, others).. Inclusion Criteria: - Confirmed diagnosis of locally advanced unresectable or metastatic NSCLC; - Aged at least 18 years at first diagnosis of locally advanced/metastatic NSCLC; - Lab-confirmed EGFR mutation; - Received a first- or second-generation EGFR TKI as first-line treatment for advanced/metastatic disease; - First-line EGFR TKI (afatinib, gefitinib, erlotinib) initiated between January 1, 2015 and June 30, 2018; - Patients may be alive or deceased at the time of medical record review. --- T790M ---

Primary Outcomes

Description: Frequency distribution of first-line EGFR TKI of first- or second generation prescribed: erlotinib, gefitinib, or afatinib

Measure: First- or second-generation EGFR TKI used in first-line therapy

Time: From date of initiating EGFR TKI in first line until the end of available follow-up or death, if this occurs before; assessed up to 60 months

Description: Proportion of patients with a progression event during first-line EGFR TKI therapy or other evidence recorded in the patient's medical records deemed by the clinician to be indicative of progression; Time to progression, defined as time from EGFR TKI therapy initiation in the first-line locally advanced or metastatic setting until the earliest of progression death, or end of available follow-up (i.e., progression-free survival); Proportion of patients discontinuing first-line EGFR therapy for reasons other than progression event or death

Measure: Proportion of patients progressing on first line EGFR TKI therapy and describe the time to progression

Time: From date of initiating EGFR TKI in first line until the earliest of progression, death or end of available follow-up, whichever occur first; assessed up to 60 months

Description: Proportion of patients prescribed second-line therapy, as well as time to second-line therapy initiation, as defined by time from first-line EGFR TKI discontinuation until the earliest of second-line initiation, death, or end of available follow-up; Frequency distribution of the second-line therapy regimen (chemotherapy, osimertinib, other EGFR TKI, I/O therapy, or other therapy) among patients initiating second-line therapy.

Measure: Proportion of patients receiving second-line therapy and type of second-line therapy among patients progressing on first line EGFR TKI therapy

Time: From date of initiating EGFR TKI in first line until date of starting second-line therapy; assessed up to 60 months

Secondary Outcomes

Description: Patients' demographics, including: sex (male/female), and age at EGFR TKI initiation. Baseline disease characteristics, including: Smoking status at initial NSCLC diagnosis, Tumor histology and disease stage at initial NSCLC diagnosis, Eastern Cooperative Oncology Group (ECOG) performance status at initial NSCLC diagnosis and at EGFR TKI initiation, Treatment history: for patients initially diagnosed at earlier-stage disease, cancer-directed and palliative therapies received before first diagnosis of or progression to advanced/metastatic EGFR-mutated NSCLC.

Measure: Patients' demographic and baseline disease characteristics

Time: From date of initial diagnosis of NSCLC or metastatic disease, whichever is diagnosed first until the end of available follow-up or death, if this occurs before; assessed up to 60 months

Description: Molecular testing patterns, including: type of sample/test used to assess the EGFR mutation, for example: primary/secondary tumor, tissue/cytology or blood sample; Molecular testing results: EGFR mutation type (exon 19 deletion, L858R mutation, other).

Measure: Type of sample & test used to determine the EGFR mutation and type of EGFR mutation identified

Time: From date of metastatic disease diagnostic until the end of available follow-up or death, if this occurs before; assessed up to 60 months

Description: Incidence and time to development of BM from first diagnosis of locally advanced or metastatic NSCLC, including: Proportion of patients with BM since diagnostic of metastatic disease and proportion of patients with BM developed during treatment, Type of test used to confirm BM diagnosis (e.g., tissue biopsy, imaging, spinal tap, neurologic exam), Proportion of patients who have BM at start of first-line EGFR TKI therapy. Proportion of patients with no development of BM, Patients' demographic and clinical characteristics associated with development of BM, Incidence of BM and time to development of BM from start of first-line EGFR TKI therapy, Proportion of patients prescribed treatments for BM and type of therapy Overall survival (in months) measured from first diagnosis of BM to the date of death from any cause, with patients last known to be alive censored at the date of last available follow-up.

Measure: Proportion of patients with brain metastases (BM) among metastatic patients and the overall survival (OS) expectation in the group of patients with BM

Time: From date of metastatic disease diagnostic until the first BM diagnosis; From first BM diagnosis to the start of first-line EGFR TKI therapy, end of available follow-up or death, if this occurs before; all assessed up to 60 months

Description: Incidence and time to development of LM disease from first diagnosis of locally advanced or metastatic NSCLC, including: Proportion of patients with LM at first diagnosis of metastatic disease, Type of test to confirm LM diagnosis (cerebrospinal fluid cytology, tissue, imaging, etc.), Proportion of patients who have LM at start of first-line EGFR TKI therapy, Proportion of patients who later develop (during treatment) LM, Proportion of patients with no development of LM, Incidence of LM and time to development of LM from start of first-line EGFR TKI therapy. Overall survival (in months) measured from first diagnosis of LM disease to the date of death from any cause, with patients last known to be alive censored at the date of last available follow-up.

Measure: Proportion of patients with leptomeningeal disease (LM) among metastatic patients and the overall survival (OS)

Time: From date of metastatic disease diagnostic until the LM diagnosis; From LM diagnosis to the start of first-line EGFR TKI therapy, end of available follow-up or death, if this occurs before; all assessed up to 60 months

Description: Proportion of patients prescribed other systemic treatments (chemotherapy, osimertinib, other EGFR TKI, I/O therapy, or other therapy) in combination with first-line EGFR TKI therapy.

Measure: Proportion of patients where the first-line therapy with first- or second-generation EGFR TKI is associated with any other systemic therapy, including the type of systemic therapy

Time: From date of initiating EGFR TKI in first line until the earliest of progression, death or end of available follow-up, whichever occurs first; assessed up to 60 months

Description: Proportion of patients tested for T790M mutation and among those tested, the proportion who were positive for the mutation, including: Binary distribution of T790M mutation testing and, among those tested, the proportion with a positive result, Type of test used to assess the T790M mutation (tissue/cytology or blood sample). Among patients tested and positive for T790M mutation, what proportion receives treatment with osimertinib - applicable study measures include binary distribution of osimertinib treatment initiation, and requency distribution of the line of therapy (second- or later-line in the metastatic setting) in which osimertinib was initiated.

Measure: Proportion of patients tested for T790M mutation and the proportion of patients with positive mutation among patients progressing on first-line EGFR TKI therapy

Time: From date of initiating EGFR TKI in first line until the earliest of progression, death or end of available follow-up, whichever occurs first; assessed up to 60 months

Description: Among patients progressing on first-line EGFR TKI therapy and tested for T790M, proportion who receive (or not) second-line therapy and the second-line therapy selection (chemotherapy, osimertinib, other EGFR TKI, I/O therapy, or other therapy), including: Proportion of patients prescribed second-line therapy, as well as time to second-line therapy initiation, as defined by time from first-line EGFR TKI discontinuation until the earliest of second-line initiation, death, or end of available follow-up, Among patients initiating second-line therapy, frequency distribution of the second-line therapy regimen observed (chemotherapy, osimertinib, other EGFR TKI, I/O therapy, or other therapy).

Measure: Proportion of patients receiving second-line therapy and type of second line therapy received among patients progressing on first-line EGFR TKI therapy and tested for T790M mutation

Time: From date of initiating second-line therapy until the earliest of progression, death or end of available follow-up, whichever occurs first; assessed up to 55 months

Description: Among patients progressing on first-line EGFR TKI therapy and not tested for T790M, proportion who receive (or not) second-line therapy and the second-line therapy selection (chemotherapy, osimertinib, other EGFR TKI, I/O therapy, or other therapy), including: Proportion of patients prescribed second-line therapy, as well as time to second-line therapy initiation, as defined by time from first-line EGFR TKI discontinuation until the earliest of second-line initiation, death, or end of available follow-up, Among patients initiating second-line therapy, frequency distribution of the second-line therapy regimen observed (chemotherapy, osimertinib, other EGFR TKI, I/O therapy, or other therapy).

Measure: Proportion of patients receiving second-line therapy and type of second line therapy received among patients progressing on first-line EGFR TKI therapy and not tested for T790M

Time: From date of initiating second-line therapy until the earliest of progression, death or end of available follow-up, whichever occurs first; assessed up to 55 months

Description: Proportion of patients prescribed second-line therapy, as well as time to second-line therapy initiation, as defined by time from first-line EGFR TKI discontinuation until the earliest of second-line initiation, death, or end of available follow-up among patients tested and not tested for T790M mutation.

Measure: How the proportion of patients receiving second-line therapy differs between patients tested for T790M mutation and patients not tested for T790M mutations

Time: From date of initiating second-line therapy until the earliest of progression, death or end of available follow-up, whichever occurs first; assessed up to 55 months

Description: Proportion of patients prescribed third- or later lines of therapy and type of therapies selected (chemotherapy, osimertinib, other EGFR TKI, I/O therapy, or other therapy), and how these proportion varies by the second-line therapy category received.

Measure: Proportion of patients receiving third- or later-line therapy and type of this therapy and to explore whether the proportion receiving third-/later-line therapies varies by the second-line therapy category received

Time: From date of initiating second-line therapy until the earliest of progression, death or end of available follow-up, whichever occurs first; assessed up to 50 months

Description: OS (in months) measured overall from first diagnosis of or progression to locally advanced or metastatic disease, OS from start of first-line EGFR TKI therapy to the date of death from any cause, with patients last known to be alive censored at the date of last available follow-up.

Measure: Overall survival (OS) expectation for all patients from first diagnosis of locally advanced or metastatic disease and from start of first-line EGFR TKI therapy

Time: From date of metastatic disease diagnostic or start of first-line EGFR TKI therapy until the end of available follow-up or death, if this occurs before; assessed up to 60 months

Description: Proportion of patients with other positive mutations, in case additional molecular testing were performed at the time of initial EGFR testing or at the time of T790M testing (e.g., KRAS, BRAF, ROS1 translocation, PD-L1 expression, MET amplification, ALK rearrangement, RET rearrangement, HER2 exon 20 insertion, TP53, others).

Measure: Incidence of other mutations, in case additional molecular testing was performed either at the time of initial EGFR testing or at the time of T790M testing

Time: From date of metastatic disease diagnostic until end of available follow-up or death, if this occurs before; assessed up to 60 months

216 A Phase III, Open-label, Randomized Study of Osimertinib With or Without Platinum Plus Pemetrexed Chemo, as First-line Treatment in Patients With Epidermal Growth Factor Receptor (EGFR) Mutation Positive, Locally Advanced or Metastatic Non-small Cell Lung Cancer (FLAURA2).

The reason for the study is to find out if an experimental combination of an oral medication called osimertinib (TAGRISSO®) when used in combination with chemotherapy is more effective than giving osimertinib alone for the treatment of locally advanced or metastatic non-small cell lung cancer. Some lung cancers are due to mutations in the Deoxyribonucleic acid (DNA) which, if known, can help physicians decide the best treatment for their patients. One type of mutation can occur in the gene that produces a protein on the surface of cells called the Epidermal Growth Factor Receptor (EGFR). Osimertinib is an Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor (TKI) that targets Epidermal Growth Factor Receptor (EGFR) mutations. Unfortunately, despite the benefit observed for patients treated with osimertinib, the vast majority of cancers are expected to develop resistance to the drug over time. The exact reasons why resistance develops are not fully understood but based upon clinical research it is hoped that combining osimertinib with another type of anti-cancer therapy known as chemotherapy will delay the onset of resistance and the worsening of a patient's cancer. In total the study aims to enroll approximately 586 patients, consisting of approximately 30 patients who will participate in a safety run-in component of the trial, and approximately 556 who will receive osimertinib alone or osimertinib in combination with chemotherapy in the main trial. In the main part of the trial there is a one in two chance of receiving osimertinib alone, and the treatment is decided at random by a computer. The study involves a Screening Period, Treatment Period, and Follow up Period. Whilst receiving study medication, it is expected patients will attend, on average, approximately 15 visits over the first 12 months and then approximately 4 visits per year afterwards. Each visit will last about 2 to 6 hours depending on the arrangement of medical assessments by the study centre.

NCT04035486
Conditions
  1. Non-Small Cell Lung Cancer
Interventions
  1. Drug: Osimertinib
  2. Drug: Pemetrexed/Carboplatin
  3. Drug: Pemetrexed/Cisplatin
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

4. The tumor harbors 1 of the 2 common epidermal growth factor receptor (EGFR) mutations known to be associated with Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) sensitivity (Ex19del or L858R), either alone or in combination with other epidermal growth factor receptor (EGFR) mutations, which may include T790M. 5. Patients must have untreated advanced Non-Small Cell Lung Cancer (NSCLC) not amenable to curative surgery or radiotherapy. --- L858R --- --- T790M ---

Primary Outcomes

Description: Progression-free survival (PFS) using Investigator assessment as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). Progression-free survival (PFS) is defined as the time from randomization until the date of objective disease progression or death (by any cause in the absence of progression), regardless of whether the patient withdraws from randomized therapy or receives another anti-cancer therapy prior to progression. Patients who have not progressed or died at the time of analysis will be censored at the time of the latest date of assessment from their last evaluable Response Evaluation Criteria in Solid Tumors (RECIST) assessment. The primary efficacy analysis of progression-free survival will be performed by investigator assessment Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). An additional sensitivity analysis will be performed for Progression-free survival (PFS) by Blinded Independent Central Review (BICR) assessment.

Measure: Progression-free survival (PFS)

Time: The primary analysis of Progression-free survival (PFS) based on investigator assessment will occur when PFS maturity is observed at approximately 33 months after the first patient is randomized.

Secondary Outcomes

Description: Overall survival is defined as the time from the date of randomization until death due to any cause.

Measure: Overall Survival (OS)

Time: Overall Survival will be analyzed at 2 time points: when PFS maturity is observed at approximately 33 months after the first patient is randomized, and when OS maturity is observed at approximately 70 months after the first patient is randomized

Description: Landmark Overall Survival at 1, 2, and 3 years will look at the number of patients alive at 1, 2 and 3 year time points.

Measure: Landmark Overall Survival (LOS)

Time: The analysis of Landmark Overall Survival will be conducted at 2 time points: when PFS maturity is observed at approximately 33 months, and when Overall Survival maturity is observed at approximately 70 months after the first patient is randomized.

Description: Objective Response Rate (ORR) (per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) using Investigator assessments) is defined as the number (%) of patients with at least 1 visit response of Complete Response or Partial Response. Data obtained up until progression, or the last evaluable assessment in the absence of progression, will be included in the assessment of Objective Response Rate

Measure: Objective Response Rate (ORR)

Time: Objective Response Rate analysis will occur when Progression-free survival (PFS) maturity is observed at approximately 33 months from the first patient being randomized.

Description: Duration of Response is defined as the time from the date of first documented response until the date of documented progression or death in the absence of disease progression.

Measure: Duration of Response (DoR)

Time: Duration of Response analysis will occur when Progression-free survival (PFS) maturity is observed at approximately 33 months from the first patient being randomized.

Description: Depth of response (ie. tumor shrinkage / change in tumor size) by Investigator is defined as the relative change in the sum of the longest diameters of Response Evaluation Criteria in Solid Tumors (RECIST) target lesions at the nadir in the absence of New Lesions (NLs) or progression of Non-Target Lesions when compared to baseline.

Measure: Depth of Response

Time: Depth of Response analysis will occur when Progression-free survival (PFS) maturity is observed at approximately 33 months from the first patient being randomized.

Description: Disease control rate (DCR) is defined as the percentage of subjects who have a best overall response of Complete Response (CR) or Partial Response (PR) or Stable Disease (SD) by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by the Investigator.

Measure: Disease Control Rate (DCR) by Investigator

Time: Disease Control Rate analysis will occur when Progression-free survival (PFS) maturity is observed at approximately 33 months from the first patient being randomized.

Description: Progression Free Survival 2 is defined as the time from the date of randomization to the earliest of the progression events subsequent to that used for the primary Progression Free Survival (PFS), or death in absence of a first or second progression. The second progression event must have occurred after subsequent treatment administered after the initial progression free survival event.

Measure: Progression Free Survival 2 (PFS2)

Time: Progression Free Survival 2 analysis will occur when Progression-free survival (PFS) maturity is observed at approximately 33 months from the first patient being randomized.

Description: Assess disease-related symptoms and health related Quality of Life (QoL) in patients treated with osimertinib plus chemotherapy compared with osimertinib.

Measure: Change from baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 items (EORTC QLQ-C30)

Time: European Organization for Research and Treatment of Cancer Quality of Life Questionnaire -Core 30 items analysis will occur when Progression-free survival (PFS) maturity is observed at approximately 33 months from the first patient being randomized.

Description: Assess disease-related symptoms and health related Quality of Life (QoL) in patients treated with osimertinib plus chemotherapy compared with osimertinib.

Measure: Change from baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 items (EORTC QLQ-LC13)

Time: European Organization for Research & Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 items analysis will occur when Progression-free survival (PFS) maturity is observed at approximately 33 months from the first patient being randomized

Description: Compare the local epidermal growth factor receptor mutation test result used for patient selection with the retrospective central cobas® epidermal growth factor receptor Mutation Test v2 results from baseline tumor samples.

Measure: Concordance of epidermal growth factor receptor mutation status between the local epidermal growth factor receptor mutation test and the central cobas® epidermal growth factor receptor Mutation Test v2 results from tumor samples with evaluable results

Time: Analysis will occur when Progression-free survival (PFS) maturity is observed at approximately 33 months from the first patient being randomized.

Description: Determine efficacy of osimertinib monotherapy vs. osimertinib combined with chemotherapy based on the cobas® epidermal growth factor receptor mutation Test v2 plasma screening test result for Exon 19 deletions or Exon 21 (L858R) epidermal growth factor receptor mutations.

Measure: Progression-free survival (PFS) by Investigator by plasma epidermal growth factor receptor mutation status.

Time: Analysis will occur when Progression-free survival (PFS)maturity is observed at approximately 33 months from the first patient being randomized.

Description: An analysis will be performed to assess whether the plasma concentration of osimertinib is affected when given with or without chemotherapy. Samples will be collected pre-dose and 1-hour post-dose on day 22 and day 106; on day 43 samples will be collected pre-dose and 1, 2, 4, and 6 hours post-dose.

Measure: Plasma concentration of osimertinib when given with or without chemotherapy

Time: Plasma concentration analysis will occur when Progression-free survival (PFS) maturity is observed at approximately 33 months from the first patient being randomized.

Description: An analysis will be performed to assess whether the plasma concentration of metabolite AZ5104 is affected when given with or without chemotherapy. Samples will be collected pre-dose and 1-hour post-dose on day 22 and day 106; on day 43 samples will be collected pre-dose and 1, 2, 4, and 6 hours post-dose.

Measure: Plasma concentration of metabolite AZ5104 when osimertinib is given with or without chemotherapy

Time: Plasma concentration analysis will occur when Progression-free survival (PFS) maturity is observed at approximately 33 months from the first patient being randomized.

217 A Multicenter, Open-Label Phase 1 Study of DS-1205c in Combination With Gefitinib in Subjects With Metastatic or Unresectable EGFR-Mutant Non-Small Cell Lung Cancer

This study has two parts: dose escalation and dose expansion. The primary objectives are: - For Dose Escalation, to assess the safety and tolerability of DS-1205c when combined with gefitinib in the study population and to determine the recommended dose for expansion of DS-1205c when combined with gefitinib in the study population - For Dose Expansion, to assess the safety and tolerability of DS-1205c when combined with gefitinib in the study population. In Dose Escalation, after a 7-day run in period (Cycle 0), there will be 21-day cycles (Cycle 1 onward). In Dose Expansion, there will be 21-day cycles. The number of treatment cycles is not fixed in this study. Participants will continue study treatment for 36 months unless they decide not to (withdraw consent), their disease gets worse [progressive disease (PD)], or side effects become unacceptable (unacceptable toxicity).

NCT03599518
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: DS-1205c
  2. Drug: Gefitinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Is willing to provide archival tumor tissue from a biopsy performed after progression during treatment with gefitinib, erlotinib, afatinib, or osimertinib OR has at least one lesion, not previously irradiated, amenable to core biopsy and is willing to undergo screening tumor biopsy 9. Demonstrates absence of EGFR T790M mutation in tumor tissue since progression during gefitinib, erlotinib, afatinib, or osimertinib treatment 10. Has Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1, with no deterioration over the previous 2 weeks Exclusion Criteria: 1. Has any evidence of small cell histology, or combined small cell and non-small cell histology, in original tumor biopsy or in screening biopsy performed since progression 2. Has previously documented evidence of anaplastic lymphoma kinase (ALK) fusion, ROS proto-oncogene 1 (ROS1) fusion, BRAF V600E mutation, rearranged during transfection (RET) rearrangement, human epidermal growth factor receptor 2 (HER2) mutation, or MET exon 14 skipping mutation - no new testing for these genomic alterations is required for Screening 3. Has received treatment with any of the following: 1. --- T790M ---

Primary Outcomes

Measure: Number pf participants with dose-limiting toxicities during the Dose Escalation period

Time: within 28 days

Description: An adverse event (AE) is any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product

Measure: Number of participants with adverse events (AEs)

Time: within 36 months

Secondary Outcomes

Measure: Plasma concentration of DS-1205a versus time

Time: during the 7 day run-in period

Measure: Maximum observed analyte concentration (Cmax)

Time: during the 7 day run-in period

Measure: Actual sampling time to reach Cmax (Tmax)

Time: during the 7 day run-in period

Measure: Area under the analyte concentration versus time curve during a dosing interval (AUCtau)

Time: during the 7 day run-in period

Measure: Minimum observed analyte concentration prior to the beginning, or at the end, of a dosing interval (Ctrough)

Time: during the 7 day run-in period

Description: Categories: DS-1205a, gefitinib

Measure: Cmax during a dosing interval (Tau) at steady state (Cmax,ss)

Time: during the dose expansion period, within 36 months

Description: Categories: DS-1205a, gefitinib

Measure: Plasma concentration of DS-1205a versus time

Time: during the dose expansion period, within 36 months

Description: Categories: DS-1205a, gefitinib

Measure: Tmax

Time: during the dose expansion period, within 36 months

Description: Categories: DS-1205a, gefitinib

Measure: Ctrough

Time: during the dose expansion period, within 36 months

Description: Categories: DS-1205a, gefitinib

Measure: AUCtau

Time: during the dose expansion period, within 36 months

Description: Objective response rate is calculated as the number of participants with best objective response [complete response (CR) or partial response (PR) determined by Investigator assessment based on Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1], divided by the number of participants in the analysis population.

Measure: Objective response rate (ORR), graded according to RECIST version 1.1

Time: within 36 months

Measure: Change from baseline in size of target lesion(s)

Time: within 36 months

Description: DOR is defined as the time from documentation of tumor response [either CR or PR] to disease progression

Measure: Duration of response (DOR)

Time: within 36 months

Description: DCR is defined as the sum of CR rate, PR rate, and stable disease (SD) rate

Measure: Disease control rate (DCR)

Time: within 36 months

Description: PFS is defined as the time from the date of the first dose to the earlier of the dates of the first objective documentation of radiographic PD, or death due to any cause

Measure: Progression-free survival (PFS)

Time: within 36 months

Measure: Overall survival (OS)

Time: within 36 months

218 A Randomized Phase II Study of Anlotinib Combined With Pemetrexed and Cisplatin in First Treatment for Advanced Non-small Cell Lung Cancer With Epidermal Growth Factor Receptor Negative Mutations

Chemotherapy is still the standard first-line treatment option for EGFR unmutated patients. After a randomized phase Ⅲ trial, BEYOND was presented the synergistic effect of progression-free survival(PFS) could be expected when chemotherapy is combined with Antiangiogenesis agent bevacizumab in China;Therefore,in this study, The investigators will investigate the efficacy and safety of Anlotinb combined With Pemetrexed and Cisplatin as first-line therapy in patients with chemotherapy-naive, stage IIIB or IV, non-squamous NSCLC without targetable EGFR or ALK genetic aberrations.

NCT03671538
Conditions
  1. Non-squamous Non-small Cell Lung Cancer
Interventions
  1. Drug: Anlotinib
  2. Drug: pemetrexed
  3. Drug: Cisplatin
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

recurrent patients, adjuvant chemotherapy, neoadjuvant chemotherapy or neoadjuvant chemotherapy plus adjuvant were assessed for eligibility, and the last treatment time must be more than 6 months before enrollment) - Patients have not been received systematic treatment,including chemotherapy and EGFR-TKIs - EGFR mutations confirmed by molecular detection (including, but not limited to, T790M, 19 exon deletion and L858R) external pathological examination was accepted (including pathological or blood test results) - There were at least one target lesions in the past three months has not yet accepted radiotherapy, and could be recorded by magnetic resonance imaging (MRI) or computer tomography (CT) measuring accurately at least in one direction(The maximum diameter needs to be recorded), including conventional CT ≥20 mm or spiral CT ≥10 mm. - Life expectancy ≥3 months. --- T790M ---

Primary Outcomes

Description: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first

Measure: progression-free survival

Time: From enrollment to completion of study. Estimated about 24 months.

Secondary Outcomes

Description: Clinical response of treatment according to RESIST v1.1 criteria (ORR, Overall Response Rate)

Measure: Overall Response Rate

Time: From enrollment to progression of disease. Estimated about 24 months

Description: Clinical response of treatment according to RESIST v1.1 criteria (DCR, disease control rate)

Measure: disease control rate

Time: From enrollment to progression of disease. Estimated about 24 months

Description: From date of randomization until the date of death or date of last visit/contact, whichever came first

Measure: Overall Survival

Time: From enrollment to completion of study. Estimated about 24 months.

Description: Proportion of people who first documented disease progression or death from any cause, whichever came first ,during 6 months

Measure: 6-month PFS rate

Time: From enrollment to analysis, Estimated about 6 months

Description: Proportion of people who first documented disease progression or death from any cause, whichever came first ,during 12 months

Measure: 12-month PFS rate

Time: From enrollment to analysis. Estimated about 12 months.

219 Ph1 Study of the Safety, PK, and PDn of Escalating Oral Doses of the Glutaminase Inhibitor CB-839, as a Single Agent and in Combination With Standard Chemotherapy in Patients With Advanced and/or Treatment-Refractory Solid Tumors

Many tumor cells, in contrast to normal cells, have been shown to require the amino acid glutamine to produce energy for growth and survival. To exploit the dependence of tumors on glutamine, CB-839, a potent and selective inhibitor of the first enzyme in glutamine utilization, glutaminase, will be tested in this Phase 1 study in patients with solid tumors. This study is an open-label Phase 1 evaluation of CB-839 in patients with advanced solid tumors. The study will be conducted in 2 parts. Part 1 is a dose escalation study enrolling patients with locally-advanced, metastatic and/or refractory solid tumors to receive CB-839 capsules orally twice or three times daily. In Part 2, patients with each of the following diseases will be enrolled: A) Triple-Negative Breast Cancer, B) Non-Small Cell Lung Cancer (adenocarcinoma), C) Renal Cell Cancer, D) Mesothelioma, E) Fumarate hydratase (FH)-deficient tumors, F) Succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumors (GIST), G) SDH-deficient non-GIST tumors, H) tumors harboring mutations in isocitrate dehydrogenase-1 (IDH1) or IDH2, and I) cMyc mutation tumors. As an extension of Parts 1 & 2, patients will be treated with CB-839 in combination with standard chemotherapy. Combination groups include: Pac-CB, CBE, CB-Erl, CBD, and CB-Cabo. Pac-CB: patients with locally-advanced or metastatic TNBC will be treated with paclitaxel and CB-839. CBE: patients with advanced clear cell RCC or papillary RCC will be treated with everolimus in combination with CB-839. CB-Erl: patients with advanced NSCLC lacking the T790M EGFR mutation will be treated with erlotinib and CB-839. CBD: patients with NSCLC harboring KRAS mutation will be treated with docetaxel and CB-839. CB-Cabo: patients with histologically confirmed diagnosis of locally-advanced, inoperable or metastatic RCC treated with cabozantinib in combination with CB-839. All patients will be assessed for safety, pharmacokinetics (plasma concentration of drug), pharmacodynamics (inhibition of glutaminase), biomarkers (biochemical markers that may predict responsiveness in later studies), and tumor response.

NCT02071862
Conditions
  1. Solid Tumors
  2. Triple-Negative Breast Cancer
  3. Non Small Cell Lung Cancer
  4. Renal Cell Carcinoma
  5. Mesothelioma
  6. Fumarate Hydratase (FH)-Deficient Tumors
  7. Succinate Dehydrogenase (SDH)-Deficient Gastrointestinal Stromal Tumors (GIST)
  8. Succinate Dehydrogenase (SDH)-Deficient Non-gastrointestinal Stromal Tumors
  9. Tumors Harboring Isocitrate Dehydrogenase-1 (IDH1) and IDH2 Mutations
  10. Tumors Harboring Amplifications in the cMyc Gene
Interventions
  1. Drug: CB-839
  2. Drug: Pac-CB
  3. Drug: CBE
  4. Drug: CB-Erl
  5. Drug: CBD
  6. Drug: CB-Cabo
MeSH:Neoplasms Carcinoma, Renal Cell Mesothelioma Triple Negative Breast Neoplasms Gastrointestinal Stromal Tumors
HPO:Clear cell renal cell carcinoma Gastrointestinal stroma tumor Neoplasm Papillary renal cell carcinoma Renal cell carcinoma

CB-Erl: patients with advanced NSCLC lacking the T790M EGFR mutation will be treated with erlotinib and CB-839. --- T790M ---

Primary Outcomes

Measure: Safety and tolerability of CB-839: Incidence of adverse events

Time: Every 21 days from study start until disease progression or unacceptable toxicity, assessed for an expected average of 6 months

Secondary Outcomes

Measure: Pharmacokinetics: Area under the Curve (AUC) of CB-839 concentration in blood

Time: Study Days 1, 15, and 22

Measure: Pharmacodynamics: % inhibition of glutaminase in blood

Time: Study Days 1 and 15

Measure: Clinical activity: Change in tumor volume from baseline

Time: Every 9 weeks until disease progression or unacceptable toxicity, assessed for an expected average of 6 months

220 A Phase I/Pharmacokinetic Study of Erlotinib for Advanced Non-small Cell Lung Cancer in Persons With HIV Infection

This phase I trial studies the side effects and best dose of erlotinib hydrochloride in treating non-small cell lung cancer that has spread to other parts of the body or cannot be removed by surgery in patients with human immunodeficiency virus (HIV) infection. Erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Erlotinib hydrochloride is a standard drug used for treating lung cancer, however, it is not yet known whether it is safe to give erlotinib hydrochloride to patients who also have HIV infection or not.

NCT02134886
Conditions
  1. HIV Infection
  2. Recurrent Non-Small Cell Lung Carcinoma
  3. Stage IIIA Non-Small Cell Lung Cancer
  4. Stage IIIB Non-Small Cell Lung Cancer
  5. Stage IV Non-Small Cell Lung Cancer
Interventions
  1. Drug: Erlotinib Hydrochloride
  2. Other: Laboratory Biomarker Analysis
  3. Other: Pharmacological Study
  4. Other: Quality-of-Life Assessment
MeSH:Infection Communicable Diseases HIV Infections Acquired Immunodeficiency Syndrome Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

m^2 for participants with creatinine levels above institutional normal - A cluster of differentiation (CD)4+ lymphocyte count > 50/mcL will be required within 2 weeks of study participation - Women of childbearing potential must have a negative pregnancy test within 7 days of enrollment; women of childbearing potential include women who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are not postmenopausal; postmenopause is defined as amenorrhea >= 12 consecutive months; note: women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, anti-estrogens, ovarian suppression, or any other reversible reason - Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of erlotinib administration - Participants MUST receive appropriate care and treatment for HIV infection, including antiretroviral medications, when clinically indicated and should be under the care of a physician experienced in HIV management; participants will be eligible regardless of antiretroviral medication (including no antiretroviral medication) provided there is no intention to initiate therapy or the regimen has been stable for at least 4 weeks with no intention to change the regimen within 8 weeks following study entry; as study-specific (antiretroviral-based) strata fill, however, only participants who are receiving the therapies eligible for the remaining open strata will be accrued - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Participants who received prior treatment with erlotinib or other EGFR-targeted agents - Participants who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier - Participants who are receiving any other investigational agents - The participant has active brain metastases or epidural disease; participants with stable brain metastases previously treated with whole brain radiation or radiosurgery or participants with epidural disease previously treated with radiation or surgery who are asymptomatic and do not require steroid treatment for at least 4 weeks before starting study treatment are eligible; neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 3 months before starting study treatment; baseline brain imaging with contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) scans for participants with known brain metastases is required to confirm eligibility - History of allergic reactions attributed to compounds of similar chemical or biologic composition to erlotinib - The participant has prothrombin time (PT)/international normalized ratio (INR) or partial thromboplastin time (PTT) test >= 1.3 the laboratory ULN within 7 days before the first dose of study treatment - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - Participants with history of chronic diarrhea, grade >= 2 prior to study participation; persons with up to grade 1 diarrhea will be eligible - The participant requires chronic concomitant treatment with the following strong cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inducers OTHER than antiretroviral agents: dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, primidone, modafinil, and other enzyme inducing anti-convulsant drugs (EIACD), and St. John's Wort; use of efavirenz or etravirine is permitted for participants considered for the CYP3A4-inducer based antiretroviral therapy (ART) regimen arm (Stratum B) of the trial - Although study participants will be eligible regardless of smoking history, smokers should be strongly advised to stop smoking while on erlotinib; smoking induces cytochrome P450, family 1, subfamily A, polypeptide 2 (CYP1A2) enzymes and alters erlotinib exposure by 64% - Participants who take medications that are not recommended for concomitant use with their current antiretroviral regimen - The participant requires concomitant treatment with the following inhibitors of CYP3A4: - Antibiotics: clarithromycin, erythromycin, telithromycin, troleandomycin - Antifungals: itraconazole, ketoconazole, voriconazole, fluconazole, posaconazole - Antidepressants: nefazodone - Antidiuretic: conivaptan - Gastrointestinal (GI): cimetidine, aprepitant - Hepatitis C: boceprevir, telaprevir - Miscellaneous: Seville oranges, grapefruit, or grapefruit juice and/or pummelos, star fruit, exotic citrus fruits, or grapefruit hybrids); use of any of anti-retrovirals (delavirdine) or protease inhibitors (ritonavir, indinavir, lopinavir/ritonavir, saquinavir, nelfinavir) is permitted; specifically, ritonavir and cobicistat is permitted for participants considered for the CYP3A4-inhibitor based ART regimen arm (Stratum A) of the trial - Participants should not have significant abnormalities of the cornea based on history (e.g., dry eye syndrome, Sjogren's syndrome), congenital abnormality (e.g., Fuch's dystrophy), abnormal slit-lamp examination using a vital dye (e.g., fluorescein, Bengal-Rose), and/or an abnormal corneal sensitivity test (Schirmer test or similar tear production test) - Female participants may not be pregnant or breastfeeding; women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately - Persons with tumors known to have biomarkers predictive of resistance to erlotinib therapy (specifically Kirsten rat sarcoma viral oncogene homolog [KRAS] mutations, anaplastic lymphoma receptor tyrosine kinase [ALK] gene rearrangements, and EGFR T790M mutations) will be ineligible for study participation; if the results of molecular studies are not available or known at the time of study registration and subsequently become available, such participants will be considered eligible and if deriving clinical benefit may continue receiving erlotinib at the discretion of the investigator and study chair Inclusion Criteria: - Participants must have known HIV infection and histologically confirmed non-small cell lung cancer that is metastatic or unresectable; patients will be eligible regardless of tumor EGFR mutation status - Participants may have received any number of prior lines of chemotherapy (other than erlotinib or other EGFR-targeted therapy) for incurable non-small cell lung cancer; (first line platinum-doublet based chemotherapy plus switch maintenance chemotherapy counts as one line of therapy; prior adjuvant chemotherapy for early stage disease does not count as one line of therapy if 12 months or greater elapsed between completion of adjuvant therapy and initiation of first-line systemic therapy; if less than 12 months elapsed, adjuvant chemotherapy counts as one line of therapy) - PARTICIPANTS WITH NO PRIOR THERAPY FOR INCURABLE LUNG CANCER: trial eligibility will be restricted to those participants whose tumors harbor known EGFR activating mutations - PARTICIPANTS WITH PRIOR LINES OF THERAPY: all other participants (those whose tumors harbor wild-type EGFR or unknown EGFR status, or those with EGFR mutations not previously treated with erlotinib/EGFR-targeted therapy) - At least 4 weeks must have elapsed since prior chemotherapy or biological therapy, 6 weeks if the regimen included carmustine (BCNU) or mitomycin C; prior radiation therapy to the thoracic cavity, abdomen, or pelvis must be completed at least 3 months prior to registration; radiotherapy to any other site (including bone or brain metastases) must be completed at least 28 days prior to registration - Molecular characterization of non-squamous non-small cell lung cancer will be recommended prior to enrollment per standard of care/institutional guidelines; consistent with current National Comprehensive Cancer Network (NCCN) guidelines and the recent Food and Drug Administration (FDA)-approval indication of erlotinib for first-line treatment of advanced non-small cell lung cancer in persons with tumor EGFR mutations, participants who have known EGFR sensitizing mutations in tumors will be permitted to enter the study and receive erlotinib as initial monotherapy; for participants who have received one or more prior lines of chemotherapy, molecular characterization of tumors is required whenever possible with an understanding that inability to obtain sufficient tissue specimen for characterization will not preclude enrollment into the study - Participants must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria; baseline measurements and evaluation of ALL sites of disease must be obtained within 4 weeks prior to registration - Serologic documentation of HIV infection at any time prior to study entry, as evidenced by positive enzyme-linked immunosorbent assay (ELISA), positive Western blot, or any other federally approved licensed HIV test; alternatively, this documentation may include a record that another physician has documented that the participant has HIV infection based on prior ELISA and Western blot, or other approved diagnostic tests - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Life expectancy of greater than 12 weeks - Leukocytes: >= 3,000/mm^3 - Absolute neutrophil count: >= 1,500/mm^3 - Platelets: >= 100,000/mm^3 - Total bilirubin: within normal institutional limits; if, however, the participant has Gilbert's disease or unconjugated hyperbilirubinemia which is felt to be secondary to with atazanavir or indinavir therapy, then the total bilirubin must be =< 3 x upper limit of normal [ULN]) - Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) / alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]): =<2.5 x institutional upper limit of normal - Hemoglobin: >= 9 g/dL - Creatinine: - Creatinine levels within normal institutional limits (< 1.5 x ULN); or, - Creatinine clearance >= 60 mL/min/1.73 --- T790M ---

m^2 for participants with creatinine levels above institutional normal - A cluster of differentiation (CD)4+ lymphocyte count > 50/mcL will be required within 2 weeks of study participation - Women of childbearing potential must have a negative pregnancy test within 7 days of enrollment; women of childbearing potential include women who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are not postmenopausal; postmenopause is defined as amenorrhea >= 12 consecutive months; note: women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, anti-estrogens, ovarian suppression, or any other reversible reason - Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of erlotinib administration - Participants MUST receive appropriate care and treatment for HIV infection, including antiretroviral medications, when clinically indicated and should be under the care of a physician experienced in HIV management; participants will be eligible regardless of antiretroviral medication (including no antiretroviral medication) provided there is no intention to initiate therapy or the regimen has been stable for at least 4 weeks with no intention to change the regimen within 8 weeks following study entry; as study-specific (antiretroviral-based) strata fill, however, only participants who are receiving the therapies eligible for the remaining open strata will be accrued - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Participants who received prior treatment with erlotinib or other EGFR-targeted agents - Participants who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier - Participants who are receiving any other investigational agents - The participant has active brain metastases or epidural disease; participants with stable brain metastases previously treated with whole brain radiation or radiosurgery or participants with epidural disease previously treated with radiation or surgery who are asymptomatic and do not require steroid treatment for at least 4 weeks before starting study treatment are eligible; neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 3 months before starting study treatment; baseline brain imaging with contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) scans for participants with known brain metastases is required to confirm eligibility - History of allergic reactions attributed to compounds of similar chemical or biologic composition to erlotinib - The participant has prothrombin time (PT)/international normalized ratio (INR) or partial thromboplastin time (PTT) test >= 1.3 the laboratory ULN within 7 days before the first dose of study treatment - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - Participants with history of chronic diarrhea, grade >= 2 prior to study participation; persons with up to grade 1 diarrhea will be eligible - The participant requires chronic concomitant treatment with the following strong cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inducers OTHER than antiretroviral agents: dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, primidone, modafinil, and other enzyme inducing anti-convulsant drugs (EIACD), and St. John's Wort; use of efavirenz or etravirine is permitted for participants considered for the CYP3A4-inducer based antiretroviral therapy (ART) regimen arm (Stratum B) of the trial - Although study participants will be eligible regardless of smoking history, smokers should be strongly advised to stop smoking while on erlotinib; smoking induces cytochrome P450, family 1, subfamily A, polypeptide 2 (CYP1A2) enzymes and alters erlotinib exposure by 64% - Participants who take medications that are not recommended for concomitant use with their current antiretroviral regimen - The participant requires concomitant treatment with the following inhibitors of CYP3A4: - Antibiotics: clarithromycin, erythromycin, telithromycin, troleandomycin - Antifungals: itraconazole, ketoconazole, voriconazole, fluconazole, posaconazole - Antidepressants: nefazodone - Antidiuretic: conivaptan - Gastrointestinal (GI): cimetidine, aprepitant - Hepatitis C: boceprevir, telaprevir - Miscellaneous: Seville oranges, grapefruit, or grapefruit juice and/or pummelos, star fruit, exotic citrus fruits, or grapefruit hybrids); use of any of anti-retrovirals (delavirdine) or protease inhibitors (ritonavir, indinavir, lopinavir/ritonavir, saquinavir, nelfinavir) is permitted; specifically, ritonavir and cobicistat is permitted for participants considered for the CYP3A4-inhibitor based ART regimen arm (Stratum A) of the trial - Participants should not have significant abnormalities of the cornea based on history (e.g., dry eye syndrome, Sjogren's syndrome), congenital abnormality (e.g., Fuch's dystrophy), abnormal slit-lamp examination using a vital dye (e.g., fluorescein, Bengal-Rose), and/or an abnormal corneal sensitivity test (Schirmer test or similar tear production test) - Female participants may not be pregnant or breastfeeding; women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately - Persons with tumors known to have biomarkers predictive of resistance to erlotinib therapy (specifically Kirsten rat sarcoma viral oncogene homolog [KRAS] mutations, anaplastic lymphoma receptor tyrosine kinase [ALK] gene rearrangements, and EGFR T790M mutations) will be ineligible for study participation; if the results of molecular studies are not available or known at the time of study registration and subsequently become available, such participants will be considered eligible and if deriving clinical benefit may continue receiving erlotinib at the discretion of the investigator and study chair HIV Infection Recurrent Non-Small Cell Lung Carcinoma Stage IIIA Non-Small Cell Lung Cancer Stage IIIB Non-Small Cell Lung Cancer Stage IV Non-Small Cell Lung Cancer Infection Communicable Diseases HIV Infections Acquired Immunodeficiency Syndrome Lung Neoplasms Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVES: I. To evaluate the safety and tolerability of erlotinib (erlotinib hydrochloride) as a single agent in non-small cell lung cancer participants with HIV infection and to determine the maximum tolerated dose of erlotinib in combination with antiretroviral therapy in this participant population. --- T790M ---

Primary Outcomes

Measure: Incidence of toxicities evaluated with National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (v4.0)

Time: Up to 30 days

Measure: Maximum tolerated dose of erlotinib hydrochloride defined as the dose level in which less than or equal to 1 out of 6 participants experiences dose-limiting toxicity evaluated with NCI CTCAE v4.0

Time: 28 days

Secondary Outcomes

Description: A repeated measures analysis of variance will be used to assess the effect of erlotinib hydrochloride on CD4+ across time points. Analyses will be done per stratum, where the data are sufficient. If the data do not meet the assumptions of normality, the data will either be transformed or Friedman's test (i.e. nonparametric analogue to a repeated measures analysis of variance) will be used.

Measure: CD4+ counts

Time: Up to 30 days

Description: A repeated measures analysis of variance will be used to assess the effect of erlotinib hydrochloride on CD8+ across time points. Analyses will be done per stratum, where the data are sufficient. If the data do not meet the assumptions of normality, the data will either be transformed or Friedman's test (i.e. nonparametric analogue to a repeated measures analysis of variance) will be used.

Measure: CD8+ counts

Time: Up to 30 days

Description: A repeated measures analysis of variance will be used to assess the effect of erlotinib hydrochloride on HIV viral loads across time points. Analyses will be done per stratum, where the data are sufficient. If the data do not meet the assumptions of normality, the data will either be transformed or Friedman's test (i.e. nonparametric analogue to a repeated measures analysis of variance) will be used.

Measure: HIV viral load

Time: Up to 30 days

Description: Spearman rank correlation coefficients will be used to investigate erlotinib-associated skin rash with immune competence. Fisher's exact tests will be used to investigate erlotinib-associated skin rash with participant response outcomes. Analyses will be done per stratum, where the data are sufficient.

Measure: Incidence of erlotinib hydrochloride-associated skin rash

Time: Up to 30 days

Description: The pharmacokinetic variables will be tabulated and descriptive statistics (e.g., geometric means and coefficients of variation) calculated for each dose level. Pharmacokinetic parameters (i.e., T1/2, Cl, and AUC) will be compared across relevant antiretroviral therapies using nonparametric statistical testing techniques.

Measure: Pharmacokinetic parameters of erlotinib hydrochloride, including half-life (T1/2), clearance (Cl), and area under the curve (AUC)

Time: Pre-treatment, 1, 2, 3, 4, 6, 8, and 24 hours post treatment

Measure: Response assessed via RECIST 1.1

Time: Up to 30 days

221 A Phase 1b Study of Intermittent Administration of High Doses of the Irreversible EGFR Inhibitor Afatinib as a Means of Achieving Plasma Levels Active Against Non-small Cell Lung Cancer With Known T790M Mutations

This trial is divided into Part A and Part B. The primary objective of Part A is to establish the Maximal Tolerated Dose of intermittent high dose afatinib. The primary objective of Part B is to assess the response rate of patients with non-small cell lung cancer with EGFR T790M mutations to a dose of intermittent afatinib established in Part A. The secondary objective is to explore tumor response and tumor-derived biological markers of response to afatinib, as well as pharmacokinetic parameters of afatinib.

NCT01647711
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Drug: Dose escalation followed by treatment with MTD
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

A Phase 1b Study of Intermittent Administration of High Doses of the Irreversible EGFR Inhibitor Afatinib as a Means of Achieving Plasma Levels Active Against Non-small Cell Lung Cancer With Known T790M Mutations. --- T790M ---

A Study of Intermittent, High-dose Afatinib to Determine the Maximal Tolerated Dose and Assess Activity of This Dose Against Non-small Cell Lung Cancer With T790M Mutations This trial is divided into Part A and Part B. The primary objective of Part A is to establish the Maximal Tolerated Dose of intermittent high dose afatinib. --- T790M ---

The primary objective of Part B is to assess the response rate of patients with non-small cell lung cancer with EGFR T790M mutations to a dose of intermittent afatinib established in Part A. The secondary objective is to explore tumor response and tumor-derived biological markers of response to afatinib, as well as pharmacokinetic parameters of afatinib. --- T790M ---

Maximum Tolerated Dose (MTD) was defined as the dose in which less than 2 of up to 6 patients developed a Dose Limiting Toxicity (DLT).. Objective Response Rate for Patients With EGFR T790M Mutations. --- T790M ---

Objective response rate for patients with Epidermal Growth Factor Receptor (EGFR) T790M mutations. --- T790M ---

Part B only: 2. Pathologically confirmed diagnosis of Stage IV (M1a or b) non-small cell lung cancer 3. Documented Epidermal Growth Factor Receptor (EGFR) T790M mutation 4. Progression of disease on a reversible tyrosine kinase inhibitor within 30 days of starting study drug. --- T790M ---

Primary Outcomes

Description: Percentage of participants with Dose Limiting Toxicities (DLTs), based on investigator assessment, for determination of Maximum Tolerated Dose (MTD). MTD was defined as the dose in which less than 2 of up to 6 patients developed a DLT.

Measure: Percentage of Participants With Dose Limiting Toxicities

Time: 28 days

Description: Maximum Tolerated Dose (MTD) was defined as the dose in which less than 2 of up to 6 patients developed a Dose Limiting Toxicity (DLT).

Measure: Maximum Tolerated Dose

Time: 28 days

Secondary Outcomes

Description: Objective response rate for patients with Epidermal Growth Factor Receptor (EGFR) T790M mutations. Objective response was defined as Complete Response (CR): Disappearance of all target lesion or Partial Response and (PR): >=30% decrease in the sum of the longest diameter of target lesions, according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. This endpoint was originally planned to be analysed in part B of the study, however as no participants were treated in part B the analysis was performed on the part A participants.

Measure: Objective Response Rate for Patients With EGFR T790M Mutations

Time: From first drug administration until last drug administration, up to 420 days

Description: Maximum measured concentration (Cmax) of afatinib as determined on day 3 of course 1 for patients in Part A

Measure: Cmax of Afatinib on Day 3 of Course 1

Time: 47 hours (h) 55 minutes (min), 49h, 50h, 51h, 52h, 53h, 54h, 55h after first dose administration (on day 3 of course 1)

Description: Determination of dosage for expansion cohort in Part B. Dosage was the MTD or less depending on tolerability.

Measure: Determination of Dosage for Expansion Cohort in Part B

Time: 28 days

222 French National Observatory of the Patients With Non-small Cell Lung (NSCLC) Benefiting From a Molecular Test on the Hospital Platforms of Molecular Genetics.

The French National Cancer Institute (INCa) support a 28 hospital platforms network for molecular testing of cancer patients. These platforms routinely assess a panel of biomarkers in order to speed up access of French cancer patients to targeted therapies (commercially available or through clinical trials). The objective of the BIOMARKERS-France study is to describe the epidemiological, clinical and molecular characteristics of these patients and their tumors and to assess the impact of these analyzes on their treatment (ie bio-guided therapy) as well as outcomes (response rate, progression free and overall survival).

NCT01700582
Conditions
  1. Carcinoma, Non-Small-Cell Lung
  2. ALK Gene Mutation
  3. KRAS Gene Mutation
  4. BRAF Gene Mutation
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Regarding stage IV non-squamous NSCLC patients, 7 biomarkers are assessed including activating EGFR mutations, EML4-ALK translocation and EGFR T790M, KRAS, BRAF, HER2 and PI3KCA mutations. --- T790M ---

Primary Outcomes

Description: Number of patients with EGF-R gene mutation

Measure: EGF-R gene mutation in nationwide cohort

Time: 1 Year

Secondary Outcomes

Description: Number of patients with K-RAS gene mutation

Measure: K-RAS gene mutation in nationwide cohort

Time: 1 year

Description: Number of patients with EML4-ALK translocation

Measure: EML4-ALK translocation in nationwide cohort

Time: 1 year

Description: Number of patients with BRAF gene mutation

Measure: BRAF gene mutation in nationwide cohort

Time: 1 year

Description: Number of patients with HER2 gene mutation

Measure: HER2 gene mutation in nationwide cohort

Time: 1 year

Description: Number of patients with PI3K gene mutation

Measure: PI3K gene mutation in nationwide cohort

Time: 1 year

223 Phase I/II Study to Assess the Safety, Tolerability, Pharmacokinetics and Anti-tumor Activity of HM61713 in NSCLC Patients With EGFR Mutation

The main objective of this study is to evaluate the safety and tolerability of HM61713.

NCT01588145
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: HM61713
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

※ For subjects with a liver metastases, AST/ALT/ALP≤ 5 x ULN is allowed; and for subjects with bone marrow metastases, ALP≤ 5 x ULN is allowed - Patients with amylase level ≤ 1.5 x ULN - Subjects who have provided voluntary consent to participate in the study, and signed the written consent document - Malignancy that has progressed after at least two prior chemotherapy regimens, including EGFR-TKI - Patients with disease progression despite anticancer therapy with EGFR-TKI (e.g., erlotinib, gefitinib, neratinib, afatinib, dacomitinib) - Patients who have provided voluntary consent for collection of tumor tissue taken and archived after the last anticancer therapy or collection of new tissue specimen and signed the written consent document & - Patients with disease progression despite anticancer therapy with EGFR TKI (e.g., erlotinib, gefitinib, neratinib, afatinib, dacomitinib) (Except treatment with EGFR mutation selective inhibitor, the same class of drug as investigational drug in this study) - T790M mutation-positive confirmed in tissue collected after PD is confirmed during or after the last anticancer therapy - At least one measurable target lesion allowing repeated measurement according to RECIST ver1.1 as of screening - Patients with disease progression despite anticancer therapy with EGFR TKI (e.g., erlotinib, gefitinib, neratinib, afatinib, dacomitinib) (Except treatment with EGFR mutation selective inhibitor, the same class of drug as investigational drug in this study) - T790M mutation-negative confirmed in tissue collected after progressive disease (PD) is confirmed during or after the last anticancer therapy - At least one measurable target lesion allowing repeated measurement according to RECIST ver1.1 as of screening Exclusion Criteria: - Hematologic malignancies - Symptomatic or uncontrolled central nervous system metastases - Interstitial lung disease, including pulmonary fibrosis - LVEF < 40% or NYHA Class III or IV heart failure - History of pancreatitis - History or current evidence, of any psychiatric or congenital disorder, including dementia or epilepsy - Compromised organ function, infection or allergy - Pregnant or breast-feeding women, or women of child-bearing potential who do not use an appropriate method of contraception (male patients should also use an appropriate method of contraception during the study period) - Patients who had received other investigational product within 30 days prior to screening Inclusion Criteria: - Patients with histologically or cytologically confirmed diagnosis of advanced NSCLC - Patients with EGFR mutation-positive tumor - Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less - Estimated life expectancy of at least 12 weeks - Subjects with adequate bone marrow (WBC ≥4,000/mm3, Platelet ≥100,000/mm3, Hemoglobin≥9.0g/dL, --- T790M ---

※ For subjects with a liver metastases, AST/ALT/ALP≤ 5 x ULN is allowed; and for subjects with bone marrow metastases, ALP≤ 5 x ULN is allowed - Patients with amylase level ≤ 1.5 x ULN - Subjects who have provided voluntary consent to participate in the study, and signed the written consent document - Malignancy that has progressed after at least two prior chemotherapy regimens, including EGFR-TKI - Patients with disease progression despite anticancer therapy with EGFR-TKI (e.g., erlotinib, gefitinib, neratinib, afatinib, dacomitinib) - Patients who have provided voluntary consent for collection of tumor tissue taken and archived after the last anticancer therapy or collection of new tissue specimen and signed the written consent document & - Patients with disease progression despite anticancer therapy with EGFR TKI (e.g., erlotinib, gefitinib, neratinib, afatinib, dacomitinib) (Except treatment with EGFR mutation selective inhibitor, the same class of drug as investigational drug in this study) - T790M mutation-positive confirmed in tissue collected after PD is confirmed during or after the last anticancer therapy - At least one measurable target lesion allowing repeated measurement according to RECIST ver1.1 as of screening - Patients with disease progression despite anticancer therapy with EGFR TKI (e.g., erlotinib, gefitinib, neratinib, afatinib, dacomitinib) (Except treatment with EGFR mutation selective inhibitor, the same class of drug as investigational drug in this study) - T790M mutation-negative confirmed in tissue collected after progressive disease (PD) is confirmed during or after the last anticancer therapy - At least one measurable target lesion allowing repeated measurement according to RECIST ver1.1 as of screening Exclusion Criteria: - Hematologic malignancies - Symptomatic or uncontrolled central nervous system metastases - Interstitial lung disease, including pulmonary fibrosis - LVEF < 40% or NYHA Class III or IV heart failure - History of pancreatitis - History or current evidence, of any psychiatric or congenital disorder, including dementia or epilepsy - Compromised organ function, infection or allergy - Pregnant or breast-feeding women, or women of child-bearing potential who do not use an appropriate method of contraception (male patients should also use an appropriate method of contraception during the study period) - Patients who had received other investigational product within 30 days prior to screening Inclusion Criteria: - Patients with histologically or cytologically confirmed diagnosis of advanced NSCLC - Patients with EGFR mutation-positive tumor - Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less - Estimated life expectancy of at least 12 weeks - Subjects with adequate bone marrow (WBC ≥4,000/mm3, Platelet ≥100,000/mm3, Hemoglobin≥9.0g/dL, --- T790M --- --- T790M ---

※ For subjects with a liver metastases, AST/ALT/ALP≤ 5 x ULN is allowed; and for subjects with bone marrow metastases, ALP≤ 5 x ULN is allowed - Patients with amylase level ≤ 1.5 x ULN - Subjects who have provided voluntary consent to participate in the study, and signed the written consent document - Malignancy that has progressed after at least two prior chemotherapy regimens, including EGFR-TKI - Patients with disease progression despite anticancer therapy with EGFR-TKI (e.g., erlotinib, gefitinib, neratinib, afatinib, dacomitinib) - Patients who have provided voluntary consent for collection of tumor tissue taken and archived after the last anticancer therapy or collection of new tissue specimen and signed the written consent document & - Patients with disease progression despite anticancer therapy with EGFR TKI (e.g., erlotinib, gefitinib, neratinib, afatinib, dacomitinib) (Except treatment with EGFR mutation selective inhibitor, the same class of drug as investigational drug in this study) - T790M mutation-positive confirmed in tissue collected after PD is confirmed during or after the last anticancer therapy - At least one measurable target lesion allowing repeated measurement according to RECIST ver1.1 as of screening - Patients with disease progression despite anticancer therapy with EGFR TKI (e.g., erlotinib, gefitinib, neratinib, afatinib, dacomitinib) (Except treatment with EGFR mutation selective inhibitor, the same class of drug as investigational drug in this study) - T790M mutation-negative confirmed in tissue collected after progressive disease (PD) is confirmed during or after the last anticancer therapy - At least one measurable target lesion allowing repeated measurement according to RECIST ver1.1 as of screening Exclusion Criteria: - Hematologic malignancies - Symptomatic or uncontrolled central nervous system metastases - Interstitial lung disease, including pulmonary fibrosis - LVEF < 40% or NYHA Class III or IV heart failure - History of pancreatitis - History or current evidence, of any psychiatric or congenital disorder, including dementia or epilepsy - Compromised organ function, infection or allergy - Pregnant or breast-feeding women, or women of child-bearing potential who do not use an appropriate method of contraception (male patients should also use an appropriate method of contraception during the study period) - Patients who had received other investigational product within 30 days prior to screening Non Small Cell Lung Cancer Carcinoma, Non-Small-Cell Lung Besides the main objective, there are 3 other objectives as follows: - To evaluate the anti-cancer effect of HM61713 in NSCLC patients with EGFR mutation - To investigate the pharmacokinetic profile of HM61713 and its metabolites after oral administration - To investigate biomarkers related to the safety and efficacy of HM61713 --- T790M ---

※ For subjects with a liver metastases, AST/ALT/ALP≤ 5 x ULN is allowed; and for subjects with bone marrow metastases, ALP≤ 5 x ULN is allowed - Patients with amylase level ≤ 1.5 x ULN - Subjects who have provided voluntary consent to participate in the study, and signed the written consent document - Malignancy that has progressed after at least two prior chemotherapy regimens, including EGFR-TKI - Patients with disease progression despite anticancer therapy with EGFR-TKI (e.g., erlotinib, gefitinib, neratinib, afatinib, dacomitinib) - Patients who have provided voluntary consent for collection of tumor tissue taken and archived after the last anticancer therapy or collection of new tissue specimen and signed the written consent document & - Patients with disease progression despite anticancer therapy with EGFR TKI (e.g., erlotinib, gefitinib, neratinib, afatinib, dacomitinib) (Except treatment with EGFR mutation selective inhibitor, the same class of drug as investigational drug in this study) - T790M mutation-positive confirmed in tissue collected after PD is confirmed during or after the last anticancer therapy - At least one measurable target lesion allowing repeated measurement according to RECIST ver1.1 as of screening - Patients with disease progression despite anticancer therapy with EGFR TKI (e.g., erlotinib, gefitinib, neratinib, afatinib, dacomitinib) (Except treatment with EGFR mutation selective inhibitor, the same class of drug as investigational drug in this study) - T790M mutation-negative confirmed in tissue collected after progressive disease (PD) is confirmed during or after the last anticancer therapy - At least one measurable target lesion allowing repeated measurement according to RECIST ver1.1 as of screening Exclusion Criteria: - Hematologic malignancies - Symptomatic or uncontrolled central nervous system metastases - Interstitial lung disease, including pulmonary fibrosis - LVEF < 40% or NYHA Class III or IV heart failure - History of pancreatitis - History or current evidence, of any psychiatric or congenital disorder, including dementia or epilepsy - Compromised organ function, infection or allergy - Pregnant or breast-feeding women, or women of child-bearing potential who do not use an appropriate method of contraception (male patients should also use an appropriate method of contraception during the study period) - Patients who had received other investigational product within 30 days prior to screening Non Small Cell Lung Cancer Carcinoma, Non-Small-Cell Lung Besides the main objective, there are 3 other objectives as follows: - To evaluate the anti-cancer effect of HM61713 in NSCLC patients with EGFR mutation - To investigate the pharmacokinetic profile of HM61713 and its metabolites after oral administration - To investigate biomarkers related to the safety and efficacy of HM61713 --- T790M --- --- T790M ---

Primary Outcomes

Measure: Safety and tolerability

Time: Dose limiting Toxicity will be evaluated on Day 24 during Cycle 1

224 A Randomized Phase II Trial of Osimertinib Alone or in Combination With Bevacizumab for EGFR- Mutant Non-small Cell Lung Cancer With Leptomeningeal Metastasis

Leptomeningeal metastasis (LM) is a devastating and terminal complication of advanced non-small-cell lung cancer (NSCLC), especially in patients harboring epidermal growth factor receptor (EGFR) mutations. Osimertinib is an oral,third-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M resistance mutations .AURA I/II study and other preclinical study suggested that Osimertinib exhibited a better blood-brain barrier(BBB) penetration than the other EGFR-TKIs (gefitinib, erlotinib, or afatinib).The BLOOM 、AURA and FLURA study demonstrated that osimertinib showed encouraging activity and manageable tolerability in pretreated EGFR-mutant NSCLC patients with LM. Bevacizumab is a monoclonal antibody against vascular endothelial growth factor (VEGF). Animal study and autopsy specimens showed that VEGF is an essential factor in LM. Recently study showed EGFR-TKIs plus bevacizumab prolonged PFS and OS in patients with EGFR-mutant NSCLC and multiple brain mteastasis when compared with EGFR-TKIs alone. Howerver osimertinib combined with bevacizumab could benefit patients with LM from EGFR- mutant NSCLC remains undetermined. Therefore, the purpose of the study is to evaluate the safety and efficacy of osimertinib combined with bevacizumab for EGFR- mutant non-small cell lung cancer with leptomeningeal metastasis

NCT04148898
Conditions
  1. Leptomeningeal Metastasis
  2. Non-small Cell Lung Cancer
  3. EGFR Activating
  4. EGFR Activating Mutation
Interventions
  1. Drug: Osimertinib
  2. Drug: Bevacizumab
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung Neoplasm Metastasis Neoplasms, Second Primary Meningeal Carcinomatosis
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Osimertinib is an oral,third-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M resistance mutations .AURA I/II study and other preclinical study suggested that Osimertinib exhibited a better blood-brain barrier(BBB) penetration than the other EGFR-TKIs (gefitinib, erlotinib, or afatinib).The BLOOM , AURA and FLURA study demonstrated that osimertinib showed encouraging activity and manageable tolerability in pretreated EGFR-mutant NSCLC patients with LM. --- T790M ---

Primary Outcomes

Description: iPFS (Time from LM diagnosis to the first documentation of intracranial lesion progression or death with documented intracranial pro- gression,)

Measure: Intracranial progression-free

Time: Every 6 weeks, up to 2 years,

Description: ORR, proportion of patients with a best overall response of complete response or partial response (CR+PR)

Measure: Objective Response Rate

Time: Every 6 weeks, up to 2 years

Secondary Outcomes

Description: LM-OS defined as time from LM diagnosis to death due to any cause or last follow-up

Measure: LM Overall survival

Time: Every 3 weeks, up to 5 years,

Description: Proportion of patients progression-free by investigator assessment per RECIST v1.1

Measure: progression-free survival

Time: Every 6 weeks, up to 2 years,

Description: Number of patients with adverse events (AEs) as a measure of safety and tolerability

Measure: adverse events

Time: Every 3 weeks, up to 2 years,

225 A Phase II Study of Atezolizumab in Combination With Bevacizumab, Carboplatin or Cisplatin, and Pemetrexed for EGFR-mutant Metastatic Non-small Cell Lung Cancer Patients After Failure of EGFR Tyrosine Kinase Inhibitors.

using Atezolizumab, a PD-L1 inhibitor, in combination with bevacizumab, platinum and pemetrexed to treat patients with EGFR mutated, advanced non-small cell lung cancer (NSCLC) after failure of EGFR tyrosine kinase inhibitors.

NCT04147351
Conditions
  1. NSCLC Stage IIIB~IV
Interventions
  1. Drug: Atezolizumab Injection; bevacizumab Injection
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

The treatment-free interval of neoadjuvant or adjuvant platinum-based chemotherapy should be more than 6 months before study enrollment is allowed - Previous exposure to VEGF inhibitor for anti-cancer treatment - Prior treatment with any other anti-programmed cell death protein-1 (anti-PD-1), or PD Ligand-1 (PD-L1) or PD Ligand-2 (PD-L2) agent or an antibody targeting other immuno-regulatory receptors or mechanisms - Patients carries EGFR genotype T790M or exon20 insertion should be excluded. --- T790M ---

Primary Outcomes

Description: The percentage of patients with radiologically complete or partial response as determined by the investigator according to RECIST version 1.1.

Measure: Objective response rate (ORR)

Time: 9 MONTHS

Secondary Outcomes

Description: PFS is measured from the date of study enrollment to radiographically documented progression according to RECIST 1.1 or death from any cause (whichever occurs first). Participants alive and without disease progression or lost to follow-up will be censored at the date of their last radiographic assessment.

Measure: Progression-free Survival (PFS)

Time: about 9 months

226 Evaluation in Real World of Molecular Testing and Treatment Patterns for EGFR Mutations in Patients With Advanced or Metastatic NSCLC at Front-line and Progression

Evaluate molecular testing and treatment patterns for EGFR mutation in two different cohorts of stage IV NSCLC, at diagnosis (treatment naïve) and at the moment of progression to EGFR-TKIs. This study is non-indication seeking (NIS), descriptive in nature and does not attempt to test any specific a priori hypotheses.

NCT03721289
Conditions
  1. Carcinoma, Non-Small-Cell Lung
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Study Measures - Patient demographic and clinical characteristics - Molecular testing rates at Stage IV and at progression to EGFR TKI - Molecular testing EGFR mutation results (common/uncommon mutations at advanced diagnosis, and T790M at progression) - Treatment patterns at frontline and progression to EGFR TKIs - Biopsy-related complications - Percentage of patinets presenting with CNS metastasis at diagnosis of stage IV and at progression to EGFR TKIsCNS Sample: All patients diagnosed with Stage IV NSCLC at diagnosis and at progression to an EGFR-TKI; from January 1st , 2017 to December 31st, 2017 in selected centers of Uruguay, Argentina, Chile, Colombia Statistical Analysis No formal hypothesis testing is specified. --- T790M ---

Primary Outcomes

Description: Test used to determine EGFRm, registered in clinical charts

Measure: Evaluation of the EGFR mutation

Time: Clinical charts from January 2013-december 2017

227 A Phase 2 Trial of Durvalumab (MEDI4736) and Tremelimumab With Chemotherapy in Metastatic EGFR Mutant Non-squamous Non-small Cell Lung Cancer (NSCLC) Following Progression on EGFR Tyrosine Kinase Inhibitors (TKIs)

The primary purpose of this trial is to evaluate the efficacy and tolerability of durvalumab and tremelimumab with platinum-pemetrexed in patients with metastatic NSCLC (T790+ve or T790M-ve) following progression on EGFR Tyrosine Kinase Inhibitors.. Study population: Individuals may be eligible to enrol in this trial if aged 18 or over and have been diagnosed with advanced non-small cell lung cancer (T790+ve or T790M-ve) following progression on EGFR Tyrosine Kinase Inhibitors. Study details: All participants enrolled in this trial will begin with induction therapy which involves 4 cycles of durvalumab 1500mg and tremelimumab 75mg with cisplatin 75mg/m2 or carboplatin AUC 5, and pemetrexed 500mg/m2 intravenously every 3 weeks. Participants will then move into a maintenance phase of durvalumab 1500mg and pemetrexed 500mg/m2 once every 4 weeks until disease progression or unacceptable side effects. All patients will be reviewed every three to four weeks by blood samples, CT scans and side effect assessments. It is hoped that the findings from this trial will provide information on whether treatment with durvalumab and tremelimumab with platinum-pemetrexed is feasible, safe and effective for the treatment of advanced non-small cell lung cancer (T790+ve or T790M-ve).

NCT03994393
Conditions
  1. EGFR Mutant Advanced Non Small Cell Lung Cancer
Interventions
  1. Drug: Tremelimumab
  2. Drug: Durvalumab
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

The primary purpose of this trial is to evaluate the efficacy and tolerability of durvalumab and tremelimumab with platinum-pemetrexed in patients with metastatic NSCLC (T790+ve or T790M-ve) following progression on EGFR Tyrosine Kinase Inhibitors.. Study population: Individuals may be eligible to enrol in this trial if aged 18 or over and have been diagnosed with advanced non-small cell lung cancer (T790+ve or T790M-ve) following progression on EGFR Tyrosine Kinase Inhibitors. --- T790M ---

The primary purpose of this trial is to evaluate the efficacy and tolerability of durvalumab and tremelimumab with platinum-pemetrexed in patients with metastatic NSCLC (T790+ve or T790M-ve) following progression on EGFR Tyrosine Kinase Inhibitors.. Study population: Individuals may be eligible to enrol in this trial if aged 18 or over and have been diagnosed with advanced non-small cell lung cancer (T790+ve or T790M-ve) following progression on EGFR Tyrosine Kinase Inhibitors. --- T790M --- --- T790M ---

It is hoped that the findings from this trial will provide information on whether treatment with durvalumab and tremelimumab with platinum-pemetrexed is feasible, safe and effective for the treatment of advanced non-small cell lung cancer (T790+ve or T790M-ve). --- T790M ---

2. Disease that has progressed and either: (i) No evidence of EGFR T790M resistance mutation in both tissue re-biopsy and plasma after one-line of EGFR tyrosine kinase inhibitor therapy (TKI) OR (ii) T790M mutation (detected in tissue re-biopsy, plasma or both) and progression on 3rd generation EGFR TKI; patients are allowed to have one prior line of TKI therapy before 3rd generation TKI 3. Measurable disease according to RECIST 1.1 4. ECOG performance status of 0 or 1 5. Adequate bone marrow function as defined below (within 14 days prior to registration and with values within the ranges specified below): - Platelets equal to or greater than 100 x 109/L - Absolute neutrophil count (ANC) equal to or greater than 1.0 x 109/L (equal to or greater than 1000 per mm3) - Haemoglobin equal to or greater than 90 x g/L 6. Adequate liver function (within 14 days prior to registration and with values within the ranges specified below): - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) equal to or less than 2.5 x institutional upper limit of normal (ULN). --- T790M ---

2. Disease that has progressed and either: (i) No evidence of EGFR T790M resistance mutation in both tissue re-biopsy and plasma after one-line of EGFR tyrosine kinase inhibitor therapy (TKI) OR (ii) T790M mutation (detected in tissue re-biopsy, plasma or both) and progression on 3rd generation EGFR TKI; patients are allowed to have one prior line of TKI therapy before 3rd generation TKI 3. Measurable disease according to RECIST 1.1 4. ECOG performance status of 0 or 1 5. Adequate bone marrow function as defined below (within 14 days prior to registration and with values within the ranges specified below): - Platelets equal to or greater than 100 x 109/L - Absolute neutrophil count (ANC) equal to or greater than 1.0 x 109/L (equal to or greater than 1000 per mm3) - Haemoglobin equal to or greater than 90 x g/L 6. Adequate liver function (within 14 days prior to registration and with values within the ranges specified below): - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) equal to or less than 2.5 x institutional upper limit of normal (ULN). --- T790M --- --- T790M ---

Primary Outcomes

Description: Objective tumour response rate (OTRR) as defined by RECIST 1.1. Objective tumour response (OTR) is defined as a partial response or compete response by RECIST 1.1. OTRR is defined as the proportion (percentage) of participants with a confirmed CR or PR according to RECIST 1.1.

Measure: Objective tumour response rate (OTRR) and Objective tumour response (OTR)

Time: 36 months post enrolment of first participant.

Secondary Outcomes

Description: Disease control (Disease Control Rate (DCR) = Complete Response (CR) + Partial Response (PR) + Stable Disease (SD) as defined by RECIST 1.1.

Measure: Disease control (Disease Control Rate (DCR)

Time: 36 months post enrolment of first participant.

Description: Objective tumour response rate (OTRR) as defined by iRECIST. Objective tumour response (OTR) is defined as a partial response or compete response by iRECIST. OTRR is defined as the proportion (percentage) of participants with a confirmed CR or PR according to iRECIST.

Measure: Objective tumour response rate (OTRR) & Objective tumour response (OTR)

Time: 36 months post enrolment of first participant.

Description: Progression-free survival (PFS) as defined by RECIST 1.1 and iRECIST. PFS is defined as the interval from date of registration to the date of first evidence of disease progression or death, whichever occurs first. Disease progression is defined according to RECIST 1.1 and iRECIST.

Measure: Progression-free survival (PFS)

Time: 36 months post enrolment of first participant.

Description: Progression-free survival at 12 months (PFS12) as defined by RECIST 1.1 and iRECIST. PFS at 12 months taken to mean 1 calendar year, i.e. 365 days. Study participants who have stable disease, partial response or complete response confirmed at the first scheduled assessment after 12 months according to RECIST v1.1 will be considered to have attained PFS at 12 months.

Measure: Progression-free survival at 12 months (PFS12)

Time: 12 months post enrolment of last participant.

Description: Overall survival (OS) is defined as the interval from the date of registration to date of death from any cause, or the date of last known follow-up alive.

Measure: Overall survival (OS)

Time: 36 months from enrolment of first participant.

Description: Number and Severity (assessed as a composite) of Adverse Events - using the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03.

Measure: Number and Severity (assessed as a composite) of Adverse Events

Time: 36 months post enrolment of first participant.

228 Study of Atezolizumab in Combination With Carboplatin + Paclitaxel +Bevacizumab vs With Pemetrexed + Cisplatin or Carboplatin With Stage IV NON-SQUAMOUS NON-SMALL CELL LUNG CANCER With EGFR(+) or ALK(+)

This randomized, Phase III, multicenter, open-label study designed to evaluate the efficacy of Atezolizumab in combination with carboplatin, paclitaxel, bevacizumab compared with treatment with pemetrexed, cisplatin in approximately 228 TKI(tyrosine kinase inhibitor) pre treated patients with Stage IV non squamous non small cell lung cancer with activating EGFR mutation or ALK translocation.

