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A Phase 1b/2 Study of Safety and Efficacy of Rociletinib in Combination With MPDL3280A in Patients With Advanced or Metastatic EGFR-mutant NSCLC

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ClinicalTrials.gov Identifier: NCT02630186
Recruitment Status : Terminated (The study terminated before Phase 1 was completed. This study was reprioritized within the rociletinib development program.)
First Posted : December 15, 2015
Results First Posted : July 4, 2019
Last Update Posted : July 4, 2019
Sponsor:
Collaborator:
Genentech, Inc.
Information provided by (Responsible Party):
Clovis Oncology, Inc.

Tracking Information
First Submitted Date  ICMJE December 2, 2015
First Posted Date  ICMJE December 15, 2015
Results First Submitted Date  ICMJE November 1, 2018
Results First Posted Date  ICMJE July 4, 2019
Last Update Posted Date July 4, 2019
Actual Study Start Date  ICMJE February 24, 2016
Actual Primary Completion Date September 5, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 28, 2019)
  • Number of Treatment-emergent Adverse Events, as Assessed by NCI CTCAE v4.03 [ Time Frame: Continuously, up to approximately 18.5 months ]
    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.
  • Maximum Concentration (Cmax) of Rociletinib and Its Metabolites [ Time Frame: Treatment Day 1 and Day 15 ]
    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.
  • Time to Maximum Concentration (Tmax) for Rociletinib and Rociletinib Metabolites [ Time Frame: Treatment Day 1 and Day 15 ]
    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.
  • Minimum Concentration (Cmin) of Rociletinib and Metabolites [ Time Frame: Approximately every 6 weeks up to 24 months ]
    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.
  • Area Under the Curve (AUC) of Rociletinib and Rociletinib Metabolites [ Time Frame: Treatment Day 1 and Day 8 ]
    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.
  • Maximum Concentration (Cmax) of MPDL3280A [ Time Frame: Cycle 1 Day 1 ]
    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.
  • Minimum Concentration (Cmin) of MPDL3280A [ Time Frame: Approximately every 6 weeks up to 24 months ]
    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.
  • Objective Response Rate Per RECIST v1.1 in Phase 2 [ Time Frame: Approximately every 6-9 weeks ]
    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.
Original Primary Outcome Measures  ICMJE
 (submitted: December 10, 2015)
  • Incidence of treatment-emergent adverse events, as assessed by NCI CTCAE v4.03 [ Time Frame: Continuously, up to approximately 24 months ]
  • Maximum Concentration (Cmax) of Rociletinib and Its Metabolites [ Time Frame: Treatment Day 1 and Day 15 ]
  • Time to Maximum Concentration (Tmax) for Rociletinib and Rociletinib Metabolites [ Time Frame: Treatment Day 1 and Day 15 ]
  • Minimum Concentration (Cmin) of Rociletinib and Metabolites [ Time Frame: Approximately every 6 weeks up to 24 months ]
  • Area Under the Curve (AUC) of Rociletinib and Rociletinib Metabolites [ Time Frame: Treatment Day 1 and Day 8 ]
  • Maximum Concentration (Cmax) of MPDL3280A [ Time Frame: Cycle 1 Day 1 ]
  • Minimum Concentration (Cmin) of MPDL3280A [ Time Frame: Approximately every 6 weeks up to 24 months ]
  • Objective Response Rate Per RECIST v1.1 in Phase 2 [ Time Frame: Approximately every 6-9 weeks ]
Change History Complete list of historical versions of study NCT02630186 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 28, 2019)
  • Objective Response Rate Per Modified RECIST v1.1, Incorporating Immune-related Criteria, in Phase 2 [ Time Frame: Approximately every 6-9 weeks, up to 24 months ]
    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).
  • Duration of Response Per RECIST v1.1 and Modified RECIST v1.1, Incorporating Immune-related Criteria, in Phase 2 [ Time Frame: Approximately every 6-9 weeks, up to 24 months ]
    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).
  • Progression-free Survival Per RECIST v1.1 and Modified RECIST v1.1, Incorporating Immune-related Criteria, in Phase 2 [ Time Frame: Approximately every 6-9 weeks, up to 24 months ]
    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).
  • Number of Patients Alive at Study Termination [ Time Frame: Up to approximately 18.5 months ]
    Patients who received the combination of rociletinib and MPDL3280A alive at the termination of this study.
  • Longitudinal Changes in Blood Based Biomarkers (eg, Mutations in EGFR) in ctDNA [ Time Frame: Blood samples will be collected from each patient approximately every 3 weeks, up to 24 months ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 10, 2015)
  • Objective Response Rate Per Modified RECIST v1.1, Incorporating Immune-related Criteria, in Phase 2 [ Time Frame: Approximately every 6-9 weeks, up to 24 months ]
  • Duration of Response Per RECIST v1.1 and Modified RECIST v1.1, Incorporating Immune-related Criteria, in Phase 2 [ Time Frame: Approximately every 6-9 weeks, up to 24 months ]
  • Progression-free Survival Per RECIST v1.1 and Modified RECIST v1.1, Incorporating Immune-related Criteria, in Phase 2 [ Time Frame: Approximately every 6-9 weeks, up to 24 months ]
  • Overall survival [ Time Frame: Every 12 weeks, up to approximately 60 months ]
  • Longitudinal Changes in Blood Based Biomarkers (eg, Mutations in EGFR) in ctDNA [ Time Frame: Blood samples will be collected from each patient approximately every 3 weeks, up to 24 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Phase 1b/2 Study of Safety and Efficacy of Rociletinib in Combination With MPDL3280A in Patients With Advanced or Metastatic EGFR-mutant NSCLC
Official Title  ICMJE 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)
Brief Summary

