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Report for Clinical Trial NCT02630186

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

A Phase 1b/2 Study of the Safety and Efficacy of Rociletinib (CO-1686) Administered in Combination With MPDL3280A in Patients With Activating EGFR Mutation-positive (EGFRm) Advanced or Metastatic Non-small Cell Lung Cancer (NSCLC)

This clinical research study is being carried out in two parts, Phase 1 and Phase 2. The primary purpose of the Phase 1 portion of the study is to observe the safety of the combination of rociletinib and MPDL3280A in EGFR-mutant NSCLC patients. The primary purpose of the Phase 2 portion of the study is to evaluate the safety and anti-tumor effects of the combination of rociletinib and MPDL3280A, at the best doses for the combination determined in Phase 1, in patients with EGFR-mutant NSCLC.

NCT02630186 Non-small Cell Lung Non-small Cell Lung Cancer
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

2 Interventions

Name: Rociletinib

Description: A novel, potent, covalent (irreversible) small molecule, tyrosine kinase inhibitor (TKI) administered orally (PO) to patients with EGFRm NSCLC.

Type: Drug

Single Arm Rociletinib and MPDL3280A

Name: MPDL3280A

Description: A human IgG1 monoclonal antibody administered intravenously (IV)

Type: Drug

Single Arm Rociletinib and MPDL3280A


Primary Outcomes

Description: The safety analyses will be performed using the safety population. Safety data analysis will be conducted on all patients receiving at least one dose of rociletinib or MPDL3280A.

Measure: Number of Treatment-emergent Adverse Events, as Assessed by NCI CTCAE v4.03

Time: Continuously, up to approximately 18.5 months

Description: Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. Cmax will be estimated for rociletinib, using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.

Measure: Maximum Concentration (Cmax) of Rociletinib and Its Metabolites

Time: Treatment Day 1 and Day 15

Description: Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. Tmax will be estimated for rociletinib, using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.

Measure: Time to Maximum Concentration (Tmax) for Rociletinib and Rociletinib Metabolites

Time: Treatment Day 1 and Day 15

Description: Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. Cmin will be estimated for rociletinib, using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.

Measure: Minimum Concentration (Cmin) of Rociletinib and Metabolites

Time: Approximately every 6 weeks up to 24 months

Description: Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. AUC0 24 will be estimated for rociletinib, using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.

Measure: Area Under the Curve (AUC) of Rociletinib and Rociletinib Metabolites

Time: Treatment Day 1 and Day 8

Description: Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. Cmax, for MPDL3280A will be assessed using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.

Measure: Maximum Concentration (Cmax) of MPDL3280A

Time: Cycle 1 Day 1

Description: Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. Cmin for MPDL3280A will be assessed using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.

Measure: Minimum Concentration (Cmin) of MPDL3280A

Time: Approximately every 6 weeks up to 24 months

Description: To determine the efficacy of the combination of rociletinib and MPDL3280A based on overall response rate per RECIST v1.1 in the following groups of patients: Group A: Patients with EGFRm advanced or metastatic NSCLC who have not previously received an EGFR TKI or chemotherapy. Group B: Patients with EGFRm advanced or metastatic NSCLC who have progressed on a prior EGFR TKI.

Measure: Objective Response Rate Per RECIST v1.1 in Phase 2

Time: Approximately every 6-9 weeks

Secondary Outcomes

Description: Conventional response criteria may not be adequate to characterize the antitumor activity of immunotherapeutic agents like MPDL3280A, which can produce delayed responses that may be preceded by initial apparent radiological progression, including the appearance of new lesions. Therefore, modified response criteria have been developed that account for the possible appearance of new lesions and allow radiological progression to be confirmed at a subsequent assessment. In this protocol, patients will be permitted to continue study treatment even after modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria for progressive disease are met if the benefit-risk ratio is judged to be favorable. These modified criteria are derived from RECIST version 1.1 (v1.1) conventions and immune related response criteria (irRC).

Measure: Objective Response Rate Per Modified RECIST v1.1, Incorporating Immune-related Criteria, in Phase 2

Time: Approximately every 6-9 weeks, up to 24 months

Description: Conventional response criteria may not be adequate to characterize the antitumor activity of immunotherapeutic agents like MPDL3280A, which can produce delayed responses that may be preceded by initial apparent radiological progression, including the appearance of new lesions. Therefore, modified response criteria have been developed that account for the possible appearance of new lesions and allow radiological progression to be confirmed at a subsequent assessment. In this protocol, patients will be permitted to continue study treatment even after modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria for progressive disease are met if the benefit-risk ratio is judged to be favorable. These modified criteria are derived from RECIST version 1.1 (v1.1) conventions and immune related response criteria (irRC).

Measure: Duration of Response Per RECIST v1.1 and Modified RECIST v1.1, Incorporating Immune-related Criteria, in Phase 2

Time: Approximately every 6-9 weeks, up to 24 months

Description: Conventional response criteria may not be adequate to characterize the antitumor activity of immunotherapeutic agents like MPDL3280A, which can produce delayed responses that may be preceded by initial apparent radiological progression, including the appearance of new lesions. Therefore, modified response criteria have been developed that account for the possible appearance of new lesions and allow radiological progression to be confirmed at a subsequent assessment. In this protocol, patients will be permitted to continue study treatment even after modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria for progressive disease are met if the benefit-risk ratio is judged to be favorable. These modified criteria are derived from RECIST version 1.1 (v1.1) conventions and immune related response criteria (irRC).

Measure: Progression-free Survival Per RECIST v1.1 and Modified RECIST v1.1, Incorporating Immune-related Criteria, in Phase 2

Time: Approximately every 6-9 weeks, up to 24 months

Description: Patients who received the combination of rociletinib and MPDL3280A alive at the termination of this study.

Measure: Number of Patients Alive at Study Termination

Time: Up to approximately 18.5 months

Description: Tumor tissue, plasma, and blood specimens will be used for pharmacodynamic assessment of rociletinib and/or MPDL3280A activity, to evaluate the concordance of mutant EGFR detection between tissue and plasma, and to explore biomarkers that may be predictive of response or resistance to rociletinib and/or MPDL3280A. Biomarkers and changes in biomarker status will be investigated for associations with rociletinib and/or MPDL3280A exposure, safety, and clinical activity. Given the limited sample size, no formal statistical analysis is planned.

Measure: Longitudinal Changes in Blood Based Biomarkers (eg, Mutations in EGFR) in ctDNA

Time: Blood samples will be collected from each patient approximately every 3 weeks, up to 24 months

Purpose: Treatment

Single Group Assignment


There are 3 SNPs

SNPs


1 L858R

Given the limited sample size, no formal statistical analysis is planned.. Inclusion Criteria: - ECOG performance status of 0 or 1 - Adequate hematological and biological function, confirmed by defined laboratory values - Histologically or cytologically documented metastatic or unresectable, locally advanced or metastatic NSCLC, with one or more activating EGFR mutation (eg, G719X, exon 19 deletion, L858R, L861Q) and absence of exon 20 insertion - Measurable disease as defined by RECIST v1.1 - Biopsy of tumor tissue for central evaluation, within 60 days prior to the first day of study treatment - For Phase 1 and Phase 2 Group B, progression after prior 1st or 2nd generation EGFR TKI (eg, erlotinib, gefitinib, afatinib). --- L858R ---

- For Phase 2 Group A, EGFR TKI treatment-naïve and chemotherapy-naïve Exclusion Criteria: - Unresolved toxicities from prior therapy - Symptomatic, untreated or unstable central nervous system or leptomeningeal metastases - Previous treatment with rociletinib or MPDL3280A, or other 3rd generation EGFR TKI (eg, AZD-9291, HM61713), or PD 1 axis targeted therapy (eg, anti PD 1 or anti-PD L1) - Prior treatment with CD137 agonists or other immune checkpoint blockade therapies, including anti-CTLA-4 therapeutic antibodies - Uncontrolled pleural effusion, pericardial effusion or ascites requiring recurrent drainage procedures - Uncontrolled hypercalcemia or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab (bisphosphonate use for prevention of skeletal events allowed) - Known hypersensitivity to any component of the MPDL3280A or rociletinib formulations or history or hypersensitivity to chimeric humanized antibodies or fusion proteins - History of autoimmune disease - History of prior allogeneic hematopoietic stem cell transplantation or prior solid organ transplantation - Treatment with systemic immunosuppressive medications within 2 weeks prior to first day of study treatment (inhaled corticosteroids and mineralocorticoids allowed) - Live attenuated vaccine within 4 weeks prior to first day of study treatment - Active tuberculosis, active hepatitis, or positive HIV status - Class II to IV heart failure as defined by the New York Heart Association functional classification system - Untreated or uncontrolled cardiovascular disease or other symptomatic cardiac dysfunction - QTCF > 450 ms, inability to measure QT interval on ECG, personal or family history of long QT syndrome, requirement for medications that have the potential to prolong the QT interval - History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computerized tomography (CT) scan (history of radiation pneumonitis in radiation field may be allowed) - Other malignancies within 5 years prior to enrollment, with the exception of carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer, or ductal carcinoma in situ Inclusion Criteria: - ECOG performance status of 0 or 1 - Adequate hematological and biological function, confirmed by defined laboratory values - Histologically or cytologically documented metastatic or unresectable, locally advanced or metastatic NSCLC, with one or more activating EGFR mutation (eg, G719X, exon 19 deletion, L858R, L861Q) and absence of exon 20 insertion - Measurable disease as defined by RECIST v1.1 - Biopsy of tumor tissue for central evaluation, within 60 days prior to the first day of study treatment - For Phase 1 and Phase 2 Group B, progression after prior 1st or 2nd generation EGFR TKI (eg, erlotinib, gefitinib, afatinib). --- L858R ---


2 L861Q

Given the limited sample size, no formal statistical analysis is planned.. Inclusion Criteria: - ECOG performance status of 0 or 1 - Adequate hematological and biological function, confirmed by defined laboratory values - Histologically or cytologically documented metastatic or unresectable, locally advanced or metastatic NSCLC, with one or more activating EGFR mutation (eg, G719X, exon 19 deletion, L858R, L861Q) and absence of exon 20 insertion - Measurable disease as defined by RECIST v1.1 - Biopsy of tumor tissue for central evaluation, within 60 days prior to the first day of study treatment - For Phase 1 and Phase 2 Group B, progression after prior 1st or 2nd generation EGFR TKI (eg, erlotinib, gefitinib, afatinib). --- L858R --- --- L861Q ---

- For Phase 2 Group A, EGFR TKI treatment-naïve and chemotherapy-naïve Exclusion Criteria: - Unresolved toxicities from prior therapy - Symptomatic, untreated or unstable central nervous system or leptomeningeal metastases - Previous treatment with rociletinib or MPDL3280A, or other 3rd generation EGFR TKI (eg, AZD-9291, HM61713), or PD 1 axis targeted therapy (eg, anti PD 1 or anti-PD L1) - Prior treatment with CD137 agonists or other immune checkpoint blockade therapies, including anti-CTLA-4 therapeutic antibodies - Uncontrolled pleural effusion, pericardial effusion or ascites requiring recurrent drainage procedures - Uncontrolled hypercalcemia or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab (bisphosphonate use for prevention of skeletal events allowed) - Known hypersensitivity to any component of the MPDL3280A or rociletinib formulations or history or hypersensitivity to chimeric humanized antibodies or fusion proteins - History of autoimmune disease - History of prior allogeneic hematopoietic stem cell transplantation or prior solid organ transplantation - Treatment with systemic immunosuppressive medications within 2 weeks prior to first day of study treatment (inhaled corticosteroids and mineralocorticoids allowed) - Live attenuated vaccine within 4 weeks prior to first day of study treatment - Active tuberculosis, active hepatitis, or positive HIV status - Class II to IV heart failure as defined by the New York Heart Association functional classification system - Untreated or uncontrolled cardiovascular disease or other symptomatic cardiac dysfunction - QTCF > 450 ms, inability to measure QT interval on ECG, personal or family history of long QT syndrome, requirement for medications that have the potential to prolong the QT interval - History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computerized tomography (CT) scan (history of radiation pneumonitis in radiation field may be allowed) - Other malignancies within 5 years prior to enrollment, with the exception of carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer, or ductal carcinoma in situ Inclusion Criteria: - ECOG performance status of 0 or 1 - Adequate hematological and biological function, confirmed by defined laboratory values - Histologically or cytologically documented metastatic or unresectable, locally advanced or metastatic NSCLC, with one or more activating EGFR mutation (eg, G719X, exon 19 deletion, L858R, L861Q) and absence of exon 20 insertion - Measurable disease as defined by RECIST v1.1 - Biopsy of tumor tissue for central evaluation, within 60 days prior to the first day of study treatment - For Phase 1 and Phase 2 Group B, progression after prior 1st or 2nd generation EGFR TKI (eg, erlotinib, gefitinib, afatinib). --- L858R --- --- L861Q ---


3 T790M

Patients who have progressed after prior first- or second-generation EGFR TKI, regardless of T790M mutation status, will be enrolled. --- T790M ---

Group B will enroll eligible patients who have progressed after prior first- or second-generation EGFR TKI, regardless of T790M mutation status. --- T790M ---



HPO Nodes


HPO:
Neoplasm of the lung
Genes 61
REST GPC3 WT1 HPGD BRAF PIK3CA TP53 TRIM28 RB1 TRIP13 SLCO2A1 AKT1 CASP8 KRAS TSC1 POU6F2 EWSR1 PRKN LMNA NAB2 TERT TSC2 SLC22A18 BRCA2 PPP2R1B STAT6 STK11 MUC5B ERBB2 TSC2 MBTPS2 BAP1 TSC2 DICER1 PDGFRB PERP EGFR TSC1 DIS3L2 NOTCH3 KEAP1 DICER1 DICER1 WT1 TSC1 C11ORF95 IRF1 CYP2A6 WRN RELA WT1 PTEN SFTPC SFTPA2 ERCC6 TRPV3 TP53 H19 TRIM28 FASLG MAP3K8
Non-small cell lung carcinoma
Genes 3
TP53 TP53 BAP1