NCT03991403
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: Atezolizumab(Tecentriq)
  2. Drug: Pemetrexed
  3. Drug: Bevacizumab
  4. Drug: Carboplatin
  5. Drug: Paclitaxel
  6. Drug: Carboplatin or cisplatin
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

If the patients have identified T790M mutation after 1st or 2nd generation EGFR TKI failure, the patient must be treated with the second line 3rd generation EGFR TKI treatment, such as osimertinib, before the study participation. --- T790M ---

Primary Outcomes

Description: To evaluate the efficacy of atezolizumab + carboplatin + paclitaxel + bevacizumab as progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (RECIST v1.1) in the following treatment:Atezolizumab + carboplatin + paclitaxel + bevacizumab versus Pemetrexed + carboplatin or cisplatin

Measure: progression-free survival, PFS

Time: through study completion, an average of 1 year

Secondary Outcomes

Measure: overall survival(OS)

Time: through study completion, an average of 1 year

Measure: objective response rate(ORR)

Time: through study completion, an average of 1 year

Measure: duration of response(DOR)

Time: through study completion, an average of 1 year

229 A Randomized, Phase II Study of Anlotinib Combined With Sintilimab(IBI 308) in First-generation EGFR-TKIs Drug Resistance Along With T790M Negative NSCLC

This is an efficacy and safety study of Anlotinib combined with Sintilimab (IBI 308) in participants with advanced or metastatic non-small cell lung cancer (NSCLC) who have received first-generation EGFR-TKIs resistance along with T790M negative.

NCT03765775
Conditions
  1. Carcinoma
  2. Non-small Cell Lung Cancer
  3. Lung Neoplasm
Interventions
  1. Biological: Sintilimab
  2. Drug: Anlotinib Hydrochloride
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

A Randomized, Phase II Study of Anlotinib Combined With Sintilimab(IBI 308) in First-generation EGFR-TKIs Drug Resistance Along With T790M Negative NSCLC. --- T790M ---

Anlotinib Plus Sintilimab for NSCLC Patients With First-generation EGFR-TKIs Drug Resistance Along With T790M Negative This is an efficacy and safety study of Anlotinib combined with Sintilimab (IBI 308) in participants with advanced or metastatic non-small cell lung cancer (NSCLC) who have received first-generation EGFR-TKIs resistance along with T790M negative. --- T790M ---

Anlotinib Plus Sintilimab for NSCLC Patients With First-generation EGFR-TKIs Drug Resistance Along With T790M Negative This is an efficacy and safety study of Anlotinib combined with Sintilimab (IBI 308) in participants with advanced or metastatic non-small cell lung cancer (NSCLC) who have received first-generation EGFR-TKIs resistance along with T790M negative. --- T790M --- --- T790M ---

Has confirmation that epidermal growth factor receptor (EGFR) mutation,with first-generation EGFR-TKIs drug resistance T790M negative . --- T790M ---

Primary Outcomes

Description: PFS was defined as the time from randomization to documented disease progression per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) or death due to any cause, whichever occurred first and was based on blinded independent central radiologists' (BICR) review. Progressive Disease (PD) was defined as ≥20% increase in the sum of diameters of target lesions and an absolute increase of ≥5 mm. (Note: the appearance of one or more new lesions was also considered progression). Participants were evaluated every 9 weeks with radiographic imaging to assess their response to treatment.

Measure: Progression-Free Survival (PFS)

Time: 6 months

Secondary Outcomes

Description: OS was defined as the time from randomization to death due to any cause. Participants without documented death at the time of the analysis were censored at the date of the last follow-up. In those instances where participants were confirmed to be alive on the visit cut-off date of 09 May 2016, survival was censored as of 09 May 2016.

Measure: Over Survival(OS)

Time: 2years

Description: ORR was defined as the percentage of participants in the analysis population who experienced a Complete Response (CR; disappearance of all target lesions) or a Partial Response (PR; at least a 30% decrease in the sum of diameters of target lesions) and was assessed using RECIST 1.1 based on BICR evaluation.

Measure: Objective Response Rate (ORR)

Time: 2yeas

230 A Prospective, Single-arm, Multicenter Study of Anlotinib Hydrochloride Combined With First-generation EGFR TKIs as Second-line Treatment in Acquired (Non-T790M Mutation) Resistance Advanced Non-small Cell Lung Cancer

After the second-line treatment of patients with non-T790M mutations, chemotherapy with platinum-containing drugs was used, and chemotherapy-related toxicity was high. Studies have shown that bevacizumab combined with EGFR TKI have a good trend of benefit. This study is aimed to evaluate the efficacy and safety of Anlotinib Hydrochloride combined with first-generation EGFR TKIs as second-line treatment in advanced non-small cell lung cancer . The patients with IV non-small lung cancer have acquired resistance to prior first-generation EGFR TKIs and have non-T790M mutation.

NCT03766490
Conditions
  1. Non-Small-Cell Lung
Interventions
  1. Drug: Anlotinib Hydrochloride
  2. Drug: Gefitinib
  3. Drug: Icotinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

A Prospective, Single-arm, Multicenter Study of Anlotinib Hydrochloride Combined With First-generation EGFR TKIs as Second-line Treatment in Acquired (Non-T790M Mutation) Resistance Advanced Non-small Cell Lung Cancer. --- T790M ---

Anlotinib Hydrochloride Combined With EGFR TKIs in Advanced Non-small Cell Lung Cancer After the second-line treatment of patients with non-T790M mutations, chemotherapy with platinum-containing drugs was used, and chemotherapy-related toxicity was high. --- T790M ---

The patients with IV non-small lung cancer have acquired resistance to prior first-generation EGFR TKIs and have non-T790M mutation. --- T790M ---

- Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1. - Previously, EGFR gene test showed EGFR exon 19 deletion or exon 21 (L858R) mutation, and the gene test showed no T790M mutation before enrollment. --- L858R --- --- T790M ---

- Patients that cannot detect EGFR gene, or patients with known T790M mutation. --- T790M ---

Primary Outcomes

Description: PFS defined as the time from first dose of study treatment until the first date of either objective disease progression or death due to any cause.

Measure: PFS(Progress free survival)

Time: each 42 days up to PD or death(up to 24 months)

Secondary Outcomes

Description: OS is defined as the time until death due to any cause.

Measure: Overall Survival (OS)

Time: From randomization until death (up to 24 months)

Description: ORR is defined as the percentage of subjects with evidence of a confirmed complete response (CR) or partial response (PR) as per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1.prior to progression or any further therapy.

Measure: Objective Response Rate (ORR)

Time: each 42 days up to intolerance the toxicity or PD (up to 24 months)

Description: use EORTC QLQ-C30(version 3) questionnaire to evaluate the quality of life.

Measure: Quality of Life(QoL)

Time: each 42 days up to intolerance the toxicity or PD (up to 24 months)

Description: Defined as the proportion of patients with a documented complete response, partial response, and stable disease (CR + PR + SD) based on RECIST 1.1.

Measure: Disease Control Rate (DCR)

Time: each 42 days up to intolerance the toxicity or PD (up to 24 months)

231 Real-world Analysis of Workup at Disease Progression and Implementation of Osimertinib for EGFR+ NSCLC

Tyrosine kinase inhibitors (TKI) have greatly improved prognosis of epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC), with tumor responses in the majority of cases and a median overall survival currently exceeding 2.5 years. However, clinical courses vary widely and eventual treatment failure is inevitable. The most common resistance mechanism against first- and second-generation EGFR inhibitors is the EGFR T790M mutation, which emerges in about 50% of cases and is amenable to next-line treatment with the third-generation compound osimertinib. However, experience in everyday clinical practice shows that implementation of EGFR TKI sequencing is often problematic, for example because a considerable number of EGFR+ NSCLC patients failing first- and second-generation EGFR inhibitors do not undergo T790M mutation testing at the time of disease progression. This study will use patient records to analyze the clinical course of EGFR+ NSCLC patients treated with first- and second-generation EGFR inhibitors at the Thoraxklinik Heidelberg (Germany) during the past years. The main aim is to analyze the diagnostic and therapeutic measures, including implementation of osimertinib, taken at the time of disease progression as well as their effect on patient outcome in a real-world, routine clinical setting.

NCT04105153
Conditions
  1. EGFR Positive Non-small Cell Lung Cancer
MeSH:Disease Progression

The most common resistance mechanism against first- and second-generation EGFR inhibitors is the EGFR T790M mutation, which emerges in about 50% of cases and is amenable to next-line treatment with the third-generation compound osimertinib. --- T790M ---

However, experience in everyday clinical practice shows that implementation of EGFR TKI sequencing is often problematic, for example because a considerable number of EGFR+ NSCLC patients failing first- and second-generation EGFR inhibitors do not undergo T790M mutation testing at the time of disease progression. --- T790M ---

the rate of rebiopsy and molecular workup (especially T790M testing) at disease progression under treatment with first-/second-generation EGFR inhibitors the frequency of T790M mutations in the molecular workup of patients with disease progression under first-/second-generation EGFR inhibitors the actual rate of osimertinib implementation after failure of first-/second-generation EGFR inhibitors in the "real-world" setting.. Progression-free survival (PFS). --- T790M ---

the rate of rebiopsy and molecular workup (especially T790M testing) at disease progression under treatment with first-/second-generation EGFR inhibitors the frequency of T790M mutations in the molecular workup of patients with disease progression under first-/second-generation EGFR inhibitors the actual rate of osimertinib implementation after failure of first-/second-generation EGFR inhibitors in the "real-world" setting.. Progression-free survival (PFS). --- T790M --- --- T790M ---

Primary Outcomes

Description: the rate of rebiopsy and molecular workup (especially T790M testing) at disease progression under treatment with first-/second-generation EGFR inhibitors the frequency of T790M mutations in the molecular workup of patients with disease progression under first-/second-generation EGFR inhibitors the actual rate of osimertinib implementation after failure of first-/second-generation EGFR inhibitors in the "real-world" setting.

Measure: Fraction of EGFR+ NSCLC patients with sequential TKI treatment

Time: assessment will performed retrospectively for all study patients from September 2019 until June 2020

Secondary Outcomes

Description: Progression-free survival (PFS) of patients treated with first-/second-generation EGFR inhibitors and/or osimertinib in the real-world setting

Measure: Progression-free survival (PFS)

Time: assessment will performed retrospectively for all study patients from September 2019 until June 2020

Description: Time-to-next-treatment (TNT) of patients treated with first-/second-generation EGFR inhibitors and/or osimertinib in the real-world setting

Measure: Time-to-next-treatment (TNT)

Time: assessment will performed retrospectively for all study patients from September 2019 until June 2020

Description: Time-to-chemotherapy (TTC) of patients treated with first-/second-generation EGFR inhibitors and/or osimertinib in the real-world setting

Measure: Time-to-chemotherapy (TTC)

Time: assessment will performed retrospectively for all study patients from September 2019 until June 2020

Description: Overall survival (OS) of patients treated with first-/second-generation EGFR inhibitors and/or osimertinib in the real-world setting

Measure: Overall survival (OS)

Time: assessment will performed retrospectively for all study patients from September 2019 until June 2020

232 A Multicentre Phase II, Open-label, Non-randomized Study Evaluating Platinum-Pemetrexed-Atezolizumab (+/- Bevacizumab) for Patients With Stage IIIB/IV Non-squamous Non-small Cell Lung Cancer With EGFR Mutations, ALK Rearrangement or ROS1 Fusion Progressing After Targeted Therapies

The objective of this study is to assess the efficacy of the combination of Platinum (carboplatin or cisplatin), Pemetrexed, Atezolizumab+/- Bevacizumab if eligible, in stage IIIB/IV non-squamous non-small cell lung cancer patients with progression-enhancing mutations following targeted therapies.

NCT04042558
Conditions
  1. NSCLC Stage IIIB
  2. NSCLC Stage IV
  3. EGFR Gene Mutation
  4. ALK Gene Rearrangement Positive
  5. ROS1 Gene Mutation
Interventions
  1. Drug: Carboplatin + Pemetrexed + Atezolizumab + Bevacizumab
  2. Drug: Carboplatin + Pemetrexed + Atezolizumab
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

After a first line of treatment with a TKI, most patients progress and are eligible according to the mechanism of progression to a TKI of 3rd generation in case of T790M resistance or chemotherapy. --- T790M ---

Primary Outcomes

Measure: Objective response rate (ORR) according to RECIST 1.1

Time: After the end of 4 cycles (15 weeks)

Secondary Outcomes

Measure: The progression-free survival (PFS)

Time: 1 year

Measure: The overall survival

Time: 1 year

Measure: The duration of response

Time: 1 year

233 A Phase 2 Study of Poziotinib in Patients With Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) With EGFR or HER2 Exon 20 Mutation in China and Korea

This is a Phase 2, open-label, multicenter study to evaluate the efficacy and the safety/tolerability of poziotinib in two patient cohorts for up to 114 previously treated NSCLC patients with any systemic therapy (57 patients with EGFR exon 20 insertion mutations and 57 patients with HER2 exon 20 insertion mutations).

NCT04044170
Conditions
  1. NSCLC
Interventions
  1. Drug: Poziotinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Exclusion Criteria: 1. Patient has EGFR T790M mutation or any other acquired EGFR exon 20 point mutation 2. Patient has had previous treatment with poziotinib or any other EGFR or HER2 exon 20 insertion mutation-selective tyrosine kinase inhibitor (TKI) prior to study participation. --- T790M ---

Primary Outcomes

Description: The proportion of subjects who achieve Complete Response (CR) and Partial Response (PR) by the best response from the first dose of poziotinib to the end of study.

Measure: Objective response rate (ORR)

Time: 24 months

Secondary Outcomes

Description: The proportion of subjects who achieve CR, PR, and Stable Disease (SD) by the best response from the first dose of poziotinib to the end of study.

Measure: Disease Control Rate (DCR)

Time: 24 months

Description: Number of days from the date that measurement criteria are first met for CR or PR (whichever status is recorded first) until the first subsequent date that progressive disease or death is documented.

Measure: Duration of Response (DoR)

Time: 24 months

Description: Number of days from the treatment start date to the date of documented disease progression or death due to any cause.

Measure: Progression-free Survival (PFS)

Time: 24 months

234 A Multicentre, Open-Label, Exploratory Phase Ib Clinical Study to Assess Safety and Efficacy of an EGFR Tyrosine Kinase Inhibitor in Combination With EGF Pathway Targeting Immunisation (EGF-PTI) in Treatment-Naïve Patients With EGFR Mutant NSCLC. The EPICAL Study

This is a multicentre, open-label, uncontrolled, Phase Ib clinical study. Patients who give informed consent will be screened for the study, including genotyping of the tumour and baseline characteristics. Eligible patients will receive a single pre-treatment of low dose of intravenous cyclophosphamide 200 mg/m2 (Day -3). Patients will commence daily oral therapy with the EGFR TKI afatinib as soon as possible, preferably on the same day as low dose cyclophosphamide. Afatinib will be prescribed according to the Summary of Product Characteristics (SmPC) of the product, and will continue in nominal 21-day cycles for as long as clinically indicated. The first day of dosing with EGF-PTI will be designated Day 1. Immunisation with EGF-PTI will commence 3 days after low dose cyclophosphamide and commencement of EGFR TKI, and will be repeated on Day 14, Day 28, Day 43, and Day 92. After the 5 th vaccination, patients will be followed up every 6 weeks for basic safety data and every 3 months for complete efficacy data, safety data, and maintenance (reduced) doses of EGF-PTI. Patients will continue in the study until disease progression, death, safety concerns (in the opinion of the investigator), non-compliance with the protocol, the patient withdraws from the study, 1 year after randomisation of the last patient, or the study is stopped the sponsor, whichever occurs sooner

NCT03623750
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Drug: EGFR-TK Inhibitor
  2. Biological: EGF-PTI
  3. Drug: Cyclophosphamide
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

4. Centrally confirmed EGFR exon 19 deletion, exon 21 (L858R, L861Q) or exon 18 (G719X) mutation before treatment (concomitant T790M pre-treatment mutation is permitted). 5. Eastern Cooperative Oncology Group (ECOG) performance status 0-1. --- L858R --- --- L861Q --- --- T790M ---

Primary Outcomes

Description: Evaluate the safety and tolerability of epidermal growth factor receptor tyrosine kinase inhibitor plus EGF-PTI in newly diagnosed patients with advanced or metastatic non-squamous NSCLC with EGFR mutations who are not candidates for local curative treatment throughout the patient's participation in the study.

Measure: Frequency and severity of Adverse Events

Time: 36 months

Secondary Outcomes

Description: Evaluate the anti-tumor activity of epidermal growth factor receptor tyrosine kinase inhibitor plus EGF-PTI in terms of clinical response. Every 3 months after the first dose of EGF-PTI and throughout the patient's participation in the study.

Measure: Clinical response efficacy assessments

Time: 36 months

235 A Phase II Trial of Gefitinib in Squamous NSCLC Patients Who Failed First-Line Chemotherapy

Gefitinib was the first epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) approved for the treatment of advanced non-small cell lung cancer (NSCLC). Results from two randomised phase II trials (IDEAL 1 and 2) suggested that gefitinib was efficacious and less toxic, compared with previous results, than was chemotherapy in patients with previously-treated non-small-cell lung cancer. Two phase III trials of gefitinib in advanced non-small-cell lung cancer followed on from the IDEAL phase II studies: Iressa Survival Evaluation in Lung cancer (ISEL) and Iressa NSCLC Trial Evaluating REsponse and Survival versus Taxotere (INTEREST). Although the phase III ISEL trial failed to prove the superiority of gefitinib treatment compared to placebo in previously treated patients, a subgroup analysis demonstrated improved survival in particular populations (Asians and non-smokers). The INTEREST study compared an EGFR tyrosine kinase inhibitor with chemotherapy in pretreated advanced non-small-cell lung cancer. In INTEREST, survival was similar for gefitinib and docetaxel in almost all subgroups; no EGFR-related biomarker or any clinical factor (including female sex, adenocarcinoma histology, never-smoker, and Asian ethnicity) appeared to be predictive of a greater survival benefit for gefitinib versus docetaxel. However, these factors may still be predictive of a greater survival benefit for gefitinib and/or docetaxel versus best supportive care; alternatively, they may just be good prognostic factors. Progression free survival and overall response rate was no statistically significant difference between gefitinib and docetaxel. This suggests gefitinib can provide similar overall survival to docetaxel in pretreated advanced non-small-cell lung cancer patients. These studies have demonstrated that gefitinib is effective for the second-line treatment of NSCLC. Now, gefitinib is recommended in advanced and metastatic NSCLC as second-line chemotherapy. But, there was no prospective study with gefitinib in NSCLC wih squamous cell histology. This trial will investigate the efficacy and safety of gefitinib in locally advanced, metastatic NSCLC patients with squamous cell histology who have failed first-line chemotherapy.

NCT01485809
Conditions
  1. Squamous Cell Carcinoma of Bronchus
Interventions
  1. Drug: Gefitinib
MeSH:Carcinoma, Bronchogenic

Presence of EGFR mutation reported to confer resistance to EGFR TKI: exon 20 point mutation (T790M or S768I EGFR) or exon 20 insertion 11. --- T790M ---

Primary Outcomes

Measure: Disease control rate (complete response, partial response, or stable disease) at 8 weeks

Time: 8 weeks

Secondary Outcomes

Description: safety & tolerability: NCI CTCAE version 4.0

Measure: number of participants with adverse events as a measure of safety and tolerability

Time: 2 years

236 Phase II Trial of Erlotinib and BKM120 in Patients With Advanced Non Small Cell Lung Cancer Previously Sensitive to Erlotinib

Preclinical data in lung cancer cell lines showed that EGFR mutation can potentially be a positive predictor for sensitivity to BKM120. Furthermore, when the erlotinib-resistant model H1975 (LR858 and T790M mutation) was treated with BKM120, significant tumor control was observed (Novartis internal data). Therefore, combining BKM120 with erlotinib could potentially down-modulate PI3K-Akt activity resulting in a synergistic effect on cell growth inhibition and enhancing the response to erlotinib.

NCT01487265
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: BKM120 and Erlotinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Furthermore, when the erlotinib-resistant model H1975 (LR858 and T790M mutation) was treated with BKM120, significant tumor control was observed (Novartis internal data). --- T790M ---

Primary Outcomes

Description: Percentage of patients who are alive and progression-free at 3 months (APF3) from first treatment.

Measure: Progression Free Survival at 3 Months

Time: 3 months

Secondary Outcomes

Description: Defined as the time from first treatment until death from any cause.

Measure: Overall Survival

Time: every 3 months after study treatment, projected 24 months

Description: Defined as the time from complete or partial response (CR or PR) until objective tumor progression. Tumor measurements will be obtained using CT scans of chest, abdomen and pelvis and assessed per RECIST v 1.1. Complete response (CR) is defined as a disappearance of all lesions; partial response (PR) is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking the baseline sum LD as reference. Stable Disease (SD) is defined as neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for progressive disease, taking as reference the smallest (nadir) sum LD since start of treatment.

Measure: Duration of Response

Time: every 8 weeks for 12 months, then every 12 weeks thereafter, estimated 18 months

Description: Defined as the percentage of complete and partial responses (CR + PR) among all patients. Complete response (CR) is defined as a disappearance of all lesions; partial response (PR) is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking the baseline sum LD as reference. Stable Disease (SD) is defined as neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for progressive disease, taking as reference the smallest (nadir) sum LD since start of treatment.

Measure: Objective Response Rate

Time: every 8 weeks for 12 months, then every 12 weeks thereafter, estimated 18 months

Description: Adverse events will be graded using CTCAE v4.3. and will be collected until 30 days after the discontinuation of study treatment for each participant. A non-serious adverse event is any untoward medical occurrence. A serious adverse event (SAE) is an event that meets one or more of the following: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; requires intervention to prevent permanent impairment or damage. Specific AE and SAE terms are provided in the Adverse event module.

Measure: Number of Participants With Serious and Non-serious Adverse Events as a Measure of Safety.

Time: Every 2 weeks for 8 weeks, then every 8 weeks thereafter, estimated 24 months

237 A Phase IB/II, Open Label, Multicenter Study of Selumetinib Administered Orally in Combination With Gefitinib in Patients With EGFR-mutated Non-small Cell Lung Cancer Who Have Developed Acquired Resistance of EGFR Inhibitor Treatment

This is an open-label, non-randomized, multicenter phase Ib/II study, which is composed of a phase Ib dose escalation part and a phase II dose expansion part. Patients will receive selumetinib in combination with gefitinib 250mg daily. This study will enroll EGFR-mutated NSCLC patients who have developed acquired resistance to EGFR TKI treatment.

NCT02025114
Conditions
  1. Non-small Cell Lung Cancer (NSCLC)
Interventions
  1. Drug: selumetinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

In the expansion phase, 10 patients with T790M and 10 patients without T790M will be enrolled. --- T790M ---

In the expansion phase, 10 patients with T790M and 10 patients without T790M will be enrolled. --- T790M --- --- T790M ---

Primary Outcomes

Description: Frequency and characteristics of DLTs to the selumetinib and gefitinib combination using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v.4.0. (an expected average of 18 weeks) If one patient experiences a DLT in a group of 3 or more evaluable patients, then the cohort will be expanded to include 6 evaluable patients. If only one DLT is observed in the complete cohort of 6 evaluable patients, then dose escalation may occur.

Measure: To determine the MTD and/or RP2D

Time: an expected average of 18 weeks

Secondary Outcomes

Description: to estimate overall clinical activity of selumetinib combined with gefitinib in EGFR-mutated NSCLC patients who have acquired resistance to EGFR TKIs

Measure: Overall Response Rate (ORR)

Time: Patients will be followed up for 2 years(post disease progression)

238 INHERIT EGFR - INvestigating HEreditary RIsk From T790M: A Multi-Centered Study to Identify and Characterize Individuals Carrying Germline EGFR Mutations

Lung cancer is a common malignancy that is associated with cigarette smoking but can also affect individuals who never smoked. It is not well understood whether there are hereditary risk factors that influence the risk of lung cancer. It has been recently found that a small number of families have an inherited (passed from parent to child) change in one of their genes that may contribute to an increased tendency to develop lung cancers, even in never smokers. In some lung cancer patients this gene, called "EGFR", contains a DNA change known as an "inherited EGFR mutation". Early data indicate that these inherited EGFR mutations may be associated with an increased risk of lung cancer. So far, only a small number of families have been found to carry inherited EGFR mutations. For this reason the risk of lung cancer associated with inherited EGFR mutations is not well understood. Understanding the risk may help investigators find ways of detecting lung cancer sooner or reducing the risk of developing lung cancer. It was recently discovered that lung cancer patients who are found to carry one rare EGFR mutation in their cancer cells, called "T790M", have an increased risk of carrying an inherited EGFR mutation in their normal cells as well. This represents a new strategy for finding individuals and families carrying inherited EGFR mutations. This research study is designed to find cancer patients whose tumors have this EGFR mutation, T790M, to find out if they also have an inherited EGFR mutation. Subjects will not have to undergo a biopsy to participate in this research study. Investigators will collect a saliva specimen from patients with a T790M in their cancer to find out if they also have an inherited EGFR mutation. Study participants found or known to carry an inherited EGFR mutation will have the option of offering their close relative the opportunity to also participate in this study. Close relatives can consider testing to see if they also carry the inherited mutation in their normal cells. Once investigators have identified individuals and relatives that carry inherited EGFR mutations in their genes, investigators will then try to understand the risk of lung cancer and other cancers. Individuals with inherited EGFR mutations will also have the opportunity to participate in future studies related to cancer and other diseases. This study is being funded in part by the Conquer Cancer Foundation of ASCO and the Bonnie J. Addario Lung Cancer Foundation.

NCT01754025
Conditions
  1. Lung Cancer

INHERIT EGFR - INvestigating HEreditary RIsk From T790M: A Multi-Centered Study to Identify and Characterize Individuals Carrying Germline EGFR Mutations. --- T790M ---

It was recently discovered that lung cancer patients who are found to carry one rare EGFR mutation in their cancer cells, called "T790M", have an increased risk of carrying an inherited EGFR mutation in their normal cells as well. --- T790M ---

This research study is designed to find cancer patients whose tumors have this EGFR mutation, T790M, to find out if they also have an inherited EGFR mutation. --- T790M ---

Investigators will collect a saliva specimen from patients with a T790M in their cancer to find out if they also have an inherited EGFR mutation. --- T790M ---

To determine the prevalence of germline EGFR mutations in lung cancer patients with EGFR T790M mutations in their tumor and in relatives of carriers of germline EGFR mutations. --- T790M ---

Explore Relationship Between High Allelic Fraction T790M in plasma genotyping and germline mutations. --- T790M ---

To explore the relationship between high allelic fraction T790M on plasma genotyping and presence of an underlying germline EGFR T790M mutation. --- T790M ---

To explore the relationship between high allelic fraction T790M on plasma genotyping and presence of an underlying germline EGFR T790M mutation. --- T790M --- --- T790M ---

Inclusion Criteria: To participate in this study a subject must meet the eligibility of one of the following cohorts: Cohort 1 - Cancer patients with T790M in their tumor must both: - Have a diagnosis of cancer of any type (lung cancer or other) - Have an EGFR mutation identified. --- T790M ---

Either EGFR T790M identified on tumor genotyping of their cancer OR on quantitative plasma genotyping with evidence of high level (>40% allelic fraction) EGFR T790M OR - Another EGFR mutation previously reported as germline detected on tumor genotyping of their cancer Cohort 2 - Relatives of carriers of germline EGFR mutations are eligible as follows: - First-degree or second-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) - Third-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) if the relative has a personal history of lung cancer or another malignancy Cohort 3 - Individuals already known to carry a germline EGFR mutation must: - Have a known germline EGFR mutation (either T790M or other novel germline EGFR mutation) Exclusion Criteria: - Subjects with lung cancer and an acquired T790M mutation first detected after exposure to an EGFR tyrosine kinase inhibitor such as erlotinib or gefitinib - Subjects who are too ill to complete the study questionnaire or provide the necessary specimen for testing - Subjects who are unable to give informed consent - Subjects who are unable to speak or read English or Brazilian Portuguese - Subjects under the age of 18 Inclusion Criteria: To participate in this study a subject must meet the eligibility of one of the following cohorts: Cohort 1 - Cancer patients with T790M in their tumor must both: - Have a diagnosis of cancer of any type (lung cancer or other) - Have an EGFR mutation identified. --- T790M ---

Either EGFR T790M identified on tumor genotyping of their cancer OR on quantitative plasma genotyping with evidence of high level (>40% allelic fraction) EGFR T790M OR - Another EGFR mutation previously reported as germline detected on tumor genotyping of their cancer Cohort 2 - Relatives of carriers of germline EGFR mutations are eligible as follows: - First-degree or second-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) - Third-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) if the relative has a personal history of lung cancer or another malignancy Cohort 3 - Individuals already known to carry a germline EGFR mutation must: - Have a known germline EGFR mutation (either T790M or other novel germline EGFR mutation) Exclusion Criteria: - Subjects with lung cancer and an acquired T790M mutation first detected after exposure to an EGFR tyrosine kinase inhibitor such as erlotinib or gefitinib - Subjects who are too ill to complete the study questionnaire or provide the necessary specimen for testing - Subjects who are unable to give informed consent - Subjects who are unable to speak or read English or Brazilian Portuguese - Subjects under the age of 18 Inclusion Criteria: To participate in this study a subject must meet the eligibility of one of the following cohorts: Cohort 1 - Cancer patients with T790M in their tumor must both: - Have a diagnosis of cancer of any type (lung cancer or other) - Have an EGFR mutation identified. --- T790M --- --- T790M ---

Either EGFR T790M identified on tumor genotyping of their cancer OR on quantitative plasma genotyping with evidence of high level (>40% allelic fraction) EGFR T790M OR - Another EGFR mutation previously reported as germline detected on tumor genotyping of their cancer Cohort 2 - Relatives of carriers of germline EGFR mutations are eligible as follows: - First-degree or second-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) - Third-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) if the relative has a personal history of lung cancer or another malignancy Cohort 3 - Individuals already known to carry a germline EGFR mutation must: - Have a known germline EGFR mutation (either T790M or other novel germline EGFR mutation) Exclusion Criteria: - Subjects with lung cancer and an acquired T790M mutation first detected after exposure to an EGFR tyrosine kinase inhibitor such as erlotinib or gefitinib - Subjects who are too ill to complete the study questionnaire or provide the necessary specimen for testing - Subjects who are unable to give informed consent - Subjects who are unable to speak or read English or Brazilian Portuguese - Subjects under the age of 18 Inclusion Criteria: To participate in this study a subject must meet the eligibility of one of the following cohorts: Cohort 1 - Cancer patients with T790M in their tumor must both: - Have a diagnosis of cancer of any type (lung cancer or other) - Have an EGFR mutation identified. --- T790M --- --- T790M --- --- T790M ---

Either EGFR T790M identified on tumor genotyping of their cancer OR on quantitative plasma genotyping with evidence of high level (>40% allelic fraction) EGFR T790M OR - Another EGFR mutation previously reported as germline detected on tumor genotyping of their cancer Cohort 2 - Relatives of carriers of germline EGFR mutations are eligible as follows: - First-degree or second-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) - Third-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) if the relative has a personal history of lung cancer or another malignancy Cohort 3 - Individuals already known to carry a germline EGFR mutation must: - Have a known germline EGFR mutation (either T790M or other novel germline EGFR mutation) Exclusion Criteria: - Subjects with lung cancer and an acquired T790M mutation first detected after exposure to an EGFR tyrosine kinase inhibitor such as erlotinib or gefitinib - Subjects who are too ill to complete the study questionnaire or provide the necessary specimen for testing - Subjects who are unable to give informed consent - Subjects who are unable to speak or read English or Brazilian Portuguese - Subjects under the age of 18 Inclusion Criteria: To participate in this study a subject must meet the eligibility of one of the following cohorts: Cohort 1 - Cancer patients with T790M in their tumor must both: - Have a diagnosis of cancer of any type (lung cancer or other) - Have an EGFR mutation identified. --- T790M --- --- T790M --- --- T790M --- --- T790M ---

Either EGFR T790M identified on tumor genotyping of their cancer OR on quantitative plasma genotyping with evidence of high level (>40% allelic fraction) EGFR T790M OR - Another EGFR mutation previously reported as germline detected on tumor genotyping of their cancer Cohort 2 - Relatives of carriers of germline EGFR mutations are eligible as follows: - First-degree or second-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) - Third-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) if the relative has a personal history of lung cancer or another malignancy Cohort 3 - Individuals already known to carry a germline EGFR mutation must: - Have a known germline EGFR mutation (either T790M or other novel germline EGFR mutation) Exclusion Criteria: - Subjects with lung cancer and an acquired T790M mutation first detected after exposure to an EGFR tyrosine kinase inhibitor such as erlotinib or gefitinib - Subjects who are too ill to complete the study questionnaire or provide the necessary specimen for testing - Subjects who are unable to give informed consent - Subjects who are unable to speak or read English or Brazilian Portuguese - Subjects under the age of 18 Inclusion Criteria: To participate in this study a subject must meet the eligibility of one of the following cohorts: Cohort 1 - Cancer patients with T790M in their tumor must both: - Have a diagnosis of cancer of any type (lung cancer or other) - Have an EGFR mutation identified. --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M ---

Either EGFR T790M identified on tumor genotyping of their cancer OR on quantitative plasma genotyping with evidence of high level (>40% allelic fraction) EGFR T790M OR - Another EGFR mutation previously reported as germline detected on tumor genotyping of their cancer Cohort 2 - Relatives of carriers of germline EGFR mutations are eligible as follows: - First-degree or second-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) - Third-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) if the relative has a personal history of lung cancer or another malignancy Cohort 3 - Individuals already known to carry a germline EGFR mutation must: - Have a known germline EGFR mutation (either T790M or other novel germline EGFR mutation) Exclusion Criteria: - Subjects with lung cancer and an acquired T790M mutation first detected after exposure to an EGFR tyrosine kinase inhibitor such as erlotinib or gefitinib - Subjects who are too ill to complete the study questionnaire or provide the necessary specimen for testing - Subjects who are unable to give informed consent - Subjects who are unable to speak or read English or Brazilian Portuguese - Subjects under the age of 18 Inclusion Criteria: To participate in this study a subject must meet the eligibility of one of the following cohorts: Cohort 1 - Cancer patients with T790M in their tumor must both: - Have a diagnosis of cancer of any type (lung cancer or other) - Have an EGFR mutation identified. --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M ---

Either EGFR T790M identified on tumor genotyping of their cancer OR on quantitative plasma genotyping with evidence of high level (>40% allelic fraction) EGFR T790M OR - Another EGFR mutation previously reported as germline detected on tumor genotyping of their cancer Cohort 2 - Relatives of carriers of germline EGFR mutations are eligible as follows: - First-degree or second-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) - Third-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) if the relative has a personal history of lung cancer or another malignancy Cohort 3 - Individuals already known to carry a germline EGFR mutation must: - Have a known germline EGFR mutation (either T790M or other novel germline EGFR mutation) Exclusion Criteria: - Subjects with lung cancer and an acquired T790M mutation first detected after exposure to an EGFR tyrosine kinase inhibitor such as erlotinib or gefitinib - Subjects who are too ill to complete the study questionnaire or provide the necessary specimen for testing - Subjects who are unable to give informed consent - Subjects who are unable to speak or read English or Brazilian Portuguese - Subjects under the age of 18 Inclusion Criteria: To participate in this study a subject must meet the eligibility of one of the following cohorts: Cohort 1 - Cancer patients with T790M in their tumor must both: - Have a diagnosis of cancer of any type (lung cancer or other) - Have an EGFR mutation identified. --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M ---

Either EGFR T790M identified on tumor genotyping of their cancer OR on quantitative plasma genotyping with evidence of high level (>40% allelic fraction) EGFR T790M OR - Another EGFR mutation previously reported as germline detected on tumor genotyping of their cancer Cohort 2 - Relatives of carriers of germline EGFR mutations are eligible as follows: - First-degree or second-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) - Third-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) if the relative has a personal history of lung cancer or another malignancy Cohort 3 - Individuals already known to carry a germline EGFR mutation must: - Have a known germline EGFR mutation (either T790M or other novel germline EGFR mutation) Exclusion Criteria: - Subjects with lung cancer and an acquired T790M mutation first detected after exposure to an EGFR tyrosine kinase inhibitor such as erlotinib or gefitinib - Subjects who are too ill to complete the study questionnaire or provide the necessary specimen for testing - Subjects who are unable to give informed consent - Subjects who are unable to speak or read English or Brazilian Portuguese - Subjects under the age of 18 Lung Cancer If a subject have lung cancer or another cancer carrying a T790M mutation in the EGFR gene, he/she may be eligible to participate in this research study. --- T790M ---

Either EGFR T790M identified on tumor genotyping of their cancer OR on quantitative plasma genotyping with evidence of high level (>40% allelic fraction) EGFR T790M OR - Another EGFR mutation previously reported as germline detected on tumor genotyping of their cancer Cohort 2 - Relatives of carriers of germline EGFR mutations are eligible as follows: - First-degree or second-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) - Third-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) if the relative has a personal history of lung cancer or another malignancy Cohort 3 - Individuals already known to carry a germline EGFR mutation must: - Have a known germline EGFR mutation (either T790M or other novel germline EGFR mutation) Exclusion Criteria: - Subjects with lung cancer and an acquired T790M mutation first detected after exposure to an EGFR tyrosine kinase inhibitor such as erlotinib or gefitinib - Subjects who are too ill to complete the study questionnaire or provide the necessary specimen for testing - Subjects who are unable to give informed consent - Subjects who are unable to speak or read English or Brazilian Portuguese - Subjects under the age of 18 Lung Cancer If a subject have lung cancer or another cancer carrying a T790M mutation in the EGFR gene, he/she may be eligible to participate in this research study. --- T790M --- --- T790M ---

Either EGFR T790M identified on tumor genotyping of their cancer OR on quantitative plasma genotyping with evidence of high level (>40% allelic fraction) EGFR T790M OR - Another EGFR mutation previously reported as germline detected on tumor genotyping of their cancer Cohort 2 - Relatives of carriers of germline EGFR mutations are eligible as follows: - First-degree or second-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) - Third-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) if the relative has a personal history of lung cancer or another malignancy Cohort 3 - Individuals already known to carry a germline EGFR mutation must: - Have a known germline EGFR mutation (either T790M or other novel germline EGFR mutation) Exclusion Criteria: - Subjects with lung cancer and an acquired T790M mutation first detected after exposure to an EGFR tyrosine kinase inhibitor such as erlotinib or gefitinib - Subjects who are too ill to complete the study questionnaire or provide the necessary specimen for testing - Subjects who are unable to give informed consent - Subjects who are unable to speak or read English or Brazilian Portuguese - Subjects under the age of 18 Lung Cancer If a subject have lung cancer or another cancer carrying a T790M mutation in the EGFR gene, he/she may be eligible to participate in this research study. --- T790M --- --- T790M --- --- T790M ---

Either EGFR T790M identified on tumor genotyping of their cancer OR on quantitative plasma genotyping with evidence of high level (>40% allelic fraction) EGFR T790M OR - Another EGFR mutation previously reported as germline detected on tumor genotyping of their cancer Cohort 2 - Relatives of carriers of germline EGFR mutations are eligible as follows: - First-degree or second-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) - Third-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) if the relative has a personal history of lung cancer or another malignancy Cohort 3 - Individuals already known to carry a germline EGFR mutation must: - Have a known germline EGFR mutation (either T790M or other novel germline EGFR mutation) Exclusion Criteria: - Subjects with lung cancer and an acquired T790M mutation first detected after exposure to an EGFR tyrosine kinase inhibitor such as erlotinib or gefitinib - Subjects who are too ill to complete the study questionnaire or provide the necessary specimen for testing - Subjects who are unable to give informed consent - Subjects who are unable to speak or read English or Brazilian Portuguese - Subjects under the age of 18 Lung Cancer If a subject have lung cancer or another cancer carrying a T790M mutation in the EGFR gene, he/she may be eligible to participate in this research study. --- T790M --- --- T790M --- --- T790M --- --- T790M ---

Either EGFR T790M identified on tumor genotyping of their cancer OR on quantitative plasma genotyping with evidence of high level (>40% allelic fraction) EGFR T790M OR - Another EGFR mutation previously reported as germline detected on tumor genotyping of their cancer Cohort 2 - Relatives of carriers of germline EGFR mutations are eligible as follows: - First-degree or second-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) - Third-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) if the relative has a personal history of lung cancer or another malignancy Cohort 3 - Individuals already known to carry a germline EGFR mutation must: - Have a known germline EGFR mutation (either T790M or other novel germline EGFR mutation) Exclusion Criteria: - Subjects with lung cancer and an acquired T790M mutation first detected after exposure to an EGFR tyrosine kinase inhibitor such as erlotinib or gefitinib - Subjects who are too ill to complete the study questionnaire or provide the necessary specimen for testing - Subjects who are unable to give informed consent - Subjects who are unable to speak or read English or Brazilian Portuguese - Subjects under the age of 18 Lung Cancer If a subject have lung cancer or another cancer carrying a T790M mutation in the EGFR gene, he/she may be eligible to participate in this research study. --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M ---

Either EGFR T790M identified on tumor genotyping of their cancer OR on quantitative plasma genotyping with evidence of high level (>40% allelic fraction) EGFR T790M OR - Another EGFR mutation previously reported as germline detected on tumor genotyping of their cancer Cohort 2 - Relatives of carriers of germline EGFR mutations are eligible as follows: - First-degree or second-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) - Third-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) if the relative has a personal history of lung cancer or another malignancy Cohort 3 - Individuals already known to carry a germline EGFR mutation must: - Have a known germline EGFR mutation (either T790M or other novel germline EGFR mutation) Exclusion Criteria: - Subjects with lung cancer and an acquired T790M mutation first detected after exposure to an EGFR tyrosine kinase inhibitor such as erlotinib or gefitinib - Subjects who are too ill to complete the study questionnaire or provide the necessary specimen for testing - Subjects who are unable to give informed consent - Subjects who are unable to speak or read English or Brazilian Portuguese - Subjects under the age of 18 Lung Cancer If a subject have lung cancer or another cancer carrying a T790M mutation in the EGFR gene, he/she may be eligible to participate in this research study. --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M ---

Either EGFR T790M identified on tumor genotyping of their cancer OR on quantitative plasma genotyping with evidence of high level (>40% allelic fraction) EGFR T790M OR - Another EGFR mutation previously reported as germline detected on tumor genotyping of their cancer Cohort 2 - Relatives of carriers of germline EGFR mutations are eligible as follows: - First-degree or second-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) - Third-degree relatives of an individual known to carry a germline EGFR mutation (either T790M or other novel germline EGFR mutation) if the relative has a personal history of lung cancer or another malignancy Cohort 3 - Individuals already known to carry a germline EGFR mutation must: - Have a known germline EGFR mutation (either T790M or other novel germline EGFR mutation) Exclusion Criteria: - Subjects with lung cancer and an acquired T790M mutation first detected after exposure to an EGFR tyrosine kinase inhibitor such as erlotinib or gefitinib - Subjects who are too ill to complete the study questionnaire or provide the necessary specimen for testing - Subjects who are unable to give informed consent - Subjects who are unable to speak or read English or Brazilian Portuguese - Subjects under the age of 18 Lung Cancer If a subject have lung cancer or another cancer carrying a T790M mutation in the EGFR gene, he/she may be eligible to participate in this research study. --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M ---

This information will be used to answer additional questions about cancers carrying EGFR T790M mutations. --- T790M ---

Primary Outcomes

Description: To determine the prevalence of germline EGFR mutations in lung cancer patients with EGFR T790M mutations in their tumor and in relatives of carriers of germline EGFR mutations

Measure: Prevalence of EGFR mutations

Time: 2 years

Secondary Outcomes

Description: To make a preliminary assessment of the natural history of lung cancers occurring in patients with germline EGFR mutations

Measure: Preliminary Assessment of History of Lung Cancers

Time: 2 years

Description: To generate an initial estimate of the prevalence of CT-detected lung nodules in individuals with germline EGFR mutations

Measure: Estimate of Prevalence of Lung Nodules

Time: 2 years

Description: To study EGFR expression in skin biopsies from patients on study

Measure: Study EGFR Expression in Skin Biopsies

Time: 2 years

Description: To explore the relationship between high allelic fraction T790M on plasma genotyping and presence of an underlying germline EGFR T790M mutation

Measure: Explore Relationship Between High Allelic Fraction T790M in plasma genotyping and germline mutations

Time: 2 years

Description: To study individuals and families with rare germline mutations, such as EGFR V843I and EGFR R776H

Measure: Examine Lung Cancer Risk Associated with Other Germline Mutations

Time: 2 years

239 A Prospective, National, Multi-centric, Non-interventional Study of First Line Osimertinib in Chinese Patients With Locally Advanced/Metastatic,EGFR Mutation-positive NSCLC in Real World Setting

The results of phase III FLAURA study showed a significant PFS benefit for first-line Osimertinib versus standard EGFR-TKIs in patients with EGFR mutation-positive NSCLC, the median PFS was 18.9 months and 10.2 months, respectively. However, only 136 Chinese patients were enrolled in FLAURA study. The objectives of this study are to assess the efficacy and safety of Osimertinib in a real world setting in Chinese patients with locally advanced or metastatic, treatment naïve, epidermal growth factor receptor (EGFR) mutation-positive Non-Small Cell Lung Cancer (NSCLC).

NCT04391283
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Drug: Osimertinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Lost to follow-up patients who have not progressed will be censored at last documented contact with patient status "survival".. de novo T790M mutation rate. --- T790M ---

The mutation rate of de novo T790M test by high sensitive technique (analyzed by Next Generation Sequencing platform). --- T790M ---

de novo T790M. --- T790M ---

Primary Outcomes

Description: Time to discontinuation (TTD), is defined as the time from the date of first dose of Osimertinib in this study until the date of Osimertinib discontinuation for any reason including disease progression, treatment toxicity, death or other reason as recorded in CRF. Subjects who are still on treatment at the time of analysis will be censored at the date of last dose received. Lost to follow-up patients will be censored at last documented contact with patient status "on treatment".

Measure: Time to discontinuation (TTD)

Time: from the date of first dose of Osimertinib in this study until the date of Osimertinib discontinuation for any reason including disease progression, treatment toxicity, death or other reason as recorded in CRF, assessed up to 36 months.

Secondary Outcomes

Description: Progression-free survival (PFS), is defined as the time from the date of first dose of Osimertinib in this study until the date of disease progression as recorded in CRF or death (by any cause in the absence of progression) regardless of whether the subject withdraws from therapy or receives another anti-cancer therapy prior to progression, which usually refer to Response Evaluation Criteria In Solid Tumours (RECIST) in clinical practice. Subjects who have not progressed or died at the time of analysis will be censored at the time of the latest date of assessment. If the subject has no evaluable visits after the baseline visit, they will be censored at 0 days unless they die before the planned visit after the baseline visit. Lost to follow-up patients who have not progressed will be censored at last documented contact with patient status "non-progression". Progression-free survival rate (PFS rate), is defined as the percentage of patients who do not progress on Osimertinib treatment

Measure: Progression-free survival (PFS) and Progression-free survival rate (PFS rate)

Time: from the date of first dose of Osimertinib in this study until the date of disease progression, assessed up to 36 months.

Description: Objective Response Rate (ORR), is defined as the percentage of patients with complete response or partial response by investigator assessment as recorded in the CRF, which usually refer to Response Evaluation Criteria In Solid Tumours (RECIST) in clinical practice. Disease Control Rate (DCR), is defined as the percentage of patients with non-progression by investigator assessment as recorded in the CRF, which usually refer to Response Evaluation Criteria In Solid Tumours (RECIST) in clinical practice.

Measure: Objective Response Rate (ORR) and Disease Control Rate (DCR)

Time: from the date of first dose of Osimertinib, assessed up to 6 months.

Description: Defined as the proportion of patients who are still alive at a particular time in the study (eg, 1 year or 2 years). The patient should be contacted 1 week after the termination of the corresponding OS analysis data to determine survival status. Lost to follow-up patients who have not progressed will be censored at last documented contact with patient status "survival".

Measure: Overall survival rate (OS rate)

Time: from the date of first dose of Osimertinib in this study until the death of patients,assessed up to 48 months.

Description: The mutation rate of de novo T790M test by high sensitive technique (analyzed by Next Generation Sequencing platform). de novo T790M

Measure: de novo T790M mutation rate

Time: the baseline and at the time of progression, assessed up to 36 months.

Description: Incidence of Adverse Events (AEs): Nature, incidence, severity and seriousness of adverse events, Incidence of Serious Adverse Events (SAEs), which usually be graded by CTCAE v4.03 based on current clinical practice.

Measure: Adverse events/Serious adverse events

Time: from the date of first dose of Osimertinib in this study assessed up to 36 months.

240 To Assess the Safety and Efficacy of Third-line and Above Therapy of Patients With Local Advanced or Metastatic NSCLC With Combined Treatment With Launched Recombinant Humanized Anti-PD-1 Monoclonal Antibody and Donafenib Tosilate

To assess the safety and efficacy of third-line and above therapy of patients with local advanced or metastatic non-small cell lung cancer (NSCLC) with combined treatment with launched recombinant humanized anti-PD-1 monoclonal antibody and Donafenib Tosilate

NCT04059874
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: donafenib tablets
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Chemotherapy treatments must include a two-drug regimen containing platinum, patients with EGFR TKI drug resistance and unknow T790M mutation, after AZD9291 treatment patients with T790M mutation could be enrolled 4, At least one measurable lesion as defined by RECIST 1.1. --- T790M ---

Chemotherapy treatments must include a two-drug regimen containing platinum, patients with EGFR TKI drug resistance and unknow T790M mutation, after AZD9291 treatment patients with T790M mutation could be enrolled 4, At least one measurable lesion as defined by RECIST 1.1. --- T790M --- --- T790M ---

Primary Outcomes

Description: safety assessments

Measure: safety assessments

Time: From signing ICF to 30 days after the end of treatment

Secondary Outcomes

Description: progression-free survival (PFS)

Measure: Effective evaluation

Time: Continue treatment until the end of treatment,an average of 12 months

Measure: Overall response rate

Time: Continue treatment until the end of treatment,an average of 12 months

Measure: Disease control rate

Time: Continue treatment until the end of treatment,an average of 12 months

241 Efficacy and Safety of the Combination of Anlotinib and JS001 in EGFR-TKI Resistant T790M-Negative NSCLC

This study is designed to evaluate the efficacy and safety of the combination of Anlotinb and JS001 in EGFR-TKI resistant T790M-negative NSCLC patients.

NCT04116918
Conditions
  1. NSCLC Stage IV
  2. EGFR T790M-negative
  3. Anlotinib
  4. JS001
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Efficacy and Safety of the Combination of Anlotinib and JS001 in EGFR-TKI Resistant T790M-Negative NSCLC. --- T790M ---

Efficacy and Safety of the Combination of Anlotinib and JS001 in EGFR-TKI Resistant T790M-Negative NSCLC This study is designed to evaluate the efficacy and safety of the combination of Anlotinb and JS001 in EGFR-TKI resistant T790M-negative NSCLC patients. --- T790M ---

Efficacy and Safety of the Combination of Anlotinib and JS001 in EGFR-TKI Resistant T790M-Negative NSCLC This study is designed to evaluate the efficacy and safety of the combination of Anlotinb and JS001 in EGFR-TKI resistant T790M-negative NSCLC patients. --- T790M --- --- T790M ---

Inclusion Criteria: - Adult patients >=18 years of age - Inoperable locally advanced, recurrent, and/or metastatic NSCLC patients with EGFR sensitive mutation - EGFR-TKI resistent - EGFR T790M negative - Expected survival ≥ 3 month; - ECOG / PS score: 0-2; - the main organ function to meet the following criteria: HB ≥ 90g / L, ANC ≥ 1.5 × 109 / L, PLT ≥ 80 × 109 / L,BIL <1.5 times the upper limit of normal (ULN); Liver ALT and AST <2.5 × ULN and if liver metastases, ALT and AST <5 × ULN; Serum Cr ≤ 1 × ULN, endogenous creatinine clearance ≥50ml/min Exclusion Criteria: - EGFR-T790M positive - with druggable gene alteration; - Patient can not comply with research program requirements or follow-up; Inclusion Criteria: - Adult patients >=18 years of age - Inoperable locally advanced, recurrent, and/or metastatic NSCLC patients with EGFR sensitive mutation - EGFR-TKI resistent - EGFR T790M negative - Expected survival ≥ 3 month; - ECOG / PS score: 0-2; - the main organ function to meet the following criteria: HB ≥ 90g / L, ANC ≥ 1.5 × 109 / L, PLT ≥ 80 × 109 / L,BIL <1.5 times the upper limit of normal (ULN); Liver ALT and AST <2.5 × ULN and if liver metastases, ALT and AST <5 × ULN; Serum Cr ≤ 1 × ULN, endogenous creatinine clearance ≥50ml/min Exclusion Criteria: - EGFR-T790M positive - with druggable gene alteration; - Patient can not comply with research program requirements or follow-up; NSCLC Stage IV EGFR T790M-negative Anlotinib JS001 Carcinoma, Non-Small-Cell Lung All EGFR mutation NSCLC patients with EGFR-TKIs eventually develop acquired resistance and in 40%-50% of these the resistance mechanism is based on the EGFR T790M mutation who could receive Osimertinib. --- T790M ---

Inclusion Criteria: - Adult patients >=18 years of age - Inoperable locally advanced, recurrent, and/or metastatic NSCLC patients with EGFR sensitive mutation - EGFR-TKI resistent - EGFR T790M negative - Expected survival ≥ 3 month; - ECOG / PS score: 0-2; - the main organ function to meet the following criteria: HB ≥ 90g / L, ANC ≥ 1.5 × 109 / L, PLT ≥ 80 × 109 / L,BIL <1.5 times the upper limit of normal (ULN); Liver ALT and AST <2.5 × ULN and if liver metastases, ALT and AST <5 × ULN; Serum Cr ≤ 1 × ULN, endogenous creatinine clearance ≥50ml/min Exclusion Criteria: - EGFR-T790M positive - with druggable gene alteration; - Patient can not comply with research program requirements or follow-up; Inclusion Criteria: - Adult patients >=18 years of age - Inoperable locally advanced, recurrent, and/or metastatic NSCLC patients with EGFR sensitive mutation - EGFR-TKI resistent - EGFR T790M negative - Expected survival ≥ 3 month; - ECOG / PS score: 0-2; - the main organ function to meet the following criteria: HB ≥ 90g / L, ANC ≥ 1.5 × 109 / L, PLT ≥ 80 × 109 / L,BIL <1.5 times the upper limit of normal (ULN); Liver ALT and AST <2.5 × ULN and if liver metastases, ALT and AST <5 × ULN; Serum Cr ≤ 1 × ULN, endogenous creatinine clearance ≥50ml/min Exclusion Criteria: - EGFR-T790M positive - with druggable gene alteration; - Patient can not comply with research program requirements or follow-up; NSCLC Stage IV EGFR T790M-negative Anlotinib JS001 Carcinoma, Non-Small-Cell Lung All EGFR mutation NSCLC patients with EGFR-TKIs eventually develop acquired resistance and in 40%-50% of these the resistance mechanism is based on the EGFR T790M mutation who could receive Osimertinib. --- T790M --- --- T790M ---

Inclusion Criteria: - Adult patients >=18 years of age - Inoperable locally advanced, recurrent, and/or metastatic NSCLC patients with EGFR sensitive mutation - EGFR-TKI resistent - EGFR T790M negative - Expected survival ≥ 3 month; - ECOG / PS score: 0-2; - the main organ function to meet the following criteria: HB ≥ 90g / L, ANC ≥ 1.5 × 109 / L, PLT ≥ 80 × 109 / L,BIL <1.5 times the upper limit of normal (ULN); Liver ALT and AST <2.5 × ULN and if liver metastases, ALT and AST <5 × ULN; Serum Cr ≤ 1 × ULN, endogenous creatinine clearance ≥50ml/min Exclusion Criteria: - EGFR-T790M positive - with druggable gene alteration; - Patient can not comply with research program requirements or follow-up; Inclusion Criteria: - Adult patients >=18 years of age - Inoperable locally advanced, recurrent, and/or metastatic NSCLC patients with EGFR sensitive mutation - EGFR-TKI resistent - EGFR T790M negative - Expected survival ≥ 3 month; - ECOG / PS score: 0-2; - the main organ function to meet the following criteria: HB ≥ 90g / L, ANC ≥ 1.5 × 109 / L, PLT ≥ 80 × 109 / L,BIL <1.5 times the upper limit of normal (ULN); Liver ALT and AST <2.5 × ULN and if liver metastases, ALT and AST <5 × ULN; Serum Cr ≤ 1 × ULN, endogenous creatinine clearance ≥50ml/min Exclusion Criteria: - EGFR-T790M positive - with druggable gene alteration; - Patient can not comply with research program requirements or follow-up; NSCLC Stage IV EGFR T790M-negative Anlotinib JS001 Carcinoma, Non-Small-Cell Lung All EGFR mutation NSCLC patients with EGFR-TKIs eventually develop acquired resistance and in 40%-50% of these the resistance mechanism is based on the EGFR T790M mutation who could receive Osimertinib. --- T790M --- --- T790M --- --- T790M ---

Inclusion Criteria: - Adult patients >=18 years of age - Inoperable locally advanced, recurrent, and/or metastatic NSCLC patients with EGFR sensitive mutation - EGFR-TKI resistent - EGFR T790M negative - Expected survival ≥ 3 month; - ECOG / PS score: 0-2; - the main organ function to meet the following criteria: HB ≥ 90g / L, ANC ≥ 1.5 × 109 / L, PLT ≥ 80 × 109 / L,BIL <1.5 times the upper limit of normal (ULN); Liver ALT and AST <2.5 × ULN and if liver metastases, ALT and AST <5 × ULN; Serum Cr ≤ 1 × ULN, endogenous creatinine clearance ≥50ml/min Exclusion Criteria: - EGFR-T790M positive - with druggable gene alteration; - Patient can not comply with research program requirements or follow-up; Inclusion Criteria: - Adult patients >=18 years of age - Inoperable locally advanced, recurrent, and/or metastatic NSCLC patients with EGFR sensitive mutation - EGFR-TKI resistent - EGFR T790M negative - Expected survival ≥ 3 month; - ECOG / PS score: 0-2; - the main organ function to meet the following criteria: HB ≥ 90g / L, ANC ≥ 1.5 × 109 / L, PLT ≥ 80 × 109 / L,BIL <1.5 times the upper limit of normal (ULN); Liver ALT and AST <2.5 × ULN and if liver metastases, ALT and AST <5 × ULN; Serum Cr ≤ 1 × ULN, endogenous creatinine clearance ≥50ml/min Exclusion Criteria: - EGFR-T790M positive - with druggable gene alteration; - Patient can not comply with research program requirements or follow-up; NSCLC Stage IV EGFR T790M-negative Anlotinib JS001 Carcinoma, Non-Small-Cell Lung All EGFR mutation NSCLC patients with EGFR-TKIs eventually develop acquired resistance and in 40%-50% of these the resistance mechanism is based on the EGFR T790M mutation who could receive Osimertinib. --- T790M --- --- T790M --- --- T790M --- --- T790M ---

Inclusion Criteria: - Adult patients >=18 years of age - Inoperable locally advanced, recurrent, and/or metastatic NSCLC patients with EGFR sensitive mutation - EGFR-TKI resistent - EGFR T790M negative - Expected survival ≥ 3 month; - ECOG / PS score: 0-2; - the main organ function to meet the following criteria: HB ≥ 90g / L, ANC ≥ 1.5 × 109 / L, PLT ≥ 80 × 109 / L,BIL <1.5 times the upper limit of normal (ULN); Liver ALT and AST <2.5 × ULN and if liver metastases, ALT and AST <5 × ULN; Serum Cr ≤ 1 × ULN, endogenous creatinine clearance ≥50ml/min Exclusion Criteria: - EGFR-T790M positive - with druggable gene alteration; - Patient can not comply with research program requirements or follow-up; Inclusion Criteria: - Adult patients >=18 years of age - Inoperable locally advanced, recurrent, and/or metastatic NSCLC patients with EGFR sensitive mutation - EGFR-TKI resistent - EGFR T790M negative - Expected survival ≥ 3 month; - ECOG / PS score: 0-2; - the main organ function to meet the following criteria: HB ≥ 90g / L, ANC ≥ 1.5 × 109 / L, PLT ≥ 80 × 109 / L,BIL <1.5 times the upper limit of normal (ULN); Liver ALT and AST <2.5 × ULN and if liver metastases, ALT and AST <5 × ULN; Serum Cr ≤ 1 × ULN, endogenous creatinine clearance ≥50ml/min Exclusion Criteria: - EGFR-T790M positive - with druggable gene alteration; - Patient can not comply with research program requirements or follow-up; NSCLC Stage IV EGFR T790M-negative Anlotinib JS001 Carcinoma, Non-Small-Cell Lung All EGFR mutation NSCLC patients with EGFR-TKIs eventually develop acquired resistance and in 40%-50% of these the resistance mechanism is based on the EGFR T790M mutation who could receive Osimertinib. --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M ---

Inclusion Criteria: - Adult patients >=18 years of age - Inoperable locally advanced, recurrent, and/or metastatic NSCLC patients with EGFR sensitive mutation - EGFR-TKI resistent - EGFR T790M negative - Expected survival ≥ 3 month; - ECOG / PS score: 0-2; - the main organ function to meet the following criteria: HB ≥ 90g / L, ANC ≥ 1.5 × 109 / L, PLT ≥ 80 × 109 / L,BIL <1.5 times the upper limit of normal (ULN); Liver ALT and AST <2.5 × ULN and if liver metastases, ALT and AST <5 × ULN; Serum Cr ≤ 1 × ULN, endogenous creatinine clearance ≥50ml/min Exclusion Criteria: - EGFR-T790M positive - with druggable gene alteration; - Patient can not comply with research program requirements or follow-up; Inclusion Criteria: - Adult patients >=18 years of age - Inoperable locally advanced, recurrent, and/or metastatic NSCLC patients with EGFR sensitive mutation - EGFR-TKI resistent - EGFR T790M negative - Expected survival ≥ 3 month; - ECOG / PS score: 0-2; - the main organ function to meet the following criteria: HB ≥ 90g / L, ANC ≥ 1.5 × 109 / L, PLT ≥ 80 × 109 / L,BIL <1.5 times the upper limit of normal (ULN); Liver ALT and AST <2.5 × ULN and if liver metastases, ALT and AST <5 × ULN; Serum Cr ≤ 1 × ULN, endogenous creatinine clearance ≥50ml/min Exclusion Criteria: - EGFR-T790M positive - with druggable gene alteration; - Patient can not comply with research program requirements or follow-up; NSCLC Stage IV EGFR T790M-negative Anlotinib JS001 Carcinoma, Non-Small-Cell Lung All EGFR mutation NSCLC patients with EGFR-TKIs eventually develop acquired resistance and in 40%-50% of these the resistance mechanism is based on the EGFR T790M mutation who could receive Osimertinib. --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M ---

Several alternative mechanisms of escape from EGFR-TKIs have been detected in NSCLC patients without the T790M, such as Met application, BRAF mutation, PIK3CA mutation, etc, who could receive the combination of EGFR-TKI with comparable target drug. --- T790M ---

Given the lack of targeted therapy for the majority of T790M-negative patients, platinum-doublet chemotherapy remains the standard of care with low effectiveness. --- T790M ---

In the present study, we aimed to evaluate the efficacy and safety of the combination of Anlotinb and JS001 in EGFR-TKI resistant T790M-negative NSCLC patients. --- T790M ---

Primary Outcomes

Description: Time from treatment beginning until disease progression

Measure: Progression-Free Survival (PFS)

Time: Evaluation of tumor burden based on RECIST criteria until first documented progress through study completion, an average of 2 months

Description: Proportion of patients with reduction in tumor burden of a predefined amount, including complete remission and partial remission.

Measure: Objective Response Rate

Time: Evaluation of tumor burden based on RECIST criteria through study completion, an average of 2 months

Secondary Outcomes

Description: Time from treatment beginning until death from any cause

Measure: Overall Survival

Time: From date of treatment beginning until the date of death from any cause, through study completion, an average of 1 months

Description: Incidence of Treatment-related adverse Events

Measure: Adverse Effect

Time: Through study completion, an average of 1 months

242 A Phase I/II, Open-Label, Multicenter Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Anti-Tumor Activity of YH25448 in Patients With EGFR Mutation Positive Advanced Non-Small Cell Lung Cancer (NSCLC)

The main purpose of this study is to evaluate the safety, tolerability, and pharmacokinetics (PK) of Lazertinib when given orally to participants with epidermal growth factor receptor single activating mutation positive (EGFRm+) locally advanced or metastatic Non Small Cell Lung Cancer (NSCLC).

NCT04075396
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Drug: Lazertinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Lazertinib is an oral, highly potent, mutant-selective and irreversible epidermal growth factor receptor (EGFR) Tyrosine kinase inhibitor (TKIs) targets both the T790M mutation and activating EGFR mutations while sparing wild type-EGFR. --- T790M ---

Primary Outcomes

Description: An adverse event is any untoward medical event that occurs in a participants administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product.

Measure: Part D: Number of Participants with Adverse Event as a Measure of Safety and Tolerability

Time: Up to 2 years

Description: Plasma Concentration of Lazertinib after administration of single dose will be evaluated.

Measure: Part D: Plasma Concentration of Lazertinib After Administration of Single Dose (SD)

Time: Up to 2 years

Description: Plasma Concentration of Lazertinib after administration of multiple dose will be evaluated.

Measure: Part D: Plasma Concentration of Lazertinib After Administration of Multiple Dose (MD)

Time: Up to 2 years

Secondary Outcomes

Description: Plasma Concentration of Lazertinib metabolites (M6 and M7) after administration of single and multiple dose will be evaluated.

Measure: Part D: Plasma Concentration of Lazertinib Metabolites (M6 and M7) After Administration of Single and Multiple Dose

Time: Up to 2 years

Description: ORR is defined as the percentage of participants who have at least one confirmed Partial response (PR) or Complete response (CR) (according to Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) prior to disease progression or recurrence. CR is defined when all target lesions (TLs) and non-target lesions (NTLs) present at baseline have disappeared (with the exception of lymph nodes which must be less than (<)10 millimeters (mm) to be considered non-pathological) and no new lesions have developed since baseline. PR is defined when the sum of diameters of the TLs has decreased by 30 percent (%) or more compared to baseline (with no evidence of progression) and the NTLs are at least stable with no evidence of new lesions.

Measure: Part D: Overall Response Rate (ORR)

Time: Up to 2 years

Description: DoR is defined as the time from the date of first documented responses until date of documented progression or death whichever comes first.

Measure: Part D: Duration of Response (DoR)

Time: Up to 2 years

Description: DCR is defined as the percentage of participants with a best overall, extracranial and intracranial response of CR, PR or Stable Disease (SD). CR is defined as disappearance of all target lesions since baseline. Any pathological lymph nodes selected as target lesions must have a reduction in short axis to < 10 mm. PR is defined as At least a 30% decrease in the sum of the diameters of TL, taking as reference the baseline sum of diameters. SD is defined as Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD). PD is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm for extracranial and intracranial lesion, respectively.

Measure: Part D: Disease Control Rate (DCR)

Time: Up to 2 years

Description: Tumor shrinkage is measured at each visit by the percentage change in the sum of the diameters of target lesions compared to baseline measured as greater than or equal to (>=) 10 mm in the longest lesion diameter with computed tomography (CT) or magnetic resonance imaging (MRI).

Measure: Part D: Tumor Shrinkage

Time: Up to 2 years

Description: PFS is defined as the time from first dosing date until documented disease progression or death from any cause whichever occur first based on investigator assessment using RECIST 1.1. PD is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm for extracranial and intracranial lesion, respectively.

Measure: Part D: Progression Free Survival (PFS)

Time: Up to 2 years

Description: OS is defined as the interval between the date of first dose and the date of participants death due to any cause.

Measure: Part D: Overall Survival (OS)

Time: Up to 2 years

243 A Phase I Study of TQ-B3456 on Tolerance and Pharmacokinetics

To study the pharmacokinetic characteristics of TQ-B3456 in the human body, recommend a reasonable regimen for subsequent research.

NCT03754244
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: TQB3456
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Inclusion Criteria: - progressive or metastatic non-small cell lung cancer that diagnosed Pathologically or cytologically diagnosed patients who have received EGFR tyrosine kinase inhibitor monotherapy (e.g., gefetinib, erlotinib, ecotinib, afatinib) for disease progression EGFR T790M mutation was confirmed ECOG PS≤1 Adequate blood cell counts, kidney function and liver function Patients should participate in the study voluntarily and sign informed consent Exclusion Criteria: Patients with non-small-cell lung cancer who have received osimertinib or other raw materials or preparations for EGFRT790M mutant drugs Hypertension (systolic BP ≥140 mmHg, diastolic BP ≥90 mmHg) still uncontrollable by one medication; Hepatitis B virus patients with active replication (DNA> 500 cps / mL), hepatitis C; Patients with immunodeficiency, including HIV positive or other acquired, congenital immunodeficiency disease, or organ transplant history - Inclusion Criteria: - progressive or metastatic non-small cell lung cancer that diagnosed Pathologically or cytologically diagnosed patients who have received EGFR tyrosine kinase inhibitor monotherapy (e.g., gefetinib, erlotinib, ecotinib, afatinib) for disease progression EGFR T790M mutation was confirmed ECOG PS≤1 Adequate blood cell counts, kidney function and liver function Patients should participate in the study voluntarily and sign informed consent Exclusion Criteria: Patients with non-small-cell lung cancer who have received osimertinib or other raw materials or preparations for EGFRT790M mutant drugs Hypertension (systolic BP ≥140 mmHg, diastolic BP ≥90 mmHg) still uncontrollable by one medication; Hepatitis B virus patients with active replication (DNA> 500 cps / mL), hepatitis C; Patients with immunodeficiency, including HIV positive or other acquired, congenital immunodeficiency disease, or organ transplant history - Non-small Cell Lung Cancer Carcinoma, Non-Small-Cell Lung null --- T790M ---

Inclusion Criteria: - progressive or metastatic non-small cell lung cancer that diagnosed Pathologically or cytologically diagnosed patients who have received EGFR tyrosine kinase inhibitor monotherapy (e.g., gefetinib, erlotinib, ecotinib, afatinib) for disease progression EGFR T790M mutation was confirmed ECOG PS≤1 Adequate blood cell counts, kidney function and liver function Patients should participate in the study voluntarily and sign informed consent Exclusion Criteria: Patients with non-small-cell lung cancer who have received osimertinib or other raw materials or preparations for EGFRT790M mutant drugs Hypertension (systolic BP ≥140 mmHg, diastolic BP ≥90 mmHg) still uncontrollable by one medication; Hepatitis B virus patients with active replication (DNA> 500 cps / mL), hepatitis C; Patients with immunodeficiency, including HIV positive or other acquired, congenital immunodeficiency disease, or organ transplant history - Inclusion Criteria: - progressive or metastatic non-small cell lung cancer that diagnosed Pathologically or cytologically diagnosed patients who have received EGFR tyrosine kinase inhibitor monotherapy (e.g., gefetinib, erlotinib, ecotinib, afatinib) for disease progression EGFR T790M mutation was confirmed ECOG PS≤1 Adequate blood cell counts, kidney function and liver function Patients should participate in the study voluntarily and sign informed consent Exclusion Criteria: Patients with non-small-cell lung cancer who have received osimertinib or other raw materials or preparations for EGFRT790M mutant drugs Hypertension (systolic BP ≥140 mmHg, diastolic BP ≥90 mmHg) still uncontrollable by one medication; Hepatitis B virus patients with active replication (DNA> 500 cps / mL), hepatitis C; Patients with immunodeficiency, including HIV positive or other acquired, congenital immunodeficiency disease, or organ transplant history - Non-small Cell Lung Cancer Carcinoma, Non-Small-Cell Lung null --- T790M --- --- T790M ---

Primary Outcomes

Description: an adverse event cccurring after initiation of TQ-B3456 that met any following criteria: >=Grade 3 of non-hematology toxicity Grade 4 hematology toxicity

Measure: Dose-Limiting Toxicities(DLT)

Time: Baseline up to 28 days

244 A Phase Ib, Multi-center, Open Label Study of Ningetinib (CT053PTSA) in Combination With Gefitinib in Stage IIIB or IV NSCLC Patients With EGFR Mutation and T790M Negative Who Have Progressed After EGFR TKI Therapy

This is a phase Ib, multi-center, open label study evaluating the safety and efficacy of CT053PTSA in combination with gefitinib in patients with EGFR mutation, T790M negative NSCLC who have progressed after EGFR TKI treatment.

NCT03758287
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: CT053PTSA
  2. Drug: Gefitinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

A Phase Ib, Multi-center, Open Label Study of Ningetinib (CT053PTSA) in Combination With Gefitinib in Stage IIIB or IV NSCLC Patients With EGFR Mutation and T790M Negative Who Have Progressed After EGFR TKI Therapy. --- T790M ---

Ningetinib (CT053PTSA) Plus Gefitinib in Stage IIIB or IV NSCLC Patients With EGFR Mutation and T790M Negative This is a phase Ib, multi-center, open label study evaluating the safety and efficacy of CT053PTSA in combination with gefitinib in patients with EGFR mutation, T790M negative NSCLC who have progressed after EGFR TKI treatment. --- T790M ---

Ningetinib (CT053PTSA) Plus Gefitinib in Stage IIIB or IV NSCLC Patients With EGFR Mutation and T790M Negative This is a phase Ib, multi-center, open label study evaluating the safety and efficacy of CT053PTSA in combination with gefitinib in patients with EGFR mutation, T790M negative NSCLC who have progressed after EGFR TKI treatment. --- T790M --- --- T790M ---

Inclusion Criteria: - Histologically or cytologically confirmed Stage IIIB or IV NSCLC - Resistance to EGFR TKI (1st, 2nd or 3rd generation) - Histological or cytological evidence of EGFR mutation and T790M negative after progression on last EGFR TKI therapy - c-Met GCN ≥ 6 or cluster amplification is required if participant is resistant to1st or 2nd generation EGFR-TKI ;c-MET GCN statue is not required, If participant is resistant to3rd generation EGFR-TKI (osimertinib); - Measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) - Toxicity recovered to NCI CTCAE v.4.03 --- T790M ---

- Serious electrolyte imbalance in the investigator's judgment - Pregnant or lactating woman - Any other reason the investigator considers the patient is not suitable to participate in the study Inclusion Criteria: - Histologically or cytologically confirmed Stage IIIB or IV NSCLC - Resistance to EGFR TKI (1st, 2nd or 3rd generation) - Histological or cytological evidence of EGFR mutation and T790M negative after progression on last EGFR TKI therapy - c-Met GCN ≥ 6 or cluster amplification is required if participant is resistant to1st or 2nd generation EGFR-TKI ;c-MET GCN statue is not required, If participant is resistant to3rd generation EGFR-TKI (osimertinib); - Measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) - Toxicity recovered to NCI CTCAE v.4.03 --- T790M ---

The part 2 portion of this study will continue to evaluate the safety and efficacy of the combination of CT053PTSA and gefitinib , at the appropriate doses recommended in Part 1, in patients with EGFR mutation, T790M negative NSCLC. --- T790M ---

Primary Outcomes

Description: The maximum tolerated dose (MTD) of the CT053PTSA and gefitinib combination will be determined according to incidence of dose-limiting toxicity (DLT) assessed by NCI CTCAE v4.03

Measure: Part 1(dose-escalation part): Maximum Tolerated Dose (MTD)

Time: Cycle 1 Day 1 to Cycle 1 Day 28

Description: Overall response rate (ORR), defined as a partial response (PR) or complete response (CR) occurring at any point post-treatment according to Response Evaluation Criteria in Solid Tumors as assessed by RECIST v1.1

Measure: Part 2(expansion part): Overall Response Rate

Time: up to approximately 36 months

Secondary Outcomes

Description: Safety and tolerability will be assessed through AEs, via monitoring changes in physical examination, clinical laboratory parameters, vital signs and ECGs

Measure: Number of patients with adverse events (AEs) as a measure of safety and tolerability

Time: up to approximately 36 months

Description: DCR, proportion of patients with best overall response of CR, PR or SD

Measure: Disease Control Rate (DCR)

Time: up to approximately 36 months

Description: PFS, defined as time from date of treatment to disease progression or death due to any cause

Measure: Progression-free Survival (PFS)

Time: up to approximately 36 months

Description: DOR, defined as time from the first documented CR or PR to first documented progression or death due to any cause

Measure: Duration of Response (DOR)

Time: up to approximately 36 months

Description: OS, defined as time from date of treatment to death due to any cause

Measure: Overall Survival (OS)

Time: up to approximately 60 months

Description: to assess the pharmacokinetic profile

Measure: Maximum observed plasma concentration (Cmax)

Time: Cycle 1 Day1 and Day 28

Description: to assess the pharmacokinetic profile

Measure: Time of maximum observed plasma concentration (Tmax)

Time: Cycle 1 Day1 and Day 28

Description: to assess the pharmacokinetic profile

Measure: Area under the plasma concentration time curve (AUC)

Time: Cycle 1 Day1 and Day 28

245 A Prospective, Single-center, One-arm Clinical Study of Apatinib Combined With Chemotherapy for Patients Who Progressed After First Line EGFR-TKI Treatment Without T790M Mutation

At present, with the increasing intensities of the tobacco industry and air pollution in China, the incidence and mortality of lung cancer have become the most important issue that threatens human health.Over the past two decades, the treatment of EGFR+ NSCLC is molecular target therapy (EGFR-TKI). However, only about 30 percent patients with T790M mutation could accept 3rd generation of EGFR-TKI(AZD9291) , most of the patients with progressive disease statuses still stays in the mode of treatment based on radiotherapy and chemotherapy. This is a prospective, single-center, one-arm clinical study designed to evaluate the efficacy and safety of apatinib plus chemotherapy for 30 patients who progressed after EGFR-TKI treatment without T790M mutation. The participants will receive apatinib 250mg qd orally combine with chemotherapy, if the patient has a grade 3/4 adverse reaction during such treatment, it can be reduced to apatinib 250mg orally once per two days. Chemotherapeutic agents are limited to platinum-based double drugs chemotherapy.The primary outcome endpoint was progression-free survival.

NCT03758677
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: Apatinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

A Prospective, Single-center, One-arm Clinical Study of Apatinib Combined With Chemotherapy for Patients Who Progressed After First Line EGFR-TKI Treatment Without T790M Mutation. --- T790M ---

Apatinib Combined With Chemotherapy for NSCLC Patients Without T790M Mutation At present, with the increasing intensities of the tobacco industry and air pollution in China, the incidence and mortality of lung cancer have become the most important issue that threatens human health.Over the past two decades, the treatment of EGFR+ NSCLC is molecular target therapy (EGFR-TKI). --- T790M ---

However, only about 30 percent patients with T790M mutation could accept 3rd generation of EGFR-TKI(AZD9291) , most of the patients with progressive disease statuses still stays in the mode of treatment based on radiotherapy and chemotherapy. --- T790M ---

This is a prospective, single-center, one-arm clinical study designed to evaluate the efficacy and safety of apatinib plus chemotherapy for 30 patients who progressed after EGFR-TKI treatment without T790M mutation. --- T790M ---

Inclusion Criteria: 1. male or female patients: 18-75 years old; 2. ECOG performance status score: 0~2 points; 3. Non small cell lung cancer patients who progressed after first line EGFR -TKI treatment without T790M mutation 4.Expected survival period ≥12 weeks; 5.The normal function of major organs, that is, the relevant inspection indicators within the first 14 days of randomness, meet the following requirements: 1. Blood tests: 1. Hemoglobin ≥ 90 g/L (without transfusion in 14 days); 2. Neutrophil count ≥ 1.5×109/L; 3. Platelet count ≥ 100×109/L; 2. Biochemical check: a .total --- T790M ---

Primary Outcomes

Description: Progression-free survival

Measure: PFS

Time: One to two years

Secondary Outcomes

Description: Overall survival

Measure: OS

Time: Five years

Description: Adverse events

Measure: AEs

Time: One year

Description: Disease control rate

Measure: DCR

Time: One year

Description: Objective response rate

Measure: ORR

Time: One year

246 Longitudinal Monitoring of Tumor Specific Mutations in Patients With Lung Cancer

This pilot research trial studies the collection of blood samples in monitoring tumor specific mutations in patients with non-small cell lung cancer that has spread to other places in the body or cannot be removed by surgery. Collecting blood samples may help measure the changes in lung cancer, better learn methods to track cancer in the bloodstream, and improve cancer treatments.

NCT03492801
Conditions
  1. Stage III Non-Small Cell Lung Cancer AJCC v7
  2. Stage IIIA Non-Small Cell Lung Cancer AJCC v7
  3. Stage IIIB Non-Small Cell Lung Cancer AJCC v7
  4. Stage IV Non-Small Cell Lung Cancer AJCC v7
Interventions
  1. Procedure: Biospecimen Collection
  2. Other: Laboratory Biomarker Analysis
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Compare the sensitivity of digital droplet polymerase chain reaction (ddPCR) to that of NGS for detecting the appearance of EGFR T790M mutations in patients treated with an EGFR tyrosine kinase inhibitor. --- T790M ---

Primary Outcomes

Description: Blood samples collected will be used to evaluate the ability of next generation sequencing (NGS) to monitor the evolution of cancer-specific mutations in patients undergoing treatment for non-small cell lung carcinoma and for whom the molecular profile of the tumor cells prior to treatment is known.

Measure: Blood sample collection for tumor specific mutations study from patients with non-small cell lung cancer

Time: Baseline to 3 years

247 A Randomised Phase II Trial of Osimertinib With or Without Stereotactic Radiosurgery for EGFR Mutated Non-Small Cell Lung Cancer (NSCLC) With Brain Metastases

20-40% of patients with NSCLC will develop brain metastases at some point during their course of disease. Osimertinib has demonstrated intracranial activity in EFGR mutated NSCLC with leptomeningeal disease in the phase 1 BLOOM study. Stereotactic radiosurgery (SRS) is one of the standard local treatment for patients with limited number of brain metastases. Currently, it is unclear whether adding SRS to Osimertinib will result in superior intracranial disease control in patients with EGFR mutated NSCLC with brain metastases diagnosed de novo or developed while on first line EGFR tyrosine kinase inhibitors (TKIs) such as Erlotinib and Gefinitib. The aim of this study is to compare the effects of Osimertinib alone versus SRS plus Osimertinib on intra-cranial disease control in EGFR mutated NSCLC with brain metastases diagnosed or developed while on first line EGFR tyrosine kinase inhibitors.

NCT03497767
Conditions
  1. Metastatic Non Small Cell Lung Cancer
Interventions
  1. Drug: Osimertinib
  2. Radiation: Stereotactic Radiosurgery (SRS)
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

6. Documented EGFR mutation; 1. Patients who developed brain metastases as a site of disease progression while on first line EGFR TKIs must have T790M mutation. --- T790M ---

2. Documented EGFR mutation (at any time since the initial diagnosis of NSCLC) known to be sensitive to Osimertinib - These include exon 19 del; L858R (exon 21); G719X (exon 18); L861G (exon 21); S768I (exon 20) and T790M (exon 20) NOTE: Mutation analysis is to be done as per local practice. --- L858R --- --- L861G --- --- S768I --- --- T790M ---

7. Are one of the following cohorts: 1. First-line metastatic cancer: All newly diagnosed participants with documented sensitising EGFR mutation (criterion 6) and intracranial metastasis (criterion 5), with/without extracranial disease 2. Second-line metastatic cancer (T790M+): Participants who progressed after first-line 1st or 2nd generation EGFR TKI therapy with intracranial progression (criterion 5), with/without extracranial disease and have documented T790M mutation 3. Second-line metastatic cancer (T790M-): Participants with no T790M mutation who progressed after first-line 1st or 2nd generation EGFR TKI therapy with intracranial progression (criterion 5) but has no extracranial disease 4. Second-line metastatic cancer (T790M-): Participants with no T790M mutation who progressed after first-line 1st or 2nd generation EGFR TKI therapy with intracranial progression (criterion 5) but has stable extracranial disease 8. Karnofsky performance status 60-100 (ECOG performance status ≤2) with no deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks 9. Female patients who; 1. are willing to use adequate contraceptive measures until 6 weeks after the final dose of study treatment 2. are not breast feeding 3. have a negative pregnancy test prior to the start of dosing if of child bearing potential or have evidence of non-child bearing potential by fulfilling one of the following criteria at screening: i. Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments ii. --- T790M ---

7. Are one of the following cohorts: 1. First-line metastatic cancer: All newly diagnosed participants with documented sensitising EGFR mutation (criterion 6) and intracranial metastasis (criterion 5), with/without extracranial disease 2. Second-line metastatic cancer (T790M+): Participants who progressed after first-line 1st or 2nd generation EGFR TKI therapy with intracranial progression (criterion 5), with/without extracranial disease and have documented T790M mutation 3. Second-line metastatic cancer (T790M-): Participants with no T790M mutation who progressed after first-line 1st or 2nd generation EGFR TKI therapy with intracranial progression (criterion 5) but has no extracranial disease 4. Second-line metastatic cancer (T790M-): Participants with no T790M mutation who progressed after first-line 1st or 2nd generation EGFR TKI therapy with intracranial progression (criterion 5) but has stable extracranial disease 8. Karnofsky performance status 60-100 (ECOG performance status ≤2) with no deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks 9. Female patients who; 1. are willing to use adequate contraceptive measures until 6 weeks after the final dose of study treatment 2. are not breast feeding 3. have a negative pregnancy test prior to the start of dosing if of child bearing potential or have evidence of non-child bearing potential by fulfilling one of the following criteria at screening: i. Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments ii. --- T790M --- --- T790M ---

7. Are one of the following cohorts: 1. First-line metastatic cancer: All newly diagnosed participants with documented sensitising EGFR mutation (criterion 6) and intracranial metastasis (criterion 5), with/without extracranial disease 2. Second-line metastatic cancer (T790M+): Participants who progressed after first-line 1st or 2nd generation EGFR TKI therapy with intracranial progression (criterion 5), with/without extracranial disease and have documented T790M mutation 3. Second-line metastatic cancer (T790M-): Participants with no T790M mutation who progressed after first-line 1st or 2nd generation EGFR TKI therapy with intracranial progression (criterion 5) but has no extracranial disease 4. Second-line metastatic cancer (T790M-): Participants with no T790M mutation who progressed after first-line 1st or 2nd generation EGFR TKI therapy with intracranial progression (criterion 5) but has stable extracranial disease 8. Karnofsky performance status 60-100 (ECOG performance status ≤2) with no deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks 9. Female patients who; 1. are willing to use adequate contraceptive measures until 6 weeks after the final dose of study treatment 2. are not breast feeding 3. have a negative pregnancy test prior to the start of dosing if of child bearing potential or have evidence of non-child bearing potential by fulfilling one of the following criteria at screening: i. Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments ii. --- T790M --- --- T790M --- --- T790M ---

7. Are one of the following cohorts: 1. First-line metastatic cancer: All newly diagnosed participants with documented sensitising EGFR mutation (criterion 6) and intracranial metastasis (criterion 5), with/without extracranial disease 2. Second-line metastatic cancer (T790M+): Participants who progressed after first-line 1st or 2nd generation EGFR TKI therapy with intracranial progression (criterion 5), with/without extracranial disease and have documented T790M mutation 3. Second-line metastatic cancer (T790M-): Participants with no T790M mutation who progressed after first-line 1st or 2nd generation EGFR TKI therapy with intracranial progression (criterion 5) but has no extracranial disease 4. Second-line metastatic cancer (T790M-): Participants with no T790M mutation who progressed after first-line 1st or 2nd generation EGFR TKI therapy with intracranial progression (criterion 5) but has stable extracranial disease 8. Karnofsky performance status 60-100 (ECOG performance status ≤2) with no deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks 9. Female patients who; 1. are willing to use adequate contraceptive measures until 6 weeks after the final dose of study treatment 2. are not breast feeding 3. have a negative pregnancy test prior to the start of dosing if of child bearing potential or have evidence of non-child bearing potential by fulfilling one of the following criteria at screening: i. Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments ii. --- T790M --- --- T790M --- --- T790M --- --- T790M ---

7. Are one of the following cohorts: 1. First-line metastatic cancer: All newly diagnosed participants with documented sensitising EGFR mutation (criterion 6) and intracranial metastasis (criterion 5), with/without extracranial disease 2. Second-line metastatic cancer (T790M+): Participants who progressed after first-line 1st or 2nd generation EGFR TKI therapy with intracranial progression (criterion 5), with/without extracranial disease and have documented T790M mutation 3. Second-line metastatic cancer (T790M-): Participants with no T790M mutation who progressed after first-line 1st or 2nd generation EGFR TKI therapy with intracranial progression (criterion 5) but has no extracranial disease 4. Second-line metastatic cancer (T790M-): Participants with no T790M mutation who progressed after first-line 1st or 2nd generation EGFR TKI therapy with intracranial progression (criterion 5) but has stable extracranial disease 8. Karnofsky performance status 60-100 (ECOG performance status ≤2) with no deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks 9. Female patients who; 1. are willing to use adequate contraceptive measures until 6 weeks after the final dose of study treatment 2. are not breast feeding 3. have a negative pregnancy test prior to the start of dosing if of child bearing potential or have evidence of non-child bearing potential by fulfilling one of the following criteria at screening: i. Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments ii. --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M ---

Primary Outcomes

Description: To assess the efficacy of Osimertinib with deferred local brain metastases directed therapies compared with upfront SRS followed by Osimertinib by assessment of intracranial progression free survival at 12 months.

Measure: Intracranial progression free survival at 12 months

Time: 12 months post randomisation

Secondary Outcomes

Description: To assess the effect of Osimertinib with deferred local brain metastases directed therapies compared with upfront SRS followed by Osimertinib on use of salvage whole-brain radiotherapy (WBRT) +/- neurosurgery.

Measure: Use of salvage whole-brain radiotherapy (WBRT)

Time: 18 months post randomisation

Description: To assess the effect of Osimertinib with deferred local brain metastases directed therapies compared with upfront SRS followed by Osimertinib on local brain failure.

Measure: Local brain failure

Time: 18 months post randomisation

Description: To assess the effect of Osimertinib with deferred local brain metastases directed therapies compared with upfront SRS followed by Osimertinib on distant brain failure.

Measure: Distant brain failure

Time: 18 months post randomisation

Description: To assess the effect of Osimertinib with deferred local brain metastases directed therapies compared with upfront SRS followed by Osimertinib on extra-cranial progression.

Measure: Extra-cranial progression

Time: 18 months post randomisation

Description: To further assess the efficacy of Osimertinib with deferred local brain metastases directed therapies compared with upfront SRS followed by Osimertinib in terms of overall survival.

Measure: Overall Survival

Time: 18 months post randomisation

248 A Phase I/II, Multi-Center, Open-Label, Dose Escalation Trial of the Safety and Pharmacokinetics of Intravenous PR610 Given Weekly in Subjects With Solid Tumors

The purpose of this study is to determine the Maximum Tolerated Dose and the Dose-Limiting Toxicity of the drug to further evaluate safety and antitumor activity.

NCT01631279
Conditions
  1. Unspecified Adult Solid Tumor, Protocol Specific
Interventions
  1. Drug: PR610
MeSH:Neoplasms
HPO:Neoplasm

Inclusion Criteria: - Signed informed consent - Age 18 years or more - Histologically-confirmed, progressive cancer with the following diagnosis: 1. Phase I: locally advanced or metastatic solid tumor that may respond to an EGFR inhibitor; 2. Phase II: Stage IIIB or IV, non-squamous, non-small cell lung cancer (NSCLC) with known sensitizing mutations in EGFR, and the T790M resistance mutation - Failed, refused, or not eligible for standard of care therapy - ECOG performance status of 0, 1, or 2 - Life expectancy of at least 12 weeks - At least 4 weeks from prior anticancer therapy including chemotherapy, hormonal, investigational, and/or biological therapies and irradiation. --- T790M ---

- Recovered from prior treatment related toxicity 1. except for grade 1 fatigue, grade 1 peripheral sensory neuropathy and grade 1 or 2 alopecia during the phase I portion of the study 2. except for grade 1 toxicity, and grade 2 peripheral neuropathy during the phase II portion of the study - At least four (4) weeks from prior major surgery - Women of child-bearing potential must be willing to use an acceptable contraceptive method and must have a negative urine or serum pregnancy test within 2 weeks prior to beginning treatment on this trial - Sexually active men must be willing to use an acceptable contraceptive method - Adequate hematological and biological function - Willingness to participate in PK sampling during cycles 1 and 2 - Willingness to provide permission to access archived tumor samples for evaluation of EGFR mutation status - Willingness to provide samples for storage of normal tissue containing wild-type DNA Additional Inclusion Criteria during Expansion Phase - At least one target lesion as defined by RECIST 1.1 that allows for evaluation of tumor response Exclusion Criteria: - Pregnant or nursing women - Any uncontrolled medical illness including, but not limited to, significant gastrointestinal disorders, cardiovascular disease, or interstitial lung disease - History of clinically significant cardiovascular abnormalities, eg., uncontrolled hypertension, CHF (NYHA classification ≥2), unstable angina, poorly controlled arrhythmias, myocardial infarction within 6 months of study entry, implantable pacemaker or implantable cardioverter defibrillator - Clinically significant abnormal 12-lead ECG with QTcF >450 msec - Use of any medications known to produce QT prolongation - Family history of Long QT Syndrome - Prior treatment with anthracyclines with a cumulative dose of doxorubicin (or equivalent) ≥400 mg/m2 - Cardiac left ventricular function with resting ejection fraction of less than 50% - Symptomatic CNS lesions or known CNS lesions that require therapy - Prior history of an allergic reaction to a tyrosine kinase inhibitor Additional Exclusion Criteria during Expansion Phase - Any other malignancy likely to effect the assessment of toxicity or efficacy of PR610 Inclusion Criteria: - Signed informed consent - Age 18 years or more - Histologically-confirmed, progressive cancer with the following diagnosis: 1. Phase I: locally advanced or metastatic solid tumor that may respond to an EGFR inhibitor; 2. Phase II: Stage IIIB or IV, non-squamous, non-small cell lung cancer (NSCLC) with known sensitizing mutations in EGFR, and the T790M resistance mutation - Failed, refused, or not eligible for standard of care therapy - ECOG performance status of 0, 1, or 2 - Life expectancy of at least 12 weeks - At least 4 weeks from prior anticancer therapy including chemotherapy, hormonal, investigational, and/or biological therapies and irradiation. --- T790M ---

Primary Outcomes

Description: The first cohort of three subjects will receive PR610 at Dose Level 1. Subsequent cohorts will receive PR610 at a dose levels determined as per dose escalation criteria. The MTD will be defined as the dose level at which one (1) or fewer subject in six exhibit DLT with the next highest dose level demonstrating two (2) or more of six (6) subjects with DLT (or for which more than ≥33% of subjects exhibit DLT if the cohort size exceeds 6 subjects).

Measure: Determine the Maximum Tolerated Dose (MTD) of PR610 for Both a 1-hour and a 24-hour Weekly IV Infusion

Time: 3 weeks (1 cycle)

Description: DLT is defined as the following: Occurs during the first cycle of PR610 Is considered PR610-related, as defined by "Definitely-related", "Probably-related" or "Possibly-related" Is clinically significant, as determined by the Principal Investigator In addition, DLT will meet at least one of the criteria listed below using grading criteria from the CTCAEv4. Grade 4 hematologic toxicity Any drug-related toxicity that prevents administration of 100% of all doses of PR610 planned for Cycle 1 Grade 3 or higher non-hematologic toxicity

Measure: Determine the Dose-Limiting Toxicity (DLT) of PR610 for Both a 1-hour and a 24-hour Weekly IV Infusion

Time: 3 weeks (1 Cycle)

Secondary Outcomes

Description: The number of adverse events experienced by participants will be measured.

Measure: Evaluate the safety profile of PR610: Adverse Events

Time: 30 days following the last administration of study treatment

Measure: Peak Plasma Concentration (Cmax) of PR610 and PR610E for Both a 1-hour and a 24-hour Weekly Infusion

Time: pre, 30 minutes into infusion, end of infusion, 1, 2, 4, 24, 48, and 72 hours post-infusion on Cycles 1 and 2

Description: Efficacy will be determined for each subject that received at least one dose of PR610 and had at least one post-baseline disease assessment. The following four outcomes will be tabulated: Tumor response Time to response Duration of response Progression-free survival

Measure: Evaluate the activity of PR610 in a general phase I population and in a subset of subjects with NSCLC genetically resistant to reversible EGFR inhibitors

Time: 30 days following the last administration of study treatment

Measure: Time of Peak Plasma Concentration (tmax) of PR610 and PR610E for Both a 1-hour and a 24-hour Weekly Infusion

Time: pre, 30 minutes into infusion, end of infusion, 1, 2, 4, 24, 48, and 72 hours post-infusion on Cycles 1 and 2

Measure: Half life (t1/2) of PR610 and PR610E for Both a 1-hour and a 24-hour Weekly Infusion

Time: pre, 30 minutes into infusion, end of infusion, 1, 2, 4, 24, 48, and 72 hours post-infusion on Cycles 1 and 2

Measure: Area Under the Curve (AUC) of PR610 and PR610E for Both a 1-hour and a 24-hour Weekly Infusion

Time: pre, 30 minutes into infusion, end of infusion, 1, 2, 4, 24, 48, and 72 hours post-infusion on Cycles 1 and 2

Measure: Clearance (CL) of PR610 and PR610E for Both a 1-hour and a 24-hour Weekly Infusion

Time: pre, 30 minutes into infusion, end of infusion, 1, 2, 4, 24, 48, and 72 hours post-infusion on Cycles 1 and 2

249 Detection of Resistance Genes From Serially Collected Plasma DNA in Non-small Cell Lung Cancer Patients Harboring EGFR Activating Mutation Who Are Being Treated With EGFR TKIs

To detect resistance gene from serially collected plasma DNA in non-small cell lung cancer harbouring EGFR activating mutation who are being treated with EGFR TKIs by using castPCR method.

NCT01776684
Conditions
  1. EGFR Mutation Positive Non-small Cell Lung Cancer
Interventions
  1. Drug: EGFR TKIs (gefitinib, erlotinib, afatinib, et al)
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

To evaluate the efficiency of castPCR method for detection of resistance genes, especially, T790M mutation from serially collected plasma DNA in non-small cell lung cancer patients harboring EGFR activating mutation who are being treated with EGFR TKIs. --- T790M ---

Primary Outcomes

Description: To evaluate the efficiency of castPCR method for detection of resistance genes, especially, T790M mutation from serially collected plasma DNA in non-small cell lung cancer patients harboring EGFR activating mutation who are being treated with EGFR TKIs

Measure: detection of resistant gene

Time: 24 months

250 ARCHER 1050: A Randomized, Open-Label Phase 3 Efficacy and Safety Study Of Dacomitinib (PF-00299804) Vs. Gefitinib For The First-Line Treatment Of Locally Advanced or Metastatic NSCLC In Subjects With EGFR-Activating Mutations

This is a multinational, multicenter, randomized, open-label, Phase 3 study comparing the efficacy and safety of treatment with dacomitinib (PF-00299804) to treatment with gefitinib in patients with locally advanced or metastatic non-small cell lung cancer, with epidermal growth factor receptor EGFR-activating mutation (s). Analyses of primary objective (Progression Free Survival) will be done as defined in the protocol.

NCT01774721
Conditions
  1. Non-small Cell Lung Cancer With EGFR-Activating Mutations
Interventions
  1. Drug: Dacomitinib (PF-00299804)
  2. Drug: Gefitinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- It is acceptable for subjects with the presence of the exon 20 T790M mutation together with either EGFR-activating mutation (exon 19 deletion or the L858R mutation in exon 21) to be included in this study - Minimum of 12 months disease free interval between completion of systemic therapy and recurrence of NSCLC - Adequate tissue sample must be available for central analyses. --- T790M ---

- Any other mutation other than exon 19 deletion or L858R in exon 21, with or without the presence of the exon 20 T790M mutation. --- L858R --- --- T790M ---

Primary Outcomes

Description: PFS: time from randomization to date of progression of disease (PD) as determined by IRC review as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria or death due to any cause, whichever occurred first. PD for target lesions: 20% increase in sum of diameters of target measurable lesions above smallest sum observed, with minimum absolute increase of 5 mm; for non-target lesions: unequivocal progression of pre-existing lesions. Overall tumor burden increased sufficiently to merit discontinuation of therapy. In presence of stable disease (did not achieve partial response, complete response or PD) or partial response (>=30% decrease under baseline of sum of diameters of all target measurable lesions, short diameter used in the sum for target nodes, longest diameter used in sum for all other target lesions) in target disease; for new lesions: appearance of any new unequivocal malignant lesion indicated PD.

Measure: Progression Free Survival (PFS) Based on Independent Radiologic Central (IRC) Review

Time: Day 28 of Cycle 1, Cycle 2 then every 8 weeks until disease progression or death due to any cause, whichever occurred first (up to 48 months)

Secondary Outcomes

Description: PFS: time from randomization to date of PD as determined by investigator assessment as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria or death due to any cause, whichever occurred first. PD for target lesions: 20% increase in sum of diameters of target measurable lesions above smallest sum observed, with minimum absolute increase of 5 mm; for non-target lesions: unequivocal progression of pre-existing lesions. Overall tumor burden increased sufficiently to merit discontinuation of therapy. In presence of stable disease (did not achieve partial response, complete response or PD) or partial response (>=30% decrease under baseline of sum of diameters of all target measurable lesions, short diameter used in the sum for target nodes, longest diameter used in sum for all other target lesions) in target disease; for new lesions: appearance of any new unequivocal malignant lesion indicated PD.

Measure: Progression Free Survival (PFS) Based on Investigator Assessment

Time: Day 28 of Cycle 1, Cycle 2 then every 8 weeks until disease progression or death due to any cause, whichever occurred first (up to 48 months)

Description: Number of participants with BOR based on IRC review(complete response[CR] or confirmed partial response[PR]) was recorded from randomization until disease progression based on RECISTv1.1. CR for target lesion: disappearance of all target lesions with exception of nodal disease. All target nodes must decreased to normal size(short axis <10 mm); for non-target lesions: disappearance of all non-target lesions and normalization of tumor marker levels. All lymph nodes must be 'normal' in size(=30% decrease under baseline of sum of all target measurable lesions, short diameter was used in sum for target nodes, longest diameter was used in sum for all other target lesions. PD was defined as 20% increase in sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm.

Measure: Number of Participants With Best Overall Response (BOR) Based on IRC Review

Time: Day 28 of Cycle 1, Cycle 2 then every 8 weeks until disease progression (up to 48 months)

Description: Number of participants with BOR based on investigator assessment (CR or confirmed PR) was recorded from randomization until disease progression based on RECIST v1.1. CR for target lesion: disappearance of all target lesions with exception of nodal disease. All target nodes must decreased to normal size (short axis <10 mm); for non-target lesions: disappearance of all non-target lesions and normalization of tumor marker levels. All lymph nodes must be 'normal' in size (=30% decrease under baseline of sum of all target measurable lesions, short diameter was used in sum for target nodes, longest diameter was used in sum for all other target lesions. PD was defined as 20% increase in sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm.

Measure: Number of Participants With Best Overall Response (BOR) Based on Investigator Assessment

Time: Day 28 of Cycle 1, Cycle 2 then every 8 weeks until disease progression (up to 48 months)

Description: Percentage of participants with a BOR of either CR or PR based on IRC review recorded from the start of treatment until disease progression based on RECIST v1.1. CR for target lesion: disappearance of all target lesions with exception of nodal disease. All target nodes must decreased to normal size (short axis <10 mm); for non-target lesions: disappearance of all non-target lesions and normalization of tumor marker levels. All lymph nodes must be 'normal' in size (=30% decrease under baseline of sum of all target measurable lesions, short diameter was used in sum for target nodes, longest diameter was used in sum for all other target lesions. PD was defined as 20% increase in sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm.

Measure: Objective Response Rate (ORR) Based on IRC Review

Time: Day 28 of Cycle 1, Cycle 2 then every 8 weeks until disease progression (up to 48 months)

Description: Percentage of participants with a BOR of either CR or PR based on investigator assessment recorded from the start of treatment until disease progression based on RECIST v1.1. CR for target lesion: disappearance of all target lesions with exception of nodal disease. All target nodes must decreased to normal size (short axis <10 mm); for non-target lesions: disappearance of all non-target lesions and normalization of tumor marker levels. All lymph nodes must be 'normal' in size (=30% decrease under baseline of sum of all target measurable lesions, short diameter was used in sum for target nodes, longest diameter was used in sum for all other target lesions. PD was defined as 20% increase in sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm.

Measure: Objective Response Rate (ORR) Based on Investigator Assessment

Time: Day 28 of Cycle 1, Cycle 2 then every 8 weeks until disease progression (up to 48 months)

Description: DoR was defined as time from first documentation of objective response(CR or PR, whichever occurred first)to date of PD or death from any cause, whichever occurred first. CR for target lesion: disappearance of all target lesions with exception of nodal disease. All target nodes decreased to normal size(short axis <10 mm); for non-target lesions: disappearance of all non-target lesions and normalization of tumor marker levels. All lymph nodes must be 'normal' in size(=30% decrease under baseline of sum of all target measurable lesions, short diameter used in sum for target nodes, longest diameter used in sum for all other target lesions. PD: 20% increase in sum of diameters of target measurable lesions above the smallest sum observed(over baseline if no decrease in sum is observed),with a minimum absolute increase of 5 mm. DoR was recorded based on IRC review and investigator's assessment.

Measure: Duration of Response (DoR)

Time: Day 28 of Cycle 1, Cycle 2 then every 8 weeks until disease progression or death due to any cause, whichever occurred first (up to 48 months)

Description: An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent AEs were events between first dose of study drug and up to 28-35 days after last dose that were absent before treatment or that worsened relative to pretreatment state. AEs included both serious and non- serious adverse events.

Measure: Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

Time: From baseline up to 28-35 days after last dose of study drug (up to 48 months)

Description: Laboratory parameters included haematological and biochemistry parameters. Haematology parameters included anaemia, activated partial thromboplastin time, haemoglobin, international normalized ratio, lymphocyte count, lymphopenia, neutrophils (absolute), platelets, prothrombin time and white blood cells. Biochemistry parameters included alanine aminotransferase (increased), alkaline phosphatase (increased), aspartate aminotransferase (increased), bilirubin (total), creatinine (increased), hypercalcaemia, hyperglycaemia, hyperkalaemia, hypermagnesaemia, hypernatraemia, hypoalbuminaemia, hypocalcaemia, hypoglycaemia, hypokalaemia, hypomagnesaemia, hyponatraemia. Test abnormalities were graded by AEs according to the Common Terminology Criteria for Adverse Events(NCI CTCAE) version 4.03 as Grade 1= mild; Grade 2= moderate; Grade 3= severe and Grade 4= life-threatening or disabling. Only categories with at least 1 participant with abnormality are reported in this outcome measure.

Measure: Number of Participants With Laboratory Test Abnormalities of Grade 3 or Higher Severity Based on NCI CTCAE Version 4.03: Biochemistry and Haematology

Time: From baseline up to 28-35 days after last dose of study drug (up to 48 months)

Description: Urinalysis parameter included urine protein, urine blood/haemoglobin, urine glucose and urine sediment. Test abnormalities was defined as deviation from normal range (higher or lower). Normal range of 24-hour urine protein test: less than 150 mg of protein per day, urine glucose: 0 to 0.8 mmol/L (millimole per liter), urine protein: 0 to 20 mg/dL (milligrams per deciliter). Urine blood/haemoglobin abnormality was defined as presence and absence of blood/haemoglobin in urine of participants. Urine sediment abnormality was defined as the presence of any bacteria, casts, crystals, and epithelial cells. Only categories with at least 1 participant with abnormality are reported in this outcome measure.

Measure: Number of Participants With Laboratory Test Abnormalities: Urinalysis

Time: From baseline up to 28-35 days after last dose of study drug (up to 48 months)

Description: Criteria for vital signs abnormalities: systolic pulse rate less than (<) 50 beats per minute (bpm) or greater than (>)130 bpm and maximum increase or decrease from baseline in pulse rate of 30 bpm. Systolic blood pressure of maximum increase from baseline (MIB) >=40 millimeters of mercury (mmHg), maximum decrease from baseline (MDB) in systolic blood pressure =<60 mmHg. Diastolic blood pressure of MIB >=20 mmHg and MDB in diastolic blood pressure >40 and =<20 mm Hg. Only categories with at least 1 participant with abnormality are reported in this outcome measure.

Measure: Number of Participants With Clinically Significant Abnormalities in Vital Signs

Time: From baseline up to 28-35 days after last dose of study drug (up to 48 months)

Description: ECG parameters included corrected QT interval using Bazett's formula (QTcB) and corrected QT interval using Fridericia's formula (QTcF). ECG criteria for abnormality: absolute value 450 - <480 msec, 480 - <500 msec >=500. The number of participants with potentially clinically significant ECG findings at any visit were reported.

Measure: Number of Participants With Clinically Significant Abnormality in Electrocardiogram (ECG)

Time: From baseline up to 28-35 days after last dose of study drug (up to 48 months)

Description: An ejection fraction (EF) was the volumetric fraction of blood ejected from a ventricle of the heart with each heartbeat; it was a measure of the pumping efficiency of the heart. The EF of the left heart, known as the left ventricular ejection fraction, was a measure of the efficiency of pumping into the body's systemic circulation.

Measure: Number of Participants With Maximum Relative Decrease From Baseline >20% in Left Ventricular Ejection Fraction (LVEF)

Time: From baseline up to 7 days of Cycle 4 (up to 91 days)

Description: HRQOL was measured by standardized questionnaires (European Organization for Research and Treatment of Cancer (EORTC)) quality of life questionnaires (OLQ-C30) and its lung cancer module (QLQ-LC13). TTD in pain (chest, arm/shoulder), dyspnea, fatigue or cough was defined as time between baseline and first occurrence of increase in score of 10 points or greater from baseline in any of these 4 symptoms for at least two consecutive cycles. For those who had not shown deterioration, the data was censored at the last date when the participants completed an assessment for pain, dyspnea, fatigue or cough.

Measure: Health Related Quality of Life (HRQOL): Time to Deterioration (TTD) in Pain, Dyspnea, Fatigue or Cough

Time: Baseline until the end of treatment (up to 48 months)

Description: The Euro Quality of Life-5 dimension (EQ-5D) is a brief self-administered, validated reliable generic health status instrument. EQ-5D general health status can also be measured by a visual analog scale (EQ-5D VAS). EQ-5D VAS measures the participant's self-rated health status on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state).

Measure: Overall Mean Scores of Euro Quality of Life-5 Dimension Visual Analog Scale (EQ-5D VAS)

Time: From Cycle 1 to 41 (up to 48 months)

Measure: Maximum Observed Plasma Concentration (Cmax) of Dacomitinib and Its Metabolite PF-05199265

Time: Pre-dose and 2, 4, 6, 8, and 24 hours post-dose on Cycle 2 Day 1 (Day 29)

Measure: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Dacomitinib and Its Metabolite PF-05199265

Time: Pre-dose and 2, 4, 6, 8, and 24 hours post-dose on Cycle 2 Day 1 (Day 29)

Measure: Area Under the Plasma Concentration-Time Curve From Time 0 to End of Dosing Interval (AUCtau) of Dacomitinib and Its Metabolite PF-05199265

Time: Pre-dose and 2, 4, 6, 8, and 24 hours post-dose on Cycle 2 Day 1 (Day 29)

Measure: Averaged Plasma Concentration at Steady State (Cavg) of Dacomitinib and Its Metabolite PF-05199265

Time: Pre-dose and 2, 4, 6, 8, and 24 hours post-dose on Cycle 2 Day 1 (Day 29)

Measure: Minimum Observed Plasma Concentration (Cmin) of Dacomitinib and Its Metabolite PF-05199265

Time: Pre-dose and 2, 4, 6, 8, and 24 hours post-dose on Cycle 2 Day 1 (Day 29)

Description: Fluctuation coefficient between trough and peak plasma concentration was determined as Cmax-Ctrough divided by Cavg, where Cmax was the maximum observed concentration within the dosing interval, Ctrough was the observed concentration prior to dose administration and Cavg was averaged plasma concentration at steady state.

Measure: Fluctuation Coefficient Between Trough and Peak Plasma Concentration (DF) of Dacomitinib and Its Metabolite PF-05199265

Time: Pre-dose and 2, 4, 6, 8, and 24 hours post-dose on Cycle 2 Day 1 (Day 29)

Description: Drug clearance was a quantitative measure of the rate at which a drug substance was removed from the blood (rate at which a drug is metabolized or eliminated by normal biological processes).

Measure: Apparent Clearance (CL) of Dacomitinib

Time: Pre-dose and 2, 4, 6, 8, and 24 hours post-dose on Cycle 2 Day 1 (Day 29)

Description: Trough plasma concentration was defined as the measured concentration at the end of a dosing interval at steady state (taken directly before next administration).

Measure: Pre-dose Plasma Concentrations (Ctrough) of Dacomitinib and Its Metabolite PF-05199265

Time: Pre-dose on Day 1 of Cycle 2, 3, 4, 5 and 6

251 A Phase III, Open Label, Randomized Study of AZD9291 Versus Platinum-Based Doublet Chemotherapy for Patients With Locally Advanced or Metastatic Non-Small Cell Lung Cancer Whose Disease Has Progressed With Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and Whose Tumours Harbour a T790M Mutation Within the Epidermal Growth Factor Receptor Gene (AURA3).

A Phase III, Open Label, Randomized Study of Osimertinib versus Platinum-Based Doublet Chemotherapy for Patients with Locally Advanced or Metastatic Non-Small Cell Lung Cancer whose Disease has Progressed with Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and whose Tumours harbour a T790M mutation within the Epidermal Growth Factor Receptor Gene

NCT02151981
Conditions
  1. Anticancer Treatment
Interventions
  1. Drug: Chemotherapy
  2. Drug: Cross-over to Osimertinib
MeSH:Lung Neoplasms Carcinoma, No Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

A Phase III, Open Label, Randomized Study of AZD9291 Versus Platinum-Based Doublet Chemotherapy for Patients With Locally Advanced or Metastatic Non-Small Cell Lung Cancer Whose Disease Has Progressed With Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and Whose Tumours Harbour a T790M Mutation Within the Epidermal Growth Factor Receptor Gene (AURA3).. AZD9291 (Osimertinib) Versus Platinum-Based Doublet-Chemotherapy in Locally Advanced or Metastatic Non-Small Cell Lung Cancer A Phase III, Open Label, Randomized Study of Osimertinib versus Platinum-Based Doublet Chemotherapy for Patients with Locally Advanced or Metastatic Non-Small Cell Lung Cancer whose Disease has Progressed with Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and whose Tumours harbour a T790M mutation within the Epidermal Growth Factor Receptor Gene Progression Free Survival (PFS) by Investigator Assessment. --- T790M ---

A Phase III, Open Label, Randomized Study of AZD9291 Versus Platinum-Based Doublet Chemotherapy for Patients With Locally Advanced or Metastatic Non-Small Cell Lung Cancer Whose Disease Has Progressed With Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and Whose Tumours Harbour a T790M Mutation Within the Epidermal Growth Factor Receptor Gene (AURA3).. AZD9291 (Osimertinib) Versus Platinum-Based Doublet-Chemotherapy in Locally Advanced or Metastatic Non-Small Cell Lung Cancer A Phase III, Open Label, Randomized Study of Osimertinib versus Platinum-Based Doublet Chemotherapy for Patients with Locally Advanced or Metastatic Non-Small Cell Lung Cancer whose Disease has Progressed with Previous Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and whose Tumours harbour a T790M mutation within the Epidermal Growth Factor Receptor Gene Progression Free Survival (PFS) by Investigator Assessment. --- T790M --- --- T790M ---

- At least 14 days since last dose of platinum-based doublet chemotherapy Anticancer Treatment Lung Neoplasms Carcinoma, No Carcinoma, Non-Small-Cell Lung This is a phase III, open label, randomized study assessing Osimertinib (80 mg, orally, once daily) versus platinum-based doublet chemotherapy (standard of care) in subjects with confirmed diagnosis of Epidermal Growth Factor Receptor (EGFR) mutation positive NSCLC, who have progressed following prior therapy with an approved Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI) agent and whose tumours harbour a T790M mutation within the EGFR Gene. --- T790M ---

Primary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. PFS is the time from date of randomisation until the date of PD (by investigator assessment) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from randomised therapy or received another anti-cancer therapy prior to progression. Patients who had not progressed or died at the time of analysis were censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 assessment.

Measure: Progression Free Survival (PFS) by Investigator Assessment

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression up to 19 months (at the time of analysis).

Secondary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. ORR is the percentage of patients with at least 1 visit response of CR or PR prior to progression or any further therapy.

Measure: Objective Response Rate (ORR) by Investigator Assessment

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression up to 19 months (at the time of analysis).

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. DoR is the time from the date of first documented response until the date of documented progression or death in the absence of disease progression.

Measure: Duration of Response (DoR) by Investigator Assessment

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression up to 19 months (at the time of analysis).

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions; Stable disease (SD): Neither sufficient shrinkage to qualify as a response nor sufficient growth to qualify as progression; Progressive Disease (PD): >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. DCR is the percentage of patients with best response of CR, PR or SD at >=6 weeks, prior to any progressive disease (PD).

Measure: Disease Control Rate (DCR) by Investigator Assessment

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression up to 19 months (at the time of analysis).

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Tumour size was calculated as the sum of the longest diameters (SLD) of the Target Lesions. Tumour shrinkage is percentage change in tumour size from baseline using RECIST v1.1 tumour response.

Measure: Tumour Shrinkage by Investigator Assessment

Time: RECIST tumour assessments every 6 weeks from randomisation until objective disease progression up to 19 months (at the time of analysis).

Other Outcomes

Description: Total number of deaths at the time of the analysis

Measure: Number of Deaths

Time: From randomisation until death, up to 19 months (at the time of analysis).

252 A Phase 1/2 Trial of Ruxolitinib and Erlotinib in Patients With EGFR-mutant Lung Adenocarcinoma With Acquired Resistance to Erlotinib

This is a phase 2 study. The goal of this study is to find out what effects, good and/or bad, taking erlotinib and ruxolitinib has on the patients and on lung cancer. Erlotinib and ruxolitinib are FDA approved for other indications, but the use of erlotinib and ruxolitinib together has not been studied before and is not FDA-approved.

NCT02155465
Conditions
  1. Lung Cancer
Interventions
  1. Drug: Ruxolitinib
  2. Drug: Erlotinib
MeSH:Adenocarcinoma Adenocarcinoma of Lung

- Received erlotinib or other EGFR TK treatment for at least 2 weeks prior to enrollment - Measurable (RECIST 1.1) indicator lesion not previously irradiated - Must have undergone biopsy after development of acquired resistance to erlotinib (which is performed as standard of care) with adequate tissue to determine EGFR T790M and tumor histology. --- T790M ---

Primary Outcomes

Measure: Maximally Tolerated Dose (MTD) (Phase I)

Time: 1 year

Description: Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), at least a 30% decrease in the sum of the longest diameter of target lesions; Progressive disease (PD), at least a 20% increase in the sum of the diameter of the target lesions or the appearance of one or more new lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD

Measure: Assess Overall Response Rate

Time: 1 year

Secondary Outcomes

Description: Toxicity grading will be performed in accordance with NCI CTCAE, version 4.0.

Measure: Number of Participants With NCI CTCAE Toxicity

Time: 2 years

Measure: Progression-free Survival

Time: 2 years

253 Phase I of Vorinostat-Iressa Combined Therapy on Resistance by BIM Polymorphysim in EGFR Mutant Lung Cancer

- Gefitinib is an orally active epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). However, 20-30% of patients with EGFR-activating mutations show intrinsic resistance to EGFR-TKI. - EGFR-mutant non-small cell lung cancer (NSCLC) cells with BIM (BCL2L11) deletion polymorphism show the impaired generation of BIM with the proapoptotic BH3 domain, as well as resistance to EGFR-TKI-induced apoptosis. - Both BIM polymorphism (12.9%) and EGFR mutations (50% in lung adenocarcinoma) are more prevalent in the East Asian than in Caucasian populations. BIM is a BH3-only proapoptotic member of the Bcl-2 protein family. BIM upregulation is required for apoptosis induction by EGFR-TKI in EGFR-mutant NSCLC. - Vorinostat (suberoylanilide hydroxamic acid [SAHA]) is a small-molecule inhibitor of histone deacetylase (HDAC) and induces cell differentiation, cell cycle arrest, and apoptosis in several tumor cells. HDAC inhibition can epigenetically restore BIM function and death sensitivity of EGFR-TKI in patients with EGFR-mutant NSCLC in whom resistance to EGFR-TKI is associated with a common BIM polymorphism. EGFR-TKI resistance due to the BIM polymorphism may be able to be circumvented in combination with HDAC inhibition of vorinostat with gefitinib in NSCLC.

NCT02151721
Conditions
  1. Non-Small-Cell Lung Carcinoma
Interventions
  1. Drug: Vorinostat, gefitinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

- Having a large volume of or uncontrollable pleural effusion, ascites, or pericardial effusion - Detection of known EGFR-TKI resistance acquired by mutations of the genes, e.g., T790M. --- T790M ---

Primary Outcomes

Description: MTD (Maximum Tolerated Dose)defined as the highest dose level at which < 2 out of 6 patients experienced a DLT.

Measure: MTD (Maximum Tolerated Dose)

Time: Second cycle (Day 28)

254 Phase 1/2 Open Label Study Of Pf 06459988 (Epidermal Growth Factor Receptor T790m Inhibitor) In Patients With Advanced Epidermal Growth Factor Receptor Mutant (Del 19 Or L858r + - T790m) Non Small Cell Lung Cancer

Phase 1 - open label, multi-center, non-randomized, safety, pharmacokinetic and pharmacodynamics dose escalation study of PF-06459988 as a single agent in patients with advance EGFRm NSCLC (del 19, L858R, +/- T790M). The resulting PF-06459988 dose selected from the phase 1 portion will undergo a series of sub-studies to fully characterize the impact of food, antacid and CYP3A4 inhibitors/inducers. The PK studies are in addition to the MTD expansion and will be completed prior to the initiation of Phase 2. Phase 2 is an open label, multi-center single-arm study of PF-06459988 for the assessment of antitumor activity in patients with advanced EGFRm (del 19 or L858R) NSCLC with T790M.

NCT02297425
Conditions
  1. Advanced EGFRm (Del 19 or L858R +/- T790M) NSCLC
Interventions
  1. Drug: PF-06459988
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

A Study For Patients With EGFRm (Epidermal Growth Factor Receptor Mutant) Lung Cancer Phase 1 - open label, multi-center, non-randomized, safety, pharmacokinetic and pharmacodynamics dose escalation study of PF-06459988 as a single agent in patients with advance EGFRm NSCLC (del 19, L858R, +/- T790M). --- L858R --- --- T790M ---

The PK studies are in addition to the MTD expansion and will be completed prior to the initiation of Phase 2. Phase 2 is an open label, multi-center single-arm study of PF-06459988 for the assessment of antitumor activity in patients with advanced EGFRm (del 19 or L858R) NSCLC with T790M. --- L858R --- --- T790M ---

Advanced EGFRm (Del 19 or L858R +/- T790M) NSCLC Lung Neoplasms null --- L858R --- --- T790M ---

Primary Outcomes

Description: The target probability of DLT at MTD will be 30%

Measure: Number of participants with Dose-limiting toxicities (DLT) (phase 1)

Time: up to 21 days

Description: Number of participants with objective response based assessment of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST). CR are those that persist on repeat imaging study at least 4 weeks after initial documentation of response. PR are those as noted in the RECIST Criteria: Greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions

Measure: Number of Participants With Objective Response (phase 2)

Time: Time from first dose of study drug to objective response of CR or PR up to 24 months

Secondary Outcomes

Description: Number of participants with objective response based assessment of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST). CR are those that persist on repeat imaging study at least 4 weeks after initial documentation of response. PR are those PR are those as noted in the RECIST Criteria: Greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions

Measure: Number of Participants With Objective Response for those patients with measurable disease (phase 1)

Time: time from first dose of study drug until objective response of CR or PR up to 24 months

Description: The period from study entry until disease progression, death or date of last contact.

Measure: Progression-Free Survival (PFS) - Phase 2

Time: time from first dose of study drug until Disease Progression or death (whichever first) up to 24 months

255 Establishment of Personalized Cancer Medicine Using Samsung Cancer Sequencing Platform in Lung Cancer/Mediastinal Tumor/ Head & Neck/Esophageal Cancer/Rare Cancer (PerSeq: Personalized Sequence)

The next generation of personalized medical treatment according to the type of personal genetic information are evolving rapidly. The genome analysis needs systematic infra and database based on personal genetic information Therefore, a big data of genome-clinical information is important.

NCT02299622
Conditions
  1. Lung Cancer
Interventions
  1. Genetic: Genetic test
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

the spectrum of targetable genetic mutation in evaluated cancer specimens (for example, % of EGFR T790M mutation, BRAF mutation, or ALK mutation). --- T790M ---

Primary Outcomes

Description: The pattern of the tumor's molecular profiling in advanced thoracic (lung, esophagus, or tthymic) cancer

Measure: the spectrum of targetable genetic mutation in evaluated cancer specimens (for example, % of EGFR T790M mutation, BRAF mutation, or ALK mutation)

Time: 3 years

256 Use of a New Blood Test to Identify Response to Targeted Treatment in Patients With EGFR Mutated Lung Cancer. Evaluation in a Multicenter Study

In non-small celled lung cancer (NSCLC) 10-15% of the patients harbor a mutation in the tumor's epidermal growth factor receptor (EGFR M+). This receptor is the target for treatment with erlotinib. Identification of EGFR M+ is done on a biopsy, which can be difficult to retrieve. A new blood based test identifies EGFR M+ in plasma, which makes it possible to monitor the level of EGFR M+ in the patient's blood during treatment. This enables both a closer monitoring of the treatment with erlotinib and a closer study of the resistance mechanisms that almost inevitably develop during treatment. A pilot study demonstrated that the quantity of EGFR M+ in plasma correlates to the response to treatment and might be used to predict disease progression. Patients with EGFR M+ NSCLC referred to a participating oncology department may be enrolled in the project. The investigators expect to include 250 patients over a four-year period. Patients will receive standard treatment and follow up. Standard 1st line treatment for patients with metastatic disease is tyrosine kinase inhibitors (TKI) eg. erlotinib. A biopsy and blood sample will be retrieved before treatment with is initiated. The patient will be monitored prospectively with blood samples every 3rd-6th week both during erlotinib treatment, subsequent lines of treatment and treatment intermissions. The blood samples are analyzed for subtypes of EGFR M+ both sensitizing mutations and mutations known to drive resistance to erlotinib treatment. In the event of occurring resistance mutations or unexpected increase in quantity of sensitizing mutations clinical action will be taken; initially in the form of additional scans searching for signs of disease progression. Clinical data will be retrieved from the patient's medical journal. Patients are followed until death or at least 24 months after inclusion. Any excess biological material will be stored for up to 15 years in a bio bank for future research purposes. We expect our results to validate the use of EGFR M+ detection and quantification via blood samples in a clinically relevant setting. The investigators expect earlier identification of disease progression to allow more cases of local treatment thus - hopefully - increasing the progression free survival. Continued blood monitoring in subsequent lines of treatment and treatment intermissions will add to our knowledge of the nature of EGFR M+ NSCLC. The sampling of biological material allows us to further investigate the biology of resistance.

NCT02284633
Conditions
  1. Lung Neoplasms
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

The most common is the T790M mutation in EGFR, but other mechanisms such as increased MET and HER3 expression is also described. --- T790M ---

It is estimated that T790M mutations in EGFR accounts for 50% of the cases with TKI resistance development. --- T790M ---

Primary Outcomes

Measure: Progression Free Survival

Time: 2 years

257 Blood Detection of EGFR Mutation For Iressa Treatment

This study was proposed to validate the efficacy of gefitinib as first-line therapy in advanced lung adenocarcinoma with EGFR mutation determined by plasma cf-DNA.

NCT02282267
Conditions
  1. Lung Adenocarcinoma
Interventions
  1. Drug: Gefitinib
MeSH:Adenocarcinoma of Lung

Meanwhile, this study was also proposed to explore the best intervention time of anti-resistant drugs (such as AZD 9291, a T790M inhibitor) through the quantitative and dynamic analysis of EGFR sensitive and resistant mutation in plasma cf-DNA during EGFR-TKI treatment process. --- T790M ---

Primary Outcomes

Measure: objective response rate of gefitinib

Time: up to 6 months

258 A Phase II Study to Assess Efficacy of Combined Treatment With Erlotinib (Tarceva) and Silybin-phytosome (Siliphos) in Patients With EGFR(Epidermal Growth Factor Receptor) Mutant Lung Adenocarcinoma

1. Title and stage of study A Phase II Study to Assess Efficacy of Combined Treatment with Erlotinib (Tarceva) and Silybin-phytosome (Siliphos) in Patients with EGFR mutant lung adenocarcinoma 2. Endpoints Primary Endpoint : tumour response rate Secondary Endpoint : progression-free survival, overall survival, and safety assessment 3. Study Rationale Even though it is commonly accepted that EGFR TKIs are effective to EGFR mutation positive lung cancer patients, still remains its resistance issue. The Silybin which is extract from mugwort bean Thistle and used for hepatoprotective drug for a long time with very low adverse events in Eastern countries. Recently, there are some reports regarding its anti-cancer effects through several preclinical studies. The safety of Siliphos which is developed agent from silybin for improving intestinal absorption was demonstrated in PhaseⅠtrial. Recently investigators found out Silybin is effective for blocking EGFR signal in different mechanism from Erlotinib and it can be expected additional impact with combination therapy with preclinical data. Our research team can expect to improve Lung cancer treatment if the combination therapy (Silybin_Erlotinib) improves patients' response and Overall survivor. 4. Treatment method Erlotinib (Tarceva 150 mg/day) and Silybin (Siliphos 1g bid/day) q 4 weeks 5. Assessment criteria For toxicity assessment, posttreatment recurrence and survival rates will be investigated based on NCI-CTCAE ver 4.0 and RTOG. Efficacy assessment will be conducted through measurement of lesions by CT and RECIST criteria. Overall survival (OS), progression-free survival (PFS), and time to tumour progression (TTP) will be estimated using a Kaplan-Meier analysis. In addition, effect of pre-treatment T790M on response and PFS will be analyzed.

NCT02146118
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Drug: Erlotinib
  2. Dietary Supplement: Silybin-phytosome
MeSH:Adenocarcinoma Carcinoma, Non-Small-Cell Lung Adenocarcinoma of Lung
HPO:Non-small cell lung carcinoma

In addition, effect of pre-treatment T790M on response and PFS will be analyzed. --- T790M ---

In addition, effect of pre-treatment T790M on response and PFS will be analyzed. --- T790M ---

Primary Outcomes

Description: Efficacy assessment will be conducted through measurement of lesions by CT and RECIST criteria.

Measure: Tumour response rate

Time: 12 months

Secondary Outcomes

Description: For toxicity assessment, posttreatment recurrence and survival rates will be investigated based on NCI-CTCAE ver 4.0 and RTOG.

Measure: Safety assessment

Time: 12 months

259 A Multi-arm, Phase Ib, Open-Label, Multicentre Study to Assess the Safety,Tolerability, Pharmacokinetics and Preliminary Anti-tumour Activity of AZD9291 in Combination With Ascending Doses of Novel Therapeutics in Patients With EGFRm+ Advanced NSCLC Who Have Progressed Following Therapy With an EGFR TKI (TATTON).

The purpose of this study is to determine the safety, tolerability and preliminary anti-tumour activity of AZD9291 when given together with AZD6094 or selumetinib in patients with EGFR mutation positive advanced lung cancer.

NCT02143466
Conditions
  1. Advanced Non Small Cell Lung Cancer
Interventions
  1. Drug: Part A - AZD9291 in combination with AZD6094
  2. Drug: Part A - AZD9291 in combination with continuous selumetinib (Asian subjects)
  3. Drug: Part A - AZD9291 in combination with continuous selumetinib (non-Asian subjects)
  4. Drug: Part A - AZD9291 in combination with intermittent selumetinib
  5. Drug: Part A - AZD9291 in combination with MEDI4736
  6. Drug: Part B - AZD9291 in combination with AZD6094
  7. Drug: Part B - AZD9291 in combination with selumetinib
  8. Drug: Part B - AZD9291 in combination with MEDI4736
  9. Drug: Part C - AZD6094 monotherapy (Japan only)
  10. Drug: Part C - AZD9291 in combination with AZD6094 (Japan only)
  11. Drug: Part D - AZD9291 in combination with AZD6094
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Local confirmation of tumour T790M status is acceptable if performed with an approved test and agreed by AstraZeneca. --- T790M ---

Prior treatment with a 3rd generation (T790M-directed) therapy (eg, AZD9291, rociletinib or HM61713) outside of this study is permitted if allocated to the 3rd generation EGFR TKI cohort. --- T790M ---

Primary Outcomes

Description: Part A: To investigate the safety and tolerability of AZD9291 when given in combination with AZD6094 or selumetinib who have progressed following prior therapy with an EGFR TKI agent, and define the combination dose(s) for further clinical evaluation.

Measure: Number of participants with Adverse Events and/or Dose Limiting Toxicities as a Measure of Safety and Tolerability of AZD9291 when given in combination with AZD6094 or selumetinib

Time: Adverse events will be collected from baseline until 28 days after the last dose in the AZD6094 or selumetinib arms.

Description: Part B: To investigate the safety and tolerability of AZD9291 when given in combination with AZD6094 or selumetinib in patients with locally advanced or metastatic NSCLC, who have progressed on prior therapy with an EGFR TKI agent. Part C monotherapy cohort (Japan only): To investigate and confirm the safety and tolerability of AZD6094 when given orally to Japanese patients with advanced solid malignancies. Part C combination cohort (Japan only): To investigate the safety and tolerability of AZD9291 when given orally to Japanese patients with EGFRm+ NSCLC in combination with AZD6094 who have progressed following prior therapy with an EGFR TKI agent, and define the combination dose(s) for further clinical evaluation. Part D: To investigate the safety and tolerability of AZD9291 when given in combination with AZD6094 (300 mg OD) in patients with locally advanced or metastatic EGFRm+ NSCLC.

Measure: Number of participants with Adverse Events as a measure of Safety and Tolerability of AZD9291 when given in combination with AZD6094 or selumetinib

Time: Adverse events: baseline until 28 days after the last dose in the AZD6094 or selumetinib arms.

Secondary Outcomes

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: Cmax after single dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: Tmax after single dosing

Time: Blood samples will be collected from each subject at pre-specified on cycle 1 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: AUC after single dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: AUC0-t after single dosing

Time: Blood samples will be collected from each subject at pre-specified on cycle 1 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: AUC0-24 after single dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: Terminal half life after single dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: CL/f after single dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: Volume of distribution after single dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: Cssmax after multiple dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 2 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: Tssmax after multiple dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 2 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: Cssmin after multiple dosing

Time: Blood samples will be collected from each subject at pre-specified times for the duration of treatment.

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: AUCss after multiple dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 2 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: CLss/f after multiple dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 2 day 1 up to 24 hours

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: Rac after multiple dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 and cycle 2 day 1

Description: To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.

Measure: Time dependency of PK after multiple dosing

Time: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 and cycle 2 day 1

Description: To obtain a preliminary assessment of the anti-tumour activity of the combination of AZD9291 and AZD6094 or selumetinib by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1.

Measure: Objective response rate

Time: At baseline and every 6 weeks until disease progression or withdrawal from study.

Description: To obtain a preliminary assessment of the anti-tumour activity of the combination of AZD9291 and AZD6094 or selumetinib by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1

Measure: Disease control rate

Time: At baseline and every 6 weeks until disease progression or withdrawal from study.

Description: To obtain a preliminary assessment of the anti-tumour activity of the combination of AZD9291 and AZD6094 or selumetinib by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1

Measure: Duration of response

Time: At baseline and every 6 weeks until disease progression or withdrawal from study.

Description: To obtain a preliminary assessment of the anti-tumour activity of the combination of AZD9291 and AZD6094 or selumetinib by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1

Measure: Percentage change in tumour size

Time: At baseline and every 6 weeks until disease progression or withdrawal from study.

Description: To obtain a preliminary assessment of the anti-tumour activity of the combination of AZD9291 and AZD6094 or selumetinib by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1 Expansion phase only

Measure: Progression free survival

Time: At baseline and every 6 weeks until disease progression or withdrawal from study.

Description: To obtain a preliminary assessment of overall survival in the AZD9291+AZD6094 combination arms of the study for Parts B and D.

Measure: Overall survival

Time: Confirmed during the FUP period and at least every 12 weeks until the data cut-off for the primary analysis and determination that no further OS collection is needed, approximately 5 years, death, or full withdrawal of consent, whichever comes first.

260 TIGER-2: A Phase 2, Open-label, Multicenter, Safety and Efficacy Study of Oral CO-1686 as 2nd Line EGFR-directed TKI in Patients With Mutant EGFR Non-small Cell Lung Cancer (NSCLC)

The purpose of this study is to evaluate the safety and anti-tumor effect of rociletinib. The trial is open-ended, which means patients will continue to take rociletinib until the study doctor determines it is no longer beneficial for them.

NCT02147990
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: Rociletinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Partial Response (PR), at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter.. Duration of Response (DOR) in T790M Positive Patients According to RECIST Version 1.1 as Determined by Investigator Assessment. --- T790M ---

DOR in patients with a T790M mutation (determined by central lab) with confirmed response per investigator. --- T790M ---

Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum longest diameter since the treatment started.. Progression-free Survival (PFS) in T790M Positive Patients by RECIST v1.1 as Determined by Investigator Assessment. --- T790M ---

Sparse blood sampling for POPPK and ER analyses in all patients treated with rociletinib.. Inclusion Criteria - Histologically or cytologically confirmed metastatic or unresectable locally advanced NSCLC - Documented evidence of a tumor with 1 or more EGFR mutations excluding exon 20 insertion - Disease progression confirmed by radiologic assessment while receiving treatment with the first single agent EGFR-TKI - EGFR TKI treatment discontinued less than or equal to 30 days prior to planned initiation of rociletinib - The washout period for an EGFR inhibitor is a minimum of 3 days - No intervening treatment between cessation of single agent EGFR TKI and planned initiation of rociletinib - Previous treatment with less than or equal to 1 prior chemotherapy (excluding prior neo-adjuvant or adjuvant chemotherapy or chemoradiotherapy with curative intent) - Any toxicity related to prior EGFR inhibitor treatment must have resolved to Grade 1 or less - Central laboratory confirmation of the presence of the T790M mutation in tumor tissue in Cohort A and the presence or absence of the T790M mutation in tumor tissue in Cohort B. Centrally indeterminate, unknown or invalid specimens are not acceptable. --- T790M ---

Sparse blood sampling for POPPK and ER analyses in all patients treated with rociletinib.. Inclusion Criteria - Histologically or cytologically confirmed metastatic or unresectable locally advanced NSCLC - Documented evidence of a tumor with 1 or more EGFR mutations excluding exon 20 insertion - Disease progression confirmed by radiologic assessment while receiving treatment with the first single agent EGFR-TKI - EGFR TKI treatment discontinued less than or equal to 30 days prior to planned initiation of rociletinib - The washout period for an EGFR inhibitor is a minimum of 3 days - No intervening treatment between cessation of single agent EGFR TKI and planned initiation of rociletinib - Previous treatment with less than or equal to 1 prior chemotherapy (excluding prior neo-adjuvant or adjuvant chemotherapy or chemoradiotherapy with curative intent) - Any toxicity related to prior EGFR inhibitor treatment must have resolved to Grade 1 or less - Central laboratory confirmation of the presence of the T790M mutation in tumor tissue in Cohort A and the presence or absence of the T790M mutation in tumor tissue in Cohort B. Centrally indeterminate, unknown or invalid specimens are not acceptable. --- T790M --- --- T790M ---

- Treatment with prohibited medications less than or equal to 14 days prior to treatment with rociletinib - Patients who are currently receiving treatment with any medications that have the potential to prolong the QT interval and the treatment cannot be either discontinued or switched to a different medication before starting rociletinib - Prior treatment with rociletinib, or other drugs that target T790M positive mutant EGFR with sparing of wild type EGFR - Any of the following cardiac abnormalities or history - Clinically significant abnormal 12-lead ECG, QT interval corrected using Fridericia's method (QTCF) greater than 450 msec - Inability to measure QT interval on ECG - Personal or family history of long QT syndrome - Implantable pacemaker or implantable cardioverter defibrillator - Resting bradycardia less than 55 beats/min - Non-study related surgical procedures less than or equal to 7 days prior to administration of rociletinib. --- T790M ---

In all cases, the patient must be sufficiently recovered and stable before treatment administration - Females who are pregnant or breastfeeding - Refusal to use adequate contraception for fertile patients (females and males) while on treatment and for 12 weeks after the last dose of rociletinib - Presence of any serious or unstable concomitant systemic disorder incompatible with the clinical study - Any other reason the investigator considers the patient should not participate in the study Inclusion Criteria - Histologically or cytologically confirmed metastatic or unresectable locally advanced NSCLC - Documented evidence of a tumor with 1 or more EGFR mutations excluding exon 20 insertion - Disease progression confirmed by radiologic assessment while receiving treatment with the first single agent EGFR-TKI - EGFR TKI treatment discontinued less than or equal to 30 days prior to planned initiation of rociletinib - The washout period for an EGFR inhibitor is a minimum of 3 days - No intervening treatment between cessation of single agent EGFR TKI and planned initiation of rociletinib - Previous treatment with less than or equal to 1 prior chemotherapy (excluding prior neo-adjuvant or adjuvant chemotherapy or chemoradiotherapy with curative intent) - Any toxicity related to prior EGFR inhibitor treatment must have resolved to Grade 1 or less - Central laboratory confirmation of the presence of the T790M mutation in tumor tissue in Cohort A and the presence or absence of the T790M mutation in tumor tissue in Cohort B. Centrally indeterminate, unknown or invalid specimens are not acceptable. --- T790M ---

In all cases, the patient must be sufficiently recovered and stable before treatment administration - Females who are pregnant or breastfeeding - Refusal to use adequate contraception for fertile patients (females and males) while on treatment and for 12 weeks after the last dose of rociletinib - Presence of any serious or unstable concomitant systemic disorder incompatible with the clinical study - Any other reason the investigator considers the patient should not participate in the study Inclusion Criteria - Histologically or cytologically confirmed metastatic or unresectable locally advanced NSCLC - Documented evidence of a tumor with 1 or more EGFR mutations excluding exon 20 insertion - Disease progression confirmed by radiologic assessment while receiving treatment with the first single agent EGFR-TKI - EGFR TKI treatment discontinued less than or equal to 30 days prior to planned initiation of rociletinib - The washout period for an EGFR inhibitor is a minimum of 3 days - No intervening treatment between cessation of single agent EGFR TKI and planned initiation of rociletinib - Previous treatment with less than or equal to 1 prior chemotherapy (excluding prior neo-adjuvant or adjuvant chemotherapy or chemoradiotherapy with curative intent) - Any toxicity related to prior EGFR inhibitor treatment must have resolved to Grade 1 or less - Central laboratory confirmation of the presence of the T790M mutation in tumor tissue in Cohort A and the presence or absence of the T790M mutation in tumor tissue in Cohort B. Centrally indeterminate, unknown or invalid specimens are not acceptable. --- T790M --- --- T790M ---

Cohort A will enroll approximately 125 eligible patients who are centrally confirmed T790M-positive. --- T790M ---

Cohort B will be a continuation of the study and will enroll up to approximately 100 eligible patients who will be either centrally confirmed T790M-positive or T790M-negative. --- T790M ---

Cohort B will be a continuation of the study and will enroll up to approximately 100 eligible patients who will be either centrally confirmed T790M-positive or T790M-negative. --- T790M --- --- T790M ---

Primary Outcomes

Description: ORR is defined as the percentage of patients with a best overall confirmed response of partial response (PR) or complete response (CR) recorded from the start of the treatment until disease progression. For patients who continued treatment post-progression, the first date of progression was used for the analysis. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions, defined by and assessed as: Complete Response (CR), is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR), at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter.

Measure: Objective Response Rate (ORR) According to RECIST Version 1.1 as Determined by Investigator Assessment

Time: Cycle 1 Day 1 to End of Treatment, up to approximately 57 months.

Secondary Outcomes

Description: DOR in patients with a T790M mutation (determined by central lab) with confirmed response per investigator. The DOR for complete response (CR) and partial response (PR) was measured from the date that any of these best responses is first recorded until the first date that progressive disease (PD) is objectively documented. For patients who continue treatment post-progression, the first date of progression was used for the analysis.

Measure: Duration of Response (DOR) in T790M Positive Patients According to RECIST Version 1.1 as Determined by Investigator Assessment

Time: From Cycle 1 Day 1 until disease progression or end of treatment, whichever came first, assessed up to 54 months

Description: DCR is defined as the percentage of patients who have achieved CR, PR, and SD lasting at least 12 weeks. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions, defined by and assessed as: Complete Response (CR), is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR), at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter. Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum longest diameter since the treatment started.

Measure: Disease Control Rate (DCR) by RECIST v1.1 as Determined by Investigator Assessment

Time: From Cycle 1 Day 1 until disease progression or end of treatment, whichever came first, assessed up to 57 months

Description: PFS was calculated as 1+ the number of days from the first dose of study drug to documented radiographic progression or death due to any cause, whichever occurs first. Patients without a documented event of radiographic progression were censored on the date of their last adequate tumor assessment (i.e., radiologic assessment) or date of first dose of study drug if no tumor assessments were performed. For patients who continued treatment post-progression, the first date of progression was used for the analysis of PFS. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression.

Measure: Progression-free Survival (PFS) in T790M Positive Patients by RECIST v1.1 as Determined by Investigator Assessment

Time: From Cycle 1 Day 1 until disease progression or end of treatment, whichever came first, assessed up to 57 months

Description: OS was calculated as 1+ the number of days from the first dose of study drug to death due to any cause. Patients without a documented date of death will be censored on the date the patient was last known to be alive.

Measure: Overall Survival (OS) Determined by Investigator Assessment

Time: Cycle 1 Day 1 to date of death, assessed up to 57 months

Description: EORTC QLC-C30 is a 30-item questionnaire to assess the quality of life in cancer patients. EORTC QLQ-C30 includes functional scales (physical, role, cognitive, emotional, social), global health status, symptom scales (fatigue, pain, nausea/vomiting), and other (dyspnoea, appetite loss, insomnia, constipation/diarrhea, financial difficulties). Most questions used 4-point scale (1 'Not at All' to 4 'Very Much'); two used 7-point scale (1 'Very Poor' to 7 'Excellent'). Scores are averaged, and transformed to 0-100 scale; higher score = better quality of life.

Measure: Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients With Cancer (EORTC QLQ-C30) Global Health Status Quality of Life Scale

Time: Baseline (Day 0), Months 5, 10 and EOT

Description: Dermatology Life Quality Index (DLQI) score is a participant-reported outcome consisting of a set of 10 questions regarding the degree to which the participant's skin has affected certain behaviors and quality of life over the last week. Responses to each are: very much (score of 3), a lot, a little, or not at all (score of 0). The DLQI score ranges from 0 (best) to 30 (worst); the higher the score, the more quality of life is impaired.

Measure: Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in Dermatology Life Quality Index (DLQI)

Time: Baseline (Day 0), Months 5, 10 and EOT

Description: EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms.

Measure: Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in EORTC QLQ-LC-13 Alopecia Scale

Time: Baseline (Day 0), Months 5, 10 and EOT

Description: EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms.

Measure: Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in EORTC QLQ-LC-13 Coughing Scale

Time: Baseline (Day 0), Months 5, 10 and EOT

Description: EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms.

Measure: Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in EORTC QLQ-LC-13 Dysphagia Scale

Time: Baseline (Day 0), Months 5, 10 and EOT

Description: EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms.

Measure: Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in EORTC QLQ-LC-13 Dyspnoea Scale

Time: Baseline (Day 0), Months 5, 10 and EOT

Description: EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms.

Measure: Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in EORTC QLQ-LC-13 Haemoptysis Scale

Time: Baseline (Day 0), Months 5, 10 and EOT

Description: EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms.

Measure: Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in EORTC QLQ-LC-13 Pain in Arm or Shoulder Scale

Time: Baseline (Day 0), Months 5, 10 and EOT

Description: EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms.

Measure: Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in EORTC QLQ-LC-13 Pain in Chest Scale

Time: Baseline (Day 0), Months 5, 10 and EOT

Description: EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms.

Measure: Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in EORTC QLQ-LC-13 Medicine for Pain Scale

Time: Baseline (Day 0), Months 5, 10 and EOT

Description: EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms.

Measure: Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in EORTC QLQ-LC-13 Pain in Other Parts Scale

Time: Baseline (Day 0), Months 5, 10 and EOT

Description: EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms.

Measure: Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in EORTC QLQ-LC-13 Peripheral Neuropathy Scale

Time: Baseline (Day 0), Months 5, 10 and EOT

Description: EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms.

Measure: Change From Baseline to Cycles 5, 10 and End of Treatment (EOT) in EORTC QLQ-LC-13 Sore Mouth Scale

Time: Baseline (Day 0), Months 5, 10 and EOT

Description: Sparse blood sampling for POPPK and ER analyses in all patients treated with rociletinib.

Measure: Population PK (POPPK) and Exposure-Response (ER) Analysis of Rociletinib

Time: Every 4 weeks for approximately 6 months (Day 1 of Cycles 2 to 7 inclusive)

261 An Investigator-Sponsored Phase 2 Single Arm Trial of Ramucirumab and Pembrolizumab in Patients With EGFR Mutant Non-Small Cell Lung Cancer

This phase II trial studies how well ramucirumab and pembrolizumab work in treating EGFR mutant non-small cell lung cancer that has come back (recurrent) or spread to other places in the body (metastatic). Ramucirumab may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body?s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving ramucirumab and pembrolizumab may work better in treating EGFR mutant non-small cell lung cancer compared to pembrolizumab alone.

NCT04120454
Conditions
  1. Metastatic Lung Non-Small Cell Carcinoma
  2. Recurrent Lung Non-Small Cell Carcinoma
  3. Stage IV Lung Cancer AJCC v8
  4. Stage IVA Lung Cancer AJCC v8
  5. Stage IVB Lung Cancer AJCC v8
Interventions
  1. Biological: Pembrolizumab
  2. Biological: Ramucirumab
MeSH:Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Carcinoma Neoplasm of the lung Non-small cell lung carcinoma

Patients who develop progressive disease after erlotinib, gefitinib, afatinib, or dacomitinib must either receive osimertintib (T790M positive) or be T790M negative. --- T790M ---

Patients who develop progressive disease after erlotinib, gefitinib, afatinib, or dacomitinib must either receive osimertintib (T790M positive) or be T790M negative. --- T790M --- --- T790M ---

Primary Outcomes

Description: Response rate will be evaluated with computed tomography (CT) scans every 2 cycles and tumor measurements using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Immune RECIST (iRECIST) will also be assessed.

Measure: Overall response rate

Time: Up to 2 years

Secondary Outcomes

Description: Common Terminology Criteria for Adverse Events version 4.0 will be used for adverse event grading. Attributions of causality will be assessed by the primary treating physician. Frequency and severity of adverse events and tolerability of the regimen will be collected and summarized by descriptive statistics for each of the disease cohorts.

Measure: Incidence of adverse events

Time: Up to 2 years

Description: Clinical benefit rate will be evaluated with CT scans every 2 cycles and tumor measurements using RECIST 1.1 criteria. iRECIST will also be assessed.

Measure: Clinical benefit rate (complete response + partial response + stable disease)

Time: Up to 2 years

Description: Kaplan-Meier curves will be calculated to estimate progression-free survival.

Measure: Progression-free survival

Time: From the date of study registration to the date of progressive disease, assessed up to 2 years

Description: Kaplan-Meier curves will be calculated to estimate overall survival.

Measure: Overall survival

Time: From the date of study registration to the date of death, assessed up to 2 years

Other Outcomes

Description: Measured by immunohistochemistry, including tumor infiltrating lymphocytes and T cell receptor (TCR) immunosequencing (immunoSEQ) and relationship to clinical outcomes, including response rate. TCR immunoSEQ data will be summarized for each patient for T-cell clonality difference, descriptive statistics and confidence interval will be obtained across patients.

Measure: Tumor immunoprofile

Time: Baseline

Description: Measured using 10-color 65 marker multiplex Clinical Laboratory Improvement Act-certified IMMUNOME flow cytometry profile on peripheral blood samples. For immune cell subpopulation data by flow cytometry, will identify differences between the paired peripheral blood mononuclear cell samples from the same patients.

Measure: Circulating immune cell profiles in response to treatment and in relation to clinical response

Time: Up to 2 years

Description: Will evaluate correlation with clinical response. A bivariate plot will be used to describe the relationship between response rate and peak VEGF via enzyme-linked immunosorbent assay over time.

Measure: Change in circulating VEGF levels

Time: Baseline up to 2 years

262 A Randomized Phase 3 Multicenter Open-label Study to Compare the Efficacy of TAK-788 as First-line Treatment Versus Platinum-Based Chemotherapy in Patients With Non-Small Cell Lung Cancer With EGFR Exon 20 Insertion Mutations

The purpose of this study is to compare the efficacy of TAK-788 as first-line treatment with that of platinum-based chemotherapy in participants with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumors harbor epidermal growth factor receptor (EGFR) exon 20 insertion mutations.

NCT04129502
Conditions
  1. Advanced/Metastatic Non-Small Cell Lung Cancer (NSCLC)
Interventions
  1. Drug: TAK-788
  2. Drug: Pemetrexed
  3. Drug: Cisplatin
  4. Drug: Carboplatin
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Higher scores represent a high level of symptomatology/problems.. Inclusion Criteria: - Histologically or cytologically confirmed nonsquamous cell locally advanced not suitable for definitive therapy, recurrent, or metastatic (Stage IV) non-small cell lung cancer (NSCLC) - Documented epithelial growth factor receptor (EGFR) in-frame exon 20 insertion mutation assessed by a clinical laboratory improvements amendment (CLIA)-certified (United States [US] sites) or an accredited (outside of the US) local laboratory The EGFR exon 20 insertion mutation can be either alone or in combination with other EGFR or HER2 mutations except EGFR mutations for which there are approved anti-EGFR TKIs (ie, exon 19 del, L858R, T790M, L861Q, G719X, or S768I, where X is any other amino acid) - Adequate tumor tissue available, either from primary or metastatic sites, for central laboratory confirmation of EGFR exon 20 insertion mutation - At least 1 measurable lesion per response evaluation criteria in solid tumors (RECIST) version 1.1 - Life expectancy ≥3 months - Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 Exclusion Criteria: - Received prior systemic treatment for locally advanced or metastatic disease - Received radiotherapy ≤14 days before randomization or has not recovered from radiotherapy-related toxicities - Received a moderate or strong cytochrome P-450 (CYP)3A inhibitor or moderate or strong CYP3A inducer within 10 days before randomization - Have been diagnosed with another primary malignancy other than NSCLC - Have current spinal cord compression or leptomeningeal disease - Have uncontrolled hypertension. --- L858R --- --- T790M ---

Participants with hypertension should be under treatment on study entry to control blood pressure - Received a live vaccine within 4 weeks before randomization per Summary of product characteristics (SmPCs) for pemetrexed, cisplatin, and carboplatin Inclusion Criteria: - Histologically or cytologically confirmed nonsquamous cell locally advanced not suitable for definitive therapy, recurrent, or metastatic (Stage IV) non-small cell lung cancer (NSCLC) - Documented epithelial growth factor receptor (EGFR) in-frame exon 20 insertion mutation assessed by a clinical laboratory improvements amendment (CLIA)-certified (United States [US] sites) or an accredited (outside of the US) local laboratory The EGFR exon 20 insertion mutation can be either alone or in combination with other EGFR or HER2 mutations except EGFR mutations for which there are approved anti-EGFR TKIs (ie, exon 19 del, L858R, T790M, L861Q, G719X, or S768I, where X is any other amino acid) - Adequate tumor tissue available, either from primary or metastatic sites, for central laboratory confirmation of EGFR exon 20 insertion mutation - At least 1 measurable lesion per response evaluation criteria in solid tumors (RECIST) version 1.1 - Life expectancy ≥3 months - Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 Exclusion Criteria: - Received prior systemic treatment for locally advanced or metastatic disease - Received radiotherapy ≤14 days before randomization or has not recovered from radiotherapy-related toxicities - Received a moderate or strong cytochrome P-450 (CYP)3A inhibitor or moderate or strong CYP3A inducer within 10 days before randomization - Have been diagnosed with another primary malignancy other than NSCLC - Have current spinal cord compression or leptomeningeal disease - Have uncontrolled hypertension. --- L858R --- --- T790M ---

Primary Outcomes

Description: PFS is defined as the time interval from the date of randomization until the first date at which the criteria for PD according to RECIST version 1.1 are met or death, whichever occurs first.

Measure: Progression Free Survival (PFS) as Assessed by Blinded Independent Review Committee (IRC) per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1

Time: Up to approximately 40 months after the first participant is randomized

Secondary Outcomes

Description: Confirmed ORR is defined as the proportion of participants who are confirmed to have achieved complete response (CR) or partial response (PR). Confirmed responses are responses that persist on repeat imaging ≥4 weeks after initial response.

Measure: Confirmed Objective Response Rate (ORR) as Assessed by Blinded Independent Review Committee (IRC) per RECIST Version 1.1

Time: Up to approximately 40 months after the first participant is randomized

Description: OS is defined as the interval from the date of randomization until death.

Measure: Overall Survival (OS)

Time: Up to approximately 40 months after the first participant is randomized

Description: PFS is defined as the time interval from the date of randomization until the first date at which the criteria for progressive disease (PD) according to RECIST version 1.1 are met or death, whichever occurs first.

Measure: Progression Free Survival (PFS) as Assessed by the Investigator

Time: Up to approximately 40 months after the first participant is randomized

Description: Confirmed ORR is defined as the proportion of participants who are confirmed to have achieved CR or PR. Confirmed responses are responses that persist on repeat imaging ≥4 weeks after initial response.

Measure: Confirmed Objective Response Rate (ORR) as Assessed by the Investigator

Time: Up to approximately 40 months after the first participant is randomized

Description: Duration of response is defined as the time interval from the time that the measurement criteria are first met for CR/PR (whichever is first recorded) until the first date that PD is objectively documented.

Measure: Duration of Response, as Assessed by the Blinded Independent Review Committee (IRC) and the Investigator

Time: Up to approximately 40 months after the first participant is randomized

Description: Time to response is defined as the time interval from the date of randomization until the initial observation of CR or PR.

Measure: Time to Response, as Assessed by the Blinded Independent Review Committee (IRC) and the Investigator

Time: Up to approximately 40 months after the first participant is randomized

Description: DCR is defined as the percentage of participants who have achieved CR, PR, or stable disease (SD) (in the case of SD, measurements must have met the SD criteria at least once after study entry at a minimum interval of 6 weeks) after the initiation of study drug.

Measure: Disease Control Rate (DCR) as Assessed by the Blinded Independent Review Committee (IRC) and the Investigator

Time: Up to approximately 40 months after the first participant is randomized

Description: EORTC QLQ-C30 is a cancer-specific questionnaire which comprises of 5 functional scales (physical, role, cognitive, emotional, and social functioning); 3 symptom scales (fatigue, pain, and nausea/vomiting); and a global health status/quality-of-life (QoL) scale. Six single-item scales are also included (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Raw scores will be converted into scale scores ranging from 0 to 100. For the functional scales and the global health status/QoL scale, higher scores represent better HRQoL, whereas for the symptom scales lower scores represent better HRQoL (i.e., a low level of symptomatology/problems).

Measure: Patient-reported Symptoms, Functioning, and Health-related Quality of Life (HRQoL) as Assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30

Time: Up to approximately 40 months after the first participant is randomized

Description: EORTC QLQ-LC13 is a cancer-specific questionnaire which comprises of 13 questions assessing lung cancer-associated symptoms (cough, hemoptysis, dyspnea, and site-specific pain), treatment-related side effects (sore mouth, dysphagia, peripheral neuropathy, and alopecia), and use of pain medication. Raw scores will be converted into scale scores ranging from 0 to 100. Higher scores represent a high level of symptomatology/problems.

Measure: Participant-reported Symptoms as Assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire, Lung Cancer Module (QLQ-LC13)

Time: Up to approximately 40 months after the first participant is randomized

263 Effect of Metformin in Combination With Tyrosine Kinase Inhibitors (TKI) on Clinical, Biochemical and Nutritional in Patients With Non-Small Cell Lung Carcinoma (NSCLC): Randomized Clinical Trial

Treatment for patients with mutation in the epidermal growth factor receptor (EGFR) with specific domain tyrosine kinase inhibitors (TKIs) has given place to objective clinical response, increase in progression-free survival (PFS) compared to cytotoxic chemotherapy. However, despite clinical success with different TKIs, most patients eventually develop acquired resistance to these agents after an average period of time of 10 months. Recently metformin, an oral hypoglycemic agent, has been associated with reduction in the global risk of incidence and mortality of different types of cancer, by exercising anti-tumor properties. Its role as a chemo-preventive and adjuvant drug in overcoming acquired resistance to chemotherapy, target therapy and immunotherapy in NSCLC is still under discussion. However, preclinical data support the role as an adjuvant drug in the treatment of NSCLC in combination with chemotherapy or EGFR-TKIs. This evidence led to examine the effects of metformin in combination with EGFR-TKIs in a NSCLC cellular line panel, obtaining a different sensibility to the unique use with EGFR-TKIs. The combination of metformin and TKIs reduced the colony forming capacity and proliferation, and induced a huge pro-apoptotic effect in NSCLC cellular lines and resistance in EGFR-TKIs. This suggests that metformin may reduce the resistance to TKIs. A retrospective study in patients from our institution from 2008 to 2014, showed significant clinical benefit in patients who used metformin, improving the global survival. Based on these considerations, we propose a phase II randomized study to assess the effect and safety of metformin in combination with TKIs as second line therapy in patients with NSCLC in advanced stages with EGFR mutation. The main objective of this study is to assess the progression-free survival period in patients with advanced non-small cell lung cancer in treatment with TKIs and metformin versus TKI alone.

NCT03071705
Conditions
  1. Non-Small Cell Adenocarcinoma
  2. Tyrosine Kinase Mutation
  3. EGFR Gene Mutation
Interventions
  1. Drug: Metformin
  2. Drug: TKI
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

By PCR it was found that 50% of patients with resistance to TKI develop a specific mutation in exon 20 (T790M). --- T790M ---

T790M mutation may be present before exposition to TKI and it's generally found with other activating mutations in EGFR (exon 19 deletion and punctual L858R mutation). --- T790M ---

A response rate of 8% has been reported in those patients treated with gefitinib or erlotinib whose T790M mutation was positive at the time of the diagnosis, with progression-free survival of 2 months and global survival median of 16 months. --- T790M ---

Despite the advances in treatment have increased response rate and progression-free survival with anti-EGFR TKI in patients with presence of activating mutations, most of them will develop resistance mutations (T790M) and disease progression. --- T790M ---

Acquired resistance will develop in a mean time of 9 to 13 months and the 50% to 60% will be secondary to development of T790M resistance mutation. --- T790M ---

We know that around 50% of cases are caused by an acquired mutation in the EGFR T790M and a lower percentage by MET oncogene amplification, nevertheless, there are other proposed molecular mechanisms, such as the activation of mesenchymal-epithelial transition. --- T790M ---

Finding an effective therapy for patients who develop T790M resistance mutation is required to overcome resistance to first generation anti-EGFR TKI. --- T790M ---

T790M mutation and MET amplification are the main resistance mechanisms to anti-EGFR TKI, other mechanisms such as epithelial-mesenchymal transition (EMT) by TGF-β are resistance mechanisms. --- T790M ---

Pre-clinical studies with cellular lines of lung cancer with anti-EGFR acquired-resistance treatment show that metformin prevents transcription of factors that activate epithelial-mesenchymal transition, inhibiting TGF-β, thus, inhibiting IL-6/JAK1/STAT3 pathway, overcoming anti-EGFR TKI resistance in patients with T790M resistance mutation, in vitro and in vivo. --- T790M ---

Primary Outcomes

Measure: Overall Survival

Time: Start of treatment until 1-year follow-up

Secondary Outcomes

Description: Inflammatory markers (IL-6, IL-12, TNF-alpha)

Measure: Response Rate

Time: 3 month evaluation after start of treatment

264 HERTHENA-Lung01: A Phase 2 Randomized Open-Label Study of Patritumab Deruxtecan (U3-1402) in Subjects With Previously Treated Metastatic or Locally Advanced EGFR-mutated Non-Small Cell Lung Cancer (NSCLC)

This study is designed to evaluate the antitumor activity of patritumab deruxtecan in participants with metastatic or locally advanced NSCLC with an activating EGFR mutation (exon 19 deletion or L858R) who have received and progressed on or after at least 1 EGFR TKI and 1 platinum-based chemotherapy-containing regimen.

NCT04619004
Conditions
  1. Non-Small Cell Lung Cancer Metastatic
  2. Non-Small Cell Lung Cancer With Mutation in Epidermal Growth Factor Receptor
Interventions
  1. Drug: Patritumab Deruxtecan (Fixed dose)
  2. Drug: Patritumab Deruxtecan (Up-Titration)
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Participants receiving an EGFR TKI at the time of signing informed should continue to take the EGFR TKI until 5 days prior to Cycle 1 Day 1. EGFR T790M mutation-positive participants (previously treated with erlotinib, gefitinib, afatinib or dacomitinib) must have received and have documentation of radiological disease progression following treatment with osimertinib. --- T790M ---

Primary Outcomes

Description: ORR is defined as the proportion of participants with a best overall response (BOR) of confirmed complete response (CR) or confirmed partial response (PR) as assessed by BICR per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

Measure: Objective Response Rate (ORR) as Assessed by Blinded Independent Central Review (BICR)

Time: Data collected from screening until time of disease progression, death, study discontinuation, or other protocol-defined reasons, whichever occurs first, assessed up to approximately 26 months

Secondary Outcomes

Description: DoR is defined as the time from the first documented confirmed response (CR or PR) to the date of progression or death due to any cause as assessed by BICR and Investigator per RECIST v1.1, respectively.

Measure: Duration of Response (DoR)

Time: Data collected from screening until time of disease progression, death, study discontinuation, or other protocol-defined reasons, whichever occurs first, assessed up to approximately 26 months

Description: PFS is defined as the time from the start of study treatment to the earlier of the dates of the first documentation of objective progressive disease (PD) per RECIST v1.1 or death due to any cause. PFS will be determined by BICR and by Investigator, respectively.

Measure: Progression-free Survival (PFS)

Time: Data collected from screening until time of disease progression, death, study discontinuation, or other protocol-defined reasons, whichever occurs first, assessed up to approximately 26 months

Description: ORR is defined as the proportion of participants with a BOR of confirmed CR or confirmed PR as assessed by the Investigator per RECIST v1.1.

Measure: Objective Response Rate (ORR) as Assessed by the Investigator

Time: Data collected from screening until time of disease progression, death, study discontinuation, or other protocol-defined reasons, whichever occurs first, assessed up to approximately 26 months

Description: DCR is defined as the proportion of participants who achieved a BOR of confirmed CR, confirmed PR, or stable disease (SD) as assessed by BICR and by the Investigator per RECIST v1.1, respectively.

Measure: Disease Control Rate (DCR)

Time: Data collected from screening until time of disease progression, death, study discontinuation, or other protocol-defined reasons, whichever occurs first, assessed up to approximately 26 months

Description: TTR is defined as the time from the start of study treatment to the date of the first documentation of confirmed response (CR or PR) as assessed by BICR and Investigator per RECIST v1.1, respectively.

Measure: Time to Tumor Response (TTR)

Time: Data collected from screening until time of disease progression, death, study discontinuation, or other protocol-defined reasons, whichever occurs first, assessed up to approximately 26 months

Description: The best percentage change in the SoD of measurable tumors is defined as the percentage change in the smallest SoD from all post-baseline tumor assessments, taking as reference the baseline SoD.

Measure: Best percentage change in the sum of diameters (SoD) of measurable tumors

Time: Data collected from screening until time of disease progression, death, study discontinuation, or other protocol-defined reasons, whichever occurs first, assessed up to approximately 26 months

Description: OS defined as the time from the start of study treatment to the date of death due to any cause.

Measure: Overall Survival (OS)

Time: Death date is collected until the participant discontinues the study or up to approximately 26 months

Description: A TEAE is defined as an adverse event (AE) with a start or worsening date during the on-treatment period. A serious AE is defined as any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, is an important medical event, or may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes noted. AESIs will also be assessed. Adverse events will be coded using MedDRA and will be graded using NCI-CTCAE v5.0.

Measure: Incidence of treatment emergent adverse events (TEAEs), serious adverse events (SAEs), and adverse events of special interest (AESIs)

Time: From baseline up to Day 47 post last dose

265 A Single-arm Exploratory Clinical Study of Anlotinib Hydrochloride Combined With Docetaxel in EGFR Mutations Advanced Non Small Cell Lung Cancer Patients Who Have Progressed After Targeted Therapy and Chemotherapy

Anlotinib is a multi-target receptor tyrosine kinase inhibitor in domestic research and development. It can inhibit angiogenesis-related kinases, such as VEGFR, FGFR, PDGFR and tumor cell proliferation related kinase c-Kit kinase. In the Phase III study, patients who failed at least two systemic chemotherapy (third-line or above) or were intolerant of the drugs were treated with anlotinib or placebo. The PFS and OS in the anlotinib group were 5.37 months and 9.63 months, respectively. The placebo group PFS and OS were 1.4 months and 6.3 months. Therefore, it is envisaged to use anlotinib combined with docetaxel to treat EGFR mutations advanced non small cell lung cancer to further improve the patient's PFS or OS.

NCT04619563
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: Anlotinib Hydrochloride plus Docetaxel
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Patients who were resistant to EGFR targeted treatment need to receive T790M mutation test. --- T790M ---

Primary Outcomes

Description: PFS is defined as the time from the date of enrollment to the first occurrence of disease progression or death due to any cause.

Measure: Progress free survival (PFS)

Time: each 42 days up to PD or death (up to 24 months)

Secondary Outcomes

Description: ORR is defined as the percentage of subjects with evidence of a confirmed complete response (CR) or partial response (PR) as per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1.prior to progression or any further therapy.

Measure: Objective Response Rate (ORR)

Time: each 42 days up to intolerance the toxicity or PD (up to 24 months)

Description: DCR is defined as the proportion of patients with a documented complete response, partial response, and stable disease (CR + PR + SD) based on RECIST 1.1.

Measure: Disease Control Rate (DCR)

Time: each 42 days up to intolerance the toxicity or PD (up to 24 months)

Description: OS is defined as the time from the date of enrollment to the date of death due to any cause.

Measure: Overall Survival (OS)

Time: From randomization until death (up to 24 months)

Description: use EORTC QLQ-C30(version 3) questionnaire to evaluate the quality of life.

Measure: Quality of Life score (QoL)

Time: each 42 days up to intolerance the toxicity or PD (up to 24 months)

266 An Observational, Retrospective, Real World Study of Osimertinib in Ethnic Chinese Patients With Locally Advanced/Metastatic T790M Mutation-Positive Non-small-cell Lung Cancer (NSCLC )Progressed on Previous Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor (TKI).

To assess the effectiveness and safety of osimertinib treatment in a real world setting.

NCT03133234
Conditions
  1. T790M Positive NSCLC Patients
Interventions
  1. Drug: osimertinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

An Observational, Retrospective, Real World Study of Osimertinib in Ethnic Chinese Patients With Locally Advanced/Metastatic T790M Mutation-Positive Non-small-cell Lung Cancer (NSCLC )Progressed on Previous Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor (TKI).. Effect of Osimertinib in Ethnic Chinese With EGFR and T790M Mutated NSCLC To assess the effectiveness and safety of osimertinib treatment in a real world setting. --- T790M ---

An Observational, Retrospective, Real World Study of Osimertinib in Ethnic Chinese Patients With Locally Advanced/Metastatic T790M Mutation-Positive Non-small-cell Lung Cancer (NSCLC )Progressed on Previous Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor (TKI).. Effect of Osimertinib in Ethnic Chinese With EGFR and T790M Mutated NSCLC To assess the effectiveness and safety of osimertinib treatment in a real world setting. --- T790M --- --- T790M ---

T790M mutation testing time. --- T790M ---

T790M mutation testing sample. --- T790M ---

To assess by proportion of testing samples types as recorded on the case report form.. T790M mutation testing platform. --- T790M ---

Inclusion Criteria: - Above 18 years of age; - Locally advanced (stage IIIB) or metastatic (stage IV) NSCLC, not amenable to curative surgery or radiotherapy - Confirmed T790M mutation - Progressed on previous EGFR TKI treatment. --- T790M ---

Patients may have also received additional lines of treatment - Received osimertinib treatment in the participating site between May 1st and Oct 31st 2016 Exclusion Criteria: • Enrolment in studies that prohibit any participation in this observational study Inclusion Criteria: - Above 18 years of age; - Locally advanced (stage IIIB) or metastatic (stage IV) NSCLC, not amenable to curative surgery or radiotherapy - Confirmed T790M mutation - Progressed on previous EGFR TKI treatment. --- T790M ---

Patients may have also received additional lines of treatment - Received osimertinib treatment in the participating site between May 1st and Oct 31st 2016 Exclusion Criteria: • Enrolment in studies that prohibit any participation in this observational study T790M Positive NSCLC Patients Carcinoma, Non-Small-Cell Lung The current study will not only assess the effectiveness of osimertinib treatment in a real world setting, but will also help us to understand the real-world testing patterns among T790M mutation positive locally advanced or metastatic NSCLC patients who have progressed after EGFR TKI treatment. --- T790M ---

Patients may have also received additional lines of treatment - Received osimertinib treatment in the participating site between May 1st and Oct 31st 2016 Exclusion Criteria: • Enrolment in studies that prohibit any participation in this observational study T790M Positive NSCLC Patients Carcinoma, Non-Small-Cell Lung The current study will not only assess the effectiveness of osimertinib treatment in a real world setting, but will also help us to understand the real-world testing patterns among T790M mutation positive locally advanced or metastatic NSCLC patients who have progressed after EGFR TKI treatment. --- T790M --- --- T790M ---

Primary Outcomes

Description: Overall response rate (ORR), defined as the proportion of patients with a best response of "responding" to treatment by investigator assessment

Measure: ORR

Time: Followed up with 6 months after last patient in

Secondary Outcomes

Description: Progression free survival (PFS), defined as the time from the date of first dose of osimertinib to the date of investigator-assessed disease progression or death from any cause during study. Subjects who have not progressed or died at the time of analysis will be censored at the time of the latest date of assessment

Measure: PFS

Time: Followed up 10 months after last subject in

Description: Average turnaround time.

Measure: T790M mutation testing time

Time: Within 14 days after enrollment date

Description: To assess by number of previous adopted/current/future therapies as recorded on the case report form

Measure: Treatment patterns

Time: Followed up 10 months after last patient in

Description: To assess by number of adverse events as recorded on the case report form.

Measure: Adverse events

Time: Follow up 10 months after last patient in.

Description: To assess by intensity of adverse events as recorded on the case report form, which will be measured by CTCAE grade system

Measure: Adverse event intensity

Time: Follow up 10 months after last patient in.

Description: To assess by proportion of testing samples types as recorded on the case report form.

Measure: T790M mutation testing sample

Time: Within 14 days after enrollment date

Description: To assess by proportion of each testing platform as recorded on the case report form.

Measure: T790M mutation testing platform

Time: Within 14 days after enrollment date

Description: To assess by proportion of EGFR mutation subtype as recorded on the case report form

Measure: EGFR testing mutation subtype

Time: Within 14 days after enrollment date

267 A Randomised Phase II Trial of Osimertinib and Bevacizumab Versus Osimertinib Alone as Second-line Treatment in Stage IIIb-IVb NSCLC With Confirmed EGFRm and T790M

BOOSTER is a randomised, controlled, phase II trial comparing osimertinib and bevacizumab versus osimertinib alone as second-line treatment in patients with stage IIIb-IVb non-small cell lung carcinoma (NSCLC) harbouring activating EGFR (exon 19 deletion or L858R) and T790M resistance mutation.

NCT03133546
Conditions
  1. Non Small Cell Lung Cancer Metastatic
Interventions
  1. Drug: Osimertinib
  2. Drug: Bevacizumab
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

A Randomised Phase II Trial of Osimertinib and Bevacizumab Versus Osimertinib Alone as Second-line Treatment in Stage IIIb-IVb NSCLC With Confirmed EGFRm and T790M. --- T790M ---

Osimertinib and Bevacizumab Versus Osimertinib Alone as Second-line Treatment in Stage IIIb-IVb NSCLC With Confirmed EGFRm and T790M (BOOSTER) BOOSTER is a randomised, controlled, phase II trial comparing osimertinib and bevacizumab versus osimertinib alone as second-line treatment in patients with stage IIIb-IVb non-small cell lung carcinoma (NSCLC) harbouring activating EGFR (exon 19 deletion or L858R) and T790M resistance mutation. --- T790M ---

Osimertinib and Bevacizumab Versus Osimertinib Alone as Second-line Treatment in Stage IIIb-IVb NSCLC With Confirmed EGFRm and T790M (BOOSTER) BOOSTER is a randomised, controlled, phase II trial comparing osimertinib and bevacizumab versus osimertinib alone as second-line treatment in patients with stage IIIb-IVb non-small cell lung carcinoma (NSCLC) harbouring activating EGFR (exon 19 deletion or L858R) and T790M resistance mutation. --- T790M --- --- L858R --- --- T790M ---

Defined as the time from date of randomisation until death from any cause.. T790M evolution in tissue and plasma/serum between baseline and disease progression on trial treatment. --- T790M ---

- Patients diagnosed with NSCLC, stage IIIb/IIIc (not amenable to radical therapy) or IVa/IVb according to 8th TNM classification, after progression following prior EGFR TKI therapy (erlotinib, gefitinib, dacomitinib or afatinib) as the most recent treatment regimen; - Pathological diagnosis of predominantly non-squamous NSCLC; - Maximum one line of previous platinum based chemotherapy; - Histological or cytological confirmation of EGFRm (exon 19 deletion or exon 21L858R); - Locally confirmed T790M mutation determined from biopsy (preferred) or on circulating tumour DNA, documented in tissue, plasma or serum after disease progression on the most recent treatment regimen; - Plasma, serum, and tumour (preferred) tissue or cytology (if biopsy was taken and FFPE tumor material is not yet fully depleted) after disease progression on the most recent EGFR TKI treatment available for central confirmation of T790M; - Measurable or evaluable disease according to RECIST 1.1; - Adequate haematological, renal and liver function; - World Health Organization (WHO) performance status 0-2. --- T790M ---

- Patients diagnosed with NSCLC, stage IIIb/IIIc (not amenable to radical therapy) or IVa/IVb according to 8th TNM classification, after progression following prior EGFR TKI therapy (erlotinib, gefitinib, dacomitinib or afatinib) as the most recent treatment regimen; - Pathological diagnosis of predominantly non-squamous NSCLC; - Maximum one line of previous platinum based chemotherapy; - Histological or cytological confirmation of EGFRm (exon 19 deletion or exon 21L858R); - Locally confirmed T790M mutation determined from biopsy (preferred) or on circulating tumour DNA, documented in tissue, plasma or serum after disease progression on the most recent treatment regimen; - Plasma, serum, and tumour (preferred) tissue or cytology (if biopsy was taken and FFPE tumor material is not yet fully depleted) after disease progression on the most recent EGFR TKI treatment available for central confirmation of T790M; - Measurable or evaluable disease according to RECIST 1.1; - Adequate haematological, renal and liver function; - World Health Organization (WHO) performance status 0-2. --- T790M --- --- T790M ---

However, all patients ultimately develop disease progression, driven - as the most prevalent identified biological mechanism - by the acquisition of a second T790M EGFR TKI resistance mutation. --- T790M ---

Osimertinib (AZD9291) is a novel oral, potent, and selective third-generation irreversible inhibitor of both EGFRm-sensitizing and T790M resistance mutants. --- T790M ---

Primary Outcomes

Description: PFS in patients with locally advanced or metastatic NSCLC will be assessed according to RECIST 1.1 criteria.The two treatment arms will be compared using the Kaplan-Meier method.

Measure: Progression Free Survival (PFS)

Time: PFS will be measured from date of patient enrolment until documented progression, or death, if progression is not documented, evaluated up to 48 months from enrolment of the first patient and compared between treatment arms.

Secondary Outcomes

Description: ORR, defined as the percentage of patients reaching a complete or partial response, based on evaluation using RECIST 1.1 criteria and disease control rate.

Measure: Objective Response Rate (ORR)

Time: ORR will be evaluated from date of patient enrolment until termination of trial treatment across all assessment timepoints, evaluated up to 48 months from enrolment of the first patient and compared between treatment arms.

Description: Disease control, defined as complete or partial response, or disease stabilisation confirmed at subsequent radiological assessment.

Measure: Disease Control

Time: Evaluated across all assessment timepoints from date of patient enrolment to termination of trial treatment, evaluated up to 48 months from enrolment of the first patient and compared between treatment arms.

Description: Adverse events, graded by CTCAE 4.0, will be recorded from date of signature of informed consent until 30 days after all trial treatment discontinuation.

Measure: Adverse Events

Time: From date of signature of informed consent until 30 days after all trial treatment discontinuation, for a maximum of 48 months from enrolment of the first patient

Description: Defined as the time from date of randomisation until death from any cause.

Measure: Overall Survival (OS)

Time: Evaluated from date of enrolment until death from any cause, assessed at 48 months from enrolment of the first patient.

Other Outcomes

Description: For this correlative studie tumour tissue blocks, plasma and serum samples will be collected at trial entry and at disease progression on trial treatment.

Measure: T790M evolution in tissue and plasma/serum between baseline and disease progression on trial treatment

Time: Assessed at baseline and disease progression on trial treatment (maximum 48 months)

268 An Open-Label, Non-randomized, Prospective Biomarker Study to Assess Analytic Concordance Between Non-invasive Testing and Tissue Testing for EGFR T790M Mutation Detection in Patients With Non-small Cell Lung Cancer

The study is being done to determine if non-invasive testing (urine and plasma testing) is as effective as tissue testing in identifying epidermal growth factor receptor (EGFR) T790M mutation status. EGFR is a type of protein found on the surface of cells in the body. When this protein is mutated and becomes too active, it can lead to cancer growth. T790M is a mutation that develops in response to treatment of the EGFR mutation. Participating patients will have tumor tissue (via cobas test), as well as 2 plasma samples (via cobas and Guardant360 tests) and 1 urine sample (via Trovera test), tested for EGFR T790M mutation status. If the results of the cobas tissue and/or plasma test show that a patient is T790M positive, they will be treated according to standard of care, which may include treatment with osimertinib. Osimertinib is approved for use in the United States for the treatment of EGFR T790M mutation-positive non-small cell lung cancer (NSCLC).

NCT03137264
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: Other
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

An Open-Label, Non-randomized, Prospective Biomarker Study to Assess Analytic Concordance Between Non-invasive Testing and Tissue Testing for EGFR T790M Mutation Detection in Patients With Non-small Cell Lung Cancer. --- T790M ---

Resistance & Activating Mutations Diagnosed Among NSCLC Community Dwelling EGFR Mutation Positive Patients The study is being done to determine if non-invasive testing (urine and plasma testing) is as effective as tissue testing in identifying epidermal growth factor receptor (EGFR) T790M mutation status. --- T790M ---

T790M is a mutation that develops in response to treatment of the EGFR mutation. --- T790M ---

Participating patients will have tumor tissue (via cobas test), as well as 2 plasma samples (via cobas and Guardant360 tests) and 1 urine sample (via Trovera test), tested for EGFR T790M mutation status. --- T790M ---

If the results of the cobas tissue and/or plasma test show that a patient is T790M positive, they will be treated according to standard of care, which may include treatment with osimertinib. --- T790M ---

Osimertinib is approved for use in the United States for the treatment of EGFR T790M mutation-positive non-small cell lung cancer (NSCLC). --- T790M ---

The percentage of patients whose T790M results on Trovera urine AND Guardant360 plasma testing match their T790M results on cobas tissue testing.. --- T790M ---

The percentage of patients whose T790M results on Trovera urine AND Guardant360 plasma testing match their T790M results on cobas tissue testing.. --- T790M --- --- T790M ---

The Overall Percent Agreement will be estimated as analytic concordance between Guardant360 plasma and Trovera urine testing versus cobas tissue testing in identifying T790M status (positive or negative). --- T790M ---

To evaluate safety and tolerability of study procedures.. Percentage of patients whose Trovera urine OR Guardant360 plasma T790M results are the same as their cobas tissue T790M results.. --- T790M ---

To evaluate safety and tolerability of study procedures.. Percentage of patients whose Trovera urine OR Guardant360 plasma T790M results are the same as their cobas tissue T790M results.. --- T790M --- --- T790M ---

The overall percent agreement will be estimate as analytic concordance between cobas tissue and Guardant360 plasma, and cobas tissue and Trovera urine testing in identifying T790M status. --- T790M ---

Biomarker results will be assessed and may be compared to T790M status and/or clinical response.. Percentage of patients whose Trovera urine OR Guardant360 plasma EGFR mutation results are the same as their cobas tissue EGFR mutation results.. --- T790M ---

Inclusion Criteria: - Provision of informed consent prior to any study-specific procedures - Females and males >/= 18 years - Primary diagnosis of NSCLC with evidence of disease progression during or following treatment with an EGFR tyrosine kinase inhibitor (diagnosis of NSCLC that is confirmed by cytology is acceptable) - Willing to undergo tumor biopsy (e.g., excision, core biopsy, or endoscopic biopsy), preferably of a progressing lesion, and provide blood and urine for biomarker testing - Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 Exclusion Criteria: - Involvement in the planning and/or conduct of the study - Prior treatment with osimertinib or another T790M directed therapy - Current participation in another clinical study with an investigational product or patients who plan to receive any treatment that is not FDA-approved for EGFR mutation positive NSCLC at any time during the course of this study - Use of any chemotherapeutic agent within 1 week of tissue, plasma, and urine sample collection - For women - currently pregnant or plan to become pregnant during the course of the study: pre-menopausal women of childbearing potential must have a urine or serum pregnancy test performed during the screening/enrollment period and prior to initiating anti-cancer treatment - Judgment by the investigator that the patient should not participate in the study due to the patient being unlikely to comply with study procedures, restrictions, and requirements, such as in the case of severe or uncontrolled systemic disease. --- T790M ---

Non-small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung RADIANCE is an open-label, prospective biomarker study to assess analytic concordance between non-invasive testing (plasma and urine) and tissue testing for the EGFR T790M mutation. --- T790M ---

All patients will have tumor tissue (via cobas test) as well as 2 plasma samples (via cobas and Guardant360) and 1 urine sample (via Trovera) tested for the EGFR T790M mutation (Part 1). --- T790M ---

Patients who are confirmed T790M negative based on both cobas biomarker tests (tissue and plasma) will have completed the study. --- T790M ---

Primary Outcomes

Description: The Overall Percent Agreement will be estimated as analytic concordance between Guardant360 plasma and Trovera urine testing versus cobas tissue testing in identifying T790M status (positive or negative). The Positive Percent Agreement will be estimated as the percentage of cobas tissue positive patients who are also Guardant360 plasma and/or Trovera urine positive. The Negative Percent Agreement will be estimated as the percentage of cobas tissue negative patients who are also Guardant360 plasma and Trovera urine negative.

Measure: The percentage of patients whose T790M results on Trovera urine AND Guardant360 plasma testing match their T790M results on cobas tissue testing.

Time: Visit 1 (Day-21 to Day 0)

Secondary Outcomes

Description: The number of patients achieving a confirmed partial response or complete response per RECIST 1.1 from treatment with osimertinib.

Measure: Objective Response Rate (ORR)

Time: Every 12 weeks for 12 months

Description: The time from first documented tumor response defined by RECIST 1.1 from osimertinib treatment until the date of documented progression or death from any cause.

Measure: Duration of Response (DoR)

Time: Every 12 weeks for the first 12 months, then at week 72

Description: Defined as the time from date of first dose of osimertinib until the date of disease progression by RECIST 1.1 or death by any cause.

Measure: Progression Free Survival (PFS)

Time: Every 12 weeks for the first 12 months, then at Week 72

Other Outcomes

Description: To evaluate safety and tolerability of study procedures.

Measure: Number of procedure-related adverse events and Serious Adverse Events (SAEs)

Time: Up to 8 weeks after Visit 1

Description: The overall percent agreement will be estimate as analytic concordance between cobas tissue and Guardant360 plasma, and cobas tissue and Trovera urine testing in identifying T790M status. The positive percent agreement will be estimated as the percentage of cobas tissue positive patients who are also Guardant360 plasma positive and cobas tissue positive patients who are Trovera urine positive. The negative percent agreement will be estimated as the percentage of cobas tissue negative patients who are also Guardant360 plasma negative and cobas tissue negative patients who are Trovera urine negative.

Measure: Percentage of patients whose Trovera urine OR Guardant360 plasma T790M results are the same as their cobas tissue T790M results.

Time: Visit 1 (Day -21 to Day 0)

Description: Biomarker results will be assessed and may be compared to T790M status and/or clinical response.

Measure: The presence of additional biomarkers from the blood and/or urine of NSCLC patients who have progressed during or following treatment with an EGFR tyrosine kinase inhibitor

Time: Visit 1 (Day -21 to Day 0)

Description: The overall percent agreement will be estimated as analytic concordance between Guardany360 plasma and Trovera urine testing versus cobas tissue testing in identifying the status of specified EGFR mutations. The positive percent agreement will be estimated as the percentage of cobas tissue positive patients who are also Guardant360 plasma and/or Trovera urine positive. The negative percent agreement will be estimated as the percentage of cobas tissue negative patients who are also Guardant360 plasma and Trovera urine negative.

Measure: Percentage of patients whose Trovera urine OR Guardant360 plasma EGFR mutation results are the same as their cobas tissue EGFR mutation results.

Time: Visit 1 (Day -21 to Day 0)

Description: Changes in physical exams from baseline

Measure: Physical Exam

Time: Up to 8 weeks after Visit 1

Description: Changes in vital signs from baseline

Measure: Vital signs

Time: Up to 8 weeks after Visit 1

Description: Changes in ECGs from baseline.

Measure: ECG

Time: Up to 8 weeks after Visit 1

Description: To evaluate the safety and tolerability of osimertinib.

Measure: Number of Adverse Events, Serious Adverse Events, and Adverse Events of Special Interest

Time: From the time of first dose of osimertinib through 30 days past the last dose of osimertinib or 30 days after Week 72, if osimertinib treatment remains ongoing at Week 72.

Description: To evaluate the safety and tolerability of osimertinib.

Measure: Physical Exam

Time: From the time of first dose of osimertinib through the date of last dose of osimertinib or at Week 72, whichever comes first.

Description: To evaluate the safety and tolerability of osimertinib

Measure: Vital signs

Time: From the time of first dose of osimertinib through the date of last dose of osimertinib or at Week 72, whichever comes first.

Description: To evaluate the safety and tolerability of osimertinib

Measure: ECG

Time: From the time of first dose of osimertinib through the date of last dose of osimertinib or at Week 72, whichever comes first.

269 A Phase 1/2, Open-label, Multicenter Study to Evaluate Safety, Tolerability, Pharmacokinetics and Efficacy of HS-10296 in Patients With Locally Advanced or Metastatic Non-Small-Cell Lung Cancer

This is a Phase 1/2, open-label, multicenter study of HS-10296 with dose escalation, dose expansion and extension cohorts in locally advanced or metastatic non-small-cell lung cancer (NSCLC) patients who have progressed following prior therapy with an epidermal growth factor receptor(EGFR) tyrosine kinase inhibitor (TKI) agent. The study is designed to evaluate safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of once-daily and orally (PO) administered HS-10296. The overall study design is shown in the flow chart below, which consists of 3 phases: dose escalation, dose expansion and extension cohort.

NCT02981108
Conditions
  1. Nonsmall Cell Lung Cancer
Interventions
  1. Drug: HS-10296
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Prior to entry, a result from the central analysis of the patient's T790M mutation status must be obtained. --- T790M ---

Primary Outcomes

Measure: Incidence of Dose Limiting Toxicity (DLT) Phase I Part

Time: 4 weeks

Measure: Overall Response Rate (ORR) Phase II Part

Time: 12 months

Measure: Progression-free survival (Phase I Part)

Time: 12 months

Measure: Overall Response Rate (Phase I Part)

Time: 6 weeks

Measure: Incidence and severity of AEs, changes in laboratory values, vital signs & ECGs

Time: 12 months

Measure: Area under the plasma concentration versus time curve (AUC) of HS-10296

Time: 4 weeks

Measure: Elimination half-life(T1/2) of HS-10241

Time: 4 weeks

270 Pilot, Phase 2 Study Assessing Intracranial Activity of AZD9291 (TAGRISSO) in Advanced EGFRm(EGFR Mutation) NSCLC Patients With Asymptomatic Brain Metastases

Patients will receive AZD9291 at a dose of 80 mg once daily. Intracranial response will be assessed with brain MRI scan, systemic evaluation will be done by PET-CT (Positron Emission Tomography-Computed Tomography) scan. In case of isolated CNS progression which may or may not be accompanied by asymptomatic systemic progression, AZD9291 dose will be escalated to 160 mg once daily. For patients whose intracranial disease will progress further, brain radiotherapy (in the form of SRS or WBRT) will be administered; treatment with AZD9291 will be interrupted and re-initiated at a standard dose after the end of radiotherapy course in the absence of symptomatic systemic progression. The treatment will be continued until symptomatic systemic progression, unacceptable toxicity or further intracranial progression following brain radiotherapy administration (whichever occurs first). All patients will be followed until death or 5 years.

NCT02736513
Conditions
  1. Lung Cancer
Interventions
  1. Drug: AZD9291

- Exon 19 deletion, L858R, T790M and uncommon sensitizing EGFR mutations in treatment-naïve patients are allowed. --- L858R --- --- T790M ---

erlotinib or afatinib) in whom T790M was diagnosed in the tumor specimen or ctDNA after testing it following the most recent disease progression. --- T790M ---

erlotinib or afatinib) who progressed unrelated to T790M (T790M-). --- T790M ---

erlotinib or afatinib) who progressed unrelated to T790M (T790M-). --- T790M --- --- T790M ---

6. T790M is allowed. --- T790M ---

Primary Outcomes

Description: Patients will receive TAGRISSO. Intracranial response will be assessed with brain MRI scan, systemic evaluation will be done by PET-CT scan.

Measure: Intracranial overall response rate as defined by modified RECIST

Time: 5 years

Secondary Outcomes

Description: Patients will receive TAGRISSO. Intracranial response will be assessed with brain MRI scan, systemic evaluation will be done by PET-CT scan.

Measure: Intracranial disease control rate (IDCR) as defined by mRECIST

Time: 5 years

Description: Patients will receive TAGRISSO. Intracranial response will be assessed with brain MRI scan, systemic evaluation will be done by PET-CT scan.

Measure: median time to intracranial response (mTTIR) as defined by mRECIST

Time: 5 years

Description: Patients will receive TAGRISSO. Intracranial response will be assessed with brain MRI scan, systemic evaluation will be done by PET-CT scan.

Measure: median intracranial progression free survival (mIPFS) as defined by mRECIST

Time: 5 years

271 Novel Detection System for Detecting Epidermal Growth Factor Receptor Mutation in Plasma in Non-small Cell Lung Cancer

The purpose of this study is to investigate the sensitivity,specificity and concordance rate of EGFR testing results in plasma in comparison of results in matched tumor tissues tested by amplification refractory mutation system(ARMS). Moreover, the investigators correlate our findings in plasma with survival of advanced patients.

NCT02666755
Conditions
  1. Lung Neoplasms
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

Unfortunately, about 50%-60% patients who accept EGFR tyrosine kinase inhibitors with sensitizing mutations will receive resistance mutations, the T790M resistance is a target of active pharmaceutical development. --- T790M ---

Primary Outcomes

Description: comparing with results in tissues, tne investigators can get the sensitivity of results in plasma for Epidermal Growth Factor Receptor mutation in Non-small cell lung cancer.

Measure: sensitivity

Time: 2 years

Secondary Outcomes

Description: comparing with results in tissues, the investigators can get the specificity of results in plasma for Epidermal Growth Factor Receptor mutation in Non-small cell lung cancer.

Measure: specificity

Time: 2 years

272 A Study of T790M Mutation Testing in Patient Tissue and Blood With Various Detection Platforms at Hospital Laboratories in Comparison With Central Testing

The study primary objective is to assess the concordance of T790M resistance mutation testing from hospital-based laboratories with T790M resistance mutation testing from a central laboratory.

NCT02991274
Conditions
  1. Locally Advanced or Metastatic EGFR(+) NSCLC Patients
Interventions
  1. Procedure: genomic testing of T790M mutation

A Study of T790M Mutation Testing in Patient Tissue and Blood With Various Detection Platforms at Hospital Laboratories in Comparison With Central Testing. --- T790M ---

ARTEMIS DIANE T790M (An Amino Acid Substitution at Position 790 in EGFR, From a Threonine (T) to a Methionine (M)) Mutation at Hospital Laboratories in Comparison With Central Laboratory The study primary objective is to assess the concordance of T790M resistance mutation testing from hospital-based laboratories with T790M resistance mutation testing from a central laboratory. --- T790M ---

ARTEMIS DIANE T790M (An Amino Acid Substitution at Position 790 in EGFR, From a Threonine (T) to a Methionine (M)) Mutation at Hospital Laboratories in Comparison With Central Laboratory The study primary objective is to assess the concordance of T790M resistance mutation testing from hospital-based laboratories with T790M resistance mutation testing from a central laboratory. --- T790M --- --- T790M ---

ARTEMIS DIANE T790M (An Amino Acid Substitution at Position 790 in EGFR, From a Threonine (T) to a Methionine (M)) Mutation at Hospital Laboratories in Comparison With Central Laboratory The study primary objective is to assess the concordance of T790M resistance mutation testing from hospital-based laboratories with T790M resistance mutation testing from a central laboratory. --- T790M --- --- T790M --- --- T790M ---

the concordance of T790M mutation testing between the test in central and local labs. --- T790M ---

Concordance (%)=(number of patients with same T790M mutation status based on central and local labs)/(total number of patients in the FAS) ×100%. --- T790M ---

The prevalence rate of T790M mutation based on the central lab testing. --- T790M ---

Prevalence (%) = (number of patients with T790M mutation positive)/(total number of patients in the FAS)×100%. --- T790M ---

Sensitivity (%)=(number of patients with T790M mutation positive based on both tissue and plasma tests)/(number of patients with T790M mutation positive based on tissue test) ×100%. --- T790M ---

Sensitivity (%)=(number of patients with T790M mutation positive based on both tissue and plasma tests)/(number of patients with T790M mutation positive based on tissue test) ×100%. --- T790M --- --- T790M ---

Specificity (%)=(number of patients with T790M mutation negative based on both tissue and plasma tests)/(number of patients with T790M mutation negative based on tissue test) ×100%. --- T790M ---

Specificity (%)=(number of patients with T790M mutation negative based on both tissue and plasma tests)/(number of patients with T790M mutation negative based on tissue test) ×100%. --- T790M --- --- T790M ---

Positive predictive value (%)=(number of patients with T790M mutation positive based on both tissue and plasma tests)/(number of patients with T790M mutation positive based on plasma test) ×100%. --- T790M ---

Positive predictive value (%)=(number of patients with T790M mutation positive based on both tissue and plasma tests)/(number of patients with T790M mutation positive based on plasma test) ×100%. --- T790M --- --- T790M ---

Negative predictive value (%)=(number of patients with T790M mutation negative based on both tissue and plasma tests)/(number of patients with T790M mutation negative based on plasma test) ×100%. --- T790M ---

Negative predictive value (%)=(number of patients with T790M mutation negative based on both tissue and plasma tests)/(number of patients with T790M mutation negative based on plasma test) ×100%. --- T790M --- --- T790M ---

Concordance (%)=(number of patients with same T790M mutation status based on tissue and plasma tests)/(total number of patients in the FAS) ×100%. --- T790M ---

800 patients from 80 different hospital sites will have local T790M testing by different molecular testing platforms and have central testing by Cobas platform. --- T790M ---

These two sets of data (local T790M testing and central T790M testing) will be analysed and compared to assess the concordance of these T790M testing platforms. --- T790M ---

These two sets of data (local T790M testing and central T790M testing) will be analysed and compared to assess the concordance of these T790M testing platforms. --- T790M --- --- T790M ---

These two sets of data (local T790M testing and central T790M testing) will be analysed and compared to assess the concordance of these T790M testing platforms. --- T790M --- --- T790M --- --- T790M ---

Primary Outcomes

Description: Concordance (%)=(number of patients with same T790M mutation status based on central and local labs)/(total number of patients in the FAS) ×100%

Measure: the concordance of T790M mutation testing between the test in central and local labs

Time: within 1 -14 days after enrolled

Secondary Outcomes

Description: Prevalence (%) = (number of patients with T790M mutation positive)/(total number of patients in the FAS)×100%

Measure: The prevalence rate of T790M mutation based on the central lab testing

Time: within 1 -14 days after enrolled

Description: Sensitivity (%)=(number of patients with T790M mutation positive based on both tissue and plasma tests)/(number of patients with T790M mutation positive based on tissue test) ×100%

Measure: The sensitivity of each platform based on the local lab plasma testing

Time: within 1 -14 days after enrolled

Description: Specificity (%)=(number of patients with T790M mutation negative based on both tissue and plasma tests)/(number of patients with T790M mutation negative based on tissue test) ×100%

Measure: The Specificity of each platform based on the local lab plasma testing

Time: within 1 -14 days after enrolled

Description: Positive predictive value (%)=(number of patients with T790M mutation positive based on both tissue and plasma tests)/(number of patients with T790M mutation positive based on plasma test) ×100%

Measure: The Positive predictive value of each platform based on the local lab plasma testing

Time: within 1 -14 days after enrolled

Description: Negative predictive value (%)=(number of patients with T790M mutation negative based on both tissue and plasma tests)/(number of patients with T790M mutation negative based on plasma test) ×100%

Measure: The Negative predictive value of each platform based on the local lab plasma testing

Time: within 1 -14 days after enrolled

Description: Concordance (%)=(number of patients with same T790M mutation status based on tissue and plasma tests)/(total number of patients in the FAS) ×100%

Measure: The Concordance of each platform based on the local lab testing

Time: within 1 -14 days after enrolled

Description: Prevalence (%) = (number of patients with C797S mutation positive)/(total number of patients with evaluable C797S testing)×100%

Measure: The prevalence of C797S (An amino acid substitution at position 797 in EGFR, from a Cysteine (C) to a Serine (S) ) resistance mutation based on the local lab testing

Time: within 1 -14 days after enrolled

Description: Prevalence (%) = (number of patients with rare EGFR mutation positive)/(total number of patients in the FAS)×100%

Measure: Rare EGFR mutation prevalence rate

Time: within 1-14 days after enrolled

273 Detect EGFR T790M Mutation in ctDNA of Chinese Advanced/Metastatic NSCLC Patients by Cobas, Super-ARMS, Digital PCR and NGS and Evaluate Clinical Outcomes of T790M Mutation Positive Patients Who Had AZD9291 Monotherapy

The aim of this study is to evaluate concordance of T790M mutation plasma testing between the Cobas test and each of other platforms: Super-ARMS, digital PCR or NGS. And to assess the efficacy of AZD9291 monotherapy by assessment of PFS in adult patients with advanced or metastatic NSCLC, who have received prior EGFR-tyrosine kinase inhibitor (TKI) therapy and are T790M mutation positive detected by any one of the four plasma testing platforms: Cobas/Super-ARMS/ digital PCR/NGS.

NCT02997501
Conditions
  1. Lung Cancer
Interventions
  1. Procedure: T790M+ Testing
  2. Procedure: Baseline Visit Blood & Urine Testing
  3. Procedure: Baseline ECG
  4. Procedure: Visual Slit-Lamp Testing
  5. Drug: AZD9291 Dosing
  6. Procedure: Plasma AZD9291 testing

Detect EGFR T790M Mutation in ctDNA of Chinese Advanced/Metastatic NSCLC Patients by Cobas, Super-ARMS, Digital PCR and NGS and Evaluate Clinical Outcomes of T790M Mutation Positive Patients Who Had AZD9291 Monotherapy. --- T790M ---

Detect EGFR T790M Mutation in ctDNA of Chinese Advanced/Metastatic NSCLC Patients by Cobas, Super-ARMS, Digital PCR and NGS and Evaluate Clinical Outcomes of T790M Mutation Positive Patients Who Had AZD9291 Monotherapy. --- T790M --- --- T790M ---

T790M Plasma Testing Methodology Comparison and Clinical Validation The aim of this study is to evaluate concordance of T790M mutation plasma testing between the Cobas test and each of other platforms: Super-ARMS, digital PCR or NGS. --- T790M ---

T790M Plasma Testing Methodology Comparison and Clinical Validation The aim of this study is to evaluate concordance of T790M mutation plasma testing between the Cobas test and each of other platforms: Super-ARMS, digital PCR or NGS. --- T790M --- --- T790M ---

And to assess the efficacy of AZD9291 monotherapy by assessment of PFS in adult patients with advanced or metastatic NSCLC, who have received prior EGFR-tyrosine kinase inhibitor (TKI) therapy and are T790M mutation positive detected by any one of the four plasma testing platforms: Cobas/Super-ARMS/ digital PCR/NGS. --- T790M ---

Concordance of T790M mutation plasma testing between Cobas test and Super-ARMS platform. --- T790M ---

To evaluate concordance of T790M mutation plasma testing between the Cobas test and Super-ARMS platform.. Progression Free Survival (PFS) using investigator assessments according to RECIST v1.1. --- T790M ---

To assess the efficacy of AZD9291 monotherapy by assessment of PFS in adult patients with advanced or metastatic NSCLC, who have received prior EGFR- TKI therapy and are T790M mutation positive detected by any one of the four plasma testing platforms: Cobas/Super-ARMS/ digital PCR/NGS.. Concordance of T790M mutation plasma testing between Cobas test and digital PCR platform. --- T790M ---

To assess the efficacy of AZD9291 monotherapy by assessment of PFS in adult patients with advanced or metastatic NSCLC, who have received prior EGFR- TKI therapy and are T790M mutation positive detected by any one of the four plasma testing platforms: Cobas/Super-ARMS/ digital PCR/NGS.. Concordance of T790M mutation plasma testing between Cobas test and digital PCR platform. --- T790M --- --- T790M ---

To evaluate concordance of T790M mutation plasma testing between the Cobas test and digital PCR platform.. Concordance of T790M mutation plasma testing between Cobas test and NGS platform. --- T790M ---

To evaluate concordance of T790M mutation plasma testing between the Cobas test and digital PCR platform.. Concordance of T790M mutation plasma testing between Cobas test and NGS platform. --- T790M --- --- T790M ---

To evaluate concordance of T790M mutation plasma testing between the Cobas test and NGS platform.. Testing sensitivity. --- T790M ---

To assess the efficacy of AZD9291 monotherapy by assessment of ORR in adult patients with advanced or metastatic NSCLC, who have received prior EGFR-TKI therapy and are T790M mutation positive detected by any one of the four plasma testing platforms: Cobas/Super-ARMS/ digital PCR/NGS.. Overall Survival (OS). --- T790M ---

To assess the efficacy of AZD9291 monotherapy by assessment of OS in adult patients with advanced or metastatic NSCLC, who have received prior EGFR-TKI therapy and are T790M mutation positive detected by any one of the four plasma testing platforms: Cobas/Super-ARMS/ digital PCR/NGS.. Testing specificity. --- T790M ---

To evaluate the NPV of Super-ARMS/digital PCR/NGS by using Cobas as the reference.. Proportion of patients with each EGFR mutation (C797S and T790M etc.) at different time point.. --- C797S --- --- T790M ---

To evaluate the efficacy of patients who receive AZD9291 monotherapy and are T790M mutation positive detected by each of the five platforms, respectively.. Progression Free Survival (PFS). --- T790M ---

To evaluate the efficacy of patients who receive AZD9291 monotherapy and are T790M mutation positive detected by each of the five platforms, respectively.. Overall Survival (OS). --- T790M ---

To evaluate the efficacy of patients who receive AZD9291 monotherapy and are T790M mutation positive detected by each of the five platforms, respectively.. Inclusion Criteria: 1. Provision of informed consent prior to any study specific procedures. --- T790M ---

Lung Cancer Objective: The primary objective of this study is to evaluate concordance of T790M mutation plasma testing between the Cobas test and each of other platforms: Super-ARMS, digital PCR or NGS. --- T790M ---

And to assess the efficacy of AZD9291 monotherapy by assessment of PFS in adult patients with advanced or metastatic NSCLC, who have received prior EGFR-tyrosine kinase inhibitor (TKI) therapy and are T790M mutation positive detected by any one of the four plasma testing platforms: Cobas/Super-ARMS/ digital PCR/NGS. --- T790M ---

Study measures: Data collected will include patient demographics, smoking history, information needed to determine patient eligibility (including medical history, past and current disease characteristics, and tumor EGFR mutations status, T790M and sensitizing mutations status results and type of test performed), AZD9291 exposure, investigator-reported efficacy (including tumor response and disease progression), overall survival (OS), and safety (including serious adverse events [SAEs], adverse events [AEs]). --- T790M ---

Statistical methods: The concordance of T790M resistance mutation testing between the Cobas test and each of other platforms will be calculated. --- T790M ---

The Kappa coefficient will be calculated to measure the agreement of T790M mutation testing between the Cobas test and each of other platforms. --- T790M ---

Primary Outcomes

Description: To evaluate concordance of T790M mutation plasma testing between the Cobas test and Super-ARMS platform.

Measure: Concordance of T790M mutation plasma testing between Cobas test and Super-ARMS platform

Time: Within 1- 28 days after enrollment and before study treatment

Description: To assess the efficacy of AZD9291 monotherapy by assessment of PFS in adult patients with advanced or metastatic NSCLC, who have received prior EGFR- TKI therapy and are T790M mutation positive detected by any one of the four plasma testing platforms: Cobas/Super-ARMS/ digital PCR/NGS.

Measure: Progression Free Survival (PFS) using investigator assessments according to RECIST v1.1

Time: From first dose intake to Progression of disease (PD), up to 3 years

Description: To evaluate concordance of T790M mutation plasma testing between the Cobas test and digital PCR platform.

Measure: Concordance of T790M mutation plasma testing between Cobas test and digital PCR platform

Time: Within 1- 28 days after enrollment and before study treatment

Description: To evaluate concordance of T790M mutation plasma testing between the Cobas test and NGS platform.

Measure: Concordance of T790M mutation plasma testing between Cobas test and NGS platform

Time: Within 1- 28 days after enrollment and before study treatment

Secondary Outcomes

Description: To evaluate the sensitivity of Super-ARMS/digital PCR/NGS by using Cobas as the reference.

Measure: Testing sensitivity

Time: Within 1- 28 days after enrollment and before study treatment

Description: To assess the efficacy of AZD9291 monotherapy by assessment of ORR in adult patients with advanced or metastatic NSCLC, who have received prior EGFR-TKI therapy and are T790M mutation positive detected by any one of the four plasma testing platforms: Cobas/Super-ARMS/ digital PCR/NGS.

Measure: Objective Response Rate (ORR)

Time: From first dose intake to end of study, up to 3 years

Description: To assess the efficacy of AZD9291 monotherapy by assessment of OS in adult patients with advanced or metastatic NSCLC, who have received prior EGFR-TKI therapy and are T790M mutation positive detected by any one of the four plasma testing platforms: Cobas/Super-ARMS/ digital PCR/NGS.

Measure: Overall Survival (OS)

Time: From first dose intake to end of study, up to 3 years

Description: To evaluate the specificity of Super-ARMS/digital PCR/NGS by using Cobas as the reference.

Measure: Testing specificity

Time: Within 1- 28 days after enrollment and before study treatment

Description: To evaluate PPV of Super-ARMS/digital PCR/NGS by using Cobas as the reference.

Measure: Testing positive predictive value (PPV)

Time: Within 1- 28 days after enrollment and before study treatment

Description: To evaluate the NPV of Super-ARMS/digital PCR/NGS by using Cobas as the reference.

Measure: Testing negative predictive value (NPV)

Time: Within 1- 28 days after enrollment and before study treatment

Other Outcomes

Description: To dynamically monitor EGFR mutations by NGS and digital PCR in ctDNA of patients receiving AZD9291 treatment.

Measure: Proportion of patients with each EGFR mutation (C797S and T790M etc.) at different time point.

Time: every 6 weeks during treatment, up to 3 years

Description: To explore the mechanisms of acquired resistance in patients who received AZD9291 treatment by NGS testing of tissue and/or blood samples from the collection at PD versus baseline.

Measure: Changes of distribution of resistance related genes at PD compared with baseline.

Time: every 6 weeks during treatment, up to 3 years

Description: To describe the genomic profile of long-term survivors, especially to find out potential genomic prognosis and/or predictive factors for AZD9291 long-term efficacy as compared to rapid PD patients.

Measure: Key genetic and proteomic markers including, but not limited to, EGFR mutations

Time: every 6 weeks during treatment, up to 3 years

Description: To evaluate concordance of EGFR mutation plasma testing by Bio-rad droplet digital PCR using other plasma test or tissue test as reference, respectively.

Measure: Testing concordance

Time: Within 1- 28 days after enrollment and before study treatment

Description: To evaluate sensitivity of EGFR mutation plasma testing by Bio-rad droplet digital PCR using other plasma test or tissue test as reference, respectively.

Measure: Testing sensitivity

Time: Within 1- 28 days after enrollment and before study treatment

Description: To evaluate specificity of EGFR mutation plasma testing by Bio-rad droplet digital PCR using other plasma test or tissue test as reference, respectively.

Measure: Testing specificity

Time: Within 1- 28 days after enrollment and before study treatment

Description: To evaluate PPV of EGFR mutation plasma testing by Bio-rad droplet digital PCR using other plasma test or tissue test as reference, respectively.

Measure: Testing positive predictive value (PPV)

Time: Within 1- 28 days after enrollment and before study treatment

Description: To evaluate NPV of EGFR mutation plasma testing by Bio-rad droplet digital PCR using other plasma test or tissue test as reference, respectively.

Measure: Testing negative predictive value (NPV)

Time: Within 1- 28 days after enrollment and before study treatment

Description: To evaluate the efficacy of patients who receive AZD9291 monotherapy and are T790M mutation positive detected by each of the five platforms, respectively.

Measure: Objective Response Rate (ORR)

Time: From first dose intake to end of study, up to 3 years

Description: To evaluate the efficacy of patients who receive AZD9291 monotherapy and are T790M mutation positive detected by each of the five platforms, respectively.

Measure: Progression Free Survival (PFS)

Time: From first dose intake to end of study, up to 3 years

Description: To evaluate the efficacy of patients who receive AZD9291 monotherapy and are T790M mutation positive detected by each of the five platforms, respectively.

Measure: Overall Survival (OS)

Time: From first dose intake to end of study, up to 3 years

274 A Phase 1/2 Study of Osimertinib in Combination With Gefitinib in EGFR Inhibitor naïve Advanced EGFR Mutant Lung Cancer

This research study is studying a combination of two drugs as a possible treatment for Non-Small Cell Lung Cancer (NSCLC) with an EGFR mutation. The interventions involved in this study are: - Osimertinib (Tagrisso) - Gefitinib (Iressa)

NCT03122717
Conditions
  1. Non-Small Cell Lung Cancer
Interventions
  1. Drug: Gefitinib
  2. Drug: Osimertinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Patients must be off warfarin for >7 days prior to enrollment - Identification of EGFR T790M in baseline cfDNA analysis - Active pregnancy or breast-feeding. --- T790M ---

However, even though these drugs can be very effective, after a period of time, most EGFR tumors will develop resistance to this treatment, most often because of a second mutation in EGFR called T790M. --- T790M ---

Osimertinib is currently approved only to treat patients whose cancers develop resistance to gefitinib (or other similar EGFR inhibitors) because of the T790M mutation. --- T790M ---

Primary Outcomes

Description: The feasibility of combination gefitinib/osimertinib dosing will be determined through evaluation of the number of patients in each cohort who are able to remain on combination therapy for 6 x 28 day cycles.

Measure: Number of patients completing combination therapy with gefitinib and osimertinib for 6 x 28 day cycles

Time: 3 years

Secondary Outcomes

Description: CTCAE v4.0 will be used to monitor toxicities in patients on combination therapy with gefitinib and osimertinib.

Measure: Rate of treatment-related Grade 3-5 adverse events

Time: 3 years

Description: RECIST 1.1 measurements of CT scans of the chest/abdomen/pelvis will be measured every 2 cycles on treatment to determine the objective response rate for patients being treated with combination gefitinib and osimertinib.

Measure: Objective response rate

Time: 3 years (each cycle is 28 days)

Description: The Kaplan-Meier method will be used to determine the progression-free survival of patients enrolled on protocol and treated with combination gefitinib and osimertinib.

Measure: Progression free survival

Time: 3 years

Description: Survival follow-up with clinic visits or phone calls will be used to monitor for overall survival from time of study randomization to death from any cause. The Kaplan-Meier method will be used to calculate overall survival.

Measure: Overall Survival

Time: 3 years

275 A Phase II Study of Poziotinib in EGFR in Exon 20 Mutant Advanced Non Small Cell Lung Cancer (NSCLC)

This phase II trial studies how well poziotinib works in treating patients with non-small lung cancer with EGFR or HER2 exon 20 mutation that is stage IV or has come back. Poziotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT03066206
Conditions
  1. EGFR Exon 20 Mutation
  2. ERBB2 Gene Mutation
  3. Recurrent Lung Non-Small Cell Carcinoma
  4. Stage IV Non-Small Cell Lung Cancer AJCC v7
Interventions
  1. Drug: Poziotinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Toxicity data will be summarized by frequency tables.. Inclusion Criteria: - Histologically or cytologically confirmed stage IV or recurrent solid tumor not amenable to curative intent therapy - Cohort 1 specific inclusion criteria: Documented EGFR exon 20 mutation by one of the following Clinical Laboratory Improvement Act (CLIA) certified tests: OncoMine Comprehensive Assay (OCA), Guardant360 Assay (using plasma), or FoundationOne Assay or by a Food and Drug Administration (FDA) approved device using cobas EGFR mutation test version (v)2 or therascreen EGFR RGQ PCt kit; eligible mutations include D770_N771insSVD, D770_N771insNPG, V769_D770insASV, H773_V774insNPH, or any other exon 20 in-frame insertion or point mutation excluding T790M - Patients must be previously treated with one or more regimens of systemic therapy for locally advanced or metastatic disease; previously untreated patients are eligible only if EGFR Exon 20 mutation is confirmed using an FDA approved device: cobas EGFR mutation test v2 or therascreen EGFR RGQ polymerase chain reaction (PCR) Kit prior to study enrollment - Cohort 2 specific inclusion criteria: documented HER2 exon 20 mutation by a CLIA certified laboratory; eligible mutations include A775_G776insYVMA, G776_V777insVC, or P780_Y781insGSP, or any other in-frame exon 20 insertion mutation or point mutation including, but not limited to, L755S, G776V, and V777L - Measurable disease by RECIST 1.1 - Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 - Ability to take pills by mouth - Leukocytes >= 3,000/mcL - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Hemoglobin >= 9.0 g/dL - Total bilirubin =< 2 x upper limit of normal (ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 institutional upper limit of normal of =< 5 x ULN if liver metastases are present - Alkaline phosphatase =< 2.5 institutional upper limit of normal of =< 5 x ULN if liver metastases are present - Creatinine clearance > 50 mL/min/1.73 --- T790M ---

condom plus spermicide, cervical/vault cap or intrauterine device), and abstinence - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - EGFR T790M mutation or any other acquired EGFR exon 20 mutation; patients with coexisting primary EGFR exon 20 and T790M mutations are eligible - Have received or are receiving an investigational medicinal product (IMP) or other systemic anticancer treatment within 2 weeks prior to the first dose of study treatment - Any concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer treatment - Have known or suspected brain metastases or spinal cord compression, unless the condition has been asymptomatic, has been treated with surgery and/or radiation, and has been stable without requiring escalating corticosteroids nor anti-convulsant medications for at least 4 weeks prior to the first dose of study medication - Known hypersensitivity to poziotinib or history of allergic reactions attributed to compounds of similar chemical or biologic composition to poziotinib - Cardiac conditions as follows: patient has a history of congestive heart failure (CHF) class III/IV according to the New York Heart Association (NYHA) Functional Classification or serious cardiac arrhythmias requiring treatment; patient has a cardiac ejection fraction < 50% by either echocardiogram or multi-gated acquisition (MUGA) scan - Have any unresolved chronic toxicity with Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 grade >= 2, from previous anticancer therapy, except for alopecia - Patient is unable to take drugs orally due to disorders or diseases that may affect gastrointestinal function, such as inflammatory bowel diseases (e.g., Crohn's disease, ulcerative colitis) or malabsorption syndrome, or procedures that may affect gastrointestinal function, such as gastrectomy, enterectomy, or colectomy - Have any condition or illness that, in the opinion of the investigator, might compromise patient safety or interfere with the evaluation of the safety of the drug - Pregnant or breastfeeding women - History of another primary malignancy within 2 years prior to starting study treatment, except for adequately treated basal or squamous cell carcinoma of the skin or cancer of the cervix in situ - Recent major surgery within 4 weeks prior to starting study treatment, with the exception of surgical placement for vascular access - Male or female patients of reproductive potential who are not employing an effective method of birth control; adequate contraception methods include: birth control pills (e.g. --- T790M ---

condom plus spermicide, cervical/vault cap or intrauterine device), and abstinence - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - EGFR T790M mutation or any other acquired EGFR exon 20 mutation; patients with coexisting primary EGFR exon 20 and T790M mutations are eligible - Have received or are receiving an investigational medicinal product (IMP) or other systemic anticancer treatment within 2 weeks prior to the first dose of study treatment - Any concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer treatment - Have known or suspected brain metastases or spinal cord compression, unless the condition has been asymptomatic, has been treated with surgery and/or radiation, and has been stable without requiring escalating corticosteroids nor anti-convulsant medications for at least 4 weeks prior to the first dose of study medication - Known hypersensitivity to poziotinib or history of allergic reactions attributed to compounds of similar chemical or biologic composition to poziotinib - Cardiac conditions as follows: patient has a history of congestive heart failure (CHF) class III/IV according to the New York Heart Association (NYHA) Functional Classification or serious cardiac arrhythmias requiring treatment; patient has a cardiac ejection fraction < 50% by either echocardiogram or multi-gated acquisition (MUGA) scan - Have any unresolved chronic toxicity with Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 grade >= 2, from previous anticancer therapy, except for alopecia - Patient is unable to take drugs orally due to disorders or diseases that may affect gastrointestinal function, such as inflammatory bowel diseases (e.g., Crohn's disease, ulcerative colitis) or malabsorption syndrome, or procedures that may affect gastrointestinal function, such as gastrectomy, enterectomy, or colectomy - Have any condition or illness that, in the opinion of the investigator, might compromise patient safety or interfere with the evaluation of the safety of the drug - Pregnant or breastfeeding women - History of another primary malignancy within 2 years prior to starting study treatment, except for adequately treated basal or squamous cell carcinoma of the skin or cancer of the cervix in situ - Recent major surgery within 4 weeks prior to starting study treatment, with the exception of surgical placement for vascular access - Male or female patients of reproductive potential who are not employing an effective method of birth control; adequate contraception methods include: birth control pills (e.g. --- T790M --- --- T790M ---

Inclusion Criteria: - Histologically or cytologically confirmed stage IV or recurrent solid tumor not amenable to curative intent therapy - Cohort 1 specific inclusion criteria: Documented EGFR exon 20 mutation by one of the following Clinical Laboratory Improvement Act (CLIA) certified tests: OncoMine Comprehensive Assay (OCA), Guardant360 Assay (using plasma), or FoundationOne Assay or by a Food and Drug Administration (FDA) approved device using cobas EGFR mutation test version (v)2 or therascreen EGFR RGQ PCt kit; eligible mutations include D770_N771insSVD, D770_N771insNPG, V769_D770insASV, H773_V774insNPH, or any other exon 20 in-frame insertion or point mutation excluding T790M - Patients must be previously treated with one or more regimens of systemic therapy for locally advanced or metastatic disease; previously untreated patients are eligible only if EGFR Exon 20 mutation is confirmed using an FDA approved device: cobas EGFR mutation test v2 or therascreen EGFR RGQ polymerase chain reaction (PCR) Kit prior to study enrollment - Cohort 2 specific inclusion criteria: documented HER2 exon 20 mutation by a CLIA certified laboratory; eligible mutations include A775_G776insYVMA, G776_V777insVC, or P780_Y781insGSP, or any other in-frame exon 20 insertion mutation or point mutation including, but not limited to, L755S, G776V, and V777L - Measurable disease by RECIST 1.1 - Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 - Ability to take pills by mouth - Leukocytes >= 3,000/mcL - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Hemoglobin >= 9.0 g/dL - Total bilirubin =< 2 x upper limit of normal (ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 institutional upper limit of normal of =< 5 x ULN if liver metastases are present - Alkaline phosphatase =< 2.5 institutional upper limit of normal of =< 5 x ULN if liver metastases are present - Creatinine clearance > 50 mL/min/1.73 --- T790M ---

Primary Outcomes

Description: According to Response Evaluation Criteria in Solid Tumors 1.1 criteria.

Measure: Objective response rate a in patients with estimated glomerular filtration rate (EGFR) exon 20 mutant non-small Cell Lung Cancer (NSCLC) (Cohort 1)

Time: Up to 4 years

Description: According to Response Evaluation Criteria in Solid Tumors 1.1 criteria.

Measure: Objective response rate a in patients with human epidermal growth factor receptor 2 (HER2) exon 20 mutant non-small Cell Lung Cancer (NSCLC) (Cohort 2)

Time: Up to 4 years

Secondary Outcomes

Description: Will be estimated along with 95% confidence intervals.

Measure: Disease control rate (complete response + partial response + stable disease) of poziotinb in cohort 1 and 2, analyzed independently

Time: Up to 4 years

Description: Will be estimated using the Kaplan-Meier method and the comparison between or among patient's characteristic groups will be evaluated by log-rank test. The Cox regression model may be applied to assess the effect of covariates of interest on progression free survival.

Measure: Progression free survival of poziotinb in cohort 1 and 2, analyzed independently

Time: Up to 4 years

Description: Will be estimated using the Kaplan-Meier method and the comparison between or among patient's characteristic groups will be evaluated by log-rank test. The Cox regression model may be applied to assess the effect of covariates of interest on overall survival.

Measure: Overall survival of poziotinb in cohort 1 and 2, analyzed independently

Time: Up to 4 years

Description: Duration of response will be measured.

Measure: Duration of response of poziotinb in cohort 1 and 2, analyzed independently

Time: Up to 4 years

Description: Assessed by Common Terminology Criteria for Adverse Events version 4.03. Toxicity data will be summarized by frequency tables.

Measure: Incidence of adverse events

Time: Up to 4 years

276 Phase 2, Single-arm, Open-label Study of DS-1062a in Advanced or Metastatic Non-small Cell Lung Cancer With Actionable Genomic Alterations and Progressed on or After Kinase Inhibitor Therapy and Platinum Based Chemotherapy (TROPION-Lung05)

This is a study of the efficacy, pharmacokinetics, and safety of DS-1062a in participants with advanced or metastatic non-small cell lung cancer (NSCLC) with known actionable genomic alterations.

NCT04484142
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: DS-1062a
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Overexpression of any of the above, in the absence of activating mutations, is NOT sufficient for enrollment Participants with EGFR genomic alterations should be evaluated for the presence of EGFR T790M mutation after relapse/progression on/after the most recent anti-EGFR TKI, unless already known to carry this mutation. --- T790M ---

Participants with EGFR mutations (regardless of T790M status) should comprise no less than 40% and no more than 50% of participants by the conclusion of study enrollment. --- T790M ---

Primary Outcomes

Description: ORR is defined as the proportion of participants with a best overall response of confirmed complete response (CR) or confirmed partial response (PR). CR is defined as a disappearance of all target lesions and PR is defined as at least a 30% decrease in the sum of diameters of target lesions.

Measure: Objective Response Rate (ORR) As Assessed by Blind Independent Central Review Per RECIST v1.1 Following DS-1062a Intravenous Infusion

Time: From baseline until disease progression, death, or other protocol defined reason, up to approximately 23 months

Secondary Outcomes

Description: DOR is defined as the time from the date of the first documentation of response (confirmed CR or confirmed PR) to the date of the first documentation of PD or death due to any cause, whichever occurs first.

Measure: Duration of Response (DOR) As Assessed by Blinded Independent Central Review and by Investigator Per RECIST v1.1 Following DS-1062a Intravenous Infusion

Time: From baseline until disease progression, death, or other protocol defined reason, up to approximately 23 months

Description: PFS is defined as the time from the start of study treatment to the earlier of the dates of the first documentation of progressive disease or death due to any cause.

Measure: Progression-free Survival (PFS) As Assessed by Blinded Independent Central Review and by Investigator Per RECIST v1.1 Following DS-1062a Intravenous (IV) Infusion

Time: From baseline until disease progression, death, or other protocol defined reason, up to approximately 23 months

Description: OS is defined as the time from the start of study treatment to the date of death due to any cause.

Measure: Overall Survival (OS) Following DS-1062a Intravenous Infusion

Time: From baseline until death due to any cause, up to approximately 23 months

Description: Reported treatment-emergent adverse events, serious adverse events, adverse events of interest, and those considered related to the study drug or study procedures, or that associated DS-1062a reduction, interruption, or discontinuation.

Measure: Percentage of Participants Who Reported Treatment-emergent Adverse Events Following DS-1062a Intravenous Infusion in Participants with Advanced or Metastatic NSCLC with Actionable Genomic Alterations

Time: From baseline up to approximately 23 months post treatment

Measure: Pharmacokinetic Parameter Maximum Concentration (Cmax) of DS-1062a, Total Anti-TROP2 Antibody, and MAAA-1181a

Time: Cycle 1, Day 1: predose (within 8 hours [h] of infusion), 30 minutes (min), 3 h, 5 h, 7 h postdose; Cycle 1, Day 2, Day 4, Day 8, and Day 15 postdose; Cycle 2 and Cycle 3, Day 1 predose (within 8 h) and postdose (within 1 h) (each cycle is 21 days)

Measure: Pharmacokinetic Parameter Time to Maximum Concentration (Tmax) of DS-1062a, Total Anti-TROP2 Antibody, and MAAA-1181a

Time: Cycle 1, Day 1: predose (within 8 hours [h] of infusion), 30 minutes (min), 3 h, 5 h, 7 h postdose; Cycle 1, Day 2, Day 4, Day 8, and Day 15 postdose; Cycle 2 and Cycle 3, Day 1 predose (within 8 h) and postdose (within 1 h) (each cycle is 21 days)

Description: AUC up to the last quantifiable time (AUClast) and AUC during dosing interval (AUCtau) will be assessed for DS-1062, total Anti-TROP2 antibody, and MAAA-1181a.

Measure: Pharmacokinetic Parameter Area Under the Concentration-Time Curve (AUC) of DS-1062a, Total Anti-TROP2 Antibody, and MAAA-1181a

Time: Cycle 1, Day 1: predose (within 8 hours [h] of infusion), 30 minutes (min), 3 h, 5 h, 7 h postdose; Cycle 1, Day 2, Day 4, Day 8, and Day 15 postdose; Cycle 2 and Cycle 3, Day 1 predose (within 8 h) and postdose (within 1 h) (each cycle is 21 days)

277 Clinical Study of Personalized Neoantigen Peptide Vaccine Combined With Targeted Drugs in the Treatment of Non-small Cell Lung Cancer

Neoantigen vaccine is a new field of research in tumor immunotherapy, and some studies have been conducted with success on Melanoma and glioblastoma. Nearly 80% of lung cancers are diagnosed in an advanced stage (IIIB, and IV) and EGFR mutant non-small cell lung cancer will be resistant after targeted drug treatment. Neoantigen vaccine is a new treatment method for lung cancer, especially for patients with drug resistance.

NCT04487093
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: neoantigen vaccine + EGFR-TKI
  2. Drug: neoantigen vaccine + anti-angioge
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: 1. Histologically confirmed locally advanced or metastatic non-small-cell lung cancer (stage III or stage IV). 2. With EGFR-TKI sensitive mutations and no T790M. --- T790M ---

Primary Outcomes

Description: Safety

Measure: Adverse events evaluated and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03.

Time: 24 months

Secondary Outcomes

Description: PFS as measured in accordance with the Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1

Measure: Progression-free Survival (PFS)

Time: Up to 2 years

Description: OS as measured in accordance with the Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1

Measure: Overall survival (OS)

Time: Up to 2 years

Description: DCR as measured in accordance with the Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1

Measure: Disease Control Rate(DCR)

Time: Up to 12 weeks

278 A Multiarm, Open-label, Multicenter, Phase 1b/2 Study to Evaluate Novel Combination Therapies in Subjects With Previously Treated Advanced EGFRm NSCLC

The objective of this study is to investigate the safety, tolerability and antitumor activity of novel combination therapies administered in subjects with advanced EGFRm NSCLC

NCT03381274
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Biological: MEDI9447
  2. Drug: Osimertinib
  3. Drug: AZD4635
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Objective Response by T790M status. --- T790M ---

Disease Control by T790M status. --- T790M ---

Inclusion Criteria: 1. Age ≥ 18 2. ECOG Performance Status of 0 or 1 3. Weight ≥ 35 kg 4. Diagnosed with histologically or cytologically confirmed locally advanced/metastatic NSCLC with EGFR mutation - For Arm A: must have received 1 prior line of therapy with an EGFR TKI and confirmed T790M negative - For Arm B: must have received at least 2 but not more than 4 prior lines of therapy. --- T790M ---

Additional Exclusion Criteria for Arm B 1. Herbal preparations/medications are not allowed throughout the study 2. History of seizures excluding those that occurred due to previously untreated CNS metastasis Inclusion Criteria: 1. Age ≥ 18 2. ECOG Performance Status of 0 or 1 3. Weight ≥ 35 kg 4. Diagnosed with histologically or cytologically confirmed locally advanced/metastatic NSCLC with EGFR mutation - For Arm A: must have received 1 prior line of therapy with an EGFR TKI and confirmed T790M negative - For Arm B: must have received at least 2 but not more than 4 prior lines of therapy. --- T790M ---

Primary Outcomes

Description: The primary endpoint is safety as assessed by the presence of adverse events and serious adverse events

Measure: Incidence of Adverse Events as a measure of safety

Time: Screening through 90 days after last dose of investigational product

Description: The primary endpoint in dose expansion phase includes efficacy assessed by objective response

Measure: Objective response rate as a measure of anti tumor activity in dose expansion phase

Time: During treatment through study completion, about 2 years after the last subject dosed

Secondary Outcomes

Description: The duration from the first documentation of objective response (OR) to the first documented disease progression or death due to any cause, whichever occurs first

Measure: Duration of Response (DoR)

Time: During treatment through study completion, about 2 years after the last subject dosed

Description: Defined as complete response (CR), partial response (PR) or stable disease (SD)

Measure: Disease Control (DC)

Time: During treatment through study completion, about 2 years after the last subject dosed

Description: From the start of treatment with investigational product until the first documentation of disease progression or death due to any cause, whichever occurs first.

Measure: Progression Free Survival (PFS)

Time: During treatment through study completion, about 2 years after the last subject dosed

Description: From the start of treatment with investigational product until death due to any cause

Measure: Overall Survival (OS)

Time: During treatment through study completion, about 2 years after the last subject dosed

Description: Defined as best overall response of confirmed CR or confirmed PR according to RECIST version 1.1

Measure: Objective Response by T790M status

Time: During treatment through study completion, about 2 years after the last subject dosed

Description: Defined as CR, PR or SD

Measure: Disease Control by T790M status

Time: During treatment through study completion, about 2 years after the last subject dosed

Description: Pharmacokinetic

Measure: Serum MEDI9447 concentration levels

Time: During treatment through 90 days after last dose of investigational product

Description: Pharmacokinetic

Measure: Serum Osimertinib concentration levels

Time: During treatment through 90 days after last dose of investigational product

Description: Pharmacokinetic

Measure: Serum AZD4635 concentration levels

Time: During treatment through 90 days after last dose of investigational product

Description: Immunogenicity

Measure: Development of detectable anti-drug antibody(ADA) to MEDI9447

Time: During treatment through 90 days after last dose of investigational product

279 A Randomized, Controlled Phase II Clinical Trial of Apatinib in Combination With EGFR-TKI Versus EGFR-TKI for Non-squamous, Non-small Cell Lung Cancer(NSCLC) With T790M-negative After the Failure of EGFR-TKI Therapy

This phase 2 study is designed to evaluate the safety and activity of apatinib,a tyrosine kinase inhibitor that selectively inhibits the vascular endothelial growth factor receptor-2, in combination with EGFR-TKI in NSCLC with T790M-negative after the failure of EGFR-TKI therapy.

NCT03389256
Conditions
  1. Lung Diseases
  2. Neoplasms
  3. Respiratory Tract Diseases
  4. Thoracic Neoplasms
  5. Non-Small-Cell Lung
Interventions
  1. Drug: Apatinib
  2. Drug: EGFR-TKI
MeSH:Neoplasms Thoracic Neoplasms Lung Diseases Respirat Respiratory Tract Diseases
HPO:Abnormal lung morphology Neoplasm

A Randomized, Controlled Phase II Clinical Trial of Apatinib in Combination With EGFR-TKI Versus EGFR-TKI for Non-squamous, Non-small Cell Lung Cancer(NSCLC) With T790M-negative After the Failure of EGFR-TKI Therapy. --- T790M ---

Apatinib in the Treatment of Patients With EGFR T790M-Negative NSCLC This phase 2 study is designed to evaluate the safety and activity of apatinib,a tyrosine kinase inhibitor that selectively inhibits the vascular endothelial growth factor receptor-2, in combination with EGFR-TKI in NSCLC with T790M-negative after the failure of EGFR-TKI therapy. --- T790M ---

Apatinib in the Treatment of Patients With EGFR T790M-Negative NSCLC This phase 2 study is designed to evaluate the safety and activity of apatinib,a tyrosine kinase inhibitor that selectively inhibits the vascular endothelial growth factor receptor-2, in combination with EGFR-TKI in NSCLC with T790M-negative after the failure of EGFR-TKI therapy. --- T790M --- --- T790M ---

Inclusion Criteria: - Pathologically confirmed stage IIIB, IV non-squamous non-small cell lung cancer, with measurable lesions (the long axis of tumor lesions ≥ 10mm with CT, the short axis of lymph node lesions ≥ 15mm with CT, the lesions not receive radiotherapy, frozen or other local treatment); - Patients with slow progression on first-line EGFR TKI(erlotinib / icotinib / gefitinib) treatment; - No T790M mutation including an assessment from tumor biopsy obtained while on or subsequent to the most recent EGFR TKI therapy; - Eastern Cooperative Oncology Group (ECOG) performance status 0-2; - Life expectancy of more than 3 months; - Adequate bone marrow function: WBC ≥ 3.0 ×10 E+9/L, neutrophil ≥ 1.5 × 10 E+9/L, platelets ≥ 80 × 10E+9/L,Hb ≥ 10.0g/dL;a total bilirubin (TBil) of ≤1.5 upper normal limitation (UNL), a alanine aminotransferase (ALAT) and aspartate aminotransferase (ASAT) of ≤3UNL or ≤5UNL in case of liver metastasis, a creatinine (Cr) of ≤ 1.5 UNL; a creatinine clearance rate ≥ 50ml/min (Cockcroft-Gault); - Female subjects of child-bearing potential must agree to use contraceptive measures starting 1 week before the administration of the first dose of apatinib until 8 weeks after discontinuing study drug. --- T790M ---

Male subjects must agree to use contraceptive measures during the study and 8 weeks after last dose of study drug; - the participants volunteered to join this study should sign the informed consent forms, have better compliance in the follow-up; Exclusion Criteria: - Squamous cell carcinoma (including adenosquamous carcinoma); Small cell lung carcinoma (including small cell carcinoma and non-small cell mixed lung carcinoma); - Active brain metastases, cancerous meningitis, patients with spinal cord compression; - Rapid progression of the disease or cancer invades vital organs; - The distance between the tumor lesion and the large blood vessel is less than 5 mm, or there is a central tumor invading local macrovascular; - obvious pulmonary cavity or tumor necrosis; - Uncontrollable high blood pressure; - Grade Ⅱ or above myocardial ischemia or myocardial infarction or arrhythmia control is not good,Ⅲ ~ Ⅳ grade cardiac insufficiency, or cardiac ultrasonography showed left ventricular ejection fraction (LVEF) <50% according to the NYHA standard; - Have a history of interstitial lung disease or patients with interstitial lung disease; - Coagulation abnormalities (INR> 1.5 or PT> ULN + 4s or APTT> 1.5 ULN) with bleeding tendency or undergoing thrombolytic or anticoagulant therapy; - There was significant hemoptysis within 2 months prior to enrollment, or a daily hemoptysis volume is 2.5 ml or above; - A clinically significant bleeding symptom or bleeding tendencies such as gastrointestinal bleeding, hemorrhagic gastric ulcer, fecal occult blood ++ and above, or vasculitis that occurred within 3 months prior to enrollment; - Aneurysm / venous thrombotic events such as cerebrovascular accident (including transient ischemic attack, cerebral hemorrhage, cerebral infarction), deep vein thrombosis and pulmonary embolism; - Arterial / venous thrombotic events such as cerebrovascular accidents (including transient ischemic attack, cerebral hemorrhage, cerebral infarction), deep vein thrombosis and pulmonary embolism within 12 months prior to enrollment; - Hereditary or acquired bleeding and thrombophilia, such as hemophilia, coagulopathy, thrombocytopenia, hypersplenism; - Long-term unhealed wounds or fractures; - Major surgery or severe traumatic injury, fracture or ulcer within 4 weeks prior to enrollment; - Unable to swallow, chronic diarrhea or intestinal obstruction; - Abdominal fistula, gastrointestinal perforation or abdominal abscess within 6 months prior to enrollment; - Urinary protein ≥ ++, 24-hour urinary protein ≥ 1.0 g; - Active infections require antimicrobial treatment; - ALK gene abnormalities (gene fusion or mutation occurred); - Pregnant or lactating women, or women unwilling or unable to take effective contraception; Inclusion Criteria: - Pathologically confirmed stage IIIB, IV non-squamous non-small cell lung cancer, with measurable lesions (the long axis of tumor lesions ≥ 10mm with CT, the short axis of lymph node lesions ≥ 15mm with CT, the lesions not receive radiotherapy, frozen or other local treatment); - Patients with slow progression on first-line EGFR TKI(erlotinib / icotinib / gefitinib) treatment; - No T790M mutation including an assessment from tumor biopsy obtained while on or subsequent to the most recent EGFR TKI therapy; - Eastern Cooperative Oncology Group (ECOG) performance status 0-2; - Life expectancy of more than 3 months; - Adequate bone marrow function: WBC ≥ 3.0 ×10 E+9/L, neutrophil ≥ 1.5 × 10 E+9/L, platelets ≥ 80 × 10E+9/L,Hb ≥ 10.0g/dL;a total bilirubin (TBil) of ≤1.5 upper normal limitation (UNL), a alanine aminotransferase (ALAT) and aspartate aminotransferase (ASAT) of ≤3UNL or ≤5UNL in case of liver metastasis, a creatinine (Cr) of ≤ 1.5 UNL; a creatinine clearance rate ≥ 50ml/min (Cockcroft-Gault); - Female subjects of child-bearing potential must agree to use contraceptive measures starting 1 week before the administration of the first dose of apatinib until 8 weeks after discontinuing study drug. --- T790M ---

Primary Outcomes

Description: the length of time during and after the treatment of a disease that a patient lives with the disease but it does not get worse

Measure: Progression-free survival (PFS)

Time: up to 24 months

Secondary Outcomes

Description: The length of time from either the date of diagnosis or the start of treatment that half of the patients in a group of patients diagnosed with the disease are still alive.

Measure: Overall survival (OS)

Time: up to 36 months

Description: From first response to the date of first documented disease progression

Measure: Duration of response (DOR)

Time: up to 24 months

Description: the proportion of patients with a best overall response of CR, PR or SD in the whole body, as assessed per RECIST 1.1 by the investigator.

Measure: Disease Control Rate (DCR)

Time: 24 weeks

Description: the proportion of patients with a best overall confirmed response of CR or PR in the whole body as assessed per RECIST 1.1 by the investigator

Measure: Overall response rate (ORR)

Time: 24 weeks

Description: Analysis of changes from baseline using the quality of life (QoL) instrument

Measure: the quality of life (QoL)

Time: up to 36 months

280 A Open-label, One-arm Trial of Gefitinib Combined With Radiotherapy as Adjuvant Therapy in Completely Resected Patients With Pathological Stage IIIA-N2 Non-small Cell Lung Cancer Harbouring Sensitive Mutations of EGFR

To explore the survival benefit of the gefitinib combined with radiotherapy as adjuvant therapy for completely resected patients with Pathological stage IIIA-N2 NSCLC harbouring sensitive mutations of EGFR.

NCT03381430
Conditions
  1. Lung Cancer
Interventions
  1. Drug: Gefitinib
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

- Patients who harbouring exon 20 T790M mutation. --- T790M ---

Primary Outcomes

Description: From start of anti-cancer therapy until progression or death. To evaluate the disease free survival of gefitinib combined with radiotherapy as adjuvant therapy in completely resected patients with Pathological stage IIIA-pN2 NSCLC harbouring sensitive mutations of EGFR.Disease free survival (DFS)- defined as the time from initial medication to the first documented disease progression or death, whichever occurs first.

Measure: Disease free survival

Time: CT scan, abdominal ultrasound every 3 months, brain MRI every 6 months, bone scan every 12 months for up to 3 years.

Secondary Outcomes

Description: evaluated in the 6 years since treatment begain

Measure: Overall survival

Time: 6 years

Description: To compare the adjuvant treatment arm in terms of 3 yeas DFS rate.

Measure: 3 yeas DFS rate

Time: 3 years

Description: To compare the adjuvant treatment arm in terms of 5 years DFS rate.

Measure: 5 years DFS rate

Time: 5 years

Description: To compare the adjuvant treatment arm in terms of 5 years OS rate.

Measure: 5 years OS rate

Time: 5 years

Description: The safety and tolerability profile of gefitinib at a 250 mg daily dose relative to that of radiotherapy.

Measure: Number of Participants with Adverse Events

Time: In the period of Gefitinib 250 mg/day oral daily for 24 months. Radiotherapy total dose 50-54Gy, divided dose 1.8-2Gy.

281 An Open-label, Single Arm, Phase I/IIa Study to Evaluate Safety, Dose Escalation Tolerability, Pharmacokinetics and Antineoplastic Activity of the BPI-7711 Capsule in Patients With EGFR Mutation Advanced or Recurrent NSCLC

Lung cancer has the highest incidence rate in China and is also a very common cancer in the world. BPI-7711 is a new drug developed for patients with non-small cell lung cancer. The purpose of this study is to evaluate the safety, efficacy and PK profile of BPI-7711. The first part of the study will recruit 3~6 patients for different dose levels to evaluate safety. The dose will increase from the lowest level. The second part of the study is the dose expansion. Once efficacy is observed in the dose increasing process, additional 20~30 patients will be enrolled to further evaluate the anti-tumor efficacy. A recommended dose will be selected for Phase II study.

NCT03386955
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: BPI-7711 Capsule
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

BPI-7711 Capsule in Patients With EGFR Mutation T790M Positive Non-small Cell Lung Cancer Lung cancer has the highest incidence rate in China and is also a very common cancer in the world. --- T790M ---

points.. Objective response rate (ORR) of BPI-7711 capsule.. Objective response rate evaluated by CT, MRI examination results according to RECIST 1.1.. Best objective response (BOR) of BPI-7711 capsule.. Best objective response evaluated by CT, MRI examination results according to RECIST 1.1.. Disease control rate ( DCR) of BPI-7711 capsule.. Disease control rate evaluated by CT, MRI examination results according to RECIST 1.1.. Duration of response ( DoR) of BPI-7711 capsule.. Duration of response evaluated by CT, MRI examination results according to RECIST 1.1.. Progression free survival (PFS) of BPI-7711 capsule.. Progression free survival evaluated by CT, MRI examination results according to RECIST 1.1.. EGFR mutation testing.. To test EGFR mutation in plasma circulating tumor DNA (ctDNA).. T790M mutation testing.. To test T790M mutation in plasma circulating tumor DNA (ctDNA).. Inclusion Criteria: - Subjects signs and dates the informed consent form before receiving any treatment or test sample collection related to the study. --- T790M ---

points.. Objective response rate (ORR) of BPI-7711 capsule.. Objective response rate evaluated by CT, MRI examination results according to RECIST 1.1.. Best objective response (BOR) of BPI-7711 capsule.. Best objective response evaluated by CT, MRI examination results according to RECIST 1.1.. Disease control rate ( DCR) of BPI-7711 capsule.. Disease control rate evaluated by CT, MRI examination results according to RECIST 1.1.. Duration of response ( DoR) of BPI-7711 capsule.. Duration of response evaluated by CT, MRI examination results according to RECIST 1.1.. Progression free survival (PFS) of BPI-7711 capsule.. Progression free survival evaluated by CT, MRI examination results according to RECIST 1.1.. EGFR mutation testing.. To test EGFR mutation in plasma circulating tumor DNA (ctDNA).. T790M mutation testing.. To test T790M mutation in plasma circulating tumor DNA (ctDNA).. Inclusion Criteria: - Subjects signs and dates the informed consent form before receiving any treatment or test sample collection related to the study. --- T790M --- --- T790M ---

- Phase I: Central lab tissue tests confirm T790M positive for the biopsy, plasma, or cytology samples collected after imaging examination with clear disease progression post last treatment. --- T790M ---

- Received treatment targeted for T790M positive mutation, or participated in clinical trials for such types of drugs, e.g., AZD9291, CO-1686 and other third-generation TKI therapy. --- T790M ---

Primary Outcomes

Description: DLT to be evaluated according to NCI CTCAE V4.03

Measure: Number of patients with dose limiting toxicity ( DLT).

Time: From first dosing ( Day -7) to the last dosing of Cycle 1 ( Day 28).

Secondary Outcomes

Description: Collect and analyze the blood concentration data of BPI-7711 and its main metabolites on Day-7~Day-1 at designated time points.

Measure: Maximum plasma concentration (Cmax) of BPI-7711 and its main metabolites.

Time: Pre-dose, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 48h, 72h, 120h, 144h post first dose on Day -7.

Description: Collect and analyze the blood concentration data of BPI-7711 and its main metabolites on Day-7~Day-1 at designated time points.

Measure: Peak Plasma Time (tmax) of BPI-7711 and its main metabolites after single dose.

Time: Pre-dose, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 48h, 72h, 120h, 144h post first dose on Day -7.

Description: Collect and analyze the blood concentration data of BPI-7711 and its main metabolites on Day-7~Day-1 at designated time points.

Measure: Area under the plasma concentration versus time curve (AUC) of BPI-7711 and its main metabolites after single dose.

Time: Pre-dose, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 48h, 72h, 120h, 144h post first dose on Day -7.

Description: Collect and analyze the blood concentration data of BPI-7711 and its main metabolites on Day-7~Day-1 at designated time points.

Measure: Clearance of BPI-7711 and its main metabolites after single dose.

Time: Pre-dose, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 48h, 72h, 120h, 144h post first dose on Day -7.

Description: Collect and analyze the blood concentration data of BPI-7711 and its main metabolites on Day-7~Day-1 at designated time points.

Measure: Half life of BPI-7711 and its main metabolites after single dose.

Time: Pre-dose, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 48h, 72h, 120h, 144h post first dose on Day -7.

Description: Collect and analyze the blood concentration data of BPI-7711 and its main metabolites on Cycle 1 Day1, Cycle Day 8, Cycle 1 Day 15 and Cycle 2 Day1 at designated time. points.

Measure: Blood concentration of BPI-7711 and its main metabolites after single dose under steady state.

Time: Pre-dose of Cycle1 Day1, 8, 15. Pre-dose, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h post dose on Cycle 2 Day1

Description: Objective response rate evaluated by CT, MRI examination results according to RECIST 1.1.

Measure: Objective response rate (ORR) of BPI-7711 capsule.

Time: At screening, and every two cycles from the first multiple dose on Cycle 1 Day 1( 21 days as one cycle) until the date of first documented progression, death or withdrawal from study, whichever came first, assessed up to 20 months.

Description: Best objective response evaluated by CT, MRI examination results according to RECIST 1.1.

Measure: Best objective response (BOR) of BPI-7711 capsule.

Time: At screening, and every two cycles from the first multiple dose on Cycle 1 Day 1( 21 days as one cycle) until the date of first documented progression, death or withdrawal from study, whichever came first, assessed up to 20 months.

Description: Disease control rate evaluated by CT, MRI examination results according to RECIST 1.1.

Measure: Disease control rate ( DCR) of BPI-7711 capsule.

Time: At screening, and every two cycles from the first multiple dose on Cycle 1 Day 1( 21 days as one cycle) until the date of first documented progression, death or withdrawal from study, whichever came first, assessed up to 20 months.

Description: Duration of response evaluated by CT, MRI examination results according to RECIST 1.1.

Measure: Duration of response ( DoR) of BPI-7711 capsule.

Time: At screening, and every two cycles from the first multiple dose on Cycle 1 Day 1( 21 days as one cycle) until the date of first documented progression, death or withdrawal from study, whichever came first, assessed up to 20 months.

Description: Progression free survival evaluated by CT, MRI examination results according to RECIST 1.1.

Measure: Progression free survival (PFS) of BPI-7711 capsule.

Time: At screening, and every two cycles from the first multiple dose on Cycle 1 Day 1( 21 days as one cycle) until the date of first documented progression, death or withdrawal from study, whichever came first, assessed up to 20 months.

Other Outcomes

Description: To test EGFR mutation in plasma circulating tumor DNA (ctDNA).

Measure: EGFR mutation testing.

Time: At screening and every two cycles( 21 days as a cycle) from Cycle 1 Day1 until the date of first documented progression, death or withdrawal from study, whichever came first, assessed up to 20 months.

Description: To test T790M mutation in plasma circulating tumor DNA (ctDNA).

Measure: T790M mutation testing.

Time: At screening and every two cycles( 21 days as a cycle) from Cycle 1 Day1 until the date of first documented progression, death or withdrawal from study, whichever came first, assessed up to 20 months.

282 Molecular Analysis of the Surnantant of Echoguidated Bronchoscopic Cytopunctions in Lung Cancer

The wide uptake of "liquid biopsy" diagnostics in the care of advanced cancer patients highlights the desire for improved access to tumor allowing accurate tumor genotyping (1). Genotyping of plasma cfDNA is now routine for detection of EGFR driver mutations at diagnosis of NSCLC, or for detection of the EGFR T790M mutation after TKI resistance, and is an emerging approach for the detection of other drivers (HER2 or BRAF mutations, ALK or ROS1 fusions…) (2) or the estimation of tumor mutation burden (TMB) (3). However, the most sensitive plasma genotyping platforms still have a sensitivity of only 70%-80%, such that a negative result requires tissue biopsy confirmation.

NCT04624373
Conditions
  1. Lung Cancer
Interventions
  1. Other: Molecular analysis of surnatant
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

Genotyping of plasma cfDNA is now routine for detection of EGFR driver mutations at diagnosis of NSCLC, or for detection of the EGFR T790M mutation after TKI resistance, and is an emerging approach for the detection of other drivers (HER2 or BRAF mutations, ALK or ROS1 fusions…) (2) or the estimation of tumor mutation burden (TMB) (3). --- T790M ---

Primary Outcomes

Description: to investigate the sensitivity of sfDNA genotyping in various clinical settings and to compare it to cell block

Measure: main aim of the study

Time: 18 months

Secondary Outcomes

Description: To assess the feasibility of TMB estimation on this specimen

Measure: TMB estimation

Time: 18 months

Description: To compare the sensitivity of plasma genotyping to cell block

Measure: sensitivity of plasma

Time: 18 months

Description: To investigate the concordance between plasma and supernatant for mutation detection and TMB estimation

Measure: concordance between plasma and supernatant

Time: 18 months

Description: To calculate the rate of patients with at least one additional mutation detected on supernatant compared to cell block

Measure: mutation rate

Time: 18 months

Description: To compare the sensitivity of supernatant and plasma to cell block for the detection of specific alterations (EGFR, HER2, BRAF, PIK3CA, KRAS, MET mutations, ALK, ROS1, NTRK, RET fusions)

Measure: Sensitivity of supernatant and plasma

Time: 18 months

Description: To compare the turnaround time of supernatant, plasma and cell block for genotyping

Measure: Turnaround time of supernatant

Time: 18 months

283 A Single-arm, Open, Multi-center Phase I/II Clinical Trial to Evaluate the Safety, Tolerability, Pharmacokinetic Characteristics and Effectiveness of XZP-5809-TT1 Tablets in Patients With T790M Mutation-positive Locally Advanced or Metastatic Non-small Cell Lung Cancer Who Have Progressed After Treatment With Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI).

The trial is divided into two parts, one is dose escalation phase, the second one is dose expansion phase. For dose escalation phase, the main purpose is to evaluate safety and tolerability of XZP-5809-TT1 tablets after treatment with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) in patients With T790M Mutation-positive Locally Advanced or Metastatic Non-small Cell Lung Cancer, and to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). For dose expansion phase, the main purpose is to evaluate Objective response rate (ORR) in patients With T790M Mutation-positive Locally Advanced or Metastatic Non-small Cell Lung Cancer.

NCT04622072
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: XZP-5809-TT1 Tablet
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

A Single-arm, Open, Multi-center Phase I/II Clinical Trial to Evaluate the Safety, Tolerability, Pharmacokinetic Characteristics and Effectiveness of XZP-5809-TT1 Tablets in Patients With T790M Mutation-positive Locally Advanced or Metastatic Non-small Cell Lung Cancer Who Have Progressed After Treatment With Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI).. XZP-5809-TT1 Tablets in Patients With T790M Mutation-positive Locally Advanced or Metastatic Non-small Cell Lung Cancer The trial is divided into two parts, one is dose escalation phase, the second one is dose expansion phase. --- T790M ---

A Single-arm, Open, Multi-center Phase I/II Clinical Trial to Evaluate the Safety, Tolerability, Pharmacokinetic Characteristics and Effectiveness of XZP-5809-TT1 Tablets in Patients With T790M Mutation-positive Locally Advanced or Metastatic Non-small Cell Lung Cancer Who Have Progressed After Treatment With Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI).. XZP-5809-TT1 Tablets in Patients With T790M Mutation-positive Locally Advanced or Metastatic Non-small Cell Lung Cancer The trial is divided into two parts, one is dose escalation phase, the second one is dose expansion phase. --- T790M --- --- T790M ---

For dose escalation phase, the main purpose is to evaluate safety and tolerability of XZP-5809-TT1 tablets after treatment with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) in patients With T790M Mutation-positive Locally Advanced or Metastatic Non-small Cell Lung Cancer, and to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). --- T790M ---

For dose expansion phase, the main purpose is to evaluate Objective response rate (ORR) in patients With T790M Mutation-positive Locally Advanced or Metastatic Non-small Cell Lung Cancer. --- T790M ---

Primary Outcomes

Description: Refers to adverse clinical events that occur during drug treatment, which may not have a causal relationship with the drug

Measure: adverse event

Time: through study completion, an average of 1.5 year

Description: According to the RECIST 1.1 standard, the best overall response (BOR) observed after enrollment of subjects is the proportion of subjects with complete remission (CR) or partial remission (PR)

Measure: Objective response rate (ORR)

Time: through study completion, an average of 1.5 year

Description: The time from the time a subject receives the first study treatment to the appearance of disease progression or death from any cause (whichever occurs first).

Measure: Progression-free survival (PFS)

Time: through study completion, an average of 1.5 year

Description: the amount of red blood cell.

Measure: blood routine

Time: through study completion, an average of 1.5 year

Description: the amount of white cell.

Measure: blood routine

Time: through study completion, an average of 1.5 year

Description: the amount of platelet.

Measure: blood routine

Time: through study completion, an average of 1.5 year

284 A Phase II Study of AMG 510 in Participants With Previously Treated Stage IV or Recurrent KRAS G12C Mutated Non-Squamous Non-Small Cell Lung Cancer (ECOG-ACRIN LUNG-MAP SUB-STUDY)

This phase II Lung-MAP treatment trial studies the effect of AMG 510 in treating non-squamous non-small cell lung cancer that is stage IV or has come back (recurrent) and has a specific mutation in the KRAS gene, known as KRAS G12C. Mutations in this gene may cause the cancer to grow. AMG 510, a targeted treatment against the KRAS G12C mutation, may help stop the growth of tumor cells.

NCT04625647
Conditions
  1. Lung Adenocarcinoma
  2. Lung Non-Small Cell Carcinoma
  3. Recurrent Lung Non-Squamous Non-Small Cell Carcinoma
  4. Stage IV Lung Cancer AJCC v8
  5. Stage IVA Lung Cancer AJCC v8
  6. Stage IVB Lung Cancer AJCC v8
Interventions
  1. Drug: Sotorasib
MeSH:Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung Adenocarcinoma of Lung
HPO:Carcinoma Neoplasm of the lung Non-small cell lung carcinoma

Participants whose only measurable disease is within a previous radiation therapy port must demonstrate clearly progressive disease (in the opinion of the treating investigator) prior to registration - Participants must have a CT or MRI scan of the brain to evaluate for central nervous system (CNS) disease within 42 days prior to sub-study registration - Participants with known human immunodeficiency virus (HIV) infection must be receiving anti-retroviral therapy and have an undetectable viral load at their most recent viral load test within 6 months prior to sub-study registration - Participants with EGFR sensitizing mutations, EGFR T790M mutation, ALK gene fusion, ROS1 gene rearrangement, or BRAF V600E mutation must have progressed following all standard of care targeted therapy - Participants with spinal cord compression or brain metastases must have received local treatment to these metastases and remained clinically controlled and asymptomatic for at least 7 days following stereotactic radiation and/or 14 days following whole brain radiation, and prior to sub-study registration - Participants must have received at least one line of systemic treatment for stage IV or recurrent NSCLC - Participants must have progressed (in the opinion of the treating physician) following the most recent line of systemic therapy for NSCLC - Participants must have recovered (=< grade 1) from side effects of prior therapy. --- T790M ---

Primary Outcomes

Measure: Response rate (confirmed, complete or partial)

Time: Up to 3 years

Secondary Outcomes

Description: The frequency and grade of individual toxicities attributable to treatment will be estimated.

Measure: Incidence of adverse events

Time: Up to 3 years

Description: Will be estimated using the method of Kaplan-Meier. Confidence intervals about medians will be estimated using the Brookmeyer-Crowley method and about landmark time points will be calculated using Greenwood's formula and based on a log-log transformation applied on the survival function. Binary proportions and associated confidence intervals will be estimated for within cohort objectives. With participants in Cohort 1 and 3 and participants in Cohort 2, binary proportions can be estimated to within 16% and 20% with 95% confidence, respectively.

Measure: Progression free survival

Time: Up to 3 years

Description: Will be estimated using the method of Kaplan-Meier. Confidence intervals about medians will be estimated using the Brookmeyer-Crowley method and about landmark time points will be calculated using Greenwood's formula and based on a log-log transformation applied on the survival function. Binary proportions and associated confidence intervals will be estimated for within cohort objectives. With participants in Cohort 1 and 3 and participants in Cohort 2, binary proportions can be estimated to within 16% and 20% with 95% confidence, respectively.

Measure: Overall survival

Time: Up to 3 years

Description: Will be estimated using the method of Kaplan-Meier. Confidence intervals about medians will be estimated using the Brookmeyer-Crowley method and about landmark time points will be calculated using Greenwood's formula and based on a log-log transformation applied on the survival function. Binary proportions and associated confidence intervals will be estimated for within cohort objectives. With participants in Cohort 1 and 3 and participants in Cohort 2, binary proportions can be estimated to within 16% and 20% with 95% confidence, respectively.

Measure: Duration of response

Time: Up to 3 years

285 A Phase I/II, Open-Label, Multicenter Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Anti-Tumor Activity of YH25448 in Patients With EGFR Mutation Positive Advanced Non-Small Cell Lung Cancer (NSCLC)

YH25448 is an oral, highly potent, mutant-selective and irreversible EGFR Tyrosine-kinase inhibitors (TKIs) targets both the T790M mutation and activating EGFR mutations while sparing wild type-EGFR. YH25448 is expected to beneficial for the NSCLC patients with brain metastasis due to good blood brain barrier (BBB) penetration property as well as for the treatment of primary lung lesion and extracranial lesions. This study will be conducted to evaluate the safety, tolerability and efficacy of YH25448 in locally advanced or metastatic NSCLC patients with EGFR mutations.

NCT03046992
Conditions
  1. EGFR Gene Mutation
Interventions
  1. Drug: YH25448

Clinical Trial of YH25448 in Patients With EGFR Mutation Positive Advanced NSCLC YH25448 is an oral, highly potent, mutant-selective and irreversible EGFR Tyrosine-kinase inhibitors (TKIs) targets both the T790M mutation and activating EGFR mutations while sparing wild type-EGFR. --- T790M ---

In dose expansion phase, further safety, tolerability, pharmacokinetic(PK) and efficacy will be evaluated at each dose level(s) of dose escalation phase in NSCLC patients who progressed following prior EGFR TKIs treatment and harbouring confirmed T790M mutation. --- T790M ---

Primary Outcomes

Description: To assess the safety and tolerability profile of YH25448 by Common Terminology Criteria for Adverse Events (CTCAE) v4.03; vital signs (blood pressure, pulse, weight); laboratory parameters (clinical chemistry, hematology, urinalysis); physical examination; centrally reviewed electrocardiograms (ECGs), echocardiogram or multiple gated acquisition scan and performance status.

Measure: Safety and tolerability by Common Terminology Criteria for Adverse Events (CTCAE) v4.03

Time: Safety and tolerability profile will be collected from baseline until 28 days after the last dose, expected average 1 year.

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) assessed by MRI or CT. ORR is the percentage of patients with at least 1 visit response of Complete Response (CR) or Partial Response (PR) (according to independent review), prior to progression or further anti-cancer therapy.

Measure: Objective Response Rate (ORR)

Time: At baseline and every 6 weeks from first dose objective disease progression or withdrawal from study, up to approximately 1 year.

Secondary Outcomes

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT.

Measure: Duration of Response (DoR)

Time: At baseline and every 6 weeks from first dose objective disease progression or withdrawal from study, up to approximately 1 year.

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT.

Measure: Disease Control Rate (DCR)

Time: At baseline and every 6 weeks from first dose objective disease progression or withdrawal from study, up to approximately 1 year.

Description: Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT. Kaplan-Meier plots will be used to summarize the progression-free survival.

Measure: Progression-Free Survival (PFS)

Time: At baseline and every 6 weeks from first dose objective disease progression or withdrawal from study, up to approximately 1 year.

Description: To obtain assessment of anti-tumor activity of YH25448 by evaluation of tumor response using RECIST version 1.1.

Measure: Overall Survival (OS)

Time: At baseline and every 6 weeks from first dose objective disease progression or withdrawal from study, up to approximately 1 year.

Description: To obtain assessment of anti-tumor activity of YH25448 by evaluation of tumor response using RECIST version 1.1.

Measure: Tumor shrinkage

Time: At baseline and every 6 weeks from first dose objective disease progression or withdrawal from study, up to approximately 1 year.

Description: To obtain assessment of anti-tumor activity of YH25448 by evaluation of tumor response using RECIST version 1.1.

Measure: Objective Intracranial Response Rate (OIRR)

Time: At baseline and every 6 weeks from first dose objective disease progression or withdrawal from study, up to approximately 1 year.

Description: To obtain assessment of anti-tumor activity of YH25448 by evaluation of tumor response using RECIST version 1.1.

Measure: Duration of Intracranial Response (DoIR)

Time: At baseline and every 6 weeks from first dose objective disease progression or withdrawal from study, up to approximately 1 year.

Description: To obtain assessment of anti-tumor activity of YH25448 by evaluation of tumor response using RECIST version 1.1. Kaplan-Meier plots will be used to summarize the progression-free survival.

Measure: Intracranial Progression Free Survival (IPFS).

Time: At baseline and every 6 weeks from first dose objective disease progression or withdrawal from study, up to approximately 1 year.

286 First-Line Erlotinib Therapy and the Subsequent Development of Mechanisms of Secondary Resistance in Patients With Non-Small Cell Lung Cancer and Known Sensitizing EGFR Mutations

Erlotinib is a drug which targets non small cell lung cancer with a genetic change (mutation) in the epidermal growth factor receptor (EGFR). This drug has been used in other cancer research studies and information from those studies suggests that Erlotinib can control the growth of these cancer cells.

NCT00997334
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: Erlotinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Participants were classified into 4 potential resistant mechanism groups (4 genetic/ 1 histologic) based on evaluation of rebiopsy tissue: EGFR mutations (T790M mutation, exon 20 insertion), KRAS mutations, MET amplification or small-cell lung cancer (SCLC) transform using established methods.. Progression-Free Survival. --- T790M ---

Non-small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVE -To prospectively assess the frequency of different genetic mechanisms of secondary resistance in patients' tumors during treatment with erlotinib (e.g., T790M mutations, MET amplification). --- T790M ---

Primary Outcomes

Description: Participants were classified into 4 potential resistant mechanism groups (4 genetic/ 1 histologic) based on evaluation of rebiopsy tissue: EGFR mutations (T790M mutation, exon 20 insertion), KRAS mutations, MET amplification or small-cell lung cancer (SCLC) transform using established methods.

Measure: Resistance Mechanism

Time: Participants were evaluated for incidence of genetic mechanisms of secondary resistance at time of disease progression at which point participants stopped treatment. Progression follow up was up to 3 years in this study cohort.

Secondary Outcomes

Description: Progression-free survival based on the Kaplan-Meier method is defined as the duration of time from study entry to documented disease progression (PD) or death. Per RECIST 1.1 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions.

Measure: Progression-Free Survival

Time: Disease was evaluated radiologically every 8 weeks on treatment (cycle duration=4 weeks). Participants were treated until evidence of disease progression or unacceptable toxicity. Progression follow-up was up to 3 years in this study cohort.

287 A Phase 1/2 Study of the Safety and Efficacy of Rociletinib When Administered in Combination With Trametinib in Patients With Activating EGFR Mutation-positive Advanced or Metastatic Non-small Lung Cancer (NSCLC)

The purpose of this study is to evaluate the safety and anti-tumor effect of rociletinib when administered in combination with trametinib.

NCT02580708
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: Rociletinib
  2. Drug: Trametinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - Written informed consent on an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved ICF before any study-specific evaluation - Histologically or cytologically confirmed metastatic or unresectable locally advanced NSCLC with EGFR activating mutation (excluding exon 20 insertion); measurable disease per RECIST 1.1 - Prior treatment with an EGFR TKI; in Phase 2, prior treatment with a T790M-directed EGFR TKI for patients in Group B. Previous chemotherapy is allowed; in Phase 2, immediate prior therapy must be EGFR TKI - Patient willingness to undergo tumor biopsy at baseline and on treatment (optional for Phase 1; mandatory for Phase 2) - Eastern Cooperative Oncology Group (ECOG) performance status 0-1; life expectancy at least 3 months - Adequate hematological and biological function; LVEF ≥50% Exclusion Criteria: - Documented evidence in tumor of exon 20 insertion, small cell transformation, or MET amplification - Leptomeningeal carcinomatosis or other untreated or symptomatic CNS metastases (asymptomatic CNS metastases allowed if clinically stable without requirement for steroids within 2 weeks) - Known preexisting interstitial lung disease or pneumonitis - Concurrent use of QT-prolonging medication - Uncontrolled diabetes (HA1C > 10%) despite optional therapy - Cardiac abnormalities: - Clinically significant abnormal 12-lead ECG, QT interval corrected using Fridericia's method (QTcF) >450 ms - Inability to measure QT interval on ECG - Personal or family history of long QT syndrome - Implantable pacemaker or implantable cardioverter defibrillator - Resting bradycardia < 55 beats/min - Inability to swallow oral study treatment or any gastrointestinal disease or condition that would preclude adequate absorption of study treatment - Presence of serious or unstable concomitant systemic disorder incompatible with the clinical study (eg, substance abuse; uncontrolled intercurrent illness including active infection; arterial thrombosis; unstable respiratory, hepatic, renal or cardiac disease; and other active malignancy) - Pregnant or breastfeeding females and male or female patients who refuse to use adequate contraception during the study and for 16 weeks after the last dose of study treatment - Any contraindication, allergy, or hypersensitivity to rociletinib, trametinib, or excipients Inclusion Criteria: - Written informed consent on an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved ICF before any study-specific evaluation - Histologically or cytologically confirmed metastatic or unresectable locally advanced NSCLC with EGFR activating mutation (excluding exon 20 insertion); measurable disease per RECIST 1.1 - Prior treatment with an EGFR TKI; in Phase 2, prior treatment with a T790M-directed EGFR TKI for patients in Group B. Previous chemotherapy is allowed; in Phase 2, immediate prior therapy must be EGFR TKI - Patient willingness to undergo tumor biopsy at baseline and on treatment (optional for Phase 1; mandatory for Phase 2) - Eastern Cooperative Oncology Group (ECOG) performance status 0-1; life expectancy at least 3 months - Adequate hematological and biological function; LVEF ≥50% Exclusion Criteria: - Documented evidence in tumor of exon 20 insertion, small cell transformation, or MET amplification - Leptomeningeal carcinomatosis or other untreated or symptomatic CNS metastases (asymptomatic CNS metastases allowed if clinically stable without requirement for steroids within 2 weeks) - Known preexisting interstitial lung disease or pneumonitis - Concurrent use of QT-prolonging medication - Uncontrolled diabetes (HA1C > 10%) despite optional therapy - Cardiac abnormalities: - Clinically significant abnormal 12-lead ECG, QT interval corrected using Fridericia's method (QTcF) >450 ms - Inability to measure QT interval on ECG - Personal or family history of long QT syndrome - Implantable pacemaker or implantable cardioverter defibrillator - Resting bradycardia < 55 beats/min - Inability to swallow oral study treatment or any gastrointestinal disease or condition that would preclude adequate absorption of study treatment - Presence of serious or unstable concomitant systemic disorder incompatible with the clinical study (eg, substance abuse; uncontrolled intercurrent illness including active infection; arterial thrombosis; unstable respiratory, hepatic, renal or cardiac disease; and other active malignancy) - Pregnant or breastfeeding females and male or female patients who refuse to use adequate contraception during the study and for 16 weeks after the last dose of study treatment - Any contraindication, allergy, or hypersensitivity to rociletinib, trametinib, or excipients Non-small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung This is a Phase 1/2, open-label, non randomized, multicenter study evaluating the safety and efficacy of rociletinib administered in combination with trametinib. --- T790M ---

Inclusion Criteria: - Written informed consent on an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved ICF before any study-specific evaluation - Histologically or cytologically confirmed metastatic or unresectable locally advanced NSCLC with EGFR activating mutation (excluding exon 20 insertion); measurable disease per RECIST 1.1 - Prior treatment with an EGFR TKI; in Phase 2, prior treatment with a T790M-directed EGFR TKI for patients in Group B. Previous chemotherapy is allowed; in Phase 2, immediate prior therapy must be EGFR TKI - Patient willingness to undergo tumor biopsy at baseline and on treatment (optional for Phase 1; mandatory for Phase 2) - Eastern Cooperative Oncology Group (ECOG) performance status 0-1; life expectancy at least 3 months - Adequate hematological and biological function; LVEF ≥50% Exclusion Criteria: - Documented evidence in tumor of exon 20 insertion, small cell transformation, or MET amplification - Leptomeningeal carcinomatosis or other untreated or symptomatic CNS metastases (asymptomatic CNS metastases allowed if clinically stable without requirement for steroids within 2 weeks) - Known preexisting interstitial lung disease or pneumonitis - Concurrent use of QT-prolonging medication - Uncontrolled diabetes (HA1C > 10%) despite optional therapy - Cardiac abnormalities: - Clinically significant abnormal 12-lead ECG, QT interval corrected using Fridericia's method (QTcF) >450 ms - Inability to measure QT interval on ECG - Personal or family history of long QT syndrome - Implantable pacemaker or implantable cardioverter defibrillator - Resting bradycardia < 55 beats/min - Inability to swallow oral study treatment or any gastrointestinal disease or condition that would preclude adequate absorption of study treatment - Presence of serious or unstable concomitant systemic disorder incompatible with the clinical study (eg, substance abuse; uncontrolled intercurrent illness including active infection; arterial thrombosis; unstable respiratory, hepatic, renal or cardiac disease; and other active malignancy) - Pregnant or breastfeeding females and male or female patients who refuse to use adequate contraception during the study and for 16 weeks after the last dose of study treatment - Any contraindication, allergy, or hypersensitivity to rociletinib, trametinib, or excipients Inclusion Criteria: - Written informed consent on an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved ICF before any study-specific evaluation - Histologically or cytologically confirmed metastatic or unresectable locally advanced NSCLC with EGFR activating mutation (excluding exon 20 insertion); measurable disease per RECIST 1.1 - Prior treatment with an EGFR TKI; in Phase 2, prior treatment with a T790M-directed EGFR TKI for patients in Group B. Previous chemotherapy is allowed; in Phase 2, immediate prior therapy must be EGFR TKI - Patient willingness to undergo tumor biopsy at baseline and on treatment (optional for Phase 1; mandatory for Phase 2) - Eastern Cooperative Oncology Group (ECOG) performance status 0-1; life expectancy at least 3 months - Adequate hematological and biological function; LVEF ≥50% Exclusion Criteria: - Documented evidence in tumor of exon 20 insertion, small cell transformation, or MET amplification - Leptomeningeal carcinomatosis or other untreated or symptomatic CNS metastases (asymptomatic CNS metastases allowed if clinically stable without requirement for steroids within 2 weeks) - Known preexisting interstitial lung disease or pneumonitis - Concurrent use of QT-prolonging medication - Uncontrolled diabetes (HA1C > 10%) despite optional therapy - Cardiac abnormalities: - Clinically significant abnormal 12-lead ECG, QT interval corrected using Fridericia's method (QTcF) >450 ms - Inability to measure QT interval on ECG - Personal or family history of long QT syndrome - Implantable pacemaker or implantable cardioverter defibrillator - Resting bradycardia < 55 beats/min - Inability to swallow oral study treatment or any gastrointestinal disease or condition that would preclude adequate absorption of study treatment - Presence of serious or unstable concomitant systemic disorder incompatible with the clinical study (eg, substance abuse; uncontrolled intercurrent illness including active infection; arterial thrombosis; unstable respiratory, hepatic, renal or cardiac disease; and other active malignancy) - Pregnant or breastfeeding females and male or female patients who refuse to use adequate contraception during the study and for 16 weeks after the last dose of study treatment - Any contraindication, allergy, or hypersensitivity to rociletinib, trametinib, or excipients Non-small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung This is a Phase 1/2, open-label, non randomized, multicenter study evaluating the safety and efficacy of rociletinib administered in combination with trametinib. --- T790M --- --- T790M ---

Primary Outcomes

Description: Treatment emergent adverse events (AEs), laboratory abnormalities and ECG abnormalities in EGFR-mutant NSCLC patients given oral rociletinib in combination with oral trametinib; defining in Phase 1 the recommended combination dose for further evaluation in Phase 2

Measure: Incidence of treatment-emergent adverse events

Time: Continuously, up to approximately 24 months

Description: ORR according to RECIST Version 1.1 as determined by Investigator assessment

Measure: Objective Response Rate (ORR)

Time: Every 6 weeks until disease progression, up to approximately 24 months

Measure: Cmax of rociletinib and trametinib at steady state

Time: Cycle 2 Day 1 to Day 2

Measure: Tmax of rociletinib and trametinib at steady state

Time: Cycle 2 Day 1 to Day 2

Measure: AUC of rociletinib and trametinib at steady state

Time: Cycle 2 Day 1 to Day 2

Measure: Cmin of rociletinib and trametinib at steady state

Time: Cycle 2 Day 1 to Day 2

Measure: t1/2 of rociletinib at steady state

Time: Cycle 2 Day 1 to Day 2

Secondary Outcomes

Description: DR according to RECIST Version 1.1 as determined by Investigator assessment

Measure: Duration of Response (DR) According to RECIST Version 1.1

Time: Every 6 weeks until disease progression, up to approximately 24 months

Description: DCR according to RECIST Version 1.1 as determined by Investigator assessment

Measure: Disease Control Rate (DCR) According to RECIST Version 1.1

Time: Every 6 weeks until disease progression, up to approximately 24 months

Description: PFS according to RECIST Version 1.1 as determined by Investigator assessment

Measure: Progression Free Survival (PFS) According to RECIST Version 1.1

Time: Every 6 weeks until disease progression, up to approximately 24 months

Measure: Overall Survival (OS)

Time: Every 12 weeks until date of death, up to approximately 60 months

Measure: Longitudinal changes in blood based biomarkers (i.e. mutations in EGFR) in ctDNA

Time: Biomarker samples will be collected from each subject approximately every 3 weeks, up to approximately 24 months

Measure: Cmax of rociletinib metabolites at steady state

Time: Cycle 2 Day 1 to Day 2

Measure: Tmax of rociletinib metabolites at steady state

Time: Cycle 2 Day 1 to Day 2

Measure: AUC of rociletinib metabolites at steady state

Time: Cycle 2 Day 1 to Day 2

Measure: Cmin of rociletinib metabolites at steady state

Time: Cycle 2 Day 1 to Day 2

288 An Open-label, Randomized Phase 3 Efficacy Study of ASP8273 vs Erlotinib or Gefitinib in First-line Treatment of Patients With Stage IIIB/IV Non-small Cell Lung Cancer Tumors With EGFR Activating Mutations

The purpose of the study was to evaluate the progression free survival (PFS), based on independent radiologic review (IRR), of ASP8273 compared to erlotinib or gefitinib in patients with locally advanced, metastatic or unresectable stage IIIB/IV adenocarcinoma non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) activating mutations. This study also assessed Overall survival (OS); Overall response rate (ORR) as assessed by IRR; PFS as assessed by the investigator; Disease control rate (DCR) as assessed by IRR; Duration of Response (DOR) by IRR; Safety of ASP8273; and Quality of Life (QOL) and patient-reported outcome (PRO) parameters.

NCT02588261
Conditions
  1. Non-small Cell Lung Cancer (NSCLC)
Interventions
  1. Drug: naquotinib mesilate
  2. Drug: Erlotinib
  3. Drug: Gefitinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Neutrophil count > 1,000/mm3 - Platelet count ≥ 7.5 x 104 /mm3 - Hemoglobin > 8.0 g/dL - Serum creatinine ˂ 2.0 x upper limit of normal (ULN) or an estimated glomerular filtration rate (eGFR) of > 50 mL/min as calculated by the Cockcroft Gault Method - Total bilirubin ˂1.5 x ULN (except for subjects with documented Gilbert's syndrome) - AST and ALT ˂ 3.0 x ULN or ≤ 5 x ULN if subject has documented liver metastases - Serum sodium level is ≥ 130 mmol/L - Subject has an EGFR activating mutation (exon 19 deletion or exon 21 L858R), with or without T790M mutation, by local or central testing on examination of a NSCLC FFPE specimen (archival or fresh biopsy). --- L858R --- --- T790M ---

Primary Outcomes

Description: PFS was defined as the time from the date of randomization until the date of radiological disease progression or until death due to any cause, based on the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, as assessed by IRR. Results are based Kaplan-Meier estimate. If a participant had neither progressed nor died, who received any further anticancer therapy for the disease before radiological progression, the participant was censored at the date of last radiological assessment. If progression or death occurred after missing 2 scheduled radiological assessments, the participant was censored at the date of last radiological assessment or at the date of randomization if no post-baseline radiological assessment was available.

Measure: Progression Free Survival (PFS) as Assessed by Independent Radiologic Review (IRR)

Time: From date of randomization up to data cut-off date 09 May 2017 (approximately 15 months)

Secondary Outcomes

Description: All events of death after the first study drug administration were included.

Measure: Percentage of Deaths

Time: From date of randomization up to data cut-off date 21 Dec 2017 (approximately 22 months)

Description: Percentage of participants with OR was defined as the proportion of participants with best overall response as complete response (CR) or partial response (PR) without confirmation based on the RECIST v1.1 as assessed by the blinded IRR. CR was defined as disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to < 10 mm from baseline measurement. PR was defined as at least a 30% decrease in the sum of diameters (longest for nonnodal lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum of diameters.

Measure: Percentage of Participants With Objective Response (OR)

Time: From date of first dose of study drug up to data cut-off date 09 May 2017 (approximately 15 months)

Description: PFS was defined as the time from the date of randomization until the date of radiological disease progression or until death due to any cause, based on RECIST V1.1, as assessed by local investigator. Results are based Kaplan-Meier estimate. If a participant had neither progressed nor died, who received any further anticancer therapy for the disease before radiological progression, the participant was censored at the date of last radiological assessment. If progression or death occurred after missing 2 scheduled radiological assessments, the participant was censored at the date of last radiological assessment or at the date of randomization if no post-baseline radiological assessment was available.

Measure: PFS as Assessed by the Investigator

Time: From date of randomization up to data cut-off date 09 May 2017 (approximately 15 months)

Description: Percentage of participants with disease control was defined as the proportion of participants whose best overall response was rated as CR, PR or stable disease (SD) among all analyzed participants based on RECIST V1.1. CR was defined as disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to < 10 mm from baseline measurement. PR was defined as at least a 30% decrease in the sum of diameters (longest for nonnodal lesions, short axis for nodal lesions) of target lesions taking as reference to the baseline sum of diameters. SD was defined as neither sufficient decrease to qualify for PR nor sufficient increase to qualify for progressive disease taking as reference the smallest sum of diameters while on study drug.

Measure: Percentage of Participants With Disease Control

Time: From date of first dose of study drug up to data cut-off date 09 May 2017 (approximately 15 months)

Description: DOR was defined as the time from the date of the first response CR/PR (whichever was first recorded) as assessed by IRR to the date of radiographical progression or date of censoring. If a participant had not progressed, the participant was censored at the date of last radiological assessment or at the date of first CR/PR if no post-baseline radiological assessment was available. Results are based Kaplan-Meier estimate.

Measure: Duration of Response (DOR)

Time: From date of first response up to data cut-off date 09 May 2017 (approximately 15 months)

Description: Safety was assessed by AEs, which included abnormalities identified during a medical test (e.g. laboratory tests, vital signs, electrocardiogram, etc.) if the abnormality induced clinical signs or symptoms, needed active intervention, interruption or discontinuation of study medication or was clinically significant. A treatment-emergent AE (TEAE) was defined as an AE observed after starting administration of the study drug. AEs were considered serious (SAEs) if the AE resulted in death, was life threatening, resulted in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, resulted in congenital anomaly, or birth defect or required inpatient hospitalization or led to prolongation of hospitalization.

Measure: Number of Participants With Adverse Events (AEs)

Time: From first dose of study drug up to 30 days after last dose of study drug taken up to data cut-off 09 May 2017

Description: ACT-EGFRI-18 is an 18-item Likert-scaled questionnaire, used to assess the effect of EGFR inhibitors on quality of life (QoL). The questionnaire is arranged in three HRQL dimensions: physical (seven items), social/emotional (six items), and functional well-being (five items). The response scores ranged from 0 to 4, and the response categories include "not at all", "a little bit", "somewhat", "quite a bit", and "very much." Negatively worded items (e.g., "My skin bleeds easily "or "My skin condition affects my mood") are reverse-scored, so that participants who experience a higher impact of symptom burden on HRQL receive a lower score (range 0-72).

Measure: Functional Assessment of Cancer Therapy - EGFR Inhibitors Subscale (FACT-EGFRI-18) Questionnaire

Time: Day 1 of each cycle up to data cut off 09 May 2017 (approximately 15 months)

Description: The EORTC-QLQ-LC13 is a validated module of the EORTC-QLQ-Core 30, which includes module items that evaluate symptoms such as cough, hemoptysis, shortness of breath, sore mouth or tongue, dysphagia, tingling hands or feet, hair loss and pain. The total score for the questionnaire ranges from 0 to 100. A high score for a functional scale represents a high/healthy level of functioning whereas a high score for a symptom scale or item represents a high level of symptomatology or problems.

Measure: European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Lung Cancer 13 (EORTC-QLQ-LC13)

Time: Day 1 of each cycle up to data cut off 09 May 2017 (approximately 15 months)

Description: EORTC-QLQ-LC30 is a 30-item cancer-specific questionnaire with multitrait scaling was used to create five functional domain scales: Physical, Role, Emotional, Social and Cognitive; two items evaluate global QoL; in addition, three symptom scales assess Fatigue, Pain and Emesis; and six single items assess other symptoms. The total score ranges from 0 to 100, with a high score for a functional scale representing a high/healthy level of functioning and a high score for a symptom scale or item representing a high level of symptomatology or problems.

Measure: European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC-QLQ-C30)

Time: Day 1 of each cycle up to data cut off 09 May 2017 (approximately 15 months)

Description: The EQ-5D is a generic preference-based measure that indirectly measures the utility for health that generates an index-based summary score based upon societal preference weights. The EQ-5D-5L consists of 6 items that cover 5 main domains (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and a general visual analog scale (VAS) for health status. Each item has 5 response levels ranging from level 1 (no problem or none) to level 5 (unable to perform activity). The VAS ranges from 0 (worst health status) and 100 (best health status).

Measure: EuroQol 5-Dimension 5-Level Questionnaire (EQ-5D-5L)

Time: Day 1 of each cycle up to data cut off 09 May 2017 (approximately 15 months)

289 Genomic Landscape of EGFR Mutant NSCLC Prior to Rociletinib and at the Time of Disease Progression Following Rociletinib

Though patients whose tumors harbor EGFR T790M mutation appear to benefit from rociletinib, there is a need to understand the molecular mechanisms that lead to primary and acquired resistance to rociletinib. The investigators propose to conduct a clinical trial of rociletinib of patients with EGFR-mutant NSCLC with activating EGFR mutations (including exon 19 deletion or L858R mutation), with or without EGFR T790M mutation. In these patients, pre-treatment and post-progression biopsy specimens will be subjected to genomic analysis to fully understand the clonal evolution and the molecular mechanisms underpinning treatment resistance.

NCT02705339
Conditions
  1. Carcinoma, Non-Small-Cell Lung
  2. Non-Small Cell Lung Cancer
  3. Nonsmall Cell Lung Cancer
Interventions
  1. Drug: Rociletinib
  2. Procedure: Biopsy
  3. Procedure: Blood draw
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Rociletinib Genomic Landscape in Non-small Cell Lung Cancer (NSCLC) Though patients whose tumors harbor EGFR T790M mutation appear to benefit from rociletinib, there is a need to understand the molecular mechanisms that lead to primary and acquired resistance to rociletinib. --- T790M ---

The investigators propose to conduct a clinical trial of rociletinib of patients with EGFR-mutant NSCLC with activating EGFR mutations (including exon 19 deletion or L858R mutation), with or without EGFR T790M mutation. --- L858R --- --- T790M ---

Inclusion Criteria: - Histologically or cytologically confirmed metastatic stage IIIB/IV lung adenocarcinoma with known activating mutations in the EGFR TK domain (including exon 19 deletion and L858R) - Prior EGFR TKI therapy with progression, and documented EGFR T790M mutation on tumor biopsy; however, this need not be only second line - Measurable disease defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 10 mm with CT scan, as ≥ 20 mm by chest x-ray, or ≥ 10 mm with calipers by clinical exam. --- L858R --- --- T790M ---

Primary Outcomes

Description: -The investigators plan to conduct exome and transcriptome sequencing of tumor before therapy with rociletinib and at the time of relapse. In addition, exome sequencing of peripheral blood DNA will be done (for germ line).

Measure: Somatic genetic changes in the tumor associated with disease progression

Time: Until the time of disease progression (estimated median of 3 months)

Secondary Outcomes

Description: ORR: Percentage of patients experiencing complete response or partial response Complete Response (CR): Disappearance of all target lesions and non-target lesions. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

Measure: Overall response rate (ORR)

Time: Until the time of disease progression (estimated median of 3 months)

Measure: Overall survival (OS)

Time: Until death (estimated median of 8 months)

Description: -PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first.

Measure: Progression-free survival (PFS)

Time: Until the time of progression (estimated median of 3 months)

Measure: Duration of treatment

Time: Until the time of removal from study (estimated median of 3 months)

290 Phase II Study Evaluating the Combination of Cetuximab With Afatinib as First-line Treatment for Patients With EGFR Mutated Non Small Cell Lung Cancer

Until recently, the first line treatment of metastatic Non Small Cell Lung Cancer (NSCLC) was a platine-based chemotherapy. It has been changed by the discovery of EGFR (Epidermal Growth Factor Receptor) mutations and associated treatment with Tyrosine Kinase Inhibitor (TKI) of EGFR. The superiority of EGFR TKI over chemotherapy for EGFR mutated patients has been proved in several phase III trials with gefitinib, erlotinib or afatinib. Nevertheless, all patients will progress after 9 to 12 months of treatment due to the appearance of a treatment resistance. Afatinib is an irreversible EGFR TKI. It binds to its receptor permanently.Contrary to erlotinib and gefitinb which inhibits only EGFR, afatinib inhibits the kinase activity of all HER family (Human Epidermal growth factor Receptor). Nevertheless, there is no proof that afatinib delay the appearance of resistance. Cetuximab is a monoclonal antibody which binds specifically with EGFR. The double inhibition of EGFR by afatinib and cetuximab has demonstrated its efficacy in pre-clinical models. The hypothesis of this study is that the combination between cetuximab and afatinib will permit to delay or decrease the appearance of resistances.

NCT02716311
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: Afatinib
  2. Drug: Cetuximab
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Principal Inclusion Criteria: - Stage III or IV NSCLC, non irradiable non operable - Non squamous NSCLC histologically or cytologically confirmed - No previous treatment of NSCLC - EGFR mutation (exon 19 deletion, L858R mutation, G719X , L861Q or S768I mutations or exon 19 insertion) - Presence of at least one lesion that can be measured - PS 0 or 1 Principal Exclusion Criteria: - Symptomatic brain metastasis or requiring immediate radiotherapy - T790M mutation or exon 20 insertion - Radiotherapy less than 2 weeks prior randomization including symptomatic radiotherapy - Interstitial pneumopathy Principal Inclusion Criteria: - Stage III or IV NSCLC, non irradiable non operable - Non squamous NSCLC histologically or cytologically confirmed - No previous treatment of NSCLC - EGFR mutation (exon 19 deletion, L858R mutation, G719X , L861Q or S768I mutations or exon 19 insertion) - Presence of at least one lesion that can be measured - PS 0 or 1 Principal Exclusion Criteria: - Symptomatic brain metastasis or requiring immediate radiotherapy - T790M mutation or exon 20 insertion - Radiotherapy less than 2 weeks prior randomization including symptomatic radiotherapy - Interstitial pneumopathy Non Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- L858R --- --- L861Q --- --- S768I --- --- T790M ---

Principal Inclusion Criteria: - Stage III or IV NSCLC, non irradiable non operable - Non squamous NSCLC histologically or cytologically confirmed - No previous treatment of NSCLC - EGFR mutation (exon 19 deletion, L858R mutation, G719X , L861Q or S768I mutations or exon 19 insertion) - Presence of at least one lesion that can be measured - PS 0 or 1 Principal Exclusion Criteria: - Symptomatic brain metastasis or requiring immediate radiotherapy - T790M mutation or exon 20 insertion - Radiotherapy less than 2 weeks prior randomization including symptomatic radiotherapy - Interstitial pneumopathy Principal Inclusion Criteria: - Stage III or IV NSCLC, non irradiable non operable - Non squamous NSCLC histologically or cytologically confirmed - No previous treatment of NSCLC - EGFR mutation (exon 19 deletion, L858R mutation, G719X , L861Q or S768I mutations or exon 19 insertion) - Presence of at least one lesion that can be measured - PS 0 or 1 Principal Exclusion Criteria: - Symptomatic brain metastasis or requiring immediate radiotherapy - T790M mutation or exon 20 insertion - Radiotherapy less than 2 weeks prior randomization including symptomatic radiotherapy - Interstitial pneumopathy Non Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- L858R --- --- L861Q --- --- S768I --- --- T790M --- --- L858R --- --- L861Q --- --- S768I --- --- T790M ---

Primary Outcomes

Measure: Time to Treatment Failure

Time: 9 months

Secondary Outcomes

Measure: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

Time: 1 month

Measure: Response Rate

Time: 9 months

Measure: Overall survival

Time: 6 months

Measure: Overall survival

Time: 9 months

Measure: Overall survival

Time: 12 months

Measure: Progression-Free Survival

Time: 6 months

Measure: Progression-Free Survival

Time: 9 months

Measure: Progression-Free Survival

Time: 12 months

Measure: Progression-Free Survival

Time: 18 months

291 A Phase 1/2 Study of the Safety, Pharmacokinetics, and Anti-Tumor Activity of the Oral EGFR/HER2 Inhibitor TAK-788 (AP32788) in Non-Small Cell Lung Cancer

The purpose of this phase 1/2 study is to evaluate the safety, recommended phase 2 dose (RP2D), dose limiting toxicities (DLTs), maximum tolerated dose (MTD), pharmacokinetics of oral TAK-788 and its active metabolites, anti-tumor activity of TAK-788 in participants with NSCLC with epidermal growth factor receptor (EGFR) or human epidermal growth factor 2 (HER2) mutations, explore relationship between tumor and/or plasma biomarkers and TAK-788 efficacy, safety, and/or cytochrome P450 (CYP) 3A induction (in Part 1 [Dose Escalation Component] and Part 2 [Expansion Cohorts] for oral TAK-788) and (in Part 1A [Dose Escalation Combination Component] when TAK-788 is taken in combination with pemetrexed/carboplatin), and anti-tumor activity of TAK-788 in participants with solid tumors other than NSCLC with EGFR or HER2 mutations in Parts 1 and 2.

NCT02716116
Conditions
  1. Carcin
  2. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Drug: TAK-788
  2. Drug: Pemetrexed
  3. Drug: Carboplatin
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Part 2: Expansion Cohort 4 Specific Inclusion Criteria: 1. Have one of the following documented by a local test: an activating mutation in EGFR including exon 19 deletions or exon 21 L858R substitution (with or without T790M), or an uncommon activating mutation other than exon 20 insertion including, but not limited to, G719X (where X is any other amino acid), S768I, L861Q, or L861R. --- L858R --- --- T790M ---

The seven expansion cohorts will be: 1. NSCLC participants with EGFR exon 20 activating insertions, who have either not received or not shown an objective response to an EGFR TKI, and who have no active, measurable CNS metastases; 2. NSCLC participants with HER2 exon 20 activating insertions or point mutations and no active, measurable CNS metastases; 3. NSCLC participants with EGFR exon 20 activating insertions or HER2 exon 20 activating insertions or point mutations and active, measurable CNS metastases; 4. NSCLC participants with other targets against which TAK-788 is active (examples include EGFR exon 19 deletions or exon 21 substitutions [with or without T790M mutations] and other uncommon EGFR activating mutations), without active CNS metastases; 5. NSCLC participants with EGFR exon 20 activating insertions, who have previously shown an objective response to an EGFR TKI and subsequently progressed, without active CNS metastases; 6. NSCLC participants with EGFR exon 20 activating insertions, who have not received prior systemic anticancer treatment for locally advanced or metastatic disease, without active CNS metastases; and 7. Participants with solid tumors other than NSCLC with EGFR/HER2 mutations against which TAK-788 is active, without active CNS metastases. --- T790M ---

Primary Outcomes

Measure: Part 1, Dose Escalation Component: RP2D of Orally Administered TAK-788

Time: Cycle 1 (Cycle length is equal to [=] 28 days)

Description: This outcome measure for Part 1A (dose escalation combination component) is specific to only selected sites in the United States.

Measure: Part 1A, Dose Escalation Combination Component: RP2D/MTD of Orally Administered TAK 788 in Combination With Pemetrexed/ Carboplatin

Time: Up to Cycle 2 (Cycle length=21 days)

Description: This outcome measure for Part 1A (dose escalation combination component) is specific to only selected sites in the United States.

Measure: Part 1A, Dose Escalation Combination Component: Identify DLTs of Orally Administered TAK 788 in Combination With Pemetrexed/ Carboplatin

Time: Up to Cycle 2 (Cycle length=21 days)

Measure: Part 2, Expansion Cohorts 1, 2, 4, 5 and 7: Confirmed Objective Response Rate (ORR) Assessed by the Investigator

Time: Up to 36 months after first dose

Measure: Part 2, Expansion Cohort 3: Intracranial ORR (iORR) Assessed by Independent Review Committee (IRC)

Time: Up to 36 months after first dose

Measure: Part 2, Expansion Cohort 6: Confirmed ORR Assessed by IRC

Time: Up to 36 months after first dose

Measure: Part 3, Extension Cohort: Confirmed ORR Assessed by IRC

Time: Up to 36 months after first dose

Secondary Outcomes

Description: This outcome measure for Part 1A (dose escalation combination component) is specific to only selected sites in the United States.

Measure: Parts 1, 1A and 2, Dose Escalation and Expansion Cohorts: Safety Analysis of TAK-788 and when TAK-788 Given in Combination With Pemetrexed/ Carboplatin Assessed by Adverse Events, Toxicity Grades, and Laboratory Test Results

Time: Up to 36 months after first dose

Measure: Part 1, Dose Escalation Component: Identify DLTs and MTD of TAK-788

Time: Cycle 1 (Cycle length=28 days)

Description: This outcome measure for Part 1A (dose escalation combination component) is specific to only selected sites in the United States.

Measure: Parts 1, 1A and 2, Dose Escalation and Expansion Cohorts: Cmax; Maximum Observed Concentration of TAK-788 and its Metabolites

Time: Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days for Parts 1 and 2, and 21 days for Part 1A)

Description: This outcome measure for Part 1A (dose escalation combination component) is specific to only selected sites in the United States.