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.

Detailed Description

This is a Phase 1b/2, open-label, non-randomized, multicenter study evaluating the safety and efficacy of rociletinib administered in combination with MPDL3280A.

Phase 1: This will be the dose finding phase of the study. Patients will be enrolled to available Dosing Cohort. Patients who have progressed after prior first- or second-generation EGFR TKI, regardless of T790M mutation status, will be enrolled.

Phase 2: Patients will be enrolled into 2 groups. Group A will enroll eligible first-line patients who are EGFR TKI treatment-naïve and chemotherapy-naïve. Group B will enroll eligible patients who have progressed after prior first- or second-generation EGFR TKI, regardless of T790M mutation status.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Non-small Cell Lung Cancer
Intervention  ICMJE
  • Drug: Rociletinib
    A novel, potent, covalent (irreversible) small molecule, tyrosine kinase inhibitor (TKI) administered orally (PO) to patients with EGFRm NSCLC.
    Other Name: CO-1686
  • Drug: MPDL3280A
    A human IgG1 monoclonal antibody administered intravenously (IV)
    Other Name: atezolizumab
Study Arms  ICMJE Experimental: Single Arm Rociletinib and MPDL3280A
Specific doses of rociletinib, taken continuously BID, will be administered in combination with a fixed dose of MPDL3280A, given intravenously on Day 1 of each 21-day cycle.
Interventions:
  • Drug: Rociletinib
  • Drug: MPDL3280A
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: May 17, 2016)
3
Original Estimated Enrollment  ICMJE
 (submitted: December 10, 2015)
93
Actual Study Completion Date  ICMJE September 5, 2017
Actual Primary Completion Date September 5, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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). Previous chemotherapy for NSCLC is allowed.
  • 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02630186
Other Study ID Numbers  ICMJE CO-1686-032
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Clovis Oncology, Inc.
Study Sponsor  ICMJE Clovis Oncology, Inc.
Collaborators  ICMJE Genentech, Inc.
Investigators  ICMJE
Study Director: Lindsey Rolfe, MD Clovis Oncology, Inc.
PRS Account Clovis Oncology, Inc.
Verification Date June 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP