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