Measure: Parts 1, 1A and 2, Dose Escalation and Expansion Cohorts: Tmax; Time of First Occurrence of Maximum Plasma Concentration (Cmax) of TAK-788 and its Metabolites

Time: Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days for Parts 1 and 2, and 21 days for Part 1A)

Description: This outcome measure for Part 1A (dose escalation combination component) is specific to only selected sites in the United States.

Measure: Parts 1, 1A and 2, Dose Escalation and Expansion Cohorts: AUC 24; Area Under the Concentration-time Curve from Time Zero to 24 hours for TAK-788 and its Metabolites

Time: Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days for Parts 1 and 2, and 21 days for Part 1A)

Description: This outcome measure for Part 1A (dose escalation combination component) is specific to only selected sites in the United States.

Measure: Parts 1, 1A and 2, Dose Escalation and Expansion Cohorts: AUCt: Area Under the Concentration-time Curve from Time Zero to Time t for TAK-788 and its Metabolites

Time: Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days for Parts 1 and 2, and 21 days for Part 1A)

Description: This outcome measure for Part 1A (dose escalation combination component) is specific to only selected sites in the United States.

Measure: Parts 1, 1A and 2, Dose Escalation and Expansion Cohorts: RAC (Cmax): Accumulation Ratio Based on Cmax of TAK-788 and its Metabolites

Time: Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days for Parts 1 and 2, and 21 days for Part 1A)

Description: This outcome measure for Part 1A (dose escalation combination component) is specific to only selected sites in the United States.

Measure: Parts 1, 1A and 2, Dose Escalation and Expansion Cohorts: RAC (AUC): Accumulation Ratio Based on AUC of TAK-788 and its Metabolites

Time: Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days for Parts 1 and 2, and 21 days for Part 1A)

Description: This outcome measure for Part 1A (dose escalation combination component) is specific to only selected sites in the United States.

Measure: Parts 1, 1A and 2, Dose Escalation and Expansion Cohorts: Cmax: Dose Proportionality for TAK-788 Exposure

Time: Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days for Parts 1 and 2, and 21 days for Part 1A)

Description: This outcome measure for Part 1A (dose escalation combination component) is specific to only selected sites in the United States.

Measure: Parts 1, 1A and 2, Dose Escalation and Expansion Cohorts: AUC: Dose Proportionality for TAK-788 Exposure

Time: Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days for Parts 1 and 2, and 21 days for Part 1A)

Measure: Part 2, Expansion Cohorts 1, 2, 3, 4, 5, and 7: Confirmed ORR as Assessed by IRC

Time: Up to 36 months after first dose

Measure: Part 2, Expansion Cohorts: Best Overall Response as Assessed by the Investigator and IRC

Time: Up to 36 months after first dose

Measure: Part 2, Expansion Cohorts: Best Target Lesion Response as Assessed by the Investigator and IRC

Time: Up to 36 months after first dose

Measure: Parts 2 and 3, Expansion and Extension Cohorts: Duration of Response as Assessed by the Investigator and IRC

Time: Up to 36 months after first dose

Measure: Part 2 and 3, Expansion and Extension Cohorts: Time to Response as Assessed by the Investigator and IRC

Time: Up to 36 months after first dose

Measure: Part 2, Expansion Cohort 3: Duration of Intracranial Response (iDOR)

Time: up to 36 months after first dose

Measure: Parts 2 and 3, Expansion and Extension Cohorts: Disease Control Rate (DCR) as Assessed by the Investigator and IRC

Time: Up to 36 months after first dose

Measure: Parts 2 and 3, Expansion and Extension Cohorts: Progression Free Survival (PFS) as Assessed by the Investigator and IRC

Time: Up to 36 months after first dose

Measure: Part 2, Expansion Cohort 3: Intracranial PFS (iPFS)

Time: up to 36 months after first dose

Measure: Parts 2 and 3, Expansion and Extension Cohorts: Overall Survival (OS)

Time: Up to 36 months after first dose

Measure: Part 2, Expansion Cohorts 6: Confirmed ORR as Assessed by the Investigator

Time: Up to 36 months after first dose

Measure: Part 3, Extension Cohort: Confirmed ORR as Assessed by the Investigator

Time: Up to 36 months after first dose

Measure: Part 3, Number of Participants With Patient-reported Symptoms (Lung Cancer), Functioning, and Health-related Quality of Life (HRQoL) Based on European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-core 30 (EORTC QLQ-C30)

Time: Up to 30 days after last dose of drug (approximately up to 37 months)

Measure: Part 3, Number of Participants With Patient-reported Symptoms (Lung Cancer), Functioning, and health-related Global Quality of Life (HRQoL) Based on Quality of Life Questionnaire Lung Cancer Module-13 (QLQ-LC13)

Time: Up to 30 days after last dose of drug (approximately up to 37 months)

292 Understanding Mechanisms of Acquired Resistance to BIBW2992

In this research study we are looking to see how effective BIBW 2992 is at suppressing the development of the T790M mutation in non-small cell lung cancer (NSCLC) patients. Epidermal growth factor receptors (EGFR) are proteins found on the surface of some cancer cells that promote a growth signal. Some cancer drugs for NSCLC work to block this signal from reaching its target on the cancer cells which in turn may slow or stop the cancer from growing. However, many times patients with EGFR mutations will stop responding to these cancer drugs and develop drug-resistance because they have developed a specific EGFR mutation called T790M. BIBW 2992 may prevent the T790M mutation from becoming active and therefore slow disease progression.

NCT01074177
Conditions
  1. Non-small Cell Lung Cancer
  2. EGFR Mutations
Interventions
  1. Drug: BIBW 2992
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Understanding Mechanisms of Acquired Resistance to BIBW2992 In this research study we are looking to see how effective BIBW 2992 is at suppressing the development of the T790M mutation in non-small cell lung cancer (NSCLC) patients. --- T790M ---

However, many times patients with EGFR mutations will stop responding to these cancer drugs and develop drug-resistance because they have developed a specific EGFR mutation called T790M. --- T790M ---

BIBW 2992 may prevent the T790M mutation from becoming active and therefore slow disease progression. --- T790M ---

Number of Participants That Have a T790M Mutation on Their Progression Biopsy.. null. --- T790M ---

The purpose of this biopsy is to assess for the presence or the absence of the mutation T790M. --- T790M ---

Primary Outcomes

Measure: Number of Participants That Have a T790M Mutation on Their Progression Biopsy.

Time: At the time of disease progression (median duration of 11.4 months from start of treatment)

Secondary Outcomes

Description: The number of participants with either a complete response (CR) or partial response (PR) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST v1.1) CR: Disappearance of all target lesions. Any pathological lymph node must have reduction in short axis to < 10 mm PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

Measure: Response Rate

Time: Baseline and then after the end of every two 28 day cycles until treatment is discontinued; median duration of followup of 19.3 months

Description: The progression-free and overall survival times. Overall survival is measured from the start of treatment until the time of death or until the participant is lost to follow-up. Progression free survival is measured from the start of treatment until the time of progression, death, or until the participant is lost to follow-up (whichever occurs first). Progression is defined as having at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study with at least a 5 mm absolute increase in the sum of all lesions. The appearance of one or more new lesions denotes disease progression.

Measure: Median Progression-free and Overall Survival

Time: start of treatment, at the time of disease progression, time of death

Description: The number of participants with biopsy complications from repeat tumor biopsies taken following disease progression. Biopsy complications are any adverse events considered to be potentially related to the biopsy.

Measure: Number of Participants With Biopsy Complications From Repeat Tumor Biopsies

Time: 7 days post biopsy and ≥ 30 days post-biopsy

293 A Phase III, Open-Label, Randomized Multicenter Study to Compare AC0010 and Pemetrexed/Cisplatin in Patients With Advanced NSCLC Who Have Progressed Following Prior EGFR TKI

A Phase III, Open-Label, Randomized Multicenter Study to Compare AC0010 and Pemetrexed/Cisplatin in Patients With Advanced NSCLC Who Have Progressed Following Prior EGFR TKI.

NCT03058094
Conditions
  1. NSCLC
Interventions
  1. Drug: Pemetrexed
  2. Drug: Cisplatin 75mg/m2
  3. Drug: AC0010
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

To assess the Progression-Free Survival (PFS) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).. Objective Response Rate (ORR). --- T790M ---

To assess the overall objective response rate (ORR) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).. Duration of Response (DoR). --- T790M ---

To assess the overall objective response rate (ORR) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).. Disease Control Rate (DCR). --- T790M ---

To assess the Disease Control Rate (DCR) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).. Overall Survival (OS). --- T790M ---

To assess the Overall Survival (OS) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).. Patient Reported Outcomes by EORTC QLQ-C30 Questionnaire. --- T790M ---

To assess the safety of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).. Incidence of toxicity, grading with CTCAE 4.03. --- T790M ---

7. Confirmation of tumor harboring of T790M mutation by central lab with a biopsy sample taken after failure of first generation EGFR TKIs. --- T790M ---

Patients must provide a biopsy for central confirmation of T790M mutation positive. --- T790M ---

Primary Outcomes

Description: To assess the Progression-Free Survival (PFS) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).

Measure: Progression-Free Survival (PFS)

Time: From the date of randomization until the date of first documented progression or the date of death from any cause, whichever came first, assessed up to 24 months.

Secondary Outcomes

Description: To assess the overall objective response rate (ORR) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).

Measure: Objective Response Rate (ORR)

Time: Baseline up to 28 days after completion of study drug, assessed up to 24 months.

Description: To assess the overall objective response rate (ORR) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).

Measure: Duration of Response (DoR)

Time: From occurring of CR or PR until progression or the date of death from any cause, whichever came first, assessed up to 24 months.

Description: To assess the Disease Control Rate (DCR) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).

Measure: Disease Control Rate (DCR)

Time: From the date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months.

Description: To assess the Overall Survival (OS) of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).

Measure: Overall Survival (OS)

Time: From the date of randomization to death or end of study, which is assessed up to 36 months.

Description: To assess the safety of AC0010 in EGFR T790M mutation-positive patients with advanced non-small cell lung cancer (NSCLC).

Measure: Patient Reported Outcomes by EORTC QLQ-C30 Questionnaire

Time: Baseline up to 28 days after completion of study drug, assessed up to 24 months.

Other Outcomes

Description: Clinical chemistry, hematology, urinalysis, vital signs, physical examination, weight, ECG and ECOG Performance status and adverse event will be used to assess safety endpoints.

Measure: Incidence of toxicity, grading with CTCAE 4.03

Time: From the date of randomization until end of treatment,which is assessed up to 24 months

294 An Open-Label, Non-Randomized, Single-Center Study to Preliminary Evaluation of Safety and Efficacy of Patients Who Participant in [14C] AC0010 Trail and Subsequent Receiving AC0010 Treatment

The purpose of this study is to evaluate safety and efficacy of male Patients With Advanced NSCLC who participant in [14C] AC0010 ADME.

NCT03053219
Conditions
  1. Carcinoma,Non-Small-Cell Lung
Interventions
  1. Drug: AC0010
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

To assess the overall Objective Response Rate(ORR) of AC0010 in EGFR T790M mutation-positive patients with advanced NSCLC.. Progression Free Survival. --- T790M ---

To assess the Progression Free Survival(PFS) of AC0010 in EGFR T790M mutation-positive patients with advanced NSCLC.. Disease control rate. --- T790M ---

To assess the Disease control rate(DCR) of AC0010 in EGFR T790M mutation-positive patients with advanced NSCLC.. Number of adverse events (AE) experienced by patients to assess safety. --- T790M ---

To assess the safety of AC0010 in EGFR T790M mutation-positive patients with advanced NSCLC.. Inclusion Criteria: - signed and dated informed consent - histologically or cytologically confirmed diagnosis of local advanced or recurrent NSCLC - failed to the treatment of EGFR-TKI and harbored T790M mutation - male, Age 18~ 65, have a body mass index (BMI)>19 kg/m2 - Eastern Cooperative Oncology Group performance status(ECOG PS):0-1,Life expectancy of more than 3 months - main organs function is normal, laboratory values as listed below: blood test without blood transfusion within 14 days 1. Haemoglobin >100 g/L 2. Absolute neutrophil count ≥2.0x10^9/L or WBC ≥3.5 x10^9/L 3. Platelet count ≥ 80x10^9/L 4. Total bilirubin ≤1.5xULN 5. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 2.5 times upper limit of normal (ULN) 6. Serum creatinine ≤1.5xULN or creatinine clearance ratio ≥60 mL/ min - Any prior treatment (chemotherapy, radiotherapy or surgery) must be completed over 4 weeks(target therapy over 2 weeks) from the screening; Patients must have recovered from all toxicities related to prior anticancer therapies to grade ≤ 1 (CTCAE v 4.03) - International normalized ratio (INR) ≤ 1.5 - Patients and their partners should be willing to use methods of contraception or total abstinence from start of dosing until 6 months after discontinuing of study treatment - Patients must withdraw from previous study of [14C] AC0010 Exclusion Criteria: - Prior treated with AC0010 or allergic to drug or its formulation ingredients - Patients receiving other anti-tumor therapy - Impairment of GI disease, renal disorders or liver disease that may significantly alter the absorption and metabolic of AC0010 (e.g., Unable to swallow, liver, kidney or gastrointestinal partial resection, chronic diarrhea and intestinal obstruction) - HCVAb positive, active hepatitis B (excluding HBV carriers), Hepatitis virus markers positive and receiving anti-virus drugs - Meningeal metastasis; brain metastasis with whole brain radiotherapy; prior received hormones or mannitol for the brain metastasis - Previous EGFR-TKI treatment related Interstitial lung disease history - Known human immunodeficiency virus infection (HIV), other acquired or congenital immunodeficiency disease, or a history of organ transplantation - Any severe and / or uncontrolled active infections - Patients receiving concomitant immunosuppressive agents or high-dose corticosteroids - Any severe and / or uncontrolled medical conditions - Patients being treated with drugs recognized as being inhibitors or inducers of the liver isoenzyme in the last 4 weeks prior to registration in the current study - Within 3 days prior to the treatment taking of dragon fruit, pomelo, grapefruit, orange, mango and other fruit may affect drug metabolizing enzymes or juice - Major surgery, incisional biopsy or traumatic injuries; - Within 4 weeks prior to the screening patients with bleeding ≥ grade 3, non-healing wound, sever ulcer or bone fracture - Patients received high dose irradiation treatment or other 14C-labeled drug within 1 year - Known a history of alcoholism or drug abuse - Investigator judgment that patient is unsuitable to participate in study Inclusion Criteria: - signed and dated informed consent - histologically or cytologically confirmed diagnosis of local advanced or recurrent NSCLC - failed to the treatment of EGFR-TKI and harbored T790M mutation - male, Age 18~ 65, have a body mass index (BMI)>19 kg/m2 - Eastern Cooperative Oncology Group performance status(ECOG PS):0-1,Life expectancy of more than 3 months - main organs function is normal, laboratory values as listed below: blood test without blood transfusion within 14 days 1. Haemoglobin >100 g/L 2. Absolute neutrophil count ≥2.0x10^9/L or WBC ≥3.5 x10^9/L 3. Platelet count ≥ 80x10^9/L 4. Total bilirubin ≤1.5xULN 5. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 2.5 times upper limit of normal (ULN) 6. Serum creatinine ≤1.5xULN or creatinine clearance ratio ≥60 mL/ min - Any prior treatment (chemotherapy, radiotherapy or surgery) must be completed over 4 weeks(target therapy over 2 weeks) from the screening; Patients must have recovered from all toxicities related to prior anticancer therapies to grade ≤ 1 (CTCAE v 4.03) - International normalized ratio (INR) ≤ 1.5 - Patients and their partners should be willing to use methods of contraception or total abstinence from start of dosing until 6 months after discontinuing of study treatment - Patients must withdraw from previous study of [14C] AC0010 Exclusion Criteria: - Prior treated with AC0010 or allergic to drug or its formulation ingredients - Patients receiving other anti-tumor therapy - Impairment of GI disease, renal disorders or liver disease that may significantly alter the absorption and metabolic of AC0010 (e.g., Unable to swallow, liver, kidney or gastrointestinal partial resection, chronic diarrhea and intestinal obstruction) - HCVAb positive, active hepatitis B (excluding HBV carriers), Hepatitis virus markers positive and receiving anti-virus drugs - Meningeal metastasis; brain metastasis with whole brain radiotherapy; prior received hormones or mannitol for the brain metastasis - Previous EGFR-TKI treatment related Interstitial lung disease history - Known human immunodeficiency virus infection (HIV), other acquired or congenital immunodeficiency disease, or a history of organ transplantation - Any severe and / or uncontrolled active infections - Patients receiving concomitant immunosuppressive agents or high-dose corticosteroids - Any severe and / or uncontrolled medical conditions - Patients being treated with drugs recognized as being inhibitors or inducers of the liver isoenzyme in the last 4 weeks prior to registration in the current study - Within 3 days prior to the treatment taking of dragon fruit, pomelo, grapefruit, orange, mango and other fruit may affect drug metabolizing enzymes or juice - Major surgery, incisional biopsy or traumatic injuries; - Within 4 weeks prior to the screening patients with bleeding ≥ grade 3, non-healing wound, sever ulcer or bone fracture - Patients received high dose irradiation treatment or other 14C-labeled drug within 1 year - Known a history of alcoholism or drug abuse - Investigator judgment that patient is unsuitable to participate in study Carcinoma,Non-Small-Cell Lung Carcinoma, Non-Small-Cell Lung The purpose of this study is to evaluate safety and efficacy of male Patients With Advanced NSCLC who participant in [14C] AC0010 ADME (absorption, distribution, metabolism and excretion) trial and subsequent receiving AC0010 treatment. --- T790M ---

To assess the safety of AC0010 in EGFR T790M mutation-positive patients with advanced NSCLC.. Inclusion Criteria: - signed and dated informed consent - histologically or cytologically confirmed diagnosis of local advanced or recurrent NSCLC - failed to the treatment of EGFR-TKI and harbored T790M mutation - male, Age 18~ 65, have a body mass index (BMI)>19 kg/m2 - Eastern Cooperative Oncology Group performance status(ECOG PS):0-1,Life expectancy of more than 3 months - main organs function is normal, laboratory values as listed below: blood test without blood transfusion within 14 days 1. Haemoglobin >100 g/L 2. Absolute neutrophil count ≥2.0x10^9/L or WBC ≥3.5 x10^9/L 3. Platelet count ≥ 80x10^9/L 4. Total bilirubin ≤1.5xULN 5. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 2.5 times upper limit of normal (ULN) 6. Serum creatinine ≤1.5xULN or creatinine clearance ratio ≥60 mL/ min - Any prior treatment (chemotherapy, radiotherapy or surgery) must be completed over 4 weeks(target therapy over 2 weeks) from the screening; Patients must have recovered from all toxicities related to prior anticancer therapies to grade ≤ 1 (CTCAE v 4.03) - International normalized ratio (INR) ≤ 1.5 - Patients and their partners should be willing to use methods of contraception or total abstinence from start of dosing until 6 months after discontinuing of study treatment - Patients must withdraw from previous study of [14C] AC0010 Exclusion Criteria: - Prior treated with AC0010 or allergic to drug or its formulation ingredients - Patients receiving other anti-tumor therapy - Impairment of GI disease, renal disorders or liver disease that may significantly alter the absorption and metabolic of AC0010 (e.g., Unable to swallow, liver, kidney or gastrointestinal partial resection, chronic diarrhea and intestinal obstruction) - HCVAb positive, active hepatitis B (excluding HBV carriers), Hepatitis virus markers positive and receiving anti-virus drugs - Meningeal metastasis; brain metastasis with whole brain radiotherapy; prior received hormones or mannitol for the brain metastasis - Previous EGFR-TKI treatment related Interstitial lung disease history - Known human immunodeficiency virus infection (HIV), other acquired or congenital immunodeficiency disease, or a history of organ transplantation - Any severe and / or uncontrolled active infections - Patients receiving concomitant immunosuppressive agents or high-dose corticosteroids - Any severe and / or uncontrolled medical conditions - Patients being treated with drugs recognized as being inhibitors or inducers of the liver isoenzyme in the last 4 weeks prior to registration in the current study - Within 3 days prior to the treatment taking of dragon fruit, pomelo, grapefruit, orange, mango and other fruit may affect drug metabolizing enzymes or juice - Major surgery, incisional biopsy or traumatic injuries; - Within 4 weeks prior to the screening patients with bleeding ≥ grade 3, non-healing wound, sever ulcer or bone fracture - Patients received high dose irradiation treatment or other 14C-labeled drug within 1 year - Known a history of alcoholism or drug abuse - Investigator judgment that patient is unsuitable to participate in study Inclusion Criteria: - signed and dated informed consent - histologically or cytologically confirmed diagnosis of local advanced or recurrent NSCLC - failed to the treatment of EGFR-TKI and harbored T790M mutation - male, Age 18~ 65, have a body mass index (BMI)>19 kg/m2 - Eastern Cooperative Oncology Group performance status(ECOG PS):0-1,Life expectancy of more than 3 months - main organs function is normal, laboratory values as listed below: blood test without blood transfusion within 14 days 1. Haemoglobin >100 g/L 2. Absolute neutrophil count ≥2.0x10^9/L or WBC ≥3.5 x10^9/L 3. Platelet count ≥ 80x10^9/L 4. Total bilirubin ≤1.5xULN 5. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 2.5 times upper limit of normal (ULN) 6. Serum creatinine ≤1.5xULN or creatinine clearance ratio ≥60 mL/ min - Any prior treatment (chemotherapy, radiotherapy or surgery) must be completed over 4 weeks(target therapy over 2 weeks) from the screening; Patients must have recovered from all toxicities related to prior anticancer therapies to grade ≤ 1 (CTCAE v 4.03) - International normalized ratio (INR) ≤ 1.5 - Patients and their partners should be willing to use methods of contraception or total abstinence from start of dosing until 6 months after discontinuing of study treatment - Patients must withdraw from previous study of [14C] AC0010 Exclusion Criteria: - Prior treated with AC0010 or allergic to drug or its formulation ingredients - Patients receiving other anti-tumor therapy - Impairment of GI disease, renal disorders or liver disease that may significantly alter the absorption and metabolic of AC0010 (e.g., Unable to swallow, liver, kidney or gastrointestinal partial resection, chronic diarrhea and intestinal obstruction) - HCVAb positive, active hepatitis B (excluding HBV carriers), Hepatitis virus markers positive and receiving anti-virus drugs - Meningeal metastasis; brain metastasis with whole brain radiotherapy; prior received hormones or mannitol for the brain metastasis - Previous EGFR-TKI treatment related Interstitial lung disease history - Known human immunodeficiency virus infection (HIV), other acquired or congenital immunodeficiency disease, or a history of organ transplantation - Any severe and / or uncontrolled active infections - Patients receiving concomitant immunosuppressive agents or high-dose corticosteroids - Any severe and / or uncontrolled medical conditions - Patients being treated with drugs recognized as being inhibitors or inducers of the liver isoenzyme in the last 4 weeks prior to registration in the current study - Within 3 days prior to the treatment taking of dragon fruit, pomelo, grapefruit, orange, mango and other fruit may affect drug metabolizing enzymes or juice - Major surgery, incisional biopsy or traumatic injuries; - Within 4 weeks prior to the screening patients with bleeding ≥ grade 3, non-healing wound, sever ulcer or bone fracture - Patients received high dose irradiation treatment or other 14C-labeled drug within 1 year - Known a history of alcoholism or drug abuse - Investigator judgment that patient is unsuitable to participate in study Carcinoma,Non-Small-Cell Lung Carcinoma, Non-Small-Cell Lung The purpose of this study is to evaluate safety and efficacy of male Patients With Advanced NSCLC who participant in [14C] AC0010 ADME (absorption, distribution, metabolism and excretion) trial and subsequent receiving AC0010 treatment. --- T790M --- --- T790M ---

To assess the safety of AC0010 in EGFR T790M mutation-positive patients with advanced NSCLC.. Inclusion Criteria: - signed and dated informed consent - histologically or cytologically confirmed diagnosis of local advanced or recurrent NSCLC - failed to the treatment of EGFR-TKI and harbored T790M mutation - male, Age 18~ 65, have a body mass index (BMI)>19 kg/m2 - Eastern Cooperative Oncology Group performance status(ECOG PS):0-1,Life expectancy of more than 3 months - main organs function is normal, laboratory values as listed below: blood test without blood transfusion within 14 days 1. Haemoglobin >100 g/L 2. Absolute neutrophil count ≥2.0x10^9/L or WBC ≥3.5 x10^9/L 3. Platelet count ≥ 80x10^9/L 4. Total bilirubin ≤1.5xULN 5. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 2.5 times upper limit of normal (ULN) 6. Serum creatinine ≤1.5xULN or creatinine clearance ratio ≥60 mL/ min - Any prior treatment (chemotherapy, radiotherapy or surgery) must be completed over 4 weeks(target therapy over 2 weeks) from the screening; Patients must have recovered from all toxicities related to prior anticancer therapies to grade ≤ 1 (CTCAE v 4.03) - International normalized ratio (INR) ≤ 1.5 - Patients and their partners should be willing to use methods of contraception or total abstinence from start of dosing until 6 months after discontinuing of study treatment - Patients must withdraw from previous study of [14C] AC0010 Exclusion Criteria: - Prior treated with AC0010 or allergic to drug or its formulation ingredients - Patients receiving other anti-tumor therapy - Impairment of GI disease, renal disorders or liver disease that may significantly alter the absorption and metabolic of AC0010 (e.g., Unable to swallow, liver, kidney or gastrointestinal partial resection, chronic diarrhea and intestinal obstruction) - HCVAb positive, active hepatitis B (excluding HBV carriers), Hepatitis virus markers positive and receiving anti-virus drugs - Meningeal metastasis; brain metastasis with whole brain radiotherapy; prior received hormones or mannitol for the brain metastasis - Previous EGFR-TKI treatment related Interstitial lung disease history - Known human immunodeficiency virus infection (HIV), other acquired or congenital immunodeficiency disease, or a history of organ transplantation - Any severe and / or uncontrolled active infections - Patients receiving concomitant immunosuppressive agents or high-dose corticosteroids - Any severe and / or uncontrolled medical conditions - Patients being treated with drugs recognized as being inhibitors or inducers of the liver isoenzyme in the last 4 weeks prior to registration in the current study - Within 3 days prior to the treatment taking of dragon fruit, pomelo, grapefruit, orange, mango and other fruit may affect drug metabolizing enzymes or juice - Major surgery, incisional biopsy or traumatic injuries; - Within 4 weeks prior to the screening patients with bleeding ≥ grade 3, non-healing wound, sever ulcer or bone fracture - Patients received high dose irradiation treatment or other 14C-labeled drug within 1 year - Known a history of alcoholism or drug abuse - Investigator judgment that patient is unsuitable to participate in study Inclusion Criteria: - signed and dated informed consent - histologically or cytologically confirmed diagnosis of local advanced or recurrent NSCLC - failed to the treatment of EGFR-TKI and harbored T790M mutation - male, Age 18~ 65, have a body mass index (BMI)>19 kg/m2 - Eastern Cooperative Oncology Group performance status(ECOG PS):0-1,Life expectancy of more than 3 months - main organs function is normal, laboratory values as listed below: blood test without blood transfusion within 14 days 1. Haemoglobin >100 g/L 2. Absolute neutrophil count ≥2.0x10^9/L or WBC ≥3.5 x10^9/L 3. Platelet count ≥ 80x10^9/L 4. Total bilirubin ≤1.5xULN 5. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 2.5 times upper limit of normal (ULN) 6. Serum creatinine ≤1.5xULN or creatinine clearance ratio ≥60 mL/ min - Any prior treatment (chemotherapy, radiotherapy or surgery) must be completed over 4 weeks(target therapy over 2 weeks) from the screening; Patients must have recovered from all toxicities related to prior anticancer therapies to grade ≤ 1 (CTCAE v 4.03) - International normalized ratio (INR) ≤ 1.5 - Patients and their partners should be willing to use methods of contraception or total abstinence from start of dosing until 6 months after discontinuing of study treatment - Patients must withdraw from previous study of [14C] AC0010 Exclusion Criteria: - Prior treated with AC0010 or allergic to drug or its formulation ingredients - Patients receiving other anti-tumor therapy - Impairment of GI disease, renal disorders or liver disease that may significantly alter the absorption and metabolic of AC0010 (e.g., Unable to swallow, liver, kidney or gastrointestinal partial resection, chronic diarrhea and intestinal obstruction) - HCVAb positive, active hepatitis B (excluding HBV carriers), Hepatitis virus markers positive and receiving anti-virus drugs - Meningeal metastasis; brain metastasis with whole brain radiotherapy; prior received hormones or mannitol for the brain metastasis - Previous EGFR-TKI treatment related Interstitial lung disease history - Known human immunodeficiency virus infection (HIV), other acquired or congenital immunodeficiency disease, or a history of organ transplantation - Any severe and / or uncontrolled active infections - Patients receiving concomitant immunosuppressive agents or high-dose corticosteroids - Any severe and / or uncontrolled medical conditions - Patients being treated with drugs recognized as being inhibitors or inducers of the liver isoenzyme in the last 4 weeks prior to registration in the current study - Within 3 days prior to the treatment taking of dragon fruit, pomelo, grapefruit, orange, mango and other fruit may affect drug metabolizing enzymes or juice - Major surgery, incisional biopsy or traumatic injuries; - Within 4 weeks prior to the screening patients with bleeding ≥ grade 3, non-healing wound, sever ulcer or bone fracture - Patients received high dose irradiation treatment or other 14C-labeled drug within 1 year - Known a history of alcoholism or drug abuse - Investigator judgment that patient is unsuitable to participate in study Carcinoma,Non-Small-Cell Lung Carcinoma, Non-Small-Cell Lung The purpose of this study is to evaluate safety and efficacy of male Patients With Advanced NSCLC who participant in [14C] AC0010 ADME (absorption, distribution, metabolism and excretion) trial and subsequent receiving AC0010 treatment. --- T790M --- --- T790M --- --- T790M ---

Primary Outcomes

Description: To assess the overall Objective Response Rate(ORR) of AC0010 in EGFR T790M mutation-positive patients with advanced NSCLC.

Measure: Objective Response Rate

Time: RECIST tumour assessments every 6 weeks from first dose until objective disease progression, up to approximately 11 months

Secondary Outcomes

Description: To assess the Progression Free Survival(PFS) of AC0010 in EGFR T790M mutation-positive patients with advanced NSCLC.

Measure: Progression Free Survival

Time: RECIST tumour assessments every 6 weeks from first dose until objective disease progression, up to approximately 11 months

Description: To assess the Disease control rate(DCR) of AC0010 in EGFR T790M mutation-positive patients with advanced NSCLC.

Measure: Disease control rate

Time: RECIST tumour assessments every 6 weeks from first dose until objective disease progression, up to approximately 11 months

Description: To assess the safety of AC0010 in EGFR T790M mutation-positive patients with advanced NSCLC.

Measure: Number of adverse events (AE) experienced by patients to assess safety

Time: From date of Signed informed consent forms until 30 days after disease progression, intolerable toxicity or withdrawal from study, approximately up to 18 months)

295 Phase I Trial of Combination Afatinib and Necitumumab in EGFR Mutation Positive NSCLC With Acquired Resistance to First or Third Generation EGFR TKIs

This phase I trial studies the side effects and best dose of afatinib and necitumumab and to see how well they work in treating patients with EGFR mutation positive non-small cell lung cancer that has spread to other places in the body. Afatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as necitumumab, may interfere with the ability of tumor cells to grow and spread. Giving afatinib and necitumumab may work better in treating patients with EGFR mutation positive non-small cell lung cancer.

NCT03054038
Conditions
  1. Non-Small Cell Lung Carcinoma
Interventions
  1. Drug: Afatinib
  2. Biological: Necitumumab
  3. Other: Laboratory Biomarker Analysis
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Inclusion Criteria: - Signed and dated written informed consent - Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 - Histologically or cytologically-confirmed advanced or metastatic non-small cell lung cancer (NSCLC) that is EGFR mutation positive; rare sensitizing mutations allowed - Progression on a first generation EGFR TKI (T790M negative), or progression on a third generation TKI (if T790M positive at time of progression on a first or second generation TKI) - At least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 that can be followed by computed tomography (CT) or magnetic resonance imaging (MRI) - Patient consents to undergo a medically safe tumor biopsy at time of disease progression for mutation analysis - Leukocytes >= 3,000/uL - Absolute neutrophil count (ANC) >= 1,500/uL - Platelets >= 100,000/uL - Hemoglobin >= 9 g/dL - Serum albumin >= 2.5 g/dL - Calculated creatinine clearance > 50 mL/min (per the Cockcroft-Gault formula) - Total bilirubin =< 1.5 times upper limit of normal (ULN) - Alkaline phosphatase (ALP) =< 3.0 x ULN - Alanine aminotransferase (ALT) and aspartate transaminase (AST) =< 3.0 x ULN; for patients with hepatic metastases, ALT and AST =< 5.0 x ULN are acceptable * Note: if a patient experiences elevated ALT > 5 x ULN and elevated total bilirubin > 2 x ULN, clinical and laboratory monitoring should be initiated by the investigator; for patients entering the study with ALT > 3 x ULN, monitoring should be triggered at ALT > 2 x baseline - Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 14 days prior to receiving first dose of study medication; and additionally agree to use at least two methods of birth control or abstain from heterosexual intercourse from the time of signing consent, and until 6 months after patient's last dose of study drug * WOCBP of childbearing potential are defined as those not surgically sterile or not post-menopausal (i.e. if a female patient has not had a bilateral tubal ligation, a bilateral oophorectomy, or a complete hysterectomy; or has not been amenorrheic for 24 months in the absence of an alternative medical cause, then patient will be considered a female of childbearing potential); postmenopausal status in females under 55 years of age should be confirmed with a serum follicle-stimulating hormone (FSH) level within laboratory reference range for postmenopausal women - WOCBP must agree to follow instructions for method(s) of contraception from the time of signing consent and until 6 months after last dose of study therapy - Men able to father children who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception from the time of signing consent and until 6 months after last dose of study therapy; men able to father children are defined as those who are not surgically sterile (i.e. --- T790M ---

Inclusion Criteria: - Signed and dated written informed consent - Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 - Histologically or cytologically-confirmed advanced or metastatic non-small cell lung cancer (NSCLC) that is EGFR mutation positive; rare sensitizing mutations allowed - Progression on a first generation EGFR TKI (T790M negative), or progression on a third generation TKI (if T790M positive at time of progression on a first or second generation TKI) - At least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 that can be followed by computed tomography (CT) or magnetic resonance imaging (MRI) - Patient consents to undergo a medically safe tumor biopsy at time of disease progression for mutation analysis - Leukocytes >= 3,000/uL - Absolute neutrophil count (ANC) >= 1,500/uL - Platelets >= 100,000/uL - Hemoglobin >= 9 g/dL - Serum albumin >= 2.5 g/dL - Calculated creatinine clearance > 50 mL/min (per the Cockcroft-Gault formula) - Total bilirubin =< 1.5 times upper limit of normal (ULN) - Alkaline phosphatase (ALP) =< 3.0 x ULN - Alanine aminotransferase (ALT) and aspartate transaminase (AST) =< 3.0 x ULN; for patients with hepatic metastases, ALT and AST =< 5.0 x ULN are acceptable * Note: if a patient experiences elevated ALT > 5 x ULN and elevated total bilirubin > 2 x ULN, clinical and laboratory monitoring should be initiated by the investigator; for patients entering the study with ALT > 3 x ULN, monitoring should be triggered at ALT > 2 x baseline - Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 14 days prior to receiving first dose of study medication; and additionally agree to use at least two methods of birth control or abstain from heterosexual intercourse from the time of signing consent, and until 6 months after patient's last dose of study drug * WOCBP of childbearing potential are defined as those not surgically sterile or not post-menopausal (i.e. if a female patient has not had a bilateral tubal ligation, a bilateral oophorectomy, or a complete hysterectomy; or has not been amenorrheic for 24 months in the absence of an alternative medical cause, then patient will be considered a female of childbearing potential); postmenopausal status in females under 55 years of age should be confirmed with a serum follicle-stimulating hormone (FSH) level within laboratory reference range for postmenopausal women - WOCBP must agree to follow instructions for method(s) of contraception from the time of signing consent and until 6 months after last dose of study therapy - Men able to father children who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception from the time of signing consent and until 6 months after last dose of study therapy; men able to father children are defined as those who are not surgically sterile (i.e. --- T790M --- --- T790M ---

infectious disease) illness - Any other serious or uncontrolled medical disorder, active infection, physical exam finding, laboratory finding, altered mental status, or psychiatric condition that, in the opinion of the investigator, would limit a subject's ability to comply with the study requirements, substantially increase risk to the subject, or impact the interpretability of study results Inclusion Criteria: - Signed and dated written informed consent - Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 - Histologically or cytologically-confirmed advanced or metastatic non-small cell lung cancer (NSCLC) that is EGFR mutation positive; rare sensitizing mutations allowed - Progression on a first generation EGFR TKI (T790M negative), or progression on a third generation TKI (if T790M positive at time of progression on a first or second generation TKI) - At least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 that can be followed by computed tomography (CT) or magnetic resonance imaging (MRI) - Patient consents to undergo a medically safe tumor biopsy at time of disease progression for mutation analysis - Leukocytes >= 3,000/uL - Absolute neutrophil count (ANC) >= 1,500/uL - Platelets >= 100,000/uL - Hemoglobin >= 9 g/dL - Serum albumin >= 2.5 g/dL - Calculated creatinine clearance > 50 mL/min (per the Cockcroft-Gault formula) - Total bilirubin =< 1.5 times upper limit of normal (ULN) - Alkaline phosphatase (ALP) =< 3.0 x ULN - Alanine aminotransferase (ALT) and aspartate transaminase (AST) =< 3.0 x ULN; for patients with hepatic metastases, ALT and AST =< 5.0 x ULN are acceptable * Note: if a patient experiences elevated ALT > 5 x ULN and elevated total bilirubin > 2 x ULN, clinical and laboratory monitoring should be initiated by the investigator; for patients entering the study with ALT > 3 x ULN, monitoring should be triggered at ALT > 2 x baseline - Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 14 days prior to receiving first dose of study medication; and additionally agree to use at least two methods of birth control or abstain from heterosexual intercourse from the time of signing consent, and until 6 months after patient's last dose of study drug * WOCBP of childbearing potential are defined as those not surgically sterile or not post-menopausal (i.e. if a female patient has not had a bilateral tubal ligation, a bilateral oophorectomy, or a complete hysterectomy; or has not been amenorrheic for 24 months in the absence of an alternative medical cause, then patient will be considered a female of childbearing potential); postmenopausal status in females under 55 years of age should be confirmed with a serum follicle-stimulating hormone (FSH) level within laboratory reference range for postmenopausal women - WOCBP must agree to follow instructions for method(s) of contraception from the time of signing consent and until 6 months after last dose of study therapy - Men able to father children who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception from the time of signing consent and until 6 months after last dose of study therapy; men able to father children are defined as those who are not surgically sterile (i.e. --- T790M ---

infectious disease) illness - Any other serious or uncontrolled medical disorder, active infection, physical exam finding, laboratory finding, altered mental status, or psychiatric condition that, in the opinion of the investigator, would limit a subject's ability to comply with the study requirements, substantially increase risk to the subject, or impact the interpretability of study results Inclusion Criteria: - Signed and dated written informed consent - Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 - Histologically or cytologically-confirmed advanced or metastatic non-small cell lung cancer (NSCLC) that is EGFR mutation positive; rare sensitizing mutations allowed - Progression on a first generation EGFR TKI (T790M negative), or progression on a third generation TKI (if T790M positive at time of progression on a first or second generation TKI) - At least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 that can be followed by computed tomography (CT) or magnetic resonance imaging (MRI) - Patient consents to undergo a medically safe tumor biopsy at time of disease progression for mutation analysis - Leukocytes >= 3,000/uL - Absolute neutrophil count (ANC) >= 1,500/uL - Platelets >= 100,000/uL - Hemoglobin >= 9 g/dL - Serum albumin >= 2.5 g/dL - Calculated creatinine clearance > 50 mL/min (per the Cockcroft-Gault formula) - Total bilirubin =< 1.5 times upper limit of normal (ULN) - Alkaline phosphatase (ALP) =< 3.0 x ULN - Alanine aminotransferase (ALT) and aspartate transaminase (AST) =< 3.0 x ULN; for patients with hepatic metastases, ALT and AST =< 5.0 x ULN are acceptable * Note: if a patient experiences elevated ALT > 5 x ULN and elevated total bilirubin > 2 x ULN, clinical and laboratory monitoring should be initiated by the investigator; for patients entering the study with ALT > 3 x ULN, monitoring should be triggered at ALT > 2 x baseline - Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 14 days prior to receiving first dose of study medication; and additionally agree to use at least two methods of birth control or abstain from heterosexual intercourse from the time of signing consent, and until 6 months after patient's last dose of study drug * WOCBP of childbearing potential are defined as those not surgically sterile or not post-menopausal (i.e. if a female patient has not had a bilateral tubal ligation, a bilateral oophorectomy, or a complete hysterectomy; or has not been amenorrheic for 24 months in the absence of an alternative medical cause, then patient will be considered a female of childbearing potential); postmenopausal status in females under 55 years of age should be confirmed with a serum follicle-stimulating hormone (FSH) level within laboratory reference range for postmenopausal women - WOCBP must agree to follow instructions for method(s) of contraception from the time of signing consent and until 6 months after last dose of study therapy - Men able to father children who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception from the time of signing consent and until 6 months after last dose of study therapy; men able to father children are defined as those who are not surgically sterile (i.e. --- T790M --- --- T790M ---

Primary Outcomes

Description: Highest dosage at which 0 or 1/6 patients

Measure: Maximum tolerated dose experience a dose-limiting toxicity

Time: Up to 28 days

Secondary Outcomes

Description: Complete response assessed by RECIST version (v) 1.1

Measure: Objective response rate

Time: Up to one year

Description: Partial response assessed by RECIST version (v) 1.1

Measure: Objective response rate

Time: Up to one year

Description: Assessed by RECIST v1.1

Measure: Overall survival

Time: From the first dose of study treatment to the time of death from any cause on study, assessed up to 1 year

Description: Assessed by RECIST v1.1

Measure: Duration of response

Time: Up to 1 year

Description: Assessed by NCI CTCAE

Measure: Incidence of adverse events

Time: Up to 1 year

296 Global PANORAMA Real World Molecular Testing, Treatment Patterns, and Clinical Outcomes in Patients With Locally Advanced or Metastatic NSCLC.

This is an observational cohort study of patients with locally advanced or metastatic NSCLC (non-small cell lung cancer). Patients will be recruited from participating sites in Europe, Asia, and Canada. The study will include 2 patient cohorts.

NCT03053297
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Other: Patient Reported Outcomes
MeSH:Carcinoma Carcinoma, Non-Small-Cell Lung
HPO:Carcinoma Non-small cell lung carcinoma

Frequencies and percentages will be used to document categorical measures of interest (e.g., number and proportion of patients with a post progression molecular test, number and proportion of patients with a T790M mutation) and will include 95% CIs for key outcome variables. --- T790M ---

Primary Outcomes

Description: Molecular testing rate defined as the number of patients identified as having received molecular testing divided by the number of patients in the cohorts Changes in testing rates over time (details will be included in the SAP) Molecular testing details including, but not limited to sample type, method of biopsy, testing turnaround time, test type, reason for testing, testing laboratory type, reason for not performing a test Molecular testing results including mutation status and type, test outcome, histologic/phenotypic transformation

Measure: Parameters in the target population associate with molecular testing patters

Time: Patients will be followed from enrolment in the study until death, loss to follow-up, withdrawal of consent or study end date. The minimum follow-up will be 12 months and the maximum allowed follow-up will be 36 months

Description: Overall survival measured from: the date of initial diagnosis to date of death from any cause to the index date to date of death from any cause (for primary cohort only) the date of first-line treatment until death the date of second-line treatment until death Overall disease progression: o from date of treatment initiation until physician-reported progression, initiation of a new cancer-directed line of therapy (proxy for progression), or death For each line of chemotherapy/targeted therapy received: Therapy regimen Therapy duration measured as time from therapy start date to time of therapy end date Number of cycles received Reason for cessation of therapy Time to initiation of new therapy defined as the time from start date of current therapy to start date of subsequent therapy For each surgery or radiotherapy received: Type Site Date Any palliative/supportive care received

Measure: Parameters in the target population associate with treatment patterns and associated clinical outcomes

Time: Patients will be followed from enrolment in the study until death, loss to follow-up, withdrawal of consent or study end date. The minimum follow-up will be 12 months and the maximum allowed follow-up will be 36 months

Secondary Outcomes

Description: For each health care setting: Number and % of patients with visits Total number of visits Total length of inpatient hospital and ICU stay

Measure: Estimation of parameters in the target population associate with cancer-related health care utilization patters including inpatient, emergency room, outpatient visits, lenght of inpatient stay

Time: Patients will be followed from enrolment in the study until death, loss to follow-up, withdrawal of consent or study end date. The minimum follow-up will be 12 months and the maximum allowed follow-up will be 36 months

Description: For each treatment complication: o Rate of occurrence defined as the number of patients reporting at least one treatment-related complications divided by the number of evaluable patients2 Treatment-related complications can include, but are not limited to nausea and vomiting, diarrhoea, constipation, skin rash, infections, mouth sores, neutropenia, hyponatremia For each biopsy-related complication: Rate of occurrence defined as the number of patients reporting at least one occurrence of the complication divided by the number of patients receiving a biopsy Biopsy-related complications can include but are not limited to collapsed lung, severe bleeding, bronchial spasms, irregular heart rhythms, death, severe chest pain, light-headedness, trouble breathing, excessive bleeding through the bandage, haemoptysis, fever, infection

Measure: Estimation of parameters in the target population associated with treatment- and biopsy-related complications

Time: Patients will be followed from enrolment in the study until death, loss to follow-up, withdrawal of consent or study end date. The minimum follow-up will be 12 months and the maximum allowed follow-up will be 36 months

Description: Overall CNS metastases rate, defined as the number of patients developing CNS metastases divided by the number of evaluable patients Brain metastases rate, defined as the number of patients developing brain metastases divided by the number of evaluable patients Leptomeningeal metastases rate, defined as the number of patients developing leptomeningeal metastases divided by the number of evaluable patients Treatments for CNS metastases, including type of treatment and dates of treatment

Measure: Estimation of the rate of CNS metastases in the target population including brain metastases and leptomeningeal metastases and treatments associated with CNS metastases

Time: Patients will be followed from enrolment in the study until death, loss to follow-up, withdrawal of consent or study end date. The minimum follow-up will be 12 months and the maximum allowed follow-up will be 36 months

Description: • Change in score from baseline for each Quality of Life (QoL) domain and for overall QoL, measured at each subsequent site visit

Measure: Assessment of patient (HRQoL) using European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 items (EORTC QLQ-C30) and EORTC QLQ - Lung Cancer 13 items (EORTC QLQ-LC13)3

Time: Patients will be followed from enrolment in the study until death, loss to follow-up, withdrawal of consent or study end date. The minimum follow-up will be 12 months and the maximum allowed follow-up will be 36 months

297 A Phase 2 Study of Osimertinib in Combination With Selumetinib in EGFR Inhibitor naïve Advanced EGFR Mutant Lung Cancer

This research study is studying a combination of two targeted therapies as a possible treatment for Non-Small Cell Lung Cancer (NSCLC) with an EGFR mutation. The drugs involved in this study are: - Osimertinib (Tagrisso) - Selumetinib

NCT03392246
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: Osimertinib
  2. Drug: Selumetinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Baseline left ventricular ejection fraction (LVEF) below the LLN or of < 45% measured by echocardiography/MUGA; atrial fibrillation with a ventricular rate > 100 bpm on ECG at rest. - Any evidence of severe or uncontrolled systemic diseases, including active bleeding diatheses, which in the investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol - Known to be T790M+ (on pre-treatment tumor or plasma) or known germline T790M. --- T790M ---

Primary Outcomes

Description: RECIST1.1 measurements of CT scans will be measured during treatment to determine the objective response rate for patients being treated with combination osimertinib and selumetinib. A response rate and a 95% confidence interval will be calculated.

Measure: Best Objective Response

Time: 2 years

Secondary Outcomes

Description: Time from registration to documented disease progression or death from any cause, whichever occurs first. The Kaplan-Meier method will be used to determine the progression-free survival of patients enrolled on protocol and treated with combination osimertinib and selumetinib.

Measure: Progression Free Survival

Time: 2 years

Description: Survival follow-up with clinic visits or phone calls will be used to monitor for overall survival, from the time of study randomization to death from any cause. The Kaplan-Meier method will be used to calculate overall survival.

Measure: Overall Survival

Time: 2 years

Description: Fraction of patients continuing on study therapy at 6 months.

Measure: Tolerability

Time: 2 years

Description: Graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 criteria.

Measure: Toxicity

Time: 2 years

298 A Phase II Study for Evaluating Anti-tumor Efficacy of TAGRISSO (Osimertinib) in NSCLC Patients in Whom T790 Mutations Are Detected by Liquid Biopsy Using Bronchoalveolar Lavage Fluid, Plasma or Pleural Effusion

In this trial, anti-tumor efficacy of TAGRISSO in NSCLC patients in whom T790 mutations are detected by liquid biopsy.

NCT03394118
Conditions
  1. NSCLC
Interventions
  1. Drug: Osimertinib
MeSH:Pleural Effusion
HPO:Pleural effusion

Progression-free survival (PFS) the time from first dose of the study drug until the date of disease progression or death by any cause.. T790M postive rate in Plasma cell free DNA. --- T790M ---

T790M postive rate in BALF free DNA. --- T790M ---

T790M postive rate in tissue. --- T790M ---

Concordance rate of T790M positivity between plasma & BALF. --- T790M ---

T790M sensitivity & specificity in Plasma & BALF (gold standard: tissue biopsy). --- T790M ---

Patients must have a life expectancy ≥ 12 weeks Exclusion Criteria: 1. Patients who were previously treated with any of the drugs targeting T790M mutation such as AZD9291 (Osimertinib), HM61713 (Olmutinib), and CO-1686 (Rociletinib) 2. Patients currently receiving medications known to be potent inhibitors of CYP3A4 and potent inducers of CYP3A4 (at least 1week prior study enrolment) 3. Patients who have preexisting or coexisting malignancies in other parts except for effectively treated non-melanoma skin cancer, CIS cervical cancer, DCIS breast cancer, thyroid cancer or malignancies that were effectively treated, have maintained at least 3 years of remission state and can be regarded as completely cured 4. Patients who have severe or unstable medical conditions such as prior or current clinically significant cardiovascular abnormality in accordance with the investigator's judgment such as uncontrolled hypertension, heart failure (NYHA classification ≥3), unstable angina or uncontrolled arrhythmia, and acute myocardial infarction within 6 months before study enrolment corrected QTcB >450msec in 12 lead EKG 5. Patients with current or prior interstitial lung disease 6. Patients with current or prior uncontrolled gastrointestinal diseases (e.g., crohn's disease, ulcerative colitis, chronic diarrhea, malabsorption) that would preclude adequate absorption of IP. 7. Patients with active hepatitis B (identified by the presence of HBsAg and/or HBV DNA), active hepatitis C (identified by the presence of HCV RNA), and known human immunodeficiency virus (HIV) 8. Patients with histories of hypersensitivity to IP or any components of the agent 9. Patients with any of the following genetic predispositions including galactose intolerance, lactose intolerance, or glucose-galactose malabsorption 10. --- T790M ---

Primary Outcomes

Description: Objective response rate (ORR) including rate of CR and PR on based of RECIST 1.1

Measure: ORR

Time: through study completion (43 months)

Secondary Outcomes

Description: Disease control rate (DCR) including rate of CR, PR and SD on based of RECIST 1.1

Measure: DCR

Time: through study completion (43 months)

Description: Progression-free survival (PFS) the time from first dose of the study drug until the date of disease progression or death by any cause.

Measure: PFS

Time: through study completion (43 months)

Measure: T790M postive rate in Plasma cell free DNA

Time: through study completion (43 months)

Measure: T790M postive rate in BALF free DNA

Time: through study completion (43 months)

Measure: T790M postive rate in tissue

Time: through study completion (43 months)

Measure: Concordance rate of T790M positivity between plasma & BALF

Time: through study completion (43 months)

Measure: T790M sensitivity & specificity in Plasma & BALF (gold standard: tissue biopsy)

Time: through study completion (43 months)

Description: AE/SAE assessement on the base of NCI-CTCAE (version 4.03).

Measure: The frequency of occurrence of grade 3 or higher AE/SAEs

Time: through study completion (43 months)

299 The Continuation of Gefitinib Treatment Beyond Progression in Non-small Cell Lung Cancer Patients With EGFR Mutation: A Phase II Single Arm Prospective Study

Although EGFR-TKIs such as gefitinib, erlotinib or afatinib are recommended as first-line therapy in patients with advanced, recurrent or metastatic nonsquamous NSCLC patients who have known active EGFR mutation and achieved response to EGFR TKIs experience disease progression eventually with 10-14 moths of median progression free survival.6 Platinum-doublets combination chemotherapy remains standard of care for patients with progressive disease. However, patients may derive benefit from EGFR TKIs after RECIST-assessed progression especially for those who experience slow progression. And previous report suggested that premature discontinuation of EGFR TKIs has resulted in rapid progression in symptoms and tumor growth.7 Recently, a prospective phase II single arm study in Asian patients with EGFR mutation-positive NSCLC to determine the continuation of erlotinib beyond progression judged by investigators showed that additional PFS of 3.1 months can be achieved with continuation of erlotinib without serious additional toxicities.8 Until now, no prospective study has been conducted for gefitinib. In this study the continuation of gefitinib beyond RECIST progression will be investigated to determine the clinical outcomes including the duration of treatment and safety. This is a single-arm phase II trial to evaluate the efficacy and safety of continuation of gefitinib in EGFR mutant NSCLC patients who experience RECIST progression. Based on the results of "ASPIRATION" study, the median PFS for continuation of gefitinib will be around 3 months. The study treatment will be of no interest if the true median PFS is 2.5 months or shorter. In contrast, it will be of interest if the true median PFS is 3.5 months or longer. Considering 1 sided alpha of 0.05 and 90% of power, 95 patients are required. A total of 100 patients will be needed considering 5% of drop-out rate. 6 months of accrual and additional 6 months of follow-up will be assumed for this study. Patients will be treated 250 mg/day of gefitinib orally (1 cycle for 28 days). Cycles were repeated until disease progression, unacceptable toxicity, or until the patient or the investigator requested therapy discontinuation.

NCT03399669
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: gefitinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - Histologically confirmed stage IIIB/IV or recurrent NSCLC with activating EGFR mutation in exon 18 through exon 21 except T790M - Patients who achieved complete/partial response more than 4 months or stable disease more than 6 months with first-line or second line gefitinib - Patients who experience disease progression by RECIST 1.1 criteria - Age ≥ 18years - ECOG performance status of 0 to 2 - Adequate organ function as evidenced by the following; Absolute neutrophil count > 1.5 x 109/L; platelets > 100 x 109/L; total bilirubin ≤1.5 UNL; AST and/or ALT < 5 UNL, CCr ≥ 50mL/min - Baseline adverse event of gefitinib ≤ Grade 2 - Written informed consent form Exclusion Criteria: - Prior treatment with EGFR TKI - Patients who required dose reduction of gefitinib - Surgery undertaken less than 4 weeks before the study - Localized radiotherapy unless completed more than 2 weeks before the study - Uncontrolled systemic illness such as DM, CHF, unstable angina, hypertension or arrhythmia - Pregnant or nursing women ( Women of reproductive potential have to agree to use an effective contraceptive method (hormonal or barrier methods)) - Uncontrolled symptomatic brain metastasis - Prior history of malignancy within 5 years from study entry except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer, well-treated thyroid cancer - Concomitant use of CYP3A4 inducers/inhibitors - Prolonged QT interval in ECG (QTc >450 msec) - Patients who cannot take a medicine orally or who have a gastrointestinal absorption disorder Inclusion Criteria: - Histologically confirmed stage IIIB/IV or recurrent NSCLC with activating EGFR mutation in exon 18 through exon 21 except T790M - Patients who achieved complete/partial response more than 4 months or stable disease more than 6 months with first-line or second line gefitinib - Patients who experience disease progression by RECIST 1.1 criteria - Age ≥ 18years - ECOG performance status of 0 to 2 - Adequate organ function as evidenced by the following; Absolute neutrophil count > 1.5 x 109/L; platelets > 100 x 109/L; total bilirubin ≤1.5 UNL; AST and/or ALT < 5 UNL, CCr ≥ 50mL/min - Baseline adverse event of gefitinib ≤ Grade 2 - Written informed consent form Exclusion Criteria: - Prior treatment with EGFR TKI - Patients who required dose reduction of gefitinib - Surgery undertaken less than 4 weeks before the study - Localized radiotherapy unless completed more than 2 weeks before the study - Uncontrolled systemic illness such as DM, CHF, unstable angina, hypertension or arrhythmia - Pregnant or nursing women ( Women of reproductive potential have to agree to use an effective contraceptive method (hormonal or barrier methods)) - Uncontrolled symptomatic brain metastasis - Prior history of malignancy within 5 years from study entry except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer, well-treated thyroid cancer - Concomitant use of CYP3A4 inducers/inhibitors - Prolonged QT interval in ECG (QTc >450 msec) - Patients who cannot take a medicine orally or who have a gastrointestinal absorption disorder Non-small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- T790M ---

Inclusion Criteria: - Histologically confirmed stage IIIB/IV or recurrent NSCLC with activating EGFR mutation in exon 18 through exon 21 except T790M - Patients who achieved complete/partial response more than 4 months or stable disease more than 6 months with first-line or second line gefitinib - Patients who experience disease progression by RECIST 1.1 criteria - Age ≥ 18years - ECOG performance status of 0 to 2 - Adequate organ function as evidenced by the following; Absolute neutrophil count > 1.5 x 109/L; platelets > 100 x 109/L; total bilirubin ≤1.5 UNL; AST and/or ALT < 5 UNL, CCr ≥ 50mL/min - Baseline adverse event of gefitinib ≤ Grade 2 - Written informed consent form Exclusion Criteria: - Prior treatment with EGFR TKI - Patients who required dose reduction of gefitinib - Surgery undertaken less than 4 weeks before the study - Localized radiotherapy unless completed more than 2 weeks before the study - Uncontrolled systemic illness such as DM, CHF, unstable angina, hypertension or arrhythmia - Pregnant or nursing women ( Women of reproductive potential have to agree to use an effective contraceptive method (hormonal or barrier methods)) - Uncontrolled symptomatic brain metastasis - Prior history of malignancy within 5 years from study entry except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer, well-treated thyroid cancer - Concomitant use of CYP3A4 inducers/inhibitors - Prolonged QT interval in ECG (QTc >450 msec) - Patients who cannot take a medicine orally or who have a gastrointestinal absorption disorder Inclusion Criteria: - Histologically confirmed stage IIIB/IV or recurrent NSCLC with activating EGFR mutation in exon 18 through exon 21 except T790M - Patients who achieved complete/partial response more than 4 months or stable disease more than 6 months with first-line or second line gefitinib - Patients who experience disease progression by RECIST 1.1 criteria - Age ≥ 18years - ECOG performance status of 0 to 2 - Adequate organ function as evidenced by the following; Absolute neutrophil count > 1.5 x 109/L; platelets > 100 x 109/L; total bilirubin ≤1.5 UNL; AST and/or ALT < 5 UNL, CCr ≥ 50mL/min - Baseline adverse event of gefitinib ≤ Grade 2 - Written informed consent form Exclusion Criteria: - Prior treatment with EGFR TKI - Patients who required dose reduction of gefitinib - Surgery undertaken less than 4 weeks before the study - Localized radiotherapy unless completed more than 2 weeks before the study - Uncontrolled systemic illness such as DM, CHF, unstable angina, hypertension or arrhythmia - Pregnant or nursing women ( Women of reproductive potential have to agree to use an effective contraceptive method (hormonal or barrier methods)) - Uncontrolled symptomatic brain metastasis - Prior history of malignancy within 5 years from study entry except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer, well-treated thyroid cancer - Concomitant use of CYP3A4 inducers/inhibitors - Prolonged QT interval in ECG (QTc >450 msec) - Patients who cannot take a medicine orally or who have a gastrointestinal absorption disorder Non-small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- T790M --- --- T790M ---

Primary Outcomes

Measure: Time from RECIST progression to secondary disease progression

Time: 3 months

300 A Phase II Study of Dacomitinib in Advanced Epidermal Growth Factor Receptor (EGFR)-Mutant Non-small Cell Lung Cancer (NSCLC) Patients Who Have Non-irradiated Brain Metastasis

This is a single-arm, phase II study of dacomitinib in advanced EGFR-mutant NSCLC patients who have non-irradiated brain metastasis.

NCT04675008
Conditions
  1. Non Small Cell Lung Cancer
  2. Brain Metastases
Interventions
  1. Drug: Dacomitinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung Neoplasm Metastasis
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Inclusion Criteria: - Biopsy proven recurrent or metastatic NSCLC (adenocarcinoma) with major EGFR mutation (exon 19 deletion or Leu858Arg mutation without the Thr790Met) - No prior systemic treatment of advanced NSCLC (Neoadjuvant or adjuvant chemotherapy are allowed, without limitation on its treatment timing) - Age ≥20 years - Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 - Had at least one measurable intracranial lesion as ≥ 5mm in the longest diameter by magnetic resonance imaging (MRI) (≥ 5mm by thin section (1.2mm) of brain MRI image, ≥ 10mm by less thin section(2.5mm) --- Leu858Arg --- --- Thr790Met ---

Primary Outcomes

Description: To evaluate the CNS efficacy of dacomitinib

Measure: CNS objective response rate (Complete response or Partial response)

Time: 1 year

Secondary Outcomes

Description: To evaluate the CNS efficacy of dacomitinib

Measure: CNS progression-free survival

Time: 1 year

Description: To evaluate the CNS efficacy of dacomitinib

Measure: Cumulative incidence of CNS failure by competing risk analysis

Time: 1 year

Description: To evaluate the efficacy of dacomitinib

Measure: Extracranial objective response rate

Time: 1 year

Description: To evaluate the efficacy of dacomitinib

Measure: Progression-free survival

Time: 1 year

Description: To evaluate the efficacy of dacomitinib

Measure: Overall survival

Time: 1 year

Description: To evaluate the safety of dacomitinib

Measure: Safety by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0

Time: 1 year

301 A Phase 2, Multicenter Study of Tesevatinib in Subjects With Non-Small Cell Lung Cancer, EGFR Activating Mutation, Prior Treatment With a Tyrosine Kinase Inhibitor, and Brain Metastases or Leptomeningeal Metastases

A study to assess the activity of tesevatinib in subjects with NSCLC and activating EGFR mutations who have disease progression with Brain Metastases (BM) or Leptomeningeal Metastases (LM) or who heave either BM or LM at initial presentation.

NCT02616393
Conditions
  1. Non-Small Cell Lung Cancer
  2. Leptomeningeal Metastases
  3. Brain Metastases
Interventions
  1. Drug: Tesevatinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung Neoplasm Metastasis Neoplasms, Second Primary Brain Neoplasms Meningeal Carcinomatosis
HPO:Brain neoplasm Neoplasm of the lung Non-small cell lung carcinoma

Patients may have received osimertinib (or other agents inhibiting the T790M EGFR mutation) as second line therapy. --- T790M ---

Primary Outcomes

Description: The primary objective is to evaluate the clinical activity of tesevatinib in subjects with non-small cell lung cancer (NSCLC), activating EGFR mutations, and BM as measured by RECIST 1.1 evaluated changes in BM size (Cohort A)

Measure: Clinical Activity of tesevatinib against BM using RECIST 1.1

Time: 12 months

Description: The primary objective is to evaluate the clinical activity of tesevatinib in subjects with NSCLC, activating EGFR mutations and/or LM as measured by improvement in CTCAE v4.03 symptoms and signs (Cohort B)

Measure: Clinical Activity of tesevatinib against LM using Symptom Resolution

Time: 12 months

Description: The primary objective is to evaluate the clinical activity of tesevatinib in subjects with non-small cell lung cancer (NSCLC), activating EGFR mutations, and BM at initial presentation as measured by RECIST 1.1 evaluated changes in BM size (Cohort C)

Measure: Clinical Activity of tesevatinib against BM at initial presentation using RECIST 1.1

Time: 12 months

Secondary Outcomes

Description: To evaluate changes in Quality of Life (QOL) in subjects receiving tesevatinib for BM using the EORTC QLQ-C30 and EORTC QLQ-BN20 Questionnaires

Measure: Quality of Life in Subjects Receiving tesevatinib for BM

Time: 12 months

Description: To evaluate changes in QOL in subjects receiving tesevatinib for LM using the EORTC QLQ-C30 and EORTC QLQ-BN20 Questionnaires

Measure: Quality of Life in Subjects Receiving tesevatinib for LM

Time: 12 months

Description: To evaluate changes in QOL in subjects receiving tesevatinib for BM at initial presentation using the EORTC QLQ-C30 and EORTC QLQ-BN20 Questionnaires

Measure: Quality of Life in Subjects Receiving tesevatinib for BM at initial presentation

Time: 12 months

Description: To determine the median progression-free survival (PFS) in Cohort A by assessing the median number of days from Cycle 1, Day 1 until disease progression or death

Measure: Median Progression-Free Survival in Cohort A

Time: 12 months

Description: To determine the rate of CNS non-progression at 3 and 6 months Cohort A by assessing the percentage of subjects in Cohort A without CNS disease progression 3 and 6 months after Cycle 1, Day 1

Measure: Rate of CNS Non-Progression in Cohort A

Time: 12 months

Description: To determine the rate of Non-CNS time to progression in Cohort A by assessing the median number of days in Cycle 1, Day 1 until non-CNS disease progression

Measure: Non-CNS Time to Progression in Cohort A

Time: 12 months

Description: To determine the rate of CNS TTPin Cohort A by assessing the median number of days in Cycle 1, Day 1 to disease progression

Measure: CNS TTP in Cohort A

Time: 12 months

Description: To determine the median progression-free survival (PFS) in Cohort B by assessing the median number of days from Cycle 1, Day 1 until disease progression or death

Measure: Median Progression-Free Survival in Cohort B

Time: 12 months

Description: To determine the rate of CNS non-progression at 3 and 6 months Cohort B by assessing the percentage of subjects in Cohort A without CNS disease progression 3 and 6 months after Cycle 1, Day 1

Measure: Rate of CNS Non-Progression in Cohort B

Time: 12 months

Description: To determine the rate of Non-CNS time to progression in Cohort B by assessing the median number of days in Cycle 1, Day 1 until non-CNS disease progression

Measure: Non-CNS Time to Progression in Cohort B

Time: 12 months

Description: To determine the rate of CNS TTP in Cohort B by assessing the median number of days in Cycle 1, Day 1 to disease progression

Measure: CNS TTP in Cohort B

Time: 12 months

Description: To determine the median overall survival (OS) in Cohort A by measuring the median number of days from Cycle 1, Day 1 until death

Measure: Median Overall Survival in Cohort A

Time: 12 months

Description: To determine the median OS in Cohort B by measuring the median number of days from Cycle 1, Day 1 until death

Measure: Median Overall Survival in Cohort B

Time: 12 months

Description: Evaluate the activity of tesevatinib in subjects with NSCLC as measured by decreases in NSCLC cells in the CSF using standard cytology as assessed by the percent change in the number of NSCLC cells in the CSF for each patient in cohort B from screening to Cycle 1, Day 14, from Day 14 to Cycle 3, Day 1, and from screening to Cycle 3, Day 1 (Cohort B)

Measure: Clinical Activity of tesevatinib against LM using Standard Cytology

Time: 12 months

Description: Evaluate the activity of tesevatinib in subjects with NSCLC as measured by changes in MRI findings consistent with leptomeningeal metastases (absent or present) for each patient in Cohort B from Cycle 1, Day 1 to Cycle 3, Day 1 and from Cycle 1, Day 1 to Cycle 5 Day 1 (Cohort B)

Measure: Clinical Activity of tesevatinib against LM using Improvement in MRI Findings

Time: 12 months

Description: To determine the median progression-free survival (PFS) in Cohort C by assessing the median number of days from Cycle 1, Day 1 until disease progression or death

Measure: Median Progression-Free Survival in Cohort C

Time: 12 months

Description: To determine the rate of CNS non-progression at 3 and 6 months Cohort C by assessing the percentage of subjects in Cohort C without CNS disease progression 3 and 6 months after Cycle 1, Day 1

Measure: Rate of CNS Non-Progression in Cohort C

Time: 12 months

Description: To determine the rate of Non-CNS time to progression in Cohort C by assessing the median number of days in Cycle 1, Day 1 until non-CNS disease progression

Measure: Non-CNS Time to Progression in Cohort C

Time: 12 months

Description: To determine the rate of CNS TTPin Cohort C by assessing the median number of days in Cycle 1, Day 1 to disease progression

Measure: CNS TTP in Cohort C

Time: 12 months

Description: To determine the median overall survival (OS) in Cohort C by measuring the median number of days from Cycle 1, Day 1 until death

Measure: Median Overall Survival in Cohort C

Time: 12 months

Description: To evaluate the concentration of tesevatinib in CSF versus plasma in Cohort B by obtaining PK analysis of plasma pre-dose on both Cycle 1 Day 14 and Cycle 3 Day 1, as well as obtaining PK samples of both plasma and CSF 4-8 hours after tesevatinib administration on Cycle 1 Day 14 and on Cycle 3 Day 1.

Measure: Pharmacokinetics in Cohort B: Concentration of tesevatinib in CSF versus plasma

Time: 12 Months

302 A Pilot Study of Local Ablative Therapy for Treatment of Oligoprogressive, EGFR-mutated, Non-Small Cell Lung Cancer (NSCLC) After Treatment With Osimertinib (AZD9291, Tagrisso)

Background: Some non-small-cell lung cancers (NSCLC) have a mutation in a gene that makes a protein called EGFR. This particular cancer can be treated with certain drugs such as Erlotinib (Tarceva), Gefitinib (Iressa) and Osimertinib (Tagrisso). But many tumors become resistant to these drugs because of a second mutation. Researchers want to test if adding local ablative therapy (LAT) extends the benefits of the drug, Osimertinib. LAT can include techniques such as surgery, radiofrequency ablation, cryotherapy or radiation therapy. Objective: To test if re-taking osimertinib after LAT is safe, tolerable, and effective for people whose NSCLC has progressed after initial treatment with osimertinib. Eligibility: Adults ages 18 and older with certain types of NSCLC. Participants will be divided into various groups as described below. Design: Participants will be screened with: Medical history Physical exam Blood, urine, and heart tests Tumor scans Eye exam Review of tumor sample. Participants will take the study drug by mouth once a day. They will continue until they can no longer tolerate it or their disease worsens. They will keep a dosage diary. All participants will start each 21-day course with physical exam; blood, urine, and saliva tests; and electrocardiogram. They will have scans every 6 weeks and echocardiogram every 3 months. Groups 1 and 2 will: Start osimertinib right away. Have LAT if their disease gets worse and is suitable for LAT. If LAT cannot be performed or LAT consists of a procedure other than surgery, a tumor biopsy will be performed. Re-start osimertinib after LAT, or other treatments if not suitable for LAT. Group 3 will: Have LAT. If LAT consists of a procedure other than surgery, a tumor biopsy will be performed. Start osimertinib after LAT. After participants stop taking the drugs, they will have a final visit. This will include: Medical history Physical exam Heart and blood tests Participants will be called every year for follow-up.

NCT02759835
Conditions
  1. Lung Adenocarcinoma
  2. Lung Neoplasms
Interventions
  1. Drug: osimertinib
  2. Other: LAT
MeSH:Lung Neoplasms Adenocarcinoma of Lung
HPO:Neoplasm of the lung

- Patients with histologically confirmed, by the NCI Laboratory of Pathology or by CLIA-certified Next Generation Sequencing or cobas EGFR Mutation Test v1/2 at an outside institution, advanced lung adenocarcinoma with EGFR-sensitizing somatic mutations or a germline T790M mutation (detected histologically or via ctDNA analysis using a CLIA assay) with: - No prior EGFR tyrosine kinase inhibitor (TKI) therapy (Cohort 1) OR -- Progressive disease after 1st or 2nd generation EGFR TKI therapy harboring somatic T790M mutation (Cohort 2) OR - Progressive disease after treatment with osimertinib who are eligible for local ablative therapy (Cohort 3) - Presence of measurable disease per RECIST version 1.1. --- T790M ---

- Patients with histologically confirmed, by the NCI Laboratory of Pathology or by CLIA-certified Next Generation Sequencing or cobas EGFR Mutation Test v1/2 at an outside institution, advanced lung adenocarcinoma with EGFR-sensitizing somatic mutations or a germline T790M mutation (detected histologically or via ctDNA analysis using a CLIA assay) with: - No prior EGFR tyrosine kinase inhibitor (TKI) therapy (Cohort 1) OR -- Progressive disease after 1st or 2nd generation EGFR TKI therapy harboring somatic T790M mutation (Cohort 2) OR - Progressive disease after treatment with osimertinib who are eligible for local ablative therapy (Cohort 3) - Presence of measurable disease per RECIST version 1.1. --- T790M --- --- T790M ---

The most common mechanism of resistance observed in approximately 50% of all cases is the emergence of a secondary mutation (T790M) in exon 20. - Osimertinib is a third-generation EGFR-TKI designed to target the T790M mutation, which has shown impressive responses in both first- and second-line settings. --- T790M ---

The most common mechanism of resistance observed in approximately 50% of all cases is the emergence of a secondary mutation (T790M) in exon 20. - Osimertinib is a third-generation EGFR-TKI designed to target the T790M mutation, which has shown impressive responses in both first- and second-line settings. --- T790M --- --- T790M ---

Objectives: - Determine the safety, tolerability, and efficacy (as assessed by PFS) of re-initiation of osimertinib following local ablative therapy (LAT) for patients with oligoprogressive disease after treatment with osimertinib - Assess mechanisms of acquired resistance to osimertinib Eligibility: - Histologically confirmed advanced lung adenocarcinoma with EGFR-sensitizing somatic mutations or a germline T790M mutation and no prior EGFR tyrosine kinase inhibitor (TKI) therapy (Cohort 1); OR progressive disease after 1st or 2nd generation EGFR TKI therapy harboring somatic T790M mutation (Cohort 2); or patients with progressive disease after treatment with osimertinib who are eligible for local ablative therapy (Cohort 3). --- T790M ---

Objectives: - Determine the safety, tolerability, and efficacy (as assessed by PFS) of re-initiation of osimertinib following local ablative therapy (LAT) for patients with oligoprogressive disease after treatment with osimertinib - Assess mechanisms of acquired resistance to osimertinib Eligibility: - Histologically confirmed advanced lung adenocarcinoma with EGFR-sensitizing somatic mutations or a germline T790M mutation and no prior EGFR tyrosine kinase inhibitor (TKI) therapy (Cohort 1); OR progressive disease after 1st or 2nd generation EGFR TKI therapy harboring somatic T790M mutation (Cohort 2); or patients with progressive disease after treatment with osimertinib who are eligible for local ablative therapy (Cohort 3). --- T790M --- --- T790M ---

Primary Outcomes

Description: progression-free survival (PFS)

Measure: determine PFS in patients with oligoprogressive disease after treatment with LAT followed by osimertinib

Time: progression of disease

Description: time to second progression (PFS2)

Measure: Patients who progress on their initial treatment with osimertinib and receive LAT therapy (surgery, radiation therapy, or RFA) followed by osimertinib will be evaluated for their time to second progression (PFS2)

Time: progression of disease

Secondary Outcomes

Description: response rate

Measure: response rate

Time: end of treatment

Description: overall survival

Measure: overall survival

Time: death

Description: EGFR mutation status using liquid biopsies

Measure: feasibility of evaluating EGFR mutation status using liquid biopsies

Time: end of treatment

303 Randomized, Open-label, Controlled Multicenter Study to Compare Bevacizumab in Combination With Erlotinib Versus Erlotinib Alone in Chinese NSCLC Patients Harbouring Activating EGFR Mutations(Artemis)

This is a randomized, open-label, controlled, multicenter, Phase III study. Patients will be randomly assigned to treatment group (1:1) through a dynamic randomization process with use of the following stratification factors: sex (female/male), disease stage (stage IIIb vs. stage IV vs. recurrence), and EGFR gene mutation (exon 19 deletion vs. exon 21 L858R).

NCT02759614
Conditions
  1. NSCLC
Interventions
  1. Drug: Bevacizumab
  2. Drug: Erlotinib
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

2. A positive result for the exon 20 T790M mutation from any high-sensitivity EGFR mutation test such as digital PCR using tumor tissue or cells. --- T790M ---

Primary Outcomes

Description: To evaluate the efficacy of bevacizumab combined with erlotinib compared with erlotinib alone in patients with NSCLC harbouring activating EGFR mutations, as measured by independent review committee assessed progression-free survival using RECIST v1.1

Measure: Progression-free survival (PFS) by IRC

Time: The primary PFS analysis will be performed when approximately 224 PFS events (disease progression or death, whichever occurs first) have occurred, which is estimated to occur at approximately 18 months after enrollment of the last patient.

Secondary Outcomes

Description: To evaluate the efficacy of bevacizumab combined with erlotinib compared with erlotinib alone in patients with NSCLC harbouring activating EGFR mutations, as measured by investigators assessed progression-free survival using RECIST v1.1

Measure: Progression-free survival (PFS) by investigator using RECIST v1.1

Time: The primary PFS analysis will be performed when approximately 224 PFS events (disease progression or death, whichever occurs first) have occurred, which is estimated to occur at approximately 18 months after enrollment of the last patient.

Description: To evaluate the efficacy of bevacizumab combined with erlotinib compared with erlotinib alone in patients with NSCLC harbouring activating EGFR mutations, as measured by independent review committee assessed objective response rate using RECIST v1.1

Measure: Objective response rate (ORR) by IRC using RECIST v1.1

Time: baseline overall tumor assessment can be performed up to 28 days prior to randomization. Post-baseline assessment will be performed every six weeks until 1st disease progression, through study completion, an average of 2 years.

Description: To evaluate the efficacy of bevacizumab combined with erlotinib compared with erlotinib alone in patients with NSCLC harbouring activating EGFR mutations, as measured by investigators assessed objective response rate using RECIST v1.1

Measure: Objective response rate (ORR) by investigator using RECIST v1.1

Time: baseline overall tumor assessment can be performed up to 28 days prior to randomization. Post-baseline assessment will be performed every six weeks until 1st disease progression, through study completion, an average of 2 years.

Description: Disease control rate (DCR) will be analyzed using similar method as objective response rate.

Measure: Disease control rate (DCR) by IRC using RECIST v1.1

Time: That is expected to be approximately 57 months.

Description: Disease control rate (DCR) will be analyzed using similar method as objective response rate.

Measure: Disease control rate (DCR) by investigator using RECIST v1.1

Time: That is expected to be approximately 57 months.

Description: Duration of response(DOR) will be analyzed using similar method as objective response rate.

Measure: Duration of response(DOR) by IRC using RECIST v1.1

Time: That is expected to be approximately 57 months.

Description: Duration of response(DOR) will be analyzed using similar method as objective response rate.

Measure: Duration of response(DOR) by investigator using RECIST v1.1

Time: That is expected to be approximately 57 months.

Description: To evaluate the efficacy of bevacizumab combined with erlotinib compared with erlotinib alone in patients with NSCLC harbouring activating EGFR mutations, as measured by investigators assessed overall survival .

Measure: Overall survival(OS)

Time: That is expected to be approximately 57 months.

304 Genomic Landscape of EGFR Mutant NSCLC Prior to Afatinib and at the Time of Disease Progression Following Afatinib

The investigators propose to conduct a pilot feasibility study of single agent afatinib in patients with previously untreated metastatic EGFR (epidermal growth factor receptor) mutant adenocarcinoma of the lung (NSCLC = non-small cell lung cancer) with the sole purpose of characterizing the genomic landscape before afatinib and at the time of disease progression.

NCT02491775
Conditions
  1. Carcinoma, Non-Small-Cell Lung
  2. Non-Small Cell Lung Cancer
  3. Non-small Lung Cancer
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Duration of response is the duration of overall response is measured from the time measurement criteria are met for complete response or partial response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).. Inclusion Criteria/Exclusion Criteria: - Diagnosis of metastatic stage IIIB/IV lung adenocarcinoma - Presence of known sensitizing mutations in EGFR TK domain (exon 19 deletion and L858R) - Absence of known resistant mutations in the EGFR TK domain (T790M) - Consented to HRPO # 201305031 ("Tissue and Blood Acquisition for Genomic Analysis and Collection of Health Information from Patients with Thoracic Malignancies, Suspected Thoracic Malignancies, or Mesothelioma") - No prior treatment for this malignancy - No prior localized therapy to the biopsy site - Planned treatment with standard of care afatinib at 40 mg QD (daily) - Not pregnant or breastfeeding - At least 18 years of age Inclusion Criteria/Exclusion Criteria: - Diagnosis of metastatic stage IIIB/IV lung adenocarcinoma - Presence of known sensitizing mutations in EGFR TK domain (exon 19 deletion and L858R) - Absence of known resistant mutations in the EGFR TK domain (T790M) - Consented to HRPO # 201305031 ("Tissue and Blood Acquisition for Genomic Analysis and Collection of Health Information from Patients with Thoracic Malignancies, Suspected Thoracic Malignancies, or Mesothelioma") - No prior treatment for this malignancy - No prior localized therapy to the biopsy site - Planned treatment with standard of care afatinib at 40 mg QD (daily) - Not pregnant or breastfeeding - At least 18 years of age Carcinoma, Non-Small-Cell Lung Non-Small Cell Lung Cancer Non-small Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung The current proposal will include exome and transcriptome sequencing from blood collected at baseline along with tumor samples obtained prior to starting afatinib and at the time of disease progression (a total of two tissue samples and one blood sample per patient). --- L858R --- --- T790M ---

Duration of response is the duration of overall response is measured from the time measurement criteria are met for complete response or partial response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).. Inclusion Criteria/Exclusion Criteria: - Diagnosis of metastatic stage IIIB/IV lung adenocarcinoma - Presence of known sensitizing mutations in EGFR TK domain (exon 19 deletion and L858R) - Absence of known resistant mutations in the EGFR TK domain (T790M) - Consented to HRPO # 201305031 ("Tissue and Blood Acquisition for Genomic Analysis and Collection of Health Information from Patients with Thoracic Malignancies, Suspected Thoracic Malignancies, or Mesothelioma") - No prior treatment for this malignancy - No prior localized therapy to the biopsy site - Planned treatment with standard of care afatinib at 40 mg QD (daily) - Not pregnant or breastfeeding - At least 18 years of age Inclusion Criteria/Exclusion Criteria: - Diagnosis of metastatic stage IIIB/IV lung adenocarcinoma - Presence of known sensitizing mutations in EGFR TK domain (exon 19 deletion and L858R) - Absence of known resistant mutations in the EGFR TK domain (T790M) - Consented to HRPO # 201305031 ("Tissue and Blood Acquisition for Genomic Analysis and Collection of Health Information from Patients with Thoracic Malignancies, Suspected Thoracic Malignancies, or Mesothelioma") - No prior treatment for this malignancy - No prior localized therapy to the biopsy site - Planned treatment with standard of care afatinib at 40 mg QD (daily) - Not pregnant or breastfeeding - At least 18 years of age Carcinoma, Non-Small-Cell Lung Non-Small Cell Lung Cancer Non-small Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung The current proposal will include exome and transcriptome sequencing from blood collected at baseline along with tumor samples obtained prior to starting afatinib and at the time of disease progression (a total of two tissue samples and one blood sample per patient). --- L858R --- --- T790M --- --- L858R --- --- T790M ---

Primary Outcomes

Description: The investigators will compare tumor sequencing prior to afatinib treatment to the time of disease progression to see if the genetic sequencing changed between pre-treatment and progression. The investigators plan to conduct exome and transcriptome sequencing of tumor before therapy with afatinib and at the time of relapse. In addition, exome sequencing of peripheral blood DNA will be done (for germline). Given the complexities of genomic analyses of paired samples in the face of limited data, the investigators will not be able to do any formal power calculations in this feasibility study. Disease progression is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study or appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.

Measure: Genetic changes associated with disease progression following treatment with afatinib

Time: Estimated to be 1 year

Secondary Outcomes

Description: Investigators will look at tumor tissue associated with a therapeutic response and compare with tumor tissue associated with disease progression and see if there are any mutation differences. Therapeutic Response Complete response is disappearance of all target lesions and non-target lesions. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

Measure: Types of mutations in signaling kinases associated with therapeutic response

Time: Estimated to be 1 year

Description: A variant is considered to have mutant biased expression if the variant is expressed and the variant allele frequency is greater than 20% higher in the RNA-seq data compared to the exome sequencing data. A variant is considered to have wild type biased expression if the gene is expressed, the region of the variant is covered at 5X or greater depth, and the VAF is at least 20% lower in the RNA-seq data compared to the exome sequencing data. Duration of response is the duration of overall response is measured from the time measurement criteria are met for complete response or partial response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).

Measure: Allelic ratio of wild type to mutant EGFR (roughly corrected for intrinsic differences in tumor cellularity) with duration of response

Time: Estimated to be 1 year

305 A Phase I Trial of AZD9291 and Necitumumab in EGFR-Mutant Non-Small Cell Lung Cancer After Progression on a Previous EGFR Tyrosine Kinase Inhibitor

This phase I trial studies the side effects and best dose of necitumumab when given together with osimertinib in treating patients with EGFR-mutant non-small cell lung cancer that is stage IV or has come back (recurrent) and who have progressed on a previous EGFR tyrosine kinase inhibitor. Immunotherapy with monoclonal antibodies, such as necitumumab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving necitumumab with osimertinib may be a better treatment for EGFR-mutant non-small cell lung cancer.

NCT02496663
Conditions
  1. Metastatic Lung Non-Small Cell Carcinoma
  2. Recurrent Lung Non-Small Cell Carcinoma
  3. Stage IV Lung Non-Small Cell Cancer AJCC v7
Interventions
  1. Biological: Necitumumab
  2. Drug: Osimertinib
MeSH:Carcinoma Carcinoma, Non-Small-Cell Lung
HPO:Carcinoma Non-small cell lung carcinoma

Testing will be one-sided, at the 0.05-level.. Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Metastatic Lung Non-Small Cell Carcinoma Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVE: I. To determine the safety and tolerability of osimertinib (AZD9291) in combination with necitumumab in patients with EGFR-mutant non-small cell lung cancer (NSCLC). --- L858R --- --- L861Q --- --- T790M ---

Testing will be one-sided, at the 0.05-level.. Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Metastatic Lung Non-Small Cell Carcinoma Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVE: I. To determine the safety and tolerability of osimertinib (AZD9291) in combination with necitumumab in patients with EGFR-mutant non-small cell lung cancer (NSCLC). --- L858R --- --- L861Q --- --- T790M --- --- T790M ---

Testing will be one-sided, at the 0.05-level.. Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Metastatic Lung Non-Small Cell Carcinoma Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVE: I. To determine the safety and tolerability of osimertinib (AZD9291) in combination with necitumumab in patients with EGFR-mutant non-small cell lung cancer (NSCLC). --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- T790M ---

Testing will be one-sided, at the 0.05-level.. Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Metastatic Lung Non-Small Cell Carcinoma Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVE: I. To determine the safety and tolerability of osimertinib (AZD9291) in combination with necitumumab in patients with EGFR-mutant non-small cell lung cancer (NSCLC). --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- T790M --- --- T790M ---

Testing will be one-sided, at the 0.05-level.. Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Metastatic Lung Non-Small Cell Carcinoma Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVE: I. To determine the safety and tolerability of osimertinib (AZD9291) in combination with necitumumab in patients with EGFR-mutant non-small cell lung cancer (NSCLC). --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M ---

Testing will be one-sided, at the 0.05-level.. Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Metastatic Lung Non-Small Cell Carcinoma Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVE: I. To determine the safety and tolerability of osimertinib (AZD9291) in combination with necitumumab in patients with EGFR-mutant non-small cell lung cancer (NSCLC). --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M ---

Testing will be one-sided, at the 0.05-level.. Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Metastatic Lung Non-Small Cell Carcinoma Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVE: I. To determine the safety and tolerability of osimertinib (AZD9291) in combination with necitumumab in patients with EGFR-mutant non-small cell lung cancer (NSCLC). --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M ---

Testing will be one-sided, at the 0.05-level.. Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Metastatic Lung Non-Small Cell Carcinoma Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVE: I. To determine the safety and tolerability of osimertinib (AZD9291) in combination with necitumumab in patients with EGFR-mutant non-small cell lung cancer (NSCLC). --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M ---

Testing will be one-sided, at the 0.05-level.. Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Metastatic Lung Non-Small Cell Carcinoma Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVE: I. To determine the safety and tolerability of osimertinib (AZD9291) in combination with necitumumab in patients with EGFR-mutant non-small cell lung cancer (NSCLC). --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M ---

Testing will be one-sided, at the 0.05-level.. Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Metastatic Lung Non-Small Cell Carcinoma Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVE: I. To determine the safety and tolerability of osimertinib (AZD9291) in combination with necitumumab in patients with EGFR-mutant non-small cell lung cancer (NSCLC). --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M ---

Testing will be one-sided, at the 0.05-level.. Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Metastatic Lung Non-Small Cell Carcinoma Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVE: I. To determine the safety and tolerability of osimertinib (AZD9291) in combination with necitumumab in patients with EGFR-mutant non-small cell lung cancer (NSCLC). --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- L858R --- --- L861Q --- --- T790M ---

Testing will be one-sided, at the 0.05-level.. Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Metastatic Lung Non-Small Cell Carcinoma Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVE: I. To determine the safety and tolerability of osimertinib (AZD9291) in combination with necitumumab in patients with EGFR-mutant non-small cell lung cancer (NSCLC). --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- L858R --- --- L861Q --- --- T790M --- --- T790M ---

Testing will be one-sided, at the 0.05-level.. Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Metastatic Lung Non-Small Cell Carcinoma Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVE: I. To determine the safety and tolerability of osimertinib (AZD9291) in combination with necitumumab in patients with EGFR-mutant non-small cell lung cancer (NSCLC). --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- T790M ---

Testing will be one-sided, at the 0.05-level.. Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Metastatic Lung Non-Small Cell Carcinoma Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVE: I. To determine the safety and tolerability of osimertinib (AZD9291) in combination with necitumumab in patients with EGFR-mutant non-small cell lung cancer (NSCLC). --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- T790M --- --- T790M ---

Testing will be one-sided, at the 0.05-level.. Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Metastatic Lung Non-Small Cell Carcinoma Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVE: I. To determine the safety and tolerability of osimertinib (AZD9291) in combination with necitumumab in patients with EGFR-mutant non-small cell lung cancer (NSCLC). --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M ---

Testing will be one-sided, at the 0.05-level.. Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Metastatic Lung Non-Small Cell Carcinoma Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVE: I. To determine the safety and tolerability of osimertinib (AZD9291) in combination with necitumumab in patients with EGFR-mutant non-small cell lung cancer (NSCLC). --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M ---

Testing will be one-sided, at the 0.05-level.. Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Metastatic Lung Non-Small Cell Carcinoma Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVE: I. To determine the safety and tolerability of osimertinib (AZD9291) in combination with necitumumab in patients with EGFR-mutant non-small cell lung cancer (NSCLC). --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M ---

Testing will be one-sided, at the 0.05-level.. Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Metastatic Lung Non-Small Cell Carcinoma Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVE: I. To determine the safety and tolerability of osimertinib (AZD9291) in combination with necitumumab in patients with EGFR-mutant non-small cell lung cancer (NSCLC). --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M ---

Testing will be one-sided, at the 0.05-level.. Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Metastatic Lung Non-Small Cell Carcinoma Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVE: I. To determine the safety and tolerability of osimertinib (AZD9291) in combination with necitumumab in patients with EGFR-mutant non-small cell lung cancer (NSCLC). --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M ---

Testing will be one-sided, at the 0.05-level.. Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Inclusion Criteria: - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell lung cancer (NSCLC) - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21 L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a Clinical Laboratory Improvement Act (CLIA) certified test - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd generation EGFR-TKI including AZD9291 allowed for dose escalation) - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M negative confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and AZD9291) and EGFR monoclonal antibodies - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib, HM61713, 2) be treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after progression on last EGFR-TKI that indicates preservation of EGFR-T790M post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for trial and for biopsy, and testing for EGFR T790M will be performed as part of initial biopsy for trial) - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20 insertion by a CLIA certified test, and 2) have progressive disease on or after platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond EGFR-TKI (i.e., osimertinib, poziotinib, TAK-778) and EGFR monoclonal antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib, gefitinib, afatinib) are eligible provided that they did not achieve a response to treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more - For Dose Expansion Cohort E: patient must have progressive disease on AZD9291 as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be treatment naive to EGFR-monoclonal antibody - Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E) - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic resonance imaging (MRI) within 42 days prior to registration; the CT from a combined positron emission tomography (PET)/CT may be used only if it is of diagnostic; laboratory parameters are not acceptable as the only evidence of disease - Any number of prior therapies is allowed - Eastern Cooperative Oncology Group (ECOG) performance status =< 1 - Patients must have the ability to swallow tablets - Life expectancy of greater 3 months - Absolute neutrophil count >= 1,500/mcL - Platelets >= 100,000/mcL - Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 ULN) - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal - Creatinine =< 1.5 x ULN OR - Creatinine clearance >= 50 mL/min - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or necitumumab: - Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration); - Vasectomized male subject or vasectomized partner of female subjects - Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 3 months after study completion; - Intrauterine device (IUD); - Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams) - Additionally, for all methods above (except for abstinence), male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must use condoms for the duration of the study and for 6 months following completion of therapy - Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post menopausal (amenorrheic for at least 12 months); should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Patients with untreated brain metastases are allowed provided that the patient is clinically asymptomatic and stable; patients with a prior history of symptomatic brain metastases are eligible provided: - The brain metastases have been treated - The patient is asymptomatic from the brain metastases at enrollment - Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration - The brain metastases are stable on pre-registration imaging - Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs - Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2 - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Major surgery within 21 days of starting protocol treatment - Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment with the exception that patients on AZD9291 for cohorts B, C and E can continue AZD9291 and need not discontinue prior to enrollment - Patients who are receiving any other investigational agents; patients must have discontinued any other investigational agents for at least 5 half-lives or 3 months, whichever is greater, prior to initiation of osimertinib in an investigational setting - Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease - Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects of CYP3A4 - Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec - Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block) - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval and cause torsades de pointes - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition (MUGA) - The effects of AZD9291 and necitumumab on the developing human fetus are unknown; for this reason and because EGFR inhibitors are known to be teratogenic, pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with AZD9291 and necitumumab; these potential risks may also apply to other agents used in this study - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD9291 Metastatic Lung Non-Small Cell Carcinoma Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 Carcinoma Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVE: I. To determine the safety and tolerability of osimertinib (AZD9291) in combination with necitumumab in patients with EGFR-mutant non-small cell lung cancer (NSCLC). --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M --- --- T790M ---

Primary Outcomes

Description: Defined as the highest dose tested in which only 0 or 1 out of 6 evaluable patients experience a dose limiting toxicity, as graded by the National Cancer Institute (NCI) Common terminology Criteria for Adverse Events (CTCAE) version 5.0. The recommended phase II dose (RP2D) will be the MTD, pending review of other safety/tolerability considerations. The RP2D will be determined based upon the MTD in the dose escalation portion as well as other considerations such as toxicities at additional courses. After completing the 4 expansion cohorts, the dose level will be re-reviewed to confirm that the RP2D is in fact well tolerated.

Measure: Maximum tolerated dose (MTD) of necitumumab combined with osimertinib

Time: 21 days

Description: Will be graded according to NCI CTCAE version 5.0. Grade and attribution will be summarized by dose level, cycle, organ system and type.

Measure: Incidence of toxicity

Time: Up to 1 year

Secondary Outcomes

Description: Will be graded according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. ORR will be calculated as the percent of patients in each of the expansion cohorts whose best confirmed response is complete response (CR) or partial response (PR). Point estimates and associated 90% confidence intervals will be calculated.

Measure: Objective response rate (ORR) in patients treated at the recommended phase II dose

Time: Up to 1 year

Description: Kaplan-Meier plots will be used to summarize the progression-free survival. Medians and associated 95% confidence intervals will be calculated.

Measure: Progression-free survival (PFS)

Time: From start of treatment to time of progression or death, whichever occurs first, assessed up to 1 year

Description: DCR will be the proportion of patients in each of the expansion cohorts whose best confirmed response is CR, PR, or stable disease. Point estimates and associated 90% confidence intervals will be calculated.

Measure: Disease control rate (DCR) with combination osimertinib and necitumumab

Time: Up to 1 year

Other Outcomes

Description: The PK analyses will be descriptive and will permit comparison of the plasma levels of osimertinib and its metabolites in the presence of necitumumab (in this trial) with levels in other studies where osimertinib is given alone or combined with other drugs. We will estimate mean PK parameters as well as the between-patient variability. Results will be listed and plotted, by dose as well as by objective response, qualitative patterns will be described, and means and standard deviations will be calculated for use in planning follow-up studies.

Measure: Pharmacokinetic (PK) parameters of osimertinib in combination with necitumumab

Time: Prior to dosing on day 1 of course 2, 1, 2, 4, 6, 8, and 24 hours after dosing in course 2 (dose escalation and cohort A); prior to treatment on day 1 of course 2 for up to 4 courses (cohorts B, C, and D)

Description: Will study biopsied tumor tissue as well as serial plasma deoxyribonucleic acid specimens. For each cohort alone, Fisher's exact test, and in a stratified analysis including all cohorts, an exact logistic regression model, will be used to examine the association with objective response and a Cox proportional hazards model will be used to examine the association with PFS. Odds ratio's and hazard ratio's will be estimated and associated 90% two-sided confidence intervals will be constructed. Testing will be one-sided, at the 0.05-level.

Measure: Presence of biomarkers of response and resistance to previous EGFR-tyrosine kinase inhibitors

Time: Up to 1 year

306 A Phase 1b/2 Study of ASP2215 in Combination With Erlotinib in Subjects With EGFR Activating Mutation-Positive (EGFRm+) Advanced NSCLC Who Have Acquired Resistance to an EGFR Tyrosine Kinase Inhibitor (TKI)

The purpose of the Phase 1b part of the study was to evaluate the safety and tolerability of ASP2215 in combination with erlotinib and determine the recommended phase 2 dose (RP2D) of ASP2215. The purpose of the Phase 2 part of the study was to evaluate the objective response rate (ORR) of the RP2D of ASP2215 in combination with erlotinib.

NCT02495233
Conditions
  1. Non-Small-Cell Lung Cancer
Interventions
  1. Drug: Gilteritinib
  2. Drug: Erlotinib
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

- Participant's baseline tumor specimen (obtained after participant developed resistance to EGFR TKI therapy) is T790M negative. --- T790M ---

- Participant received any agent with antitumor activity (other than an EGFR inhibitor, including a T790M inhibitor) including chemotherapy, radiotherapy, immunotherapy, within 14 days prior to the first dose of study drug (palliative radiotherapy is allowed). --- T790M ---

Primary Outcomes

Measure: Number of Participants With Dose Limiting Toxicities (DLTs)

Time: Cycle 1 and Cycle ≥2 (up to 141 days)

Description: Treatment-emergent adverse events (TEAE) was defined as an adverse event (AE) that started after administration of the study drugs and occurred within 30 days of the last dose of the study drugs. If a participant experienced an event both during the preinvestigational period and during the investigational period, the event was considered a TEAE only if it worsened in severity.

Measure: Number of Participants With Adverse Events

Time: From first dose of study drug up to 30 days after the last dose of study (maximum study drug exposure 114 days)

Secondary Outcomes

Measure: Area Under the Concentration-time Curve at 24 Hours (AUC24) for Gilteritinib

Time: 0, 0.5, 1, 2, 4, 6, 24 hours post-dose on Days 1 and 28 of cycle 1

Measure: Maximum Concentration (Cmax) for Gilteritinib

Time: 0, 0.5, 1, 2, 4, 6, 24 hours post-dose on Days 1 and 28 of cycle 1

Measure: Time After Dosing When Cmax Occurs (Tmax) for Gilteritinib

Time: 0, 0.5, 1, 2, 4, 6, 24 hours post-dose on Days 1 and 28 of cycle 1

Description: All participants in Gilteritinib 120 mg + Erlotinib 150 mg group discontinued before cycle 3.

Measure: Concentration Immediately Prior to Dosing at Multiple Dosing (Ctrough) of Gilteritinib

Time: Predose on Day 1, 3, 8, 15, 22, 28 of cycle 1, Day 1 of cycle 3 and Day 1 of cycle 4

Measure: AUC24 of Erlotinib

Time: 0, 0.5, 1, 2, 4, 6, 24 hours post-dose on Day 28 of cycle 1

Measure: Cmax of Erlotinib

Time: 0, 0.5, 1, 2, 4, 6, 24 hours post-dose on Day 28 of cycle 1

Measure: Tmax of Erlotinib

Time: 0, 0.5, 1, 2, 4, 6, 24 hours post-dose on Day 28 of cycle 1

Measure: Ctrough of Erlotinib

Time: Day 8, 15, 22, 28 of cycle 1

Description: ORR was defined as Objective Response Rate (ORR) was the proportion of patients whose best overall response was complete response (CR) or partial response (PR) per RECIST version 1.1. Only patients with measurable disease at baseline were to be included in the analysis of ORR.

Measure: Objective Response Rate (ORR) in Phase 1b

Time: End of treatment (approximately 4 months)

307 A Randomized, Open-label, Phase II Study of Maintaining Pan-ERBB Blockade Following Platinum-based Induction Chemotherapy in Patients With EGFR Mutated, Metastatic Non-small-cell Lung Cancer Progressing After Treatment With Afatinib as First EGFR-targeting Agent

This study aims to compare the efficacy of afatinib maintenance with pemetrexed maintenance following induction therapy with platinum/ pemetrexed in patients with metastatic epidermal growth factor receptor (EGFR) mutated non-small-cell lung cancer (NSCLC) progressing after first-line treatment with afatinib with respect to progression-free survival.

NCT02488694
Conditions
  1. Non-small-cell Lung Cancer With Somatic EGFR Mutations
Interventions
  1. Drug: Afatinib
  2. Drug: Pemetrexed
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Ability to comply with the protocol for the duration of the study, including hospital/office visits for treatment and scheduled follow-up visits and examinations Exclusion Criteria: 1. Systemic therapy for metastatic disease or relapse other than (a) first-line therapy with afatinib or (b) afatinib given as first EGFR-targeting agent following up to 4 courses of platinum-based chemotherapy with no disease progression between first-line chemotherapy and initiation of afatinib (prior adjuvant chemotherapy is allowed) and 3 to 4 cycles of induction chemotherapy with cisplatin or carboplatin and pemetrexed following afatinib failure 2. Prior treatment with erlotinib, gefitinib or other investigational or approved EGFR-targeting small molecules or antibodies 3. Known EGFR T790M mutation (analysis not mandatory) 4. Major surgery within 4 weeks before starting study treatment or scheduled for surgery during the projected course of the study 5. Extended radiotherapy within 4 weeks prior to randomization, except as follows: 1. Palliative, limited local radiation to non-target lesions (e.g. --- T790M ---

Primary Outcomes

Description: The primary endpoint of this study is progression-free survival (RECIST 1.1).

Measure: Progression-free survival

Time: 40 months

Secondary Outcomes

Description: Efficacy measure

Measure: Overall survival

Time: 40 months

Description: Objective response rate (ORR), clinical benefit rate (RECIST 1.1); Efficacy measure

Measure: Objective response rate

Time: 40 months

Description: Health-Related Quality of Life (HRQoL)

Measure: Quality of Life

Time: 40 month

Description: Safety, toxicity (intensity and incidence of adverse events, graded according to US NCI CTCAE Version 4.03)

Measure: Safety (intensity and incidence of adverse events, graded according to US NCI CTCAE Version 4.03)

Time: 40 month

308 A Single Arm, Open-label, Phase 2 Study Evaluating the Efficacy, Safety and PK of HM61713 in Patients With T790M-positive NSCLC After Treatment With an Epidermal Growth Factor Receptor-tyrosine Kinase Inhibitor

The purpose of this study is to evaluate the efficacy, safety and pharmacokinetics of HM61713 in patients with T790M-positive non-small cell lung cancer (NSCLC) after treatment with an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI).

NCT02485652
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: HM61713
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

A Single Arm, Open-label, Phase 2 Study Evaluating the Efficacy, Safety and PK of HM61713 in Patients With T790M-positive NSCLC After Treatment With an Epidermal Growth Factor Receptor-tyrosine Kinase Inhibitor. --- T790M ---

Phase II Trial of HM61713 for the Treatment of ≥2nd Line T790M Mutation Positive Adenocarcinoma of the Lung The purpose of this study is to evaluate the efficacy, safety and pharmacokinetics of HM61713 in patients with T790M-positive non-small cell lung cancer (NSCLC) after treatment with an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). --- T790M ---

Phase II Trial of HM61713 for the Treatment of ≥2nd Line T790M Mutation Positive Adenocarcinoma of the Lung The purpose of this study is to evaluate the efficacy, safety and pharmacokinetics of HM61713 in patients with T790M-positive non-small cell lung cancer (NSCLC) after treatment with an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). --- T790M --- --- T790M ---

The QT interval will be rate-corrected using 3 methods: QTcF, QTcB and QTcS.. To assess the safety and tolerability of HM61713.. Inclusion Criteria: - Age: at least 20 years of age - Cytologically or histologically confirmed adenocarcinoma of locally advanced or metastatic NSCLC which is not amenable to curative surgery or radiotherapy - Radiologically confirmed disease progression after at least one line of treatment with an EGFR-TKI - At least one documented EGFR mutation which is known to be related with susceptibility to EGFR-TKIs (including G719X, exon 19 deletion, L858R, and L861Q) - World Health Organization (WHO) performance score of 0 to 1 with life expectancy of at least 3 months - Centrally confirmed T790M mutation positive tumor status from a tumor sample taken after confirmation of disease progression on the most recent anticancer treatment regimen - At least one lesion (excluding the brain), not previously irradiated that can be accurately measured per RECIST version 1.1 - Adequate hematological and biological function - Females of child-bearing potential must agree to use adequate contraception and for 3 months after the last dose of study drug - Male patients should be documented to be sterile or agree to use barrier contraception - Recovery to ≤ Grade 1 or baseline of any toxicities, except for stable sensory neuropathy ≤ Grade 2 and alopecia Exclusion Criteria: - Known history of hypersensitivity to active or inactive excipients of HM61713 or drugs with a similar chemical structure of HM61713 - Previous treatment with anticancer therapies, EGFR-TKI, HM61713, or other drugs that target T790M-positive mutant EGFR with sparing of wild-type, investigational agent(s) within 28 days prior to the first administration of study drug, radiotherapy - Any non-study related significant surgical procedures within the past 28 days prior to the first administration of study drug - Spinal cord compression, leptomeningeal carcinomatosis or active symptomatic brain metastases - History of any other malignancy - Clinically significant uncontrolled condition(s) - Active or chronic pancreatitis - Anyone with cardiac abnormalities or history - Presence or history of ILD, drug-induced ILD, or presence of radiation pneumonitis - Pregnant or breast feeding - In the opinion of the investigator, the patient is an unsuitable candidate to receive HM61713 Inclusion Criteria: - Age: at least 20 years of age - Cytologically or histologically confirmed adenocarcinoma of locally advanced or metastatic NSCLC which is not amenable to curative surgery or radiotherapy - Radiologically confirmed disease progression after at least one line of treatment with an EGFR-TKI - At least one documented EGFR mutation which is known to be related with susceptibility to EGFR-TKIs (including G719X, exon 19 deletion, L858R, and L861Q) - World Health Organization (WHO) performance score of 0 to 1 with life expectancy of at least 3 months - Centrally confirmed T790M mutation positive tumor status from a tumor sample taken after confirmation of disease progression on the most recent anticancer treatment regimen - At least one lesion (excluding the brain), not previously irradiated that can be accurately measured per RECIST version 1.1 - Adequate hematological and biological function - Females of child-bearing potential must agree to use adequate contraception and for 3 months after the last dose of study drug - Male patients should be documented to be sterile or agree to use barrier contraception - Recovery to ≤ Grade 1 or baseline of any toxicities, except for stable sensory neuropathy ≤ Grade 2 and alopecia Exclusion Criteria: - Known history of hypersensitivity to active or inactive excipients of HM61713 or drugs with a similar chemical structure of HM61713 - Previous treatment with anticancer therapies, EGFR-TKI, HM61713, or other drugs that target T790M-positive mutant EGFR with sparing of wild-type, investigational agent(s) within 28 days prior to the first administration of study drug, radiotherapy - Any non-study related significant surgical procedures within the past 28 days prior to the first administration of study drug - Spinal cord compression, leptomeningeal carcinomatosis or active symptomatic brain metastases - History of any other malignancy - Clinically significant uncontrolled condition(s) - Active or chronic pancreatitis - Anyone with cardiac abnormalities or history - Presence or history of ILD, drug-induced ILD, or presence of radiation pneumonitis - Pregnant or breast feeding - In the opinion of the investigator, the patient is an unsuitable candidate to receive HM61713 Non Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung This is a single-arm, open-label, Phase 2 study to assess the anti-tumor efficacy of oral single agent HM61713 administered to patients with T790M-positive NSCLC after treatment with an EGFR-TKI as measured by objective response rate (ORR). --- L858R --- --- L861Q --- --- T790M ---

The QT interval will be rate-corrected using 3 methods: QTcF, QTcB and QTcS.. To assess the safety and tolerability of HM61713.. Inclusion Criteria: - Age: at least 20 years of age - Cytologically or histologically confirmed adenocarcinoma of locally advanced or metastatic NSCLC which is not amenable to curative surgery or radiotherapy - Radiologically confirmed disease progression after at least one line of treatment with an EGFR-TKI - At least one documented EGFR mutation which is known to be related with susceptibility to EGFR-TKIs (including G719X, exon 19 deletion, L858R, and L861Q) - World Health Organization (WHO) performance score of 0 to 1 with life expectancy of at least 3 months - Centrally confirmed T790M mutation positive tumor status from a tumor sample taken after confirmation of disease progression on the most recent anticancer treatment regimen - At least one lesion (excluding the brain), not previously irradiated that can be accurately measured per RECIST version 1.1 - Adequate hematological and biological function - Females of child-bearing potential must agree to use adequate contraception and for 3 months after the last dose of study drug - Male patients should be documented to be sterile or agree to use barrier contraception - Recovery to ≤ Grade 1 or baseline of any toxicities, except for stable sensory neuropathy ≤ Grade 2 and alopecia Exclusion Criteria: - Known history of hypersensitivity to active or inactive excipients of HM61713 or drugs with a similar chemical structure of HM61713 - Previous treatment with anticancer therapies, EGFR-TKI, HM61713, or other drugs that target T790M-positive mutant EGFR with sparing of wild-type, investigational agent(s) within 28 days prior to the first administration of study drug, radiotherapy - Any non-study related significant surgical procedures within the past 28 days prior to the first administration of study drug - Spinal cord compression, leptomeningeal carcinomatosis or active symptomatic brain metastases - History of any other malignancy - Clinically significant uncontrolled condition(s) - Active or chronic pancreatitis - Anyone with cardiac abnormalities or history - Presence or history of ILD, drug-induced ILD, or presence of radiation pneumonitis - Pregnant or breast feeding - In the opinion of the investigator, the patient is an unsuitable candidate to receive HM61713 Inclusion Criteria: - Age: at least 20 years of age - Cytologically or histologically confirmed adenocarcinoma of locally advanced or metastatic NSCLC which is not amenable to curative surgery or radiotherapy - Radiologically confirmed disease progression after at least one line of treatment with an EGFR-TKI - At least one documented EGFR mutation which is known to be related with susceptibility to EGFR-TKIs (including G719X, exon 19 deletion, L858R, and L861Q) - World Health Organization (WHO) performance score of 0 to 1 with life expectancy of at least 3 months - Centrally confirmed T790M mutation positive tumor status from a tumor sample taken after confirmation of disease progression on the most recent anticancer treatment regimen - At least one lesion (excluding the brain), not previously irradiated that can be accurately measured per RECIST version 1.1 - Adequate hematological and biological function - Females of child-bearing potential must agree to use adequate contraception and for 3 months after the last dose of study drug - Male patients should be documented to be sterile or agree to use barrier contraception - Recovery to ≤ Grade 1 or baseline of any toxicities, except for stable sensory neuropathy ≤ Grade 2 and alopecia Exclusion Criteria: - Known history of hypersensitivity to active or inactive excipients of HM61713 or drugs with a similar chemical structure of HM61713 - Previous treatment with anticancer therapies, EGFR-TKI, HM61713, or other drugs that target T790M-positive mutant EGFR with sparing of wild-type, investigational agent(s) within 28 days prior to the first administration of study drug, radiotherapy - Any non-study related significant surgical procedures within the past 28 days prior to the first administration of study drug - Spinal cord compression, leptomeningeal carcinomatosis or active symptomatic brain metastases - History of any other malignancy - Clinically significant uncontrolled condition(s) - Active or chronic pancreatitis - Anyone with cardiac abnormalities or history - Presence or history of ILD, drug-induced ILD, or presence of radiation pneumonitis - Pregnant or breast feeding - In the opinion of the investigator, the patient is an unsuitable candidate to receive HM61713 Non Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung This is a single-arm, open-label, Phase 2 study to assess the anti-tumor efficacy of oral single agent HM61713 administered to patients with T790M-positive NSCLC after treatment with an EGFR-TKI as measured by objective response rate (ORR). --- L858R --- --- L861Q --- --- T790M --- --- T790M ---

The QT interval will be rate-corrected using 3 methods: QTcF, QTcB and QTcS.. To assess the safety and tolerability of HM61713.. Inclusion Criteria: - Age: at least 20 years of age - Cytologically or histologically confirmed adenocarcinoma of locally advanced or metastatic NSCLC which is not amenable to curative surgery or radiotherapy - Radiologically confirmed disease progression after at least one line of treatment with an EGFR-TKI - At least one documented EGFR mutation which is known to be related with susceptibility to EGFR-TKIs (including G719X, exon 19 deletion, L858R, and L861Q) - World Health Organization (WHO) performance score of 0 to 1 with life expectancy of at least 3 months - Centrally confirmed T790M mutation positive tumor status from a tumor sample taken after confirmation of disease progression on the most recent anticancer treatment regimen - At least one lesion (excluding the brain), not previously irradiated that can be accurately measured per RECIST version 1.1 - Adequate hematological and biological function - Females of child-bearing potential must agree to use adequate contraception and for 3 months after the last dose of study drug - Male patients should be documented to be sterile or agree to use barrier contraception - Recovery to ≤ Grade 1 or baseline of any toxicities, except for stable sensory neuropathy ≤ Grade 2 and alopecia Exclusion Criteria: - Known history of hypersensitivity to active or inactive excipients of HM61713 or drugs with a similar chemical structure of HM61713 - Previous treatment with anticancer therapies, EGFR-TKI, HM61713, or other drugs that target T790M-positive mutant EGFR with sparing of wild-type, investigational agent(s) within 28 days prior to the first administration of study drug, radiotherapy - Any non-study related significant surgical procedures within the past 28 days prior to the first administration of study drug - Spinal cord compression, leptomeningeal carcinomatosis or active symptomatic brain metastases - History of any other malignancy - Clinically significant uncontrolled condition(s) - Active or chronic pancreatitis - Anyone with cardiac abnormalities or history - Presence or history of ILD, drug-induced ILD, or presence of radiation pneumonitis - Pregnant or breast feeding - In the opinion of the investigator, the patient is an unsuitable candidate to receive HM61713 Inclusion Criteria: - Age: at least 20 years of age - Cytologically or histologically confirmed adenocarcinoma of locally advanced or metastatic NSCLC which is not amenable to curative surgery or radiotherapy - Radiologically confirmed disease progression after at least one line of treatment with an EGFR-TKI - At least one documented EGFR mutation which is known to be related with susceptibility to EGFR-TKIs (including G719X, exon 19 deletion, L858R, and L861Q) - World Health Organization (WHO) performance score of 0 to 1 with life expectancy of at least 3 months - Centrally confirmed T790M mutation positive tumor status from a tumor sample taken after confirmation of disease progression on the most recent anticancer treatment regimen - At least one lesion (excluding the brain), not previously irradiated that can be accurately measured per RECIST version 1.1 - Adequate hematological and biological function - Females of child-bearing potential must agree to use adequate contraception and for 3 months after the last dose of study drug - Male patients should be documented to be sterile or agree to use barrier contraception - Recovery to ≤ Grade 1 or baseline of any toxicities, except for stable sensory neuropathy ≤ Grade 2 and alopecia Exclusion Criteria: - Known history of hypersensitivity to active or inactive excipients of HM61713 or drugs with a similar chemical structure of HM61713 - Previous treatment with anticancer therapies, EGFR-TKI, HM61713, or other drugs that target T790M-positive mutant EGFR with sparing of wild-type, investigational agent(s) within 28 days prior to the first administration of study drug, radiotherapy - Any non-study related significant surgical procedures within the past 28 days prior to the first administration of study drug - Spinal cord compression, leptomeningeal carcinomatosis or active symptomatic brain metastases - History of any other malignancy - Clinically significant uncontrolled condition(s) - Active or chronic pancreatitis - Anyone with cardiac abnormalities or history - Presence or history of ILD, drug-induced ILD, or presence of radiation pneumonitis - Pregnant or breast feeding - In the opinion of the investigator, the patient is an unsuitable candidate to receive HM61713 Non Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung This is a single-arm, open-label, Phase 2 study to assess the anti-tumor efficacy of oral single agent HM61713 administered to patients with T790M-positive NSCLC after treatment with an EGFR-TKI as measured by objective response rate (ORR). --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- L858R --- --- L861Q --- --- T790M ---

The QT interval will be rate-corrected using 3 methods: QTcF, QTcB and QTcS.. To assess the safety and tolerability of HM61713.. Inclusion Criteria: - Age: at least 20 years of age - Cytologically or histologically confirmed adenocarcinoma of locally advanced or metastatic NSCLC which is not amenable to curative surgery or radiotherapy - Radiologically confirmed disease progression after at least one line of treatment with an EGFR-TKI - At least one documented EGFR mutation which is known to be related with susceptibility to EGFR-TKIs (including G719X, exon 19 deletion, L858R, and L861Q) - World Health Organization (WHO) performance score of 0 to 1 with life expectancy of at least 3 months - Centrally confirmed T790M mutation positive tumor status from a tumor sample taken after confirmation of disease progression on the most recent anticancer treatment regimen - At least one lesion (excluding the brain), not previously irradiated that can be accurately measured per RECIST version 1.1 - Adequate hematological and biological function - Females of child-bearing potential must agree to use adequate contraception and for 3 months after the last dose of study drug - Male patients should be documented to be sterile or agree to use barrier contraception - Recovery to ≤ Grade 1 or baseline of any toxicities, except for stable sensory neuropathy ≤ Grade 2 and alopecia Exclusion Criteria: - Known history of hypersensitivity to active or inactive excipients of HM61713 or drugs with a similar chemical structure of HM61713 - Previous treatment with anticancer therapies, EGFR-TKI, HM61713, or other drugs that target T790M-positive mutant EGFR with sparing of wild-type, investigational agent(s) within 28 days prior to the first administration of study drug, radiotherapy - Any non-study related significant surgical procedures within the past 28 days prior to the first administration of study drug - Spinal cord compression, leptomeningeal carcinomatosis or active symptomatic brain metastases - History of any other malignancy - Clinically significant uncontrolled condition(s) - Active or chronic pancreatitis - Anyone with cardiac abnormalities or history - Presence or history of ILD, drug-induced ILD, or presence of radiation pneumonitis - Pregnant or breast feeding - In the opinion of the investigator, the patient is an unsuitable candidate to receive HM61713 Inclusion Criteria: - Age: at least 20 years of age - Cytologically or histologically confirmed adenocarcinoma of locally advanced or metastatic NSCLC which is not amenable to curative surgery or radiotherapy - Radiologically confirmed disease progression after at least one line of treatment with an EGFR-TKI - At least one documented EGFR mutation which is known to be related with susceptibility to EGFR-TKIs (including G719X, exon 19 deletion, L858R, and L861Q) - World Health Organization (WHO) performance score of 0 to 1 with life expectancy of at least 3 months - Centrally confirmed T790M mutation positive tumor status from a tumor sample taken after confirmation of disease progression on the most recent anticancer treatment regimen - At least one lesion (excluding the brain), not previously irradiated that can be accurately measured per RECIST version 1.1 - Adequate hematological and biological function - Females of child-bearing potential must agree to use adequate contraception and for 3 months after the last dose of study drug - Male patients should be documented to be sterile or agree to use barrier contraception - Recovery to ≤ Grade 1 or baseline of any toxicities, except for stable sensory neuropathy ≤ Grade 2 and alopecia Exclusion Criteria: - Known history of hypersensitivity to active or inactive excipients of HM61713 or drugs with a similar chemical structure of HM61713 - Previous treatment with anticancer therapies, EGFR-TKI, HM61713, or other drugs that target T790M-positive mutant EGFR with sparing of wild-type, investigational agent(s) within 28 days prior to the first administration of study drug, radiotherapy - Any non-study related significant surgical procedures within the past 28 days prior to the first administration of study drug - Spinal cord compression, leptomeningeal carcinomatosis or active symptomatic brain metastases - History of any other malignancy - Clinically significant uncontrolled condition(s) - Active or chronic pancreatitis - Anyone with cardiac abnormalities or history - Presence or history of ILD, drug-induced ILD, or presence of radiation pneumonitis - Pregnant or breast feeding - In the opinion of the investigator, the patient is an unsuitable candidate to receive HM61713 Non Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung This is a single-arm, open-label, Phase 2 study to assess the anti-tumor efficacy of oral single agent HM61713 administered to patients with T790M-positive NSCLC after treatment with an EGFR-TKI as measured by objective response rate (ORR). --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- L858R --- --- L861Q --- --- T790M --- --- T790M ---

The QT interval will be rate-corrected using 3 methods: QTcF, QTcB and QTcS.. To assess the safety and tolerability of HM61713.. Inclusion Criteria: - Age: at least 20 years of age - Cytologically or histologically confirmed adenocarcinoma of locally advanced or metastatic NSCLC which is not amenable to curative surgery or radiotherapy - Radiologically confirmed disease progression after at least one line of treatment with an EGFR-TKI - At least one documented EGFR mutation which is known to be related with susceptibility to EGFR-TKIs (including G719X, exon 19 deletion, L858R, and L861Q) - World Health Organization (WHO) performance score of 0 to 1 with life expectancy of at least 3 months - Centrally confirmed T790M mutation positive tumor status from a tumor sample taken after confirmation of disease progression on the most recent anticancer treatment regimen - At least one lesion (excluding the brain), not previously irradiated that can be accurately measured per RECIST version 1.1 - Adequate hematological and biological function - Females of child-bearing potential must agree to use adequate contraception and for 3 months after the last dose of study drug - Male patients should be documented to be sterile or agree to use barrier contraception - Recovery to ≤ Grade 1 or baseline of any toxicities, except for stable sensory neuropathy ≤ Grade 2 and alopecia Exclusion Criteria: - Known history of hypersensitivity to active or inactive excipients of HM61713 or drugs with a similar chemical structure of HM61713 - Previous treatment with anticancer therapies, EGFR-TKI, HM61713, or other drugs that target T790M-positive mutant EGFR with sparing of wild-type, investigational agent(s) within 28 days prior to the first administration of study drug, radiotherapy - Any non-study related significant surgical procedures within the past 28 days prior to the first administration of study drug - Spinal cord compression, leptomeningeal carcinomatosis or active symptomatic brain metastases - History of any other malignancy - Clinically significant uncontrolled condition(s) - Active or chronic pancreatitis - Anyone with cardiac abnormalities or history - Presence or history of ILD, drug-induced ILD, or presence of radiation pneumonitis - Pregnant or breast feeding - In the opinion of the investigator, the patient is an unsuitable candidate to receive HM61713 Inclusion Criteria: - Age: at least 20 years of age - Cytologically or histologically confirmed adenocarcinoma of locally advanced or metastatic NSCLC which is not amenable to curative surgery or radiotherapy - Radiologically confirmed disease progression after at least one line of treatment with an EGFR-TKI - At least one documented EGFR mutation which is known to be related with susceptibility to EGFR-TKIs (including G719X, exon 19 deletion, L858R, and L861Q) - World Health Organization (WHO) performance score of 0 to 1 with life expectancy of at least 3 months - Centrally confirmed T790M mutation positive tumor status from a tumor sample taken after confirmation of disease progression on the most recent anticancer treatment regimen - At least one lesion (excluding the brain), not previously irradiated that can be accurately measured per RECIST version 1.1 - Adequate hematological and biological function - Females of child-bearing potential must agree to use adequate contraception and for 3 months after the last dose of study drug - Male patients should be documented to be sterile or agree to use barrier contraception - Recovery to ≤ Grade 1 or baseline of any toxicities, except for stable sensory neuropathy ≤ Grade 2 and alopecia Exclusion Criteria: - Known history of hypersensitivity to active or inactive excipients of HM61713 or drugs with a similar chemical structure of HM61713 - Previous treatment with anticancer therapies, EGFR-TKI, HM61713, or other drugs that target T790M-positive mutant EGFR with sparing of wild-type, investigational agent(s) within 28 days prior to the first administration of study drug, radiotherapy - Any non-study related significant surgical procedures within the past 28 days prior to the first administration of study drug - Spinal cord compression, leptomeningeal carcinomatosis or active symptomatic brain metastases - History of any other malignancy - Clinically significant uncontrolled condition(s) - Active or chronic pancreatitis - Anyone with cardiac abnormalities or history - Presence or history of ILD, drug-induced ILD, or presence of radiation pneumonitis - Pregnant or breast feeding - In the opinion of the investigator, the patient is an unsuitable candidate to receive HM61713 Non Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung This is a single-arm, open-label, Phase 2 study to assess the anti-tumor efficacy of oral single agent HM61713 administered to patients with T790M-positive NSCLC after treatment with an EGFR-TKI as measured by objective response rate (ORR). --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- L858R --- --- L861Q --- --- T790M --- --- T790M --- --- T790M ---

Primary Outcomes

Description: To assess the anti-tumor efficacy of HM61713 as measured by objective response rate (ORR).

Measure: Objective response rate (ORR)

Time: At baseline and every 6 weeks from time of first dose until date of progression, assessed up to 12 months

Secondary Outcomes

Description: To assess clinical efficacy of HM61713 regarding disease control rate (DCR).

Measure: Disease control rate (DCR), defined as the proportion of patients with a documented CR, PR, and SD during the treatment cycles according to the RECIST version 1.1

Time: At baseline and every 6 weeks from time of first dose until date of progression, assessed up to 12 months

Description: To assess clinical efficacy of HM61713 regarding Duration of overall tumor response (DR).

Measure: Duration of overall tumor response (DR), defined as the interval between the date of the first observation of tumor response (CR or PR) and the date of disease progression or death

Time: At baseline and every 6 weeks from time of first dose until date of progression, assessed up to 12 months

Description: To assess clinical efficacy of HM61713 regarding Progression-free survival (PFS).

Measure: Progression-free survival (PFS), defined as the time from first administration of study drug to determination of tumor progression by RECIST version 1.1 or death due to any cause, whichever occurs first

Time: At baseline and every 6 weeks from time of first dose until date of progression, assessed up to 12 months

Description: To assess clinical efficacy of HM61713 regarding Overall survival (OS).

Measure: Overall survival (OS), defined as the time from first administration of study drug until death from any cause

Time: From first dose to end of study or date of death from any cause whichever came first, assessed up to 48 months

Description: To assess clinical efficacy of HM61713 regarding Time to progression (TTP).

Measure: Time to progression (TTP), defined as the time from first administration of study drug to determination of tumor progression by RECIST version 1.1

Time: At baseline and every 6 weeks from time of first dose until date of progression, assessed up to 12 months

Description: To assess clinical efficacy of HM61713 regarding tumor shrinkage.

Measure: Tumor shrinkage calculated as absolute change and percentage change from baseline in sum of tumor size at each assessment using RECIST tumor response

Time: At baseline and every 6 weeks from time of first dose until date of progression, assessed up to 12 months

Description: To determine the pharmacokinetic (PK) profile of HM61713.

Measure: Peak concentration (Cmax) of HM61713

Time: Pre-dose (-30 to 0 mins) and 1 hour (± 5 mins), 3, 4, 6 hours (± 10 mins) on Day 1 and Day 15 of Cycle 1 and pre-dose (-30 to 0 mins) only on Day 8 of Cycle 1 and Day 1 of Cycle 2 (Day 22)

Description: To determine the pharmacokinetic (PK) profile of HM61713.

Measure: Trough plasma concentration (Ctrough) of HM61713

Time: Pre-dose (-30 to 0 mins) and 1 hour (± 5 mins), 3, 4, 6 hours (± 10 mins) on Day 1 and Day 15 of Cycle 1 and pre-dose (-30 to 0 mins) only on Day 8 of Cycle 1 and Day 1 of Cycle 2 (Day 22)

Description: To determine the pharmacokinetic (PK) profile of HM61713.

Measure: Area under the plasma concentration time curve over the 24-hour dosing interval (AUC) of HM61713

Time: Pre-dose (-30 to 0 mins) and 1 hour (± 5 mins), 3, 4, 6 hours (± 10 mins) on Day 1 and Day 15 of Cycle 1 and pre-dose (-30 to 0 mins) only on Day 8 of Cycle 1 and Day 1 of Cycle 2 (Day 22)

Description: To assess patient reported outcomes (PROs) of health-related quality of life (HRQoL), disease/treatment-related symptoms of lung cancer, and general health status.

Measure: Patient reported outcomes (PROs)

Time: At baseline and every 6 weeks from time of discontinuation, assessed up to 24 months

Description: To evaluate the effect of HM61713 on the QT interval.

Measure: ECG/QTc (absolute values and change from baseline)

Time: Adverse events will be collected from baseline until 28 days after the last dose

Description: To assess the safety and tolerability of HM61713.

Measure: Incidence of reported AEs and abnormal laboratory tests (AEs will be assessed using the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version 4).

Time: Adverse events will be collected from baseline until 28 days after the last dose

Description: To assess the safety and tolerability of HM61713.

Measure: QTc interval as assessed by digital ECG with central reading. The QT interval will be rate-corrected using 3 methods: QTcF, QTcB and QTcS.

Time: Adverse events will be collected from baseline until 28 days after the last dose

309 A Phase II Study of RRx-001 in Platinum Refractory/Resistant Small Cell Carcinoma, EGFR TKI Resistant EGFR+ T790M Negative Non-Small Cell Lung Cancer, High Grade Neuroendocrine Tumors and Resistant/Refractory Ovarian Cancer Prior to Re-administration of Platinum Based Doublet Regimens (QUADRUPLE THREAT)

This study is designed to explore the potential of the epigenetic agent RRx-001 to sensitize patients who previously received and now have failed a platinum based doublet regimen. RRx-001 is administered with autologous blood once weekly followed by or in combination with reintroduction of platinum-based doublet therapy.

NCT02489903
Conditions
  1. Small Cell Carcinoma
  2. Carcinoma, Non-Small-Cell Lung
  3. Neuroendocrine Tumors
  4. Ovarian Epithelial Cancer
Interventions
  1. Drug: RRx-001
  2. Drug: Cisplatin
  3. Drug: Etoposide
  4. Drug: Carboplatin
  5. Drug: Irinotecan
  6. Drug: Vinorelbine
  7. Drug: Doxil
  8. Drug: Gemcitabine
  9. Drug: Taxane
  10. Drug: Paclitaxel
  11. Drug: Nab-Paclitaxel
  12. Drug: Pemetrexed
MeSH:Carcinoma Carcinoma, Ovarian Epithelial Neuroendocrine Tumors Carcinoma, Non-Small-Cell Lung Carcinoma, Small Cell Small Cell Lung Carcinoma
HPO:Carcinoma Neuroendocrine neoplasm Non-small cell lung carcinoma Small cell lung carcinoma

A Phase II Study of RRx-001 in Platinum Refractory/Resistant Small Cell Carcinoma, EGFR TKI Resistant EGFR+ T790M Negative Non-Small Cell Lung Cancer, High Grade Neuroendocrine Tumors and Resistant/Refractory Ovarian Cancer Prior to Re-administration of Platinum Based Doublet Regimens (QUADRUPLE THREAT). --- T790M ---

Primary Outcomes

Description: the time from enrollment until the time of death from any cause or last follow-up. Patients will be followed clinically as outlined in the treatment schedule and will be followed off study for death.

Measure: Overall Survival

Time: up to one year

Secondary Outcomes

Description: The proportion of patients who achieve a reduction in the sum of target lesions by 30% following the re-administration of chemotherapy. Radiographic assessment of disease burden will be evaluated by CT and disease RR will be documented using RECIST v1.1.

Measure: Overall Response Rate (ORR)

Time: 12 weeks

Description: The percentage of patients who have achieved complete response, partial response and stable disease (as per RECIST v1.1).

Measure: Disease Control Rate (DCR)

Time: 12weeks

Description: the time from enrollment to the time of the first radiographic documentation of objective progression as defined by RECIST v1.1 or death from any cause.

Measure: Progression Free Survival (PFS)

Time: 12 weeks

Measure: Number of Participants with Adverse Events as a Measure of Safety and Tolerability of platinum doublet therapy post RRx-001

Time: 12 weeks

Measure: Changes in the level of serum biomarkers will be calculated and treatment samples will be compared to baseline samples using one-sample tests (e.g., paired t test or Wilcoxon signed rank test).

Time: 12 weeks

310 A Randomized Phase 2 Trial Of Pf-00299804 Versus Erlotinib For The Treatment Of Advanced Non-small Cell Lung Cancer After Failure Of At Least One Prior Chemotherapy Regimen

This study will compare PF-00299804 given orally on continuous schedule to the approved drug, erlotinib, in patients whose non-small cell lung cancer has progressed after chemotherapy; patients will be randomized to receive one of these drugs, and followed for efficacy and tolerance of each.

NCT00769067
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: Erlotinib
  2. Drug: PF-00299804
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

OS was calculated as (the death date or last known alive date (if death date unavailable) minus the date of randomization plus 1) divided by 7.. Number of Participants With Kirsten Rat Sarcoma (KRAS) and Epidermal Growth Factor Receptor (EGFR) Status and EGFR T790M Mutation. --- T790M ---

Additionally blood specimens were analyzed at a sponsor-designated laboratory for T790M mutation in EGFR.. Soluble Protein Biomarkers Level. --- T790M ---

Primary Outcomes

Description: PFS: Time in weeks from randomization to date of objective disease progression or death due to any cause, whichever occurred first. PFS was calculated as (first event date or last known event-free date [if the event date unavailable] minus the date of randomization plus 1) divided by 7. Objective progression is defined using Response Evaluation Criteria in Solid Tumors (RECIST), as at least 20 percent (%) increase in the sum of longest dimensions (LDs) of target lesions, taking as reference the smallest sum of LD recorded since the treatment started and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.

Measure: Progression-Free Survival (PFS)

Time: Baseline until disease progression or death, assessed at Cycle 2, 3, 4, 5, 6, thereafter every other cycle up to end of treatment (121 weeks), followed by every 8 weeks >284 weeks

Secondary Outcomes

Description: EORTC QLQ-C30: included global health status/quality of life (QoL), functional (Fn) scales (physical, role, cognitive, emotional, and social), symptom scales (fatigue, pain, nausea/vomiting), and single items (dyspnea, appetite loss, insomnia, constipation, diarrhea, and financial difficulties). Scores were averaged, transformed to 0-100 scale; higher score for Global Qol/Fn scales=better level of QoL/functioning or higher score for symptom scales/items=greater degree of symptoms. Overall scale change is categorized as Improved (if average scales change from baseline: for Global QoL/Fn scales >=10; for symptom scale/item <=-10), Worsened (if average scales change from baseline: for Global QoL/Fn scales <=-10; for symptom scale/item >=10), and Stable (if average scales change from baseline >-10 but <10 for Global QoL/Fn scales and symptom scale/item) and participants in each category are reported.

Measure: Categorical Summary of Overall Scale Change in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30)

Time: Baseline up to Cycle 44 (Week 188)

Description: QLQ-LC13 consisted of 13 questions relating to disease symptoms specific to lung cancer and treatment side effects typical of treatment with chemotherapy and radiotherapy. The 13 questions comprised 1 multi-item scale for dyspnea and 10 single-item symptoms and side effects (coughing, hemoptysis, sore mouth, dysphagia, peripheral neuropathy, alopecia, chest pain, arm pain, other pain, and medicine for pain). Scores averaged, transformed to 0-100 scale; higher symptom score = greater degree of symptoms. Overall scale change is categorized as Improved (if average scales change from baseline <=-10), Worsened (if average scales change from baseline >=10), and Stable (if average scales change from baseline >-10 but <10) and participants in each category are reported.

Measure: Categorical Summary of Overall Scale Change in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer Module (EORTC QLQ-LC13)

Time: Baseline up to Cycle 44 (Week 188)

Description: DLQI: 10-item questionnaire to measure how much the participant's skin problem has impacted their life over the previous week on following 6 domains: symptoms/feelings (2 questions), daily activities (2 questions), leisure (2 questions), work/school (1 question), personal relationships (2 questions), and treatment (1 question). All questions were answered on a 4-point Likert scale ranging from 0 (not at all/not relevant) to 3 (very much/prevented work or studying). The DLQI total evaluable score was calculated by summing the score of each question and ranged from 0 to 30, where higher scores indicated more quality of life impairment.

Measure: Dermatology Life Quality Index (DLQI)

Time: Cycle (C) 1 Day (D) 1 (baseline), C1D10-14, D1 of subsequent cycles up to C44

Description: Percentage of participants with objective response based on assessment of confirmed complete response (CR) or confirmed partial response (PR) according to RECIST version 1.0. CR: disappearance of all target and non-target lesions. PR: at least 30 % decrease in sum of the LDs of target lesion, taking as reference the baseline sum LD. Confirmed responses are those that persist on repeat imaging study at least 4 weeks after initial documentation of response.

Measure: Percentage of Participants With Objective Response

Time: Baseline until disease progression or death, assessed at Cycle 2, 3, 4, 5, 6, thereafter every other cycle up to end of treatment (121 weeks), followed by every 8 weeks >284 weeks

Description: Number of participants with BOR according to RECIST version 1.0: CR= disappearance of all target and non-target lesions. PR= at least 30% decrease in sum of LDs of target lesion, taking as reference baseline sum LD. Stable/no response= neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of LDs since treatment started. Objective progression= at least a 20% increase in sum of LDs of target lesions, taking as reference the smallest sum of LDs recorded since treatment started and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.

Measure: Best Overall Response (BOR)

Time: Baseline until disease progression or death, assessed at Cycle 2, 3, 4, 5, 6, thereafter every other cycle up to end of treatment (121 weeks), followed by every 8 weeks >284 weeks

Description: Time in weeks from first documentation of objective tumor response to objective tumor progression or symptomatic deterioration or death due to any cause, whichever occurred first. Duration of tumor response was calculated as (the date of the first documentation of objective tumor progression or symptomatic deterioration or death due to any cause or last known progression-free date [if none of the event dates available] minus the date of the first CR or PR [which ever occurred first] that was subsequently confirmed plus 1) divided by 7. DR was calculated for the subgroup of participants with a confirmed objective tumor response.

Measure: Duration of Response (DR)

Time: Baseline until disease progression or death, assessed at Cycle 2, 3, 4, 5, 6, thereafter every other cycle up to end of treatment (121 weeks), followed by every 8 weeks >284 weeks

Description: Time in weeks from randomization to date of death due to any cause. OS was calculated as (the death date or last known alive date (if death date unavailable) minus the date of randomization plus 1) divided by 7.

Measure: Overall Survival (OS)

Time: Baseline until end of treatment (15 August 2014); followed up every 8 weeks after discontinuation from study treatment.

Other Outcomes

Description: Tumor tissue were analyzed at a sponsor-designated laboratory to investigate KRAS and EGFR status (wild type or mutated). Participants who did not provide samples for central laboratory analysis confirmation were classified as "unknown". Additionally blood specimens were analyzed at a sponsor-designated laboratory for T790M mutation in EGFR.

Measure: Number of Participants With Kirsten Rat Sarcoma (KRAS) and Epidermal Growth Factor Receptor (EGFR) Status and EGFR T790M Mutation

Time: Baseline

Description: Blood specimens were analyzed at a sponsor-designated laboratory for analysis of shed proteins/receptors related to Human Epidermal Growth Factor Receptor (HER) signaling (EGFR, HER-2, Epithelial-cadherin [E-cadherin]). The data collection after C12D1 was not performed, as there were too few participants across both treatment arms after C12D1.

Measure: Soluble Protein Biomarkers Level

Time: Cycle (C) 1 Day (D) 1 (baseline), D1 of each subsequent cycle up to end of treatment (up to 121 weeks)

Description: Only participants from "Dacomitinib" treatment arm were planned to be analyzed for this outcome.

Measure: Trough Plasma Concentration (Ctrough) of Dacomitinib (PF-00299804)

Time: C1D10-14, C2D1, C3D1, C4D1

311 An Open-Label, Non-Randomized, Single-Center Study to Determine the Absorption, Metabolism and Excretion of A Single Dose [14C] AC0010 in Patients With Advanced NSCLC

The purpose of this study is to investigate Pharmacokinetics parameters of a single dose [14C] AC0010 in male Patients With Advanced NSCLC.

NCT03001609
Conditions
  1. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Drug: AC0010
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Inclusion Criteria: - signed and dated informed consent - histologically or cytologically confirmed diagnosis of local advanced or recurrent NSCLC - failed to the treatment of EGFR-TKI and harbored T790M mutation - male, Age 18~ 65, have a body mass index (BMI) >19 kg/m2 - ECOG PS:0-1,Life expectancy of more than 3 months - main organs function is normal, laboratory values as listed below: blood test without blood transfusion within 14 days 1. Haemoglobin >100 g/L 2. Absolute neutrophil count ≥2.0x10^9/L or WBC ≥3.5 x10^9/L 3. Platelet count ≥ 80x10^9/L 4. Total bilirubin ≤1.5xULN 5. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 2.5 times upper limit of normal (ULN) 6. BUN≤1.5xULN 7. Serum creatinine ≤1.5xULN or creatinine clearance ratio ≥60 mL/min - Any prior treatment (chemotherapy, radiotherapy or surgery) must be completed over 4 weeks(target therapy over 2 weeks) from the screening; Patients must have recovered from all toxicities related to prior anticancer therapies to grade ≤ 1 (CTCAE v 4.03) - International normalized ratio (INR) ≤ 1.5 - Patients and their partners should be willing to use methods of contraception or total abstinence from start of dosing until 6 months after discontinuing of study treatment Exclusion Criteria: - Prior treated with AC0010 or allergic to drug or its formulation ingredients - Patients receiving other anti-tumor therapy - Impairment of GI disease, renal disorders or liver disease that may significantly alter the absorption and metabolic of AC0010 (e.g., Unable to swallow, liver, kidney or gastrointestinal partial resection, chronic diarrhea and intestinal obstruction) - HCVAb positive, active hepatitis B (excluding HBV carriers), Hepatitis virus markers positive and receiving anti-virus drugs - Meningeal metastasis; brain metastasis with whole brain radiotherapy; prior received hormones or mannitol for the brain metastasis - Previous EGFR-TKI treatment related Interstitial lung disease history - Known human immunodeficiency virus infection (HIV), other acquired or congenital immunodeficiency disease, or a history of organ transplantation - Any severe and / or uncontrolled active infections - Patients receiving concomitant immunosuppressive agents or high-dose corticosteroids - Any severe and / or uncontrolled medical conditions - Patients being treated with drugs recognized as being inhibitors or inducers of the liver isoenzyme in the last 4 weeks prior to registration in the current study - Within 3 days prior to the treatment intaking of pitaya, pomelo, grapefruit, orange, mango and other fruit may affect drug metabolizing enzymes or juice - Within 2 days prior to the treatment intaking of coffee, tea, cola, chocolate, or other caffeine containing beverages, alcoholic beverages and / or other alcoholic products - Major surgery, incisional biopsy or traumatic injuries; - Within 4 weeks prior to the screening patients with bleeding ≥ grade 3, non-healing wound, sever ulcer or bone fracture - Patients received high dose irradiation treatment or other 14C-labeled drug within 1 year - Known a history of alcoholism or drug abuse - Nicotine or urine drug testing was positive - Participate in any clinical trial within 4 weeks prior to the screening - Investigator judgment that patient is unsuitable to participate in study Inclusion Criteria: - signed and dated informed consent - histologically or cytologically confirmed diagnosis of local advanced or recurrent NSCLC - failed to the treatment of EGFR-TKI and harbored T790M mutation - male, Age 18~ 65, have a body mass index (BMI) >19 kg/m2 - ECOG PS:0-1,Life expectancy of more than 3 months - main organs function is normal, laboratory values as listed below: blood test without blood transfusion within 14 days 1. Haemoglobin >100 g/L 2. Absolute neutrophil count ≥2.0x10^9/L or WBC ≥3.5 x10^9/L 3. Platelet count ≥ 80x10^9/L 4. Total bilirubin ≤1.5xULN 5. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 2.5 times upper limit of normal (ULN) 6. BUN≤1.5xULN 7. Serum creatinine ≤1.5xULN or creatinine clearance ratio ≥60 mL/min - Any prior treatment (chemotherapy, radiotherapy or surgery) must be completed over 4 weeks(target therapy over 2 weeks) from the screening; Patients must have recovered from all toxicities related to prior anticancer therapies to grade ≤ 1 (CTCAE v 4.03) - International normalized ratio (INR) ≤ 1.5 - Patients and their partners should be willing to use methods of contraception or total abstinence from start of dosing until 6 months after discontinuing of study treatment Exclusion Criteria: - Prior treated with AC0010 or allergic to drug or its formulation ingredients - Patients receiving other anti-tumor therapy - Impairment of GI disease, renal disorders or liver disease that may significantly alter the absorption and metabolic of AC0010 (e.g., Unable to swallow, liver, kidney or gastrointestinal partial resection, chronic diarrhea and intestinal obstruction) - HCVAb positive, active hepatitis B (excluding HBV carriers), Hepatitis virus markers positive and receiving anti-virus drugs - Meningeal metastasis; brain metastasis with whole brain radiotherapy; prior received hormones or mannitol for the brain metastasis - Previous EGFR-TKI treatment related Interstitial lung disease history - Known human immunodeficiency virus infection (HIV), other acquired or congenital immunodeficiency disease, or a history of organ transplantation - Any severe and / or uncontrolled active infections - Patients receiving concomitant immunosuppressive agents or high-dose corticosteroids - Any severe and / or uncontrolled medical conditions - Patients being treated with drugs recognized as being inhibitors or inducers of the liver isoenzyme in the last 4 weeks prior to registration in the current study - Within 3 days prior to the treatment intaking of pitaya, pomelo, grapefruit, orange, mango and other fruit may affect drug metabolizing enzymes or juice - Within 2 days prior to the treatment intaking of coffee, tea, cola, chocolate, or other caffeine containing beverages, alcoholic beverages and / or other alcoholic products - Major surgery, incisional biopsy or traumatic injuries; - Within 4 weeks prior to the screening patients with bleeding ≥ grade 3, non-healing wound, sever ulcer or bone fracture - Patients received high dose irradiation treatment or other 14C-labeled drug within 1 year - Known a history of alcoholism or drug abuse - Nicotine or urine drug testing was positive - Participate in any clinical trial within 4 weeks prior to the screening - Investigator judgment that patient is unsuitable to participate in study Carcinoma, Non-Small-Cell Lung Carcinoma, Non-Small-Cell Lung The purpose of this study is to investigate the Absorption, Metabolism, Excretion and Pharmacokinetics of a single dose [14C] AC0010 in male Patients With Advanced NSCLC. --- T790M ---

Inclusion Criteria: - signed and dated informed consent - histologically or cytologically confirmed diagnosis of local advanced or recurrent NSCLC - failed to the treatment of EGFR-TKI and harbored T790M mutation - male, Age 18~ 65, have a body mass index (BMI) >19 kg/m2 - ECOG PS:0-1,Life expectancy of more than 3 months - main organs function is normal, laboratory values as listed below: blood test without blood transfusion within 14 days 1. Haemoglobin >100 g/L 2. Absolute neutrophil count ≥2.0x10^9/L or WBC ≥3.5 x10^9/L 3. Platelet count ≥ 80x10^9/L 4. Total bilirubin ≤1.5xULN 5. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 2.5 times upper limit of normal (ULN) 6. BUN≤1.5xULN 7. Serum creatinine ≤1.5xULN or creatinine clearance ratio ≥60 mL/min - Any prior treatment (chemotherapy, radiotherapy or surgery) must be completed over 4 weeks(target therapy over 2 weeks) from the screening; Patients must have recovered from all toxicities related to prior anticancer therapies to grade ≤ 1 (CTCAE v 4.03) - International normalized ratio (INR) ≤ 1.5 - Patients and their partners should be willing to use methods of contraception or total abstinence from start of dosing until 6 months after discontinuing of study treatment Exclusion Criteria: - Prior treated with AC0010 or allergic to drug or its formulation ingredients - Patients receiving other anti-tumor therapy - Impairment of GI disease, renal disorders or liver disease that may significantly alter the absorption and metabolic of AC0010 (e.g., Unable to swallow, liver, kidney or gastrointestinal partial resection, chronic diarrhea and intestinal obstruction) - HCVAb positive, active hepatitis B (excluding HBV carriers), Hepatitis virus markers positive and receiving anti-virus drugs - Meningeal metastasis; brain metastasis with whole brain radiotherapy; prior received hormones or mannitol for the brain metastasis - Previous EGFR-TKI treatment related Interstitial lung disease history - Known human immunodeficiency virus infection (HIV), other acquired or congenital immunodeficiency disease, or a history of organ transplantation - Any severe and / or uncontrolled active infections - Patients receiving concomitant immunosuppressive agents or high-dose corticosteroids - Any severe and / or uncontrolled medical conditions - Patients being treated with drugs recognized as being inhibitors or inducers of the liver isoenzyme in the last 4 weeks prior to registration in the current study - Within 3 days prior to the treatment intaking of pitaya, pomelo, grapefruit, orange, mango and other fruit may affect drug metabolizing enzymes or juice - Within 2 days prior to the treatment intaking of coffee, tea, cola, chocolate, or other caffeine containing beverages, alcoholic beverages and / or other alcoholic products - Major surgery, incisional biopsy or traumatic injuries; - Within 4 weeks prior to the screening patients with bleeding ≥ grade 3, non-healing wound, sever ulcer or bone fracture - Patients received high dose irradiation treatment or other 14C-labeled drug within 1 year - Known a history of alcoholism or drug abuse - Nicotine or urine drug testing was positive - Participate in any clinical trial within 4 weeks prior to the screening - Investigator judgment that patient is unsuitable to participate in study Inclusion Criteria: - signed and dated informed consent - histologically or cytologically confirmed diagnosis of local advanced or recurrent NSCLC - failed to the treatment of EGFR-TKI and harbored T790M mutation - male, Age 18~ 65, have a body mass index (BMI) >19 kg/m2 - ECOG PS:0-1,Life expectancy of more than 3 months - main organs function is normal, laboratory values as listed below: blood test without blood transfusion within 14 days 1. Haemoglobin >100 g/L 2. Absolute neutrophil count ≥2.0x10^9/L or WBC ≥3.5 x10^9/L 3. Platelet count ≥ 80x10^9/L 4. Total bilirubin ≤1.5xULN 5. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 2.5 times upper limit of normal (ULN) 6. BUN≤1.5xULN 7. Serum creatinine ≤1.5xULN or creatinine clearance ratio ≥60 mL/min - Any prior treatment (chemotherapy, radiotherapy or surgery) must be completed over 4 weeks(target therapy over 2 weeks) from the screening; Patients must have recovered from all toxicities related to prior anticancer therapies to grade ≤ 1 (CTCAE v 4.03) - International normalized ratio (INR) ≤ 1.5 - Patients and their partners should be willing to use methods of contraception or total abstinence from start of dosing until 6 months after discontinuing of study treatment Exclusion Criteria: - Prior treated with AC0010 or allergic to drug or its formulation ingredients - Patients receiving other anti-tumor therapy - Impairment of GI disease, renal disorders or liver disease that may significantly alter the absorption and metabolic of AC0010 (e.g., Unable to swallow, liver, kidney or gastrointestinal partial resection, chronic diarrhea and intestinal obstruction) - HCVAb positive, active hepatitis B (excluding HBV carriers), Hepatitis virus markers positive and receiving anti-virus drugs - Meningeal metastasis; brain metastasis with whole brain radiotherapy; prior received hormones or mannitol for the brain metastasis - Previous EGFR-TKI treatment related Interstitial lung disease history - Known human immunodeficiency virus infection (HIV), other acquired or congenital immunodeficiency disease, or a history of organ transplantation - Any severe and / or uncontrolled active infections - Patients receiving concomitant immunosuppressive agents or high-dose corticosteroids - Any severe and / or uncontrolled medical conditions - Patients being treated with drugs recognized as being inhibitors or inducers of the liver isoenzyme in the last 4 weeks prior to registration in the current study - Within 3 days prior to the treatment intaking of pitaya, pomelo, grapefruit, orange, mango and other fruit may affect drug metabolizing enzymes or juice - Within 2 days prior to the treatment intaking of coffee, tea, cola, chocolate, or other caffeine containing beverages, alcoholic beverages and / or other alcoholic products - Major surgery, incisional biopsy or traumatic injuries; - Within 4 weeks prior to the screening patients with bleeding ≥ grade 3, non-healing wound, sever ulcer or bone fracture - Patients received high dose irradiation treatment or other 14C-labeled drug within 1 year - Known a history of alcoholism or drug abuse - Nicotine or urine drug testing was positive - Participate in any clinical trial within 4 weeks prior to the screening - Investigator judgment that patient is unsuitable to participate in study Carcinoma, Non-Small-Cell Lung Carcinoma, Non-Small-Cell Lung The purpose of this study is to investigate the Absorption, Metabolism, Excretion and Pharmacokinetics of a single dose [14C] AC0010 in male Patients With Advanced NSCLC. --- T790M --- --- T790M ---

Primary Outcomes

Description: Pharmacokinetics of 14C-labeled AC0010 Radioactivity in whole blood and plasma,Cumulative excretion of 14C-labeled AC0010 radioactivity in feces and urine,Metabolite identification of 14C-labeled AC0010 in plasma, urine and feces

Measure: Pharmacokinetics, Cumalative excretion and Metabolite of 14C-labeled AC0010

Time: up to 8 Days

Secondary Outcomes

Description: Quantitative analysis of plasma concentrations of unlabeled AC0010 using a validated LC-MS/MS method

Measure: Quantitative analysis of plasma concentrations of unlabeled AC0010

Time: up to 8 Days

Description: Number of adverse events (AE) experienced by patients to assess safety and tolerability

Measure: Number of adverse events (AE) experienced by patients

Time: up to 8 Days

312 A Study of Almonertinib With Chemotherapy as 1st Line Treatment in Patients With Mutated Epidermal Growth Factor Receptor Non-Small Cell Lung Cancer

The reason for the study is to find out if an experimental combination of an oral medication called Almonertinib when used in combination with chemotherapy is more effective for the treatment of locally advanced or metastatic non-small cell lung cancer. Some lung cancers are due to mutations in the Deoxyribonucleic acid (DNA) which, if known, can help physicians decide the best treatment for patients. One type of mutation can occur in the gene that produces a protein on the surface of cells called the Epidermal Growth Factor Receptor (EGFR).

NCT04646824
Conditions
  1. Non-Small Cell Lung Cancer Metastatic
Interventions
  1. Drug: Almonertinib Pemetrexed/Cisplatin
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

4. The tumor harbors 1 of the 2 common epidermal growth factor receptor (EGFR) mutations known to be associated with Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) sensitivity (Ex19del or L858R), either alone or in combination with other epidermal growth factor receptor (EGFR) mutations, which may include T790M. 5. Patients must have untreated advanced Non-Small Cell Lung Cancer (NSCLC) not amenable to curative surgery or radiotherapy. --- L858R --- --- T790M ---

Primary Outcomes

Description: Progression-free survival

Measure: PFS

Time: The primary analysis of Progressionfree survival (PFS) based on investigator assessment will occur when PFS maturity is observed at approximately 33 months

313 Programmed Death-ligand 1(PD-L1) and Other Immuno-markers Influenced by Osimertinib Treatment in Advanced Non-small Cell Lung Cancer (NSCLC) Patients

The study will investigate whether PD-L1 and other immuno-markers will be influenced by osimertinib treatment in advanced epidermal growth factor receptor (EGFR)T790M positive advanced NSCLC patients. In addition, we will explore whether PD-L1 and other immuno-markers can predict the safety and efficacy of subsequent use of immune checkpoint inhibitors at the time of PD due to osimertinib resistance.

NCT03029858
Conditions
  1. Small Cell Lung Cancer, Polygonal Type
Interventions
  1. Other: No interventions will be taken in this Observational study
MeSH:Lung Neoplasms Small Cell Lung Carcinoma
HPO:Neoplasm of the lung Small cell lung carcinoma

Small Cell Lung Cancer, Polygonal Type Lung Neoplasms Small Cell Lung Carcinoma Investigate whether PD-L1 and other immuno-markers will be influenced by osimertinib treatment in advanced EGFR T790M positive advanced NSCLC patients. --- T790M ---

Primary Outcomes

Description: Measure PD-L1 value Change by tumor cells(TC)/immune cells(IC) staining from the baseline to progressive disease(PD)

Measure: Measure PD-L1 value

Time: baseline and PD,up to 24 months

Description: Measure PD-L1 expression positive rate (%) change from the baseline to progressive disease(PD)

Measure: Measure PD-L1 expression positive rate (%)

Time: baseline and PD,up to 24 months

314 An Open-label Phase I Dose Finding Trial With BI 891065 Alone and in Combination With BI 754091 to Characterise Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy in Patients With Advanced and/or Metastatic Malignancies

The main objective of the dose-escalation parts of the trial is to determine the maximum tolerated dose (MTD), based on the frequency of patients experiencing dose-limiting toxicities (DLTs), and/or the recommended dose for further development of BI 891065 monotherapy as well as of BI 891065 in combination with BI 754091, and to evaluate its safety and tolerability by monitoring the occurrence and severity of adverse events (AEs). Secondary objectives are the determination of the pharmacokinetic (PK) profile of BI 891065 monotherapy as well as of BI 891065 in combination with BI 754091, and the preliminary assessment of anti-tumour activity.

NCT03166631
Conditions
  1. Neoplasms
  2. Neoplasm Metastasis
  3. Carcinoma, Non-Small-Cell Lung
Interventions
  1. Drug: BI 891065
  2. Drug: BI 754091
MeSH:Neoplasms Neoplasm Metastasis Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm Non-small cell lung carcinoma

- For Parts A and B: Patients with known epidermal growth factor receptor (EGFR), known anaplastic lymphoma kinase (ALK), or known ROS Proto-Oncogene 1 (ROS1) genomic tumour aberrations, unless disease has progressed following available EGFR or ALK targeted therapy (including osimertinib for EGFR T790M-mutated NSCLC) - Out of range lab values as defined: - Absolute neutrophil count (ANC) <1.5 x 109/L (<1500/mm3) - Platelet (PLT) count <100 x 109/L - Haemoglobin <90 g/L (<9 g/dL) -- Creatinine >1.5 times ULN (patients may enter if creatinine is >1.5 x ULN and estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 --- T790M ---

Primary Outcomes

Measure: Part A - Maximum tolerated dose of BI 891065

Time: 9 months

Measure: Part A - number of patients with Dose-limiting toxicities (DLTs) during the first treatment cycle.

Time: 3 weeks

Measure: Part B - Maximum tolerated dose of BI 891065 in combination with BI 754091

Time: 9 months

Measure: Part B - number of patients with Dose-limiting toxicities (DLTs) during the first treatment cycle.

Time: 3 weeks

Measure: Part C - Objective response (OR) is defined as best overall response of Complete response (CR) or partial response (PR), where best overall response is determined according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1

Time: 18 weeks

Secondary Outcomes

Measure: Part A - The number of patients with Dose-limiting toxicities (DLTs) observed during the entire treatment period.

Time: 12 months

Measure: Part A - Cmax(,ss) of BI 891065 in the first treatment cycle.

Time: 3 weeks

Measure: Part A - Objective response (OR) based on RECIST v1.1.

Time: 12 months

Measure: Part B - The number of patients with Dose-limiting toxicities (DLTs) observed during the entire treatment period.

Time: 12 months

Measure: Part B - Cmax(,ss) of BI 891065

Time: 3 weeks

Measure: Part B - Objective response (OR) based on RECIST v1.1.

Time: 12 months

Measure: Part C - Duration of Objective response (OR) based on RECIST 1.1 (for the NSCLC cohort)

Time: 18 months

Measure: Part A - AUC0-tz of BI 891065 in the first treatment cycle.

Time: 3 weeks

Measure: Part A - AUC tau,ss of BI 891065 in the first treatment cycle.

Time: 3 weeks

Measure: Part B - AUC0-tz of BI 891065

Time: 3 weeks

Measure: Part B - AUCtau,ss of BI 891065

Time: 3 weeks

Measure: Part B - Cmax of BI 754091 in the first treatment cycle.

Time: 3 weeks

Measure: Part B - AUC0-tz of BI 754091 in the first treatment cycle.

Time: 3 weeks

315 A Study to Determine the Concordance of Key Actionable Genomic Alterations as Assessed in Tumor Tissue and Plasma From Patients With Non Small Cell Lung Carcinoma (NSCLC)

A study to determine the concordance of key actionable genomic alterations as assessed in tumor tissue and plasma from patients with non small cell lung carcinoma (NSCLC)

NCT02762877
Conditions
  1. Non Small Cell Lung Carcinoma
MeSH:Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Carcinoma Neoplasm of the lung Non-small cell lung carcinoma

Assess concordance of genomic alterations in EGFR detected in plasma (using the OncotypeSEQ Liquid Select assay) versus tumor tissue (assessed centrally using FoundationOne, or locally based on the patient's clinic) in stage IV non squamous NSCLC patients who are newly diagnosed or progressing on treatment.. Concordance of Genomic Alterations in ALK (EML4-ALK Fusions) Detected in Plasma Versus Tumor Tissue.. Assess concordance of genomic alterations in ALK (EML4-ALK fusions) detected in plasma (using the OncotypeSEQ Liquid Select assay) versus tumor tissue (assessed centrally using FoundationOne OR locally based on the patient's clinic) in stage IV non squamous NSCLC patients who are newly diagnosed or progressing on treatment.. Percentage of Participants With EGFR T790M Alterations in Plasma in Patients Progressing on EGFR Targeting Therapy (Erlotinib, Gefitinib, Afatinib).. Detection of EGFR T790M alterations in plasma using the OncotypeSEQ Liquid Select assay. --- T790M ---

Assess concordance of genomic alterations in EGFR detected in plasma (using the OncotypeSEQ Liquid Select assay) versus tumor tissue (assessed centrally using FoundationOne, or locally based on the patient's clinic) in stage IV non squamous NSCLC patients who are newly diagnosed or progressing on treatment.. Concordance of Genomic Alterations in ALK (EML4-ALK Fusions) Detected in Plasma Versus Tumor Tissue.. Assess concordance of genomic alterations in ALK (EML4-ALK fusions) detected in plasma (using the OncotypeSEQ Liquid Select assay) versus tumor tissue (assessed centrally using FoundationOne OR locally based on the patient's clinic) in stage IV non squamous NSCLC patients who are newly diagnosed or progressing on treatment.. Percentage of Participants With EGFR T790M Alterations in Plasma in Patients Progressing on EGFR Targeting Therapy (Erlotinib, Gefitinib, Afatinib).. Detection of EGFR T790M alterations in plasma using the OncotypeSEQ Liquid Select assay. --- T790M --- --- T790M ---

Primary Outcomes

Description: Assess concordance of genomic alterations in EGFR detected in plasma (using the OncotypeSEQ Liquid Select assay) versus tumor tissue (assessed centrally using FoundationOne, or locally based on the patient's clinic) in stage IV non squamous NSCLC patients who are newly diagnosed or progressing on treatment.

Measure: Concordance of Genomic Alterations in EGFR Detected in Plasma Versus Tumor Tissue in Stage IV Non Squamous NSCLC Patients Who Are Newly Diagnosed or Progressing on Treatment

Time: Time between patient tumor tissue biopsy and and blood collection, up to 8 weeks

Secondary Outcomes

Description: Assess concordance of genomic alterations in ALK (EML4-ALK fusions) detected in plasma (using the OncotypeSEQ Liquid Select assay) versus tumor tissue (assessed centrally using FoundationOne OR locally based on the patient's clinic) in stage IV non squamous NSCLC patients who are newly diagnosed or progressing on treatment.

Measure: Concordance of Genomic Alterations in ALK (EML4-ALK Fusions) Detected in Plasma Versus Tumor Tissue.

Time: Time between patient tumor tissue biopsy and and blood collection, up to 8 weeks

Description: Detection of EGFR T790M alterations in plasma using the OncotypeSEQ Liquid Select assay. Progression on EGFR targeting therapy (erlotinib, gefitinib, afatinib) assessed clinically or radiologically

Measure: Percentage of Participants With EGFR T790M Alterations in Plasma in Patients Progressing on EGFR Targeting Therapy (Erlotinib, Gefitinib, Afatinib).

Time: Time between patient tumor tissue biopsy and and blood collection (blood collected after the patient progressed on EGFR targeted therapy)

316 Phase II Trial of AZD9291 in First Line Treatment of Lung Cancer Harboring Activating EGFR Mutation From Circulating Tumor DNA and Second Line Treatment After Acquired Resistance With T790M Mutation Detected From Circulating Tumor DNA

Treatment efficacy of osimertinib will be assessed in patients with lung cancer harboring activating epidermal growth factor receptor (EGFR) mutations (cohort 1) and those harboring T790M (cohort 2) which were detected from circulating tumor DNA

NCT02769286
Conditions
  1. Lung Neoplasms
  2. EGFR Gene Mutations
Interventions
  1. Drug: Osimertinib
MeSH:Lung Neoplasms
HPO:Neoplasm of the lung

Phase II Trial of AZD9291 in First Line Treatment of Lung Cancer Harboring Activating EGFR Mutation From Circulating Tumor DNA and Second Line Treatment After Acquired Resistance With T790M Mutation Detected From Circulating Tumor DNA. --- T790M ---

Osimertinib in First and Second Line Treatment of NSCLC Harboring EGFR Mutations From Circulating Tumor DNA Treatment efficacy of osimertinib will be assessed in patients with lung cancer harboring activating epidermal growth factor receptor (EGFR) mutations (cohort 1) and those harboring T790M (cohort 2) which were detected from circulating tumor DNA Response rate. --- T790M ---

5. Patients must fulfil one of the following: 5.1) Activating EGFR mutation (G719X, exon 19 deletion, L858R, L861Q) from tumor tissue or cytology or circulating tumor DNA 5.2) Must have experienced clinical benefit from prior EGFR-TKI, according to the Jackman criteria (Jackman 2010) followed by systemic objective progression (RECIST) while on continuous treatment with EGFR-TKI 6. T790M mutation detected from circulating tumor DNA either by PANA mutyper® or Cobas® EGFR mutation test. --- L858R --- --- L861Q --- --- T790M ---

Lung Neoplasms EGFR Gene Mutations Lung Neoplasms This is a phase II, open-label, single centre study of AZD9291 administered orally in patients with advanced lung cancer with activating mutations of EGFR gene with or without T790M which were detected from circulating tumor DNA. --- T790M ---

EGFR-TKI naïve patients with activating EGFR mutation will be enrolled in cohort 1. Patients with acquired resistance to prior EGFR tyrosine kinase inhibitor (TKI) due to T790M mutation is going to be enrolled in cohort 2. --- T790M ---

Primary Outcomes

Description: RECIST v1.1

Measure: Response rate

Time: 2 months

Secondary Outcomes

Description: Percentage of positive cases among cases tested with Mutyper or Cobas

Measure: Sensitivity of testing methods

Time: 2 weeks

Measure: Progression free survival

Time: 2 years

Measure: Duration of response

Time: 2 years

Measure: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

Time: 2 years

317 A Phase 1b/2 Study of the Safety and Efficacy of Rociletinib (CO-1686) Administered in Combination With MPDL3280A in Patients With Activating EGFR Mutation-positive (EGFRm) Advanced or Metastatic Non-small Cell Lung Cancer (NSCLC)

This clinical research study is being carried out in two parts, Phase 1 and Phase 2. The primary purpose of the Phase 1 portion of the study is to observe the safety of the combination of rociletinib and MPDL3280A in EGFR-mutant NSCLC patients. The primary purpose of the Phase 2 portion of the study is to evaluate the safety and anti-tumor effects of the combination of rociletinib and MPDL3280A, at the best doses for the combination determined in Phase 1, in patients with EGFR-mutant NSCLC.

NCT02630186
Conditions
  1. Non-small Cell Lung Cancer
Interventions
  1. Drug: Rociletinib
  2. Drug: MPDL3280A
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Patients who have progressed after prior first- or second-generation EGFR TKI, regardless of T790M mutation status, will be enrolled. --- T790M ---

Group B will enroll eligible patients who have progressed after prior first- or second-generation EGFR TKI, regardless of T790M mutation status. --- T790M ---

Primary Outcomes

Description: The safety analyses will be performed using the safety population. Safety data analysis will be conducted on all patients receiving at least one dose of rociletinib or MPDL3280A.

Measure: Number of Treatment-emergent Adverse Events, as Assessed by NCI CTCAE v4.03

Time: Continuously, up to approximately 18.5 months

Description: Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. Cmax will be estimated for rociletinib, using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.

Measure: Maximum Concentration (Cmax) of Rociletinib and Its Metabolites

Time: Treatment Day 1 and Day 15

Description: Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. Tmax will be estimated for rociletinib, using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.

Measure: Time to Maximum Concentration (Tmax) for Rociletinib and Rociletinib Metabolites

Time: Treatment Day 1 and Day 15

Description: Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. Cmin will be estimated for rociletinib, using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.

Measure: Minimum Concentration (Cmin) of Rociletinib and Metabolites

Time: Approximately every 6 weeks up to 24 months

Description: Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. AUC0 24 will be estimated for rociletinib, using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.

Measure: Area Under the Curve (AUC) of Rociletinib and Rociletinib Metabolites

Time: Treatment Day 1 and Day 8

Description: Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. Cmax, for MPDL3280A will be assessed using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.

Measure: Maximum Concentration (Cmax) of MPDL3280A

Time: Cycle 1 Day 1

Description: Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. Cmin for MPDL3280A will be assessed using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.

Measure: Minimum Concentration (Cmin) of MPDL3280A

Time: Approximately every 6 weeks up to 24 months

Description: To determine the efficacy of the combination of rociletinib and MPDL3280A based on overall response rate per RECIST v1.1 in the following groups of patients: Group A: Patients with EGFRm advanced or metastatic NSCLC who have not previously received an EGFR TKI or chemotherapy. Group B: Patients with EGFRm advanced or metastatic NSCLC who have progressed on a prior EGFR TKI.

Measure: Objective Response Rate Per RECIST v1.1 in Phase 2

Time: Approximately every 6-9 weeks

Secondary Outcomes

Description: Conventional response criteria may not be adequate to characterize the antitumor activity of immunotherapeutic agents like MPDL3280A, which can produce delayed responses that may be preceded by initial apparent radiological progression, including the appearance of new lesions. Therefore, modified response criteria have been developed that account for the possible appearance of new lesions and allow radiological progression to be confirmed at a subsequent assessment. In this protocol, patients will be permitted to continue study treatment even after modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria for progressive disease are met if the benefit-risk ratio is judged to be favorable. These modified criteria are derived from RECIST version 1.1 (v1.1) conventions and immune related response criteria (irRC).

Measure: Objective Response Rate Per Modified RECIST v1.1, Incorporating Immune-related Criteria, in Phase 2

Time: Approximately every 6-9 weeks, up to 24 months

Description: Conventional response criteria may not be adequate to characterize the antitumor activity of immunotherapeutic agents like MPDL3280A, which can produce delayed responses that may be preceded by initial apparent radiological progression, including the appearance of new lesions. Therefore, modified response criteria have been developed that account for the possible appearance of new lesions and allow radiological progression to be confirmed at a subsequent assessment. In this protocol, patients will be permitted to continue study treatment even after modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria for progressive disease are met if the benefit-risk ratio is judged to be favorable. These modified criteria are derived from RECIST version 1.1 (v1.1) conventions and immune related response criteria (irRC).

Measure: Duration of Response Per RECIST v1.1 and Modified RECIST v1.1, Incorporating Immune-related Criteria, in Phase 2

Time: Approximately every 6-9 weeks, up to 24 months

Description: Conventional response criteria may not be adequate to characterize the antitumor activity of immunotherapeutic agents like MPDL3280A, which can produce delayed responses that may be preceded by initial apparent radiological progression, including the appearance of new lesions. Therefore, modified response criteria have been developed that account for the possible appearance of new lesions and allow radiological progression to be confirmed at a subsequent assessment. In this protocol, patients will be permitted to continue study treatment even after modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria for progressive disease are met if the benefit-risk ratio is judged to be favorable. These modified criteria are derived from RECIST version 1.1 (v1.1) conventions and immune related response criteria (irRC).

Measure: Progression-free Survival Per RECIST v1.1 and Modified RECIST v1.1, Incorporating Immune-related Criteria, in Phase 2

Time: Approximately every 6-9 weeks, up to 24 months

Description: Patients who received the combination of rociletinib and MPDL3280A alive at the termination of this study.

Measure: Number of Patients Alive at Study Termination

Time: Up to approximately 18.5 months

Description: Tumor tissue, plasma, and blood specimens will be used for pharmacodynamic assessment of rociletinib and/or MPDL3280A activity, to evaluate the concordance of mutant EGFR detection between tissue and plasma, and to explore biomarkers that may be predictive of response or resistance to rociletinib and/or MPDL3280A. Biomarkers and changes in biomarker status will be investigated for associations with rociletinib and/or MPDL3280A exposure, safety, and clinical activity. Given the limited sample size, no formal statistical analysis is planned.

Measure: Longitudinal Changes in Blood Based Biomarkers (eg, Mutations in EGFR) in ctDNA

Time: Blood samples will be collected from each patient approximately every 3 weeks, up to 24 months

318 A Randomized Open-label Phase 3 Trial Comparing Bevacizumab + Erlotinib vs Erlotinib Alone as First Line Treatment of Patients With EGFR Mutated Advanced Non Squamous Non Small Cell Lung Cancer

The purpose of this study is to test whether the combination of bevacizumab and erlotinib can prolong progression free survival as compared with erlotinib alone as first-line treatment in patients with non small cell lung cancer (NSCLC) with activating mutation of EGFR.

NCT02633189
Conditions
  1. Non-squamous Non-small Cell Lung Cancer
Interventions
  1. Drug: Erlotinib
  2. Drug: Bevacizumab
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Exclusion Criteria: 1. EGFR T790M mutation alone or exon 20 insertions as unique mutation 2. Tumors with a squamous component 3. Prior chemotherapy or any other medical treatment for advanced NSCLC (previous neoadjuvant or adjuvant chemotherapy is allowed if > 6 months before randomisation) 4. Radiotherapy to any site for any reason within 28 days prior to randomization (palliative radiotherapy to bone lesions is allowed if ≥ 14 days before randomization) 5. Full-dose anticoagulation with warfarin 6. --- T790M ---

Primary Outcomes

Description: as determined by investigator

Measure: progression free survival

Time: up to 2 years

Description: as determined by an independent central review board blinded to study treatment

Measure: progression free survival

Time: up to 2 years

Secondary Outcomes

Measure: overall survival

Time: 1 year

Measure: changes in quality of life scores from baseline

Time: up to 2 years

Measure: number of patients with complete and partial responses , investigator assessed

Time: 6 months

Measure: number of patients with complete and partial responses , centrally reviewed

Time: 6 months

Measure: worst grade toxicity per patient

Time: up to one year

Measure: progression free survival according to type of EGFR mutation (exon 19del, exon 21L858R, other)

Time: 2 years

Other Outcomes

Description: samples taken at baseline, 6 weeks, 6 months, and at progression

Measure: number and type of EGFR mutations in plasma samples

Time: up to 2 years

319 PANORAMA - Real World Molecular Testing, Treatment Patterns, and Clinical Outcomes in Patients With EGFR Mutation-Positive Locally Advanced or Advanced NSCLC

The objectives of this study are to assess molecular testing, treatment patterns, and associated outcomes among patients with EGFR (Epidermal Growth Factor Receptor) mutation-positive locally advanced or advanced NSCLC (Non-Small Cell Lung Cancer) who have progressed on or after EGFR-TKI (EGFR-Tyrosine Kinase Inhibitor) therapy post availability of a third-generation TKI (primary study cohort). Additionally, molecular testing and treatment patterns will be assessed among a secondary cohort of patients which will include patients diagnosed with de-novo EGFR T790M mutation-positive locally advanced or advanced NSCLC.

NCT02777658
Conditions
  1. Carcinoma, Non-Small-Cell Lung
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

Additionally, molecular testing and treatment patterns will be assessed among a secondary cohort of patients which will include patients diagnosed with de-novo EGFR T790M mutation-positive locally advanced or advanced NSCLC. --- T790M ---

Inclusion Criteria - Primary Study Cohort - Provision of written informed consent (patient consent should be within 6 weeks of disease progression, defined elsewhere as the Index Date) - Adult male or female subjects (according to age of majority/adulthood as defined by local regulations) - Patients with prior confirmed EGFR mutation-positive (all mutations) locally advanced or advanced NSCLC - Patients who developed resistance to an EGFR-TKI due to any other phenotypic/histologic transformations (e.g., small-cell lung cancer, EMT) or other mutations (e.g., HER2, MET amplifications) at the index-date will be eligible for participation in this study as long as they have prior confirmed diagnosis of EGFR mutation-positive (all mutations) locally advanced or advanced NSCLC - Patients who have progressed on or after EGFR-TKI therapy (i.e., gefitinib, erlotinib or afatinib) within the patient selection period Inclusion Criteria - Secondary Study Cohort - Provision of written informed consent (patient consent should be within 6 weeks of NSCLC diagnosis, defined elsewhere as the Index Date) - Adult male or female subjects (according to age of majority/adulthood as defined by local regulations) - Patients diagnosed with de-novo EGFR T790M mutation-positive locally advanced or advanced NSCLC during the patient selection period. --- T790M ---

The de-novo T790M mutation can be alone or in combination with other mutations (e.g., L858R and T790M). --- T790M ---

The de-novo T790M mutation can be alone or in combination with other mutations (e.g., L858R and T790M). --- T790M --- --- L858R --- --- T790M ---

Primary Outcomes

Description: Molecular testing patterns including: Molecular testing rate defined as the number of patients identified as having received molecular testing divided by the number of patients in the primary study cohort (applicable to patients in the primary study cohort); Change in testing rates over time - testing rate over time will be described; Molecular testing details including sample type, method of biopsy, testing turnaround time, test type, reason for testing, testing laboratory type, reason for not performing a test; Molecular testing results including mutation status and type, test outcome, histologic/phenotypic transformation;

Measure: To evaluate molecular testing patterns among patients with EGFR mutation-positive locally advanced or advanced NSCLC

Time: Date of enrollment in the study until end of follow-up or death if this occurs before, assessed approximately up to 36 months

Description: Treatment patterns and associated clinical outcomes including: Overall survival measured from: date of initial diagnosis to date of death from any cause (for primary and secondary cohorts), date of progression to date of death from any cause (for primary cohort only); Time to initiation of new therapy defined as the time from start date of current therapy to start date of subsequent therapy; Treatment(s) received post diagnosis and post progression including chemotherapy, radiation, surgery, targeted therapy, immunotherapy; Treatment sequence patterns, line(s) of therapy, treatment regimen(s), treatment duration, number of cycles;

Measure: To assess treatment patterns and associated clinical outcomes among patients with EGFR mutation-positive locally advanced or advanced NSCLC

Time: Date of enrollment in the study until end of follow-up or death if this occurs before, assessed approximately up to 36 months

Secondary Outcomes

Description: Health care utilization patterns will be presented by the following care settings: hospitalization and length of stay, emergency room and physician office visits

Measure: To assess health care utilization patterns

Time: Date of enrollment in the study until end of follow-up or death if this occurs before, assessed approximately up to 36 months

Description: Assessment of treatment related complications observed with chemotherapy and targeted therapies among patients with NSCLC.

Measure: To assess treatment related complications

Time: Date of enrollment in the study until end of follow-up or death if this occurs before, assessed approximately up to 36 months

Description: Assessment of biopsy related complications for each documented biopsy procedure

Measure: To assess biopsy related complications

Time: Date of enrollment in the study until end of follow-up or death if this occurs before, assessed approximately up to 36 months

Measure: To document rate of central nervous system (CNS) metastases

Time: Date of enrollment in the study until end of follow-up or death if this occurs before, assessed approximately up to 36 months

Description: Health related quality of life (HRQoL): Assessment of general cancer-associated and specific lung cancer associated parameters by use of standardized HRQoL questionnaires: European Organization For Research And Treatment Of Cancer Quality Of Life Questionnaire - Core 30 (EORTC QLQ-C30) European Organisation For Research And Treatment Of Cancer Quality Of Life Questionnaire - Lung Cancer 13 (EORTC QLQ-LC13) (adminstered to patients included in primary study cohort)

Measure: Assessment of health-related quality of life (HRQoL)

Time: Date of first visit to last visit. HRQoL are collected every 6 months (plus or minus 1.5 months) up to 36 months

320 Open Label, Multicenter, Real World Treatment Study of Single Agent Tagrisso for Patients With Advanced/Metastatic Epidermal Growth Factor Receptor (EGFR) T790M Mutation-Positive Non-Small Cell Lung Cancer (NSCLC), Who Have Progressed on or After EGFR Tyrosine Kinase Receptor (TKI) Therapy

The objectives of this study are to assess the safety and efficacy of single agent Tagrisso (Osimertinib, hereinafter "the study drug") in a real world setting in adult patients with advanced or metastatic, epidermal growth factor receptor (EGFR) T790M mutation-positive Non-Small Cell Lung Cancer (NSCLC), Who Have Progressed on or after EGFR tyrosine kinase receptor (TKI) therapy.

NCT02777567
Conditions
  1. Non-Small Cell Lung Cancer
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Open Label, Multicenter, Real World Treatment Study of Single Agent Tagrisso for Patients With Advanced/Metastatic Epidermal Growth Factor Receptor (EGFR) T790M Mutation-Positive Non-Small Cell Lung Cancer (NSCLC), Who Have Progressed on or After EGFR Tyrosine Kinase Receptor (TKI) Therapy. --- T790M ---

KOREA Study (Korea Osimertinib Real World Evidence Study to Assess Safety and Efficacy) The objectives of this study are to assess the safety and efficacy of single agent Tagrisso (Osimertinib, hereinafter "the study drug") in a real world setting in adult patients with advanced or metastatic, epidermal growth factor receptor (EGFR) T790M mutation-positive Non-Small Cell Lung Cancer (NSCLC), Who Have Progressed on or after EGFR tyrosine kinase receptor (TKI) therapy. --- T790M ---

Inclusion Criteria: - 1. Eligible for, or on active study drug treatment according to the approved label; patients with locally advanced or metastatic, EGFR T790M mutation-positive NSCLC, who have progressed on or after EGFR tyrosine kinase receptor (TKI) therapy - 2. Provision of signed and dated written informed consent by the patient or legally acceptable representative Exclusion Criteria: - 1. History of hypersensitivity to excipients of the study drug or to drugs with a similar chemical structure or class to the study drug - 2. Pregnancy and/or breast feeding - 3. Current participation in any interventional trial Inclusion Criteria: - 1. Eligible for, or on active study drug treatment according to the approved label; patients with locally advanced or metastatic, EGFR T790M mutation-positive NSCLC, who have progressed on or after EGFR tyrosine kinase receptor (TKI) therapy - 2. Provision of signed and dated written informed consent by the patient or legally acceptable representative Exclusion Criteria: - 1. History of hypersensitivity to excipients of the study drug or to drugs with a similar chemical structure or class to the study drug - 2. Pregnancy and/or breast feeding - 3. Current participation in any interventional trial Non-Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- T790M ---

Inclusion Criteria: - 1. Eligible for, or on active study drug treatment according to the approved label; patients with locally advanced or metastatic, EGFR T790M mutation-positive NSCLC, who have progressed on or after EGFR tyrosine kinase receptor (TKI) therapy - 2. Provision of signed and dated written informed consent by the patient or legally acceptable representative Exclusion Criteria: - 1. History of hypersensitivity to excipients of the study drug or to drugs with a similar chemical structure or class to the study drug - 2. Pregnancy and/or breast feeding - 3. Current participation in any interventional trial Inclusion Criteria: - 1. Eligible for, or on active study drug treatment according to the approved label; patients with locally advanced or metastatic, EGFR T790M mutation-positive NSCLC, who have progressed on or after EGFR tyrosine kinase receptor (TKI) therapy - 2. Provision of signed and dated written informed consent by the patient or legally acceptable representative Exclusion Criteria: - 1. History of hypersensitivity to excipients of the study drug or to drugs with a similar chemical structure or class to the study drug - 2. Pregnancy and/or breast feeding - 3. Current participation in any interventional trial Non-Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- T790M --- --- T790M ---

Primary Outcomes

Description: Proportion (%) of patients with adverse events (AEs), serious adverse events (SAEs) and AEs of special interest (AESI)

Measure: Proportion (%) of patients with adverse events (AEs), serious adverse events (SAEs) and AEs of special interest (AESI)

Time: up to one year

Description: Severity of (S)AEs

Measure: Severity of (S)AEs

Time: up to one year

Secondary Outcomes

Description: ORR (Objective response rate), if available

Measure: ORR (Objective response rate), if available

Time: up to one year

Description: PFS (Progression free survival), if available

Measure: PFS (Progression free survival), if available

Time: up to one year

321 A Longitudinal Study Evaluating Molecular Changes Associated With Resistance to First and Third (AZD9291) Generation EGFR TKIs in Patients With EGFR Mutant NSCLC Using "Liquid Biopsy"

Based on the possibilities that both plasma and circulating tumor cells (CTCs) (the "liquid biopsy") may offer, we consider that it could be feasible to longitudinally monitor the genetic evolution and the biologic characteristics of CTCs, by using Circulating tumor DNA (ctDNA) and CTCs as a source of biologic material. This approach could provide information regarding the genetic/molecular changes associated with primary and acquired resistance to AZD9291 and, thus, to facilitate to more appropriately adapt the tailored treatment in this particular group of NSCLC patients. It has been recently reported that the detection of resistant clones, based on the tumor-associated genetic aberrations in the blood, can identify treatment resistance up to 10 months earlier than the radiological methods providing, thus, the potential for an early switch to a non cross-resistant therapy in order to improve patients' outcome.

NCT02771314
Conditions
  1. Non Small Cell Lung Cancer
Interventions
  1. Drug: AZD9291
MeSH:Carcinoma, Non-Small-Cell Lung
HPO:Non-small cell lung carcinoma

The patients will be followed every 3 months for the detection of mutations (T790M), (C797S), (L858R), del 19 EGFR mutations as well as the mutations [(KRAS)/(NRAS), (BRAF), (PI3K)] in the serum/plasma, the determination of the serum levels of Hepatocyte Growth Factor (HGF), the presence of T790M (+) and C797S(+) CTCs as well as the molecular (c-MET) and (HER2 amplification) and phenotypic characterization of CTCs using the filtration platform (ISET). --- T790M ---

The patients will be followed every 3 months for the detection of mutations (T790M), (C797S), (L858R), del 19 EGFR mutations as well as the mutations [(KRAS)/(NRAS), (BRAF), (PI3K)] in the serum/plasma, the determination of the serum levels of Hepatocyte Growth Factor (HGF), the presence of T790M (+) and C797S(+) CTCs as well as the molecular (c-MET) and (HER2 amplification) and phenotypic characterization of CTCs using the filtration platform (ISET). --- T790M --- --- C797S --- --- L858R --- --- T790M ---

Primary Outcomes

Measure: Biomarkers of resistance to first and third (AZD9291) generation EGFR TKIs, explored by studying baseline serial serum or plasma DNA specimens and baseline Circulating Tumor Cells (CTCs)

Time: Up to 2.5 years

Secondary Outcomes

Measure: Progression free survival (PFS)

Time: Up to 2.5 years

Measure: Overall Survival

Time: Up to 2.5 years

Measure: Response rate, assessed using RECIST 1.1

Time: Up to 2.5 years

322 Almonertinib Plus Pemetrexed and Carboplatin Versus Almonertinib Alone in Advanced NSCLC With EGFR T790M After First- or Second-generation TKIs Therapy: a Randomized, Controlled, Open-label, Phase 2 Study

Almonertinib Plus Pemetrexed and Carboplatin Versus Almonertinib Alone in Advanced NSCLC With EGFR T790M After First- or Second-generation TKIs Therapy: a Randomized, Controlled, Open-label, Phase 2 Study

NCT04592666
Conditions
  1. Lung Cancer, Non-small Cell
  2. EGFR T790M
  3. EGFR Gene Mutation
Interventions
  1. Drug: Almonertinib
  2. Drug: Pemetrexed
  3. Drug: Carboplatin
MeSH:Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO:Neoplasm of the lung Non-small cell lung carcinoma

Almonertinib Plus Pemetrexed and Carboplatin Versus Almonertinib Alone in Advanced NSCLC With EGFR T790M After First- or Second-generation TKIs Therapy: a Randomized, Controlled, Open-label, Phase 2 Study. --- T790M ---

Almonertinib/Pemetrexed/Carboplatin in EGFR T790M+ Advanced Lung Cancer Almonertinib Plus Pemetrexed and Carboplatin Versus Almonertinib Alone in Advanced NSCLC With EGFR T790M After First- or Second-generation TKIs Therapy: a Randomized, Controlled, Open-label, Phase 2 Study PFS. --- T790M ---

After drug resistance, it was confirmed to be positive for EGFR T790M mutation by biopsy or free DNA test. --- T790M ---

Lung Cancer, Non-small Cell EGFR T790M EGFR Gene Mutation Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- T790M ---

Primary Outcomes

Description: progression free survival

Measure: PFS

Time: from the first cycle of treatment (day one) to two month after the last cycle (each cycle is 21 days)


HPO Nodes


HP:0002664: Neoplasm
Genes 1522
SF3B1 GFI1B IGF2 FIBP RPS7 WT1 COL7A1 TREX1 HSPG2 CASP8 SLC22A18 MC1R TFE3 KRAS PLAG1 OFD1 BRAF NUMA1 KRT16 PSENEN CTPS1 APC SOX9 FANCM OPCML CDKN2A RPS15A CTNNB1 SDHD EDN3 FCN3 NELFA GJC2 MALT1 HPGD GLI1 CD70 SPINK1 LETM1 PMS1 LRP5 HNF1B EXT1 TCF4 ELMO2 MET ANTXR1 KRT16 KRT10 PAX4 SETBP1 TERT WT1 SMARCB1 GJB6 HRAS STK11 BUB1B GNPTAB MYD88 MCC GJB2 BRCA1 TP63 PDGFRL TARS1 NF1 FGFR3 KARS1 BARD1 BRIP1 GATA2 IL1RN BRAF CD81 TNFRSF13B TYROBP AR LIG4 KLF11 ABL1 MVK BMPR1A PIK3CA B3GALT6 SLC37A4 SOS1 TSC1 FGFR3 ATRX FANCG TET2 KIT SRP72 MPL TP53 SMAD4 EVC2 MAPRE2 DLST BRCA1 DICER1 HRAS AKT1 RNR1 TSC1 TNPO3 XRCC4 DNMT3A NEUROD1 THPO MN1 NOD2 SRSF2 PPM1D FLT4 ATP7A IL7 KRAS GDNF WNT10A EPAS1 COL1A1 IL1B MRAP ADAMTS3 PRKCD SUFU PTCH1 ERCC3 KRT14 CXCR4 HOXD13 IGF2 LIG4 PALB2 BLM NRAS ERCC3 FOXP1 SDHD TP53 PKD2 PDX1 TINF2 ADA2 MYF6 RHBDF2 POU6F2 PHKG2 CDKN2A RUNX1 ERCC2 MAP2K2 WT1 USB1 GATA4 FGFR2 ACD CR2 MUTYH ARL6IP6 FAH MSH2 RASA1 NEK1 SOX6 NR0B1 LIG4 CDKN2B NF1 NF1 POLE RPL35 SRY SDHAF2 FANCL CPLX1 FAS PRKAR1A PHB SDHA CALR PIK3R1 FAN1 TET2 TMEM216 RSPO1 SEMA3D MDM4 SDHD HRAS NUP214 GJA1 PIK3CA CCND1 RNF6 MSH2 C11ORF95 MVK MCM4 FLI1 TINF2 KIAA0753 ECM1 ARSA ERCC2 SOX2 SDHC SLC26A2 MPL VANGL1 PUF60 RAD51D POT1 CR2 ESCO2 FOXE1 PMVK SRY GJB4 TRIM37 KIT EXT2 PDGFB KIF1B FANCF IGF2R MLH1 GDNF PIK3CA ASCC1 ASCL1 TCIRG1 APPL1 RPS19 BCL10 IGF2 NRAS FLT3 STAT1 BCL10 RMRP GNAI3 KRAS GPR101 BAP1 NKX2-1 MAX BMPR1A DDB2 SMARCB1 RAD51 FGFR3 ALX4 BTK MSH6 NOTCH3 DICER1 CXCR4 CCBE1 RET WT1 TP53 PALLD RNASEH2B WT1 ATR CCND1 KCNQ1OT1 SMAD4 AHCY STK11 FANCC TRNK BCL6 SMAD4 SKIV2L HMBS TP53 TERT PHOX2B SNAI2 BRAF TCOF1 FANCI NRAS REST SDHC HBB HFE CREBBP MET SEC23A CEP57 CTLA4 TRIM28 SMAD7 GNAS BRCA2 PALB2 FGF8 SBDS RET ALK GJB2 CPLANE1 GPC3 TCTN3 PTEN RB1 INTU CYP26C1 LEMD3 PRLR CDON NLRP1 GPR101 DHH HNF4A MMEL1 DNASE1L3 RASGRP1 ATRX CHEK2 FANCA SPRED1 DNM2 FLT4 CHEK2 RPS19 KLLN HACE1 HNF1A PTPN11 CDKN1B GAS1 BRCA2 KCNQ1OT1 NPM1 FGFR3 MC1R MINPP1 PTPN11 TSC2 ABCA5 BRCA2 PLCB4 SCN11A HNF1A BRAF RB1 CBL ARHGAP26 SUFU PTPRJ C1S APC IRF5 GNAQ GDNF TERT MYSM1 XPC TMC8 COL4A5 ERBB3 SLC26A4 CD96 NSUN2 PDGFRA FERMT1 TYR DNAJC21 MSH2 SH3GL1 TUBB RET BRAF ESR1 PAX3 RHBDF2 RTL1 WRN DYNC2LI1 ELANE EXOC6B RPS26 EWSR1 VHL PIGA GCGR POU6F2 RNF43 POLE BRAF MNX1 SFTPA2 CDH23 ASCL1 APC ACVR1 PIGL BAX RAG2 RSPO1 MSH3 PGM3 FGF3 FANCE MPL TP53 COL7A1 BUB1 TET2 PALB2 ACTB PNP SDHC EDN3 XPA TMC6 NEK1 GNA11 KAT6B KRT1 RUNX1 PAX7 NOTCH1 ENG CTNNB1 ETV6 MPLKIP PARN CDKN2A PTPN3 STAG3 MDM2 TP53 LAMC2 NBEAL2 VAMP7 GNA14 DCLRE1C CBL GCDH FANCC AXIN2 PYGL SOS1 BLK WRAP53 IDH1 KRAS CCM2 APC ASXL1 ATP7B ERCC3 SF3B1 EP300 BRCA2 MGAT2 NRTN CDKN2A DICER1 PMS1 RPS10 TBC1D24 FAH BRCA2 ASXL1 BCR C2CD3 KRAS IDH1 IGLL1 RASA1 BRCA2 CHEK2 PTCH1 RNF113A BRAF MBTPS2 EDNRB IGHM PDGFRB RAF1 MEN1 FASLG TUBB NDUFAF6 FOXI1 TGFBR1 EPCAM CYLD SDHB APC CYP2D6 TAF1 KRT17 BRCA1 BUB1B BAP1 GDF2 BUB1B ERCC2 TP53 KRT5 GATA2 BRCA1 RAD54B MRE11 STAC3 DNMT3A MLH1 BCHE EDN3 CDKN1B AURKA NRAS FLCN IDH2 EDN1 ESCO2 USF3 IGH POT1 ACVRL1 JAK2 NBN NRAS SQSTM1 TMEM127 ZFPM2 SLC12A3 NTHL1 ADA CHIC2 STAT3 SETBP1 FANCB FIBP STAT3 STK11 MLLT10 SFTPC HDAC4 NUP214 GLI2 SLX4 TSC1 ERCC6 TP53 CLCNKB KLF6 OGG1 JAK2 PAX6 RECQL4 RPL31 MYO1H FH RPGRIP1L SLC45A2 RPL10 RPL10 HMBS GDF5 TNFRSF10B PIK3CA GABRD TP53 BRCA2 SEMA4A BCR PALB2 ASXL1 KRT6B CCDC22 SAMD9 DMPK DCC ERCC5 RPL5 CTNNB1 RPS27 TRNS2 PTCH1 PTEN TFAP2A RPS24 RPL35A RET AXIN1 HNF1B ARMC5 UBE2T SRP54 SSX2 DKC1 ERCC3 JAK2 GNA11 LAMB3 GJB2 NFKB1 KCNQ1 GLI3 PIK3CA KANSL1 CASP8 MYC RECQL4 ACAN CACNA1S BDNF KIF11 MDH2 MSL3 FGFR1 TERF2IP HFE NFKB2 TOP2A GFI1 SRD5A3 PHKA2 MAX POLE MAP2K1 EYA1 RNF43 ALX3 SETD2 ERCC4 CTLA4 SIX3 LEMD3 OCRL CDH23 DZIP1L MSH3 AR CDC73 PDGFRL TWIST1 POU2AF1 DKC1 CALR LIN28B KRT6A GATA1 MC1R DIS3L2 CD28 CDC73 ADA2 UROD CIB1 TSR2 WNT5A TET2 PHOX2B BMPER KIT DLC1 MSTO1 H19-ICR SLC25A13 ADAR TMEM67 BMPR1A MLH3 POLR1C KRT6B FH EFL1 TERC BUB3 FOXC2 NOTCH3 KIT NSD1 FGFR2 SLC6A17 MAP3K1 TRIP13 MEG3 RRAS2 BMPR1A NF1 DPM1 LIG4 PARN RHOH BRCA2 NF1 TAF15 RFWD3 VHL H19 BCR KRAS VANGL2 KRAS SDHD DVL3 BIN1 ABL1 GPC3 HAX1 FANCA GDNF NHP2 IGF2 VHL CCL2 EXTL3 RUNX1 PRKCD BLNK MSH6 SLC22A18 IL2RG PTH1R SDHB AIP WDPCP APC KCNJ10 ASPSCR1 OCA2 TP53 WT1 SPRTN TET2 TAL1 L2HGDH KIT SDHC ERCC4 GPR143 PRKN SMAD4 SEMA3C TRNS1 BRCA1 SHOX PCNA FANCG CREB1 TRNH VHL MYLK BAP1 SUFU ANTXR1 POLD1 NODAL IGH JAK2 MS4A1 MEN1 TSC2 GATA2 DHCR7 TINF2 F13B RB1 COL7A1 SCN4A BMPR1A DDB2 CDKN2A SDHD CYP11B2 IL7 ARID1B KIT FGFR1 RET CDKN2A LAMA3 CHEK2 TBX2 TBX18 HNF4A GPC4 SHH LMNA BMP2 YY1 AKT1 WT1 BAP1 FZD2 SH2B3 BTK GATA1 RAD54L ATM CTBP1 PTEN SRY RYR1 CTHRC1 MFN2 PTEN RAD21 PTEN MYC SLC26A2 TP53 CTNNB1 RAD51C NAB2 NLRP1 SUFU DLL1 PSAP SDHB REST TGFBR2 TRIP13 IGH ABCC8 IL6 CPLANE1 H19 FANCD2 FGFR2 RET PKD1 DNMT3A REST CHEK2 GNAQ MXI1 BRIP1 DYNC2LI1 GNAS TP53 GLI3 DIS3L2 NRAS PICALM WT1 BAP1 MEN1 TXNRD2 MGMT PTEN MYD88 GNAS POT1 AGGF1 BUB1 PTEN PORCN HFE NUTM1 PHOX2B MSX2 PMS2 SLX4 H19 USP9X RPL27 GNAS SEC23B CBL CD28 PKHD1 AXIN2 TRPV3 KLLN SSX1 TSC1 PPOX KRT17 CARD14 HRAS TCF3 RPL11 CC2D2A GREM1 CHEK2 AP2S1 NRAS TRNL1 ALX1 CREBBP TCTN3 TET2 ESCO2 DOCK8 NRAS STK11 GCM2 TTC37 WT1 SMAD4 DAXX MITF BCL2 DIS3L2 POLR1D TDGF1 KRAS TNFRSF13C KIT PHOX2B SF3B1 RPL15 NF1 TERT TNFRSF1B FANCD2 MLH3 IL7R GPC4 H19-ICR SLC17A9 MEN1 MST1R KIT RAD50 TJP2 DNAJC21 PDCD10 MUTYH IL12RB1 SH2D1A FGFR2 NBN KRAS KIT CASR ENPP1 SDHB HRAS IKBKG PNP EXT2 BRD4 SMARCB1 REST COL11A2 TG KIT LIG4 SUFU NBN RSPRY1 CYSLTR2 SDHD AAGAB BLM RAG1 RNF139 RB1CC1 ACD PTPN11 SLC26A2 TREX1 BMPR1B DDR2 ZAP70 MNX1 MAGT1 AIP GATA2 AR STAR IFIH1 IDH2 BRCA1 USP8 RB1 FGFRL1 SMO USP8 RMRP SLC25A11 MLH3 FUZ DOCK8 SUFU NF2 KDR KRAS RPS14 CASP10 SRP54 ZSWIM6 TBXT PTCH2 EWSR1 TNFRSF13C MTAP NQO2 RPL18 DNAJC21 GCK ERCC6 KDM6B EXT1 SBDS CCND1 SDHAF2 KCNH1 CYLD LMOD1 PDGFRA CAT CHRNG TRNQ ADA NRAS TLR2 SHOX FGFR3 BCL10 TYR KRAS COL2A1 PTCH2 SMO GBA MSTO1 TREM2 JAK2 TMEM231 MSH2 ASXL1 RET DHCR7 NBN PIK3CA NSD2 SDHB EIF2AK4 PALB2 KIF7 PTPN11 PIK3CA HLA-DRB1 STIM1 TMC6 KIF1B TNFSF15 RELA AKT1 NPM1 APC SDHA SDHB STAT6 CDKN1C CDC73 PTCH2 KANSL1 ZSWIM6 FLCN HBB LZTS1 FN1 TRAF7 ACP5 CTNNB1 MLH1 EXT2 RNASEL RNASEH2A IL2RG ATP7A CDK4 CYP11B1 MMP1 SDHB ATRX ACTG2 FOXH1 OFD1 NEK9 STS MUC5B PRKCD PTPN11 PTCH2 LRRC8A RPL26 MSH6 NNT LZTR1 CDC73 PTEN AKT1 AKT1 SASH1 HRAS ANAPC1 PTPN12 KCNJ11 TCF4 GATA2 MLH3 ERCC4 GNB1 DISP1 IDH1 BCR GANAB MSH6 NR5A1 TSC2 GFI1 TNFSF12 TRNP MAPK1 IFNG FLT4 MTM1 WWOX HABP2 RPS28 HRAS SLCO2A1 ND5 SDHB CHD7 BRIP1 SLC37A4 MC2R XRCC3 TNFRSF4 NAGS PHF21A ZIC2 PCGF2 SMARCE1 CTNNB1 SRP54 CDH1 CDK4 RPS20 KCNJ10 RAD21 RNF6 COL14A1 SMO CD19 WRN SRGAP1 CDKN2C AXIN2 GPC6 WWOX HSPA9 FOXI1 CPOX RPS17 APC2 MYH8 SERPINA1 ATM LMX1B ENG POLH TGFBR2 DHX37 VEGFC KIF1B KRT17 DDX41 SPIB CBFB HRAS BCL10 PIGL FGFR1 NSD1 F5 KCNN3 BAX PIEZO2 RECQL4 CREBBP KIT PDGFB PDE6D ABCA5 AKT1 KLHDC8B TNFSF12 EPCAM RARA MLH1 GINS1 EVC PIK3CA FANCE WIPF1 NF2 PDGFRA PRKAR1A CDH1 SDHD PRCC TRNF PTCH1 TNFRSF1B WNT10A WWOX MAD1L1 MTOR WDPCP RNASEH2C NSD2 SAMD9L FH LPP NF1 KRIT1 NTHL1 IL12A HNF1A CDH1 SMARCB1 SMARCE1 CD19 FH FDPS TRPS1 ERCC4 SMPD1 SMARCD2 BRCA1 MPL CRKL SEC23A EXT1 PERP ATM FOXE1 CDKN2B CTSC SIX1 FAM149B1 CDH1 RAD51C ALX3 DLST TRIP13 ING1 PDGFRB FLT3 COL18A1 MST1 TGIF1 TMEM107 SRSF2 TRIM28 BAP1 ANTXR2 CD79A PIK3R1 MAP3K1 NOP10 PIK3CA POLD1 KDSR CCND1 TP53 TMC8 ALK MAP2K1 CD79B SDHC ECE1 PALLD CTSA PRDM16 IVNS1ABP CALR FLNA GPR101 BRCA2 ERCC2 DYNC2H1 TFAP2A COL2A1 DVL1 TERT APC TERT TEK EXT2 TERC ALX4 OFD1 LMO1 PDGFRB RPS14 DCC RTEL1 INS TSC2 FAM20C MYH11 GPC3 SCN9A SMAD4 RASGRP1 HBB TGFBR2 RERE NDP PLA2G2A TCF4 MAD2L2 SKI AIP HMMR SDHC SNAI2 PIK3CA LMNA PGM3 ABCB11 TAL2 WT1 VHL PIK3CA TCTN3 SAMD9L ICOS GLI3 RB1 SLC25A13 SDHC DCLRE1C GCM2 VANGL1 SIX6 WT1 PMS2 KCNH1 BARD1 H19-ICR GNAS TERT CIB1 B3GALT6 GJB3 ERBB2 SDHA KRAS CDC73 TNFRSF13B TET2 FGFR3 WAS SEC23B TGFBR2 TP53 NF2 SMARCA4 NF2 SLC26A4 ANTXR2 WRAP53 FAS SAMHD1 TP53 TET2 ATP7A PTEN SH3KBP1 CARMIL2 MVD PDGFB ABCC6 G6PC1 TRNK KRAS GPC3 PTEN NF2 JAK2 DMRT3 GNAQ RAD51 GTF2H5 TMEM127 TERT RUNX1 FAT4 AR HABP2 NR4A3 EP300 MINPP1 OFD1 RASA1 DLEC1 BIRC3 AIP CD27 PHOX2B BMPR1A KCNE3 PLCD1 RAD51 KRT1 MSH3 MITF EPHB2 DHCR24 RABL3 KRT17 XRCC2 NRAS ITK VHL BICC1 RECQL4 SMARCAD1 MYCN RET CTC1 PTCH1 JAK2 SRC SDHB PHOX2B AKT1 KEAP1 JAG1 VHL LETM1 NLRP1 MEN1 BRCA2 FLCN C2CD3 RFWD3 XPA APC APC SDHD FOXO1 MAFA WHCR GPC4 MLH1 ICOS CDKN1B MTMR14 KIT DICER1 EP300 ZFHX3 MMP1 PRKAR1A KRT9 F13A1 CTNNB1 MPL INPP5E NF1 DKC1 TERT DLK1 SCN10A STS RPS29 PTEN FLCN LRBA ELANE GTF2E2 ATM PIK3CA GPR35 CYLD RAD51C CDKN1A WT1 DICER1 PIK3CA TERC PIK3CA SLC25A11 GNAS CEBPA ATP6V1B2 RET XPC EXT1 BRCA2 SH2B3 ERCC3 BRCA2 RTEL1 WASHC5 ERCC2 AKT1 KCNAB2 CYLD STK4 POLH ERCC5 CDH1 CEL XIAP MSR1 TP53 TET2 DHH PRKAR1A
HP:0002088: Abnormal lung morphology
Genes 1425
KMT2D SMARCB1 ABCA12 MAT2A TNFSF11 TRAIP MAGEL2 DNAAF1 NFE2L2 MITF NFKB2 LCK MAGEL2 SGCG ALG9 TECPR2 GTF2IRD1 CALCRL KAT6B CHAMP1 OFD1 CTRC SCNN1G CD247 MGP TGFBR2 SPINK5 CTPS1 RASA2 NHLRC2 PHGDH RTEL1 NTRK1 NGLY1 ARVCF SLC2A10 RELB ZNF341 RSPH9 FCN3 NELFA RREB1 NAA10 MALT1 HPGD CFTR GLI1 OCA2 LETM1 NPHP3 PIK3CD FSHR FMO3 USP9X TCF4 WDR35 PRSS1 HLA-DPA1 DNAH11 RIT1 ZAP70 STK11 NKX2-5 UNC119 CDC45 BUB1B SNAI2 WAS SIM1 GNPTAB DYNC2H1 FOXH1 CFAP221 TARS1 NF1 NEB LAMB2 TTC7A CCR6 RARA ACTL6B MYO5A CD81 ADNP TNFRSF13B SEC24C TBX1 MYH6 COL3A1 TSC1 CYBA HLA-DPB1 TERT GNS FOXH1 EVC2 LIPN KATNIP TPM2 RRAS2 TSC1 EPHB4 COL6A1 NIPBL SPAG1 FLNB IL17RA HSPG2 ITGA8 GAS1 SLC12A6 EFEMP2 CRLF1 SLC26A2 GMNN DGCR8 ACTA2 CTLA4 SLC35A1 ADAMTS3 TAPBP SLC25A24 PRKCD SPECC1L CCR6 CXCR4 HOXD13 BLM RNU4ATAC CFAP300 FOXP1 CDON CD79A TTC21B CBL RAG1 VPS51 DISP1 USB1 NUP107 NEPRO COL11A2 FLNA CR2 ACVRL1 LAMTOR2 NEK1 SNORD115-1 GLE1 MAP3K20 DNMT3B SLC26A2 FAS MKRN3-AS1 LYST PIK3R1 ACADVL LIFR TDGF1 TAPT1 RFX5 VPS33A MYRF MDM4 HRAS TBC1D24 NGLY1 GLI2 FGF8 ODAD4 CCDC40 MYH11 C11ORF95 MCM4 CTLA4 CRELD1 ZBTB24 TINF2 ECM1 CAV1 NAA10 LRRC6 PUF60 CFTR FLCN COL11A2 CR2 FOXE1 CCBE1 ELP1 TFRC AGA SMPD1 PWRN1 MMP21 IPW GATA6 LACC1 TCIRG1 SERPINF2 BLNK IFT80 FLI1 UBB KIF20A STAT1 DLL4 MBTPS2 PAX3 ELP1 SNRPN DISP1 RMRP TGFBR2 KRAS STAG2 IRF8 SIX3 SOX10 KIF1A RYR1 IGHM BTK NOTCH3 DICER1 CYP4F22 CXCR4 RSPH1 MEFV CCBE1 DNAH11 ZIC2 WDFY3 CCND1 CSF2RA POLR3A BCL6 LAMA2 SMAD4 SKIV2L STAT1 SNX10 TERT FGF8 BRAF SFTPC FOXJ1 ATP11A AICDA SHH RYR1 ODAD1 SCARB2 SIK1 HACD1 CHRNG CREBBP TNFRSF13B CITED2 OCA2 MYBPC3 NODAL NOTCH2 CFAP298 SELENON CEP57 CTLA4 TRIM28 ZIC2 ALMS1 DOK7 ODAD4 IDUA DLL1 ELN SBDS COG6 TBX6 RFXAP PEX13 TCTN3 PTPN22 DGCR6 SFTPC RAG1 INTU EDNRB FGF20 MAGEL2 DNASE1L3 RASGRP1 STRA6 IFT81 COG4 MARS1 EPM2A MESP2 TTC12 SOS1 TBC1D23 IL12A-AS1 ENG SCNN1B CSF2RA TGFB1 CCN2 FBXW11 MAN2B1 HLA-DRB1 PTCH1 NPM1 EPG5 UGP2 GLI2 GAS2L2 TSC2 PPP1CB RANBP2 SCN11A GPKOW CBL CTLA4 IL12A MESP2 IL21R CRELD1 IL17RC UMPS TERT SLC18A3 MYSM1 DSE TRPS1 PEX1 MKRN3 RTEL1 RPGR DYNC2H1 PRKG1 DSG1 ACP5 FLT4 JAK3 TCF20 EXOSC9 MIR140 DNAL1 NCF4 ACTC1 IFT80 FGFR3 ALG14 VAMP1 RTL1 ESS2 WRN TGFB1 MKS1 DYNC2LI1 EWSR1 FGF20 CD3E POU6F2 ELN IDUA SFTPA2 SFTPB ATP5F1A FANCF PLCG2 SLC29A3 NDN PIGL RAG2 RAG2 SLC46A1 SLC2A10 RET PGM3 GBA IL2RG SULT2B1 DNAJB13 JMJD1C TP53 SDR9C7 BUB1 MSN MYOD1 FCGR3A SHROOM4 PNP COQ7 ACTA1 ERF MYSM1 ZEB2 ETFDH AGTR1 LEPR TBX1 PIGT FLNC DGCR2 NCF4 ODAD2 IFT172 RFXANK KAT6B DNAI1 GBA NEK10 DNAI1 KIAA0586 MPLKIP CCNQ MDM2 AGA LAMC2 RAG2 LEPR IL17F DCLRE1C SPIDR LIMK1 PEPD CCN2 ITGA3 MYT1L ZBTB24 STAT5B NCF1 CD3D EP300 RIT1 IL2RB GLI2 DICER1 COL6A3 FBLN5 TASP1 DCLRE1C FARSA CDC42 PYROXD1 IL7R TBC1D24 PLCG2 GAA ODAD3 STAT4 LTBP4 NFKBIA PKHD1 IL17RA KRAS MCTP2 BPTF IGLL1 SCNN1A ODAD3 TK2 PSMC3IP TPM3 RNF113A MBTPS2 IGHM PDGFRB RAF1 FASLG CCDC39 MUSK FAM111B NDUFAF6 TRIP4 MS4A1 SMN1 MUSK PRKAG2 SMARCC2 HLA-DRB1 CFH LEP CYBB LMNA PSMD12 NEU1 CD3E PTPRC STAT3 PLG CHRNA1 FOXH1 TNNI3 PRKAR1A TYK2 LOX FLCN NEK9 ORC6 RNF168 PTPN11 CARD11 CD3G LONP1 TGFBR1 CC2D2A GNPTAB IDUA TREX1 CYBB NBN NRAS LPIN2 DNAAF6 TGIF1 WAC ADA FBN1 STAT3 SETBP1 ACTA1 STRA6 CD3D STAT3 ZMIZ1 ETFB RSPH4A SFTPC HLA-B TBX5 TSC1 DNMT3B A2ML1 RPL10 RPL10 MEFV TP53 ITCH BRCA2 IRF2BP2 GAS1 ASXL1 NEK10 CCDC22 SAMD9 MYH7 WNT4 DOCK3 CD247 CFI RCBTB1 UFD1 TREX1 ASAH1 INPPL1 NOTCH2 SERPINF2 MECP2 DKC1 KAT6B MEFV GLDN CHRNG HYDIN CDT1 DNAAF2 IL6R LAMB3 NFKB1 RUNX2 IL1RN GLI3 IRAK1 KANSL1 DLL3 PTCH1 TGFBR1 NDUFB10 REN TDGF1 ABCA3 RAG1 KIF11 FGFR1 UBE2A MYOD1 NFKB2 PIK3CD SMN1 FREM2 TGIF1 LAT HELLS ZEB2 RSPH9 NSDHL SERPINH1 MTHFD1 FAM13A SETD2 PAX6 SOX18 SMARCD1 OCRL SLC52A3 BMPR2 DZIP1L TDGF1 WDR1 ALB CD28 ADA2 RAPSN DLL1 RBPJ WDR19 HLA-DRB1 SHH BMPER MYLK TMEM94 SIX3 PML TGFB3 MYL2 STAG2 TBL1XR1 FBN1 EFL1 TERC BUB3 HES7 FOXC2 RBM10 CFAP410 MASP2 TRIP13 GLB1 MEG3 MYH3 LIG4 PARN RHOH NFKB2 EDARADD DNAAF6 BCR RNF125 TLL1 DCLRE1C SCNN1A GPC3 ASAH1 SNAP25 NR5A1 NHP2 DNAAF5 DLL1 EXTL3 PRPS1 MAN2B1 FANCB COMT ZMYND10 FOXN1 PRKCD BLNK NTNG1 IL2RG IL7R EMG1 TRPV4 SMPD1 ETFA IRF5 NODAL WT1 NECTIN1 LAMTOR2 RAG2 ROR2 ADA FCGR2A IER3IP1 CYTB KDM6A BTNL2 WNT3 TLL1 ALOXE3 TGIF1 ASCC1 PIGN BNC1 RIPPLY2 BAP1 NOS1 NXN DSP DNAH1 ITPR1 IGH PIEZO1 CSPP1 COL3A1 ARHGAP31 MS4A1 NODAL USB1 LRRC56 NPM1 TSC2 ATP6V0A2 DHCR7 ZBTB16 EPG5 TINF2 CASP8 PRPS1 IKBKB ARID2 SHH ARID1B RLIM EGFR CDKN2A LAMA3 SFTPA1 IKZF1 CAV1 PLOD1 PRKDC LMNA JAK3 BMP2 AKT1 CFTR ELN AGT DNAAF4 ATP6V1E1 IFT140 BTK BTNL2 COPA PEPD SCNN1B KCNJ6 GAA MCIDAS PTEN SOX4 ZMYND10 UNG GATA6 DYNC2I1 PSAT1 GATA4 SLC26A2 NDN BCOR NAB2 CD81 NKX2-1 PLOD1 PLEC FUZ CRTAP FGF8 GAS1 ABCA12 REST B3GLCT IGH CLIP2 SCNN1B H19 CYBC1 ELN RAG1 ALDH18A1 MYT1L KLHL41 ACE RSPO2 CLEC7A HIRA GP1BB DRC1 GDF1 TP53 GLI3 SVBP TCIRG1 FRAS1 IRF5 GDF1 PMM2 PAFAH1B1 ZMPSTE24 TGM1 DLL1 SIX3 CCNQ TIMM8A ELN PTEN FUCA1 MYD88 SPAG1 ARID1B AGGF1 THOC2 ABCA3 ARSB CFB PORCN HFE SOX11 NOTCH1 FOXP3 TERC USP9X P4HTM DRC1 AP3B1 CBL POLA1 CDON PKHD1 TAF1 COLQ SON TRPV3 TSC1 DVL3 TCF3 TRIP4 CHEK2 FLNB STAT5B STXBP2 CREBBP NPAP1 FAM20C STK36 DOCK8 SLC7A7 DDR2 TTC37 CD8A DOCK6 CD46 CCDC65 BCL2 INPPL1 DIS3L2 MFAP5 TNFRSF13C KNSTRN RPS15A GLA SELENON LRRC6 KMT2E SLC5A7 TERT GRIP1 DYNC2I2 PTPN22 FAT4 SHH IFIH1 IL7R PARN ARHGAP31 CSF2RB CHST14 TANC2 CIITA ZIC2 FLNA G6PC3 MARS1 BACH2 ZNHIT3 DNAJC21 SH2D1A CCNO COL13A1 DISP1 IL21 HYDIN MGP IL2RA MED25 GSN FOXH1 SLC35C1 PNP PRTN3 SP110 ARID1A MEFV NOD2 SERPINA1 NHP2 MED13 FRAS1 NBN MCIDAS FCGR2B KLHL40 BLM RAG1 RRAS TAP1 SNRPN ADGRG6 NADK2 SLC26A2 DDR2 ZAP70 MAGT1 FGFR1 GATA2 ALOX12B TMEM260 IFNGR1 SMAD4 SLC7A7 NFKB1 RB1 RARB APOE GATA6 DOCK8 AP3D1 SOS2 STING1 CASP10 B2M FLCN SRP54 ZEB2 TNFRSF13C FADD C4A TTC12 TAP2 KPTN STN1 LBR SNRPN DNAI2 MRAS COL2A1 RNF168 CHRM3 CCNO CHRNG RAC1 FGFR3 LGI4 ADA NUP88 TBX20 ODAD2 BCL10 FLNA SLC25A22 ELN SMO GBA TGFB2 NUMA1 RAG2 GATA4 DNAH9 SMARCA4 TNFRSF11A IRAK4 GUSB CD40LG SCNN1G SLC34A2 DHCR7 MIF GUSB KITLG KIAA0586 GRIP1 NSD2 DPF2 SLC35A1 EIF2AK4 GBA SPP1 NCF2 MKKS GAS2L2 MYH3 TBCD HLA-DRB1 PTPN22 RAC2 DDX6 CEP57 RELA PTCH1 DNAI2 ZFPM2 TPP2 RAG1 STAT6 IFT43 KANSL1 PURA LRRC56 DNAAF1 SCNN1G IL6ST ACP5 XIAP IL2RG FANCB IGLL1 AFF4 SCNN1B BCORL1 BTK PCNT MUC5B MRPS22 CDON COG4 PRKCD PTPN11 LRRC8A PHGDH BGN DVL3 PSAP HLA-DQA1 DYNC2I2 SLC35C1 PWAR1 SLC1A4 CR2 TBCE AGRN CTCF FBLN5 VANGL1 TRIP11 NKX2-5 TSC2 GFI1 TNFSF12 GAS8 MAPK1 SLC11A1 IFNG FBN1 DNAAF2 SCNN1A ACTA1 MESP2 HABP2 NDN SLCO2A1 FOXE3 IDS PANK2 FGFR1 CHD7 DNAAF3 NABP1 DNAAF3 CFI DPM2 OCA2 PCGF2 SFTPB MANBA TNNT2 SRP54 PLVAP CD79B SOX18 INVS DYNC2LI1 RARB CD19 FOXJ1 BMPR2 PIGN LEP PKD1L1 NHLRC1 GPC6 ITCH APC2 GATA6 SCNN1A SERPINA1 ATM GBA DNAJB13 CEP120 TNFRSF1A KIAA0319L CLCN7 NSD1 CACNA1C SPEF2 PIEZO2 DYNC2I1 NKX2-5 CREBBP TBX1 TNFSF12 COL6A2 EFEMP2 RAC2 PRSS2 TBL2 CFTR IL10 CFAP298 DONSON RSPH3 ABL1 EVC SDCCAG8 DNAH5 WIPF1 PARN PDGFRA TINF2 NCF2 TNFRSF1B CEP120 FOXP1 RFC2 NPHP3 BCOR GATA4 SNORD116-1 POLR2A NOP10 CCDC103 OFD1 DNAAF5 GATA6 IL6 POLA1 PDHA1 LMNA CD19 SFTPC SIX3 LTBP3 SMPD1 SMARCD2 RIPK4 CSF2RB PSMB8 HPS4 CRKL PTH1R EP300 RSPH1 PERP ATM ABCA3 DCTN4 CLCA4 CTSC STAT3 CCND1 POLR3H TRIP13 FCGR2A MST1 MUC5B DNAH5 CDON TRAF3IP2 IDS SRSF2 SLC18A3 TRIM28 CD79A PIK3R1 GRHL3 NOP10 HPS6 WNT3 RPGR DPP9 RAF1 SCNN1G CD79B RSPO2 BCL11B IVNS1ABP ACTL6A ZIC2 AFF4 SMAD3 ITGA7 CITED2 ERCC2 RAB3GAP2 TRIP11 IL23R SPINK1 TERC RTEL1 CYBA TSC2 CITED2 GLE1 GPC3 TGFB2 SCN9A RASGRP1 FGF8 SNRPN DYNC2I1 CARD11 POLE ICOS FADD NME8 HLA-DQB1 LMNA PGM3 EOGT CDCA7 WT1 SAMD9L SMC1A ICOS GLI3 SREBF1 CHAT RFX5 FOXF1 TDGF1 CHST14 CCDC40 SMARCE1 DCLRE1C ALMS1 TLR4 NCF1 RSPH3 CYBC1 SLC25A1 PTCH1 IL2RG B3GALT6 GLI2 GAS1 TNFRSF13B TET2 NRAS WAS ZMPSTE24 EHMT1 WRAP53 FAS WDR35 HPS1 NSMCE3 TGIF1 GLUL SH3KBP1 RFXAP CARMIL2 BCOR GTF2I TNFRSF1A MAGEL2 STAT4 HGSNAT SMAD3 FBLN5 MYO9A GTF2H5 NEK8 TERT RUNX1 RYR1 FAT4 CLPB RIPK1 COL13A1 JAGN1 CIITA TBX20 CSPP1 DNAAF4 CCR1 HK1 MINPP1 UBAC2 NFIX RNU4ATAC BIRC3 WNT4 IKBKB CD27 FAS NLRC4 SFTPA2 NDN AARS2 TGFB1 DHCR24 PIK3R1 HYLS1 CREBBP CHRND ALPL ITK VHL CCDC103 GREB1L ERAP1 FARSB RAB27A NAGLU ODAD1 CTC1 ZCCHC8 TRMT1 SNRPN CEP55 PRPS1 DLL3 LYST KEAP1 GBA JAG1 NME8 MYPN STX1A TNFRSF13C FIP1L1 HERC2 ELANE CORO1A SYT2 CCDC39 CFTR GPC4 ITGA8 ICOS RFXANK KLRC4 DNASE1 DICER1 EP300 PRKAR1A MAGEL2 MLXIPL LZTR1 PIGN BMP15 HLA-DRB1 COL2A1 ADAMTS2 WDR19 ALG12 AK2 CD55 HLA-DRB1 GAS8 DKC1 NKX2-1 DLK1 SCN10A DYNC2I2 HELLPAR LMOD3 FLCN WT1 NODAL LRBA ELANE GTF2E2 SGSH GPR35 BAZ1B SFTPB TRAPPC4 PLP1 CACNA1B RSPH4A FSHR TERT CCDC65 WT1 TERC MID1 NR2F2 DHCR24 ERCC3 WASHC5 NIPAL4 LFNG VPS33A CD19 RLIM GALNS OSTM1 XIAP ASAH1 HLA-B DISP1 NAA10