The study will include a safety run-in phase (Stage 1) and a randomization phase (Stage 2). The purpose of Stage 1 is to evaluate the safety of cobimetinib when administered in combination with niraparib (Cohort 1) and cobimetinib with niraparib plus atezolizumab (Cohort 2). Stage 1 will enable patient enrollment in the randomized phase of the study (Stage 2) with both regimens at the recommended dose levels from Stage 1. Stage 2 is a randomized, dose-expansion phase, evaluating clinical outcomes in patients with advanced platinum-sensitive ovarian cancer. All patients will continue to receive study treatment until disease progression (according to "Response Evaluation Criteria in Solid Tumors" (RECIST), Version 1.1, unacceptable toxicity, death, or patient or investigator decision to withdraw, whichever occurs first.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
77
Cobimetinib will be administered at a starting dose of 60 mg by mouth (PO) daily (QD) on Days 1-21 of each 28-day cycle (Stage 1) and PO QD on Days 1-21 (21/7 schedule) at the established dose for the doublet regimen in Stage 1 (Stage 2).
Niraparib will be administered at a starting dose of 200 mg of niraparib PO QD on Days 1-28 of each 28-day cycle (Stage 1) and PO QD on Days 1-28 of each 28-day cycle at the established dose for the doublet regimen in Stage 1 (Stage 2).
Atezolizumab will be administered by IV infusion at the fixed dose of 840 mg on Days 1 and 15 (+/-3 days) of each 28-day cycle (Stages 1 and 2).
University of Arizona Cancer Center, North
Tucson, Arizona, United States
Moores Cancer Center at UC San Diego Health
La Jolla, California, United States
Mayo Clinic-Jacksonville
Jacksonville, Florida, United States
Florida Hospital Cancer Institute; Clinical Research Department
Orlando, Florida, United States
Medical College of Georgia; Obstetrics & Gynecolog
Augusta, Georgia, United States
Washington University School of Medicine; Dept of Medicine/Div of Medical Oncology
St Louis, Missouri, United States
Stephenson Cancer Center Investigational Pharmacy
Oklahoma City, Oklahoma, United States
Tennessee Oncology; Sarah Cannon Research Institute
Nashville, Tennessee, United States
Medical College of Wisconsin; Department of Obstetrics and Gynecology
Milwaukee, Wisconsin, United States
Istituto Nazionale Tumori Fondazione G. Pascale
Naples, Campania, Italy
...and 10 more locations
Number of patients reporting Adverse Events (AEs)
The safety profiles of Cobimetinib plus Niraparib and Cobimetinib plus Niraparib plus Atezolizumab will be evaluated in terms of number of patients reporting serious and non-serious AEs with severity graded according to National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI - CTCAE v5.0)
Time frame: From baseline up to 48 months
Change from baseline in targeted clinical laboratory test results
The safety profiles of Cobimetinib plus Niraparib and Cobimetinib plus Niraparib plus Atezolizumabwill be evaluated in terms of number of patients reporting change from baseline in targeted clinical laboratory test results.
Time frame: From baseline up to 48 months
Investigator-assessed confirmed objective response rate (ORR)
The efficacy profiles of Cobimetinib plus Niraparib and Cobimetinib plus Niraparib plus Atezolizumab will be evaluated in terms of investigator-assessed confirmed ORR, as determined using RECIST v1.1 in the Intention To Treat (ITT) population and in molecularly defined subgroups by loss of heterozygosity (LOH) status.
Time frame: From baseline up to 48 months
Progression-free survival (PFS)
The efficacy profiles of Cobimetinib plus Niraparib and Cobimetinib plus Niraparib plus Atezolizumab will be evaluated in terms of PFS after randomization, defined as the time from randomization to the first occurrence of disease progression or relapse, as determined by the investigator using RECIST v1.1, or death from any cause during the study, whichever occurs first, in the ITT population and in the molecularly defined subgroups by LOH status.
Time frame: From Baseline up to 48 months
Duration of response (DOR)
The efficacy profiles of Cobimetinib plus Niraparib and Cobimetinib plus Niraparib plus Atezolizumab will be evaluated in terms of DOR, defined for patients achieving at least one confirmed Partial Response (PR), which is measured from the first observation of a Complete Response (CR) or a PR to the time of disease progression in the ITT population and in the molecularly defined subgroups by LOH status.
Time frame: From baseline up to 48 months
Overall survival (OS)
The efficacy profiles of Cobimetinib plus Niraparib and Cobimetinib plus Niraparib plus Atezolizumab will be evaluated in terms of OS after randomization, defined as the time from randomization until death from any cause in the ITT population and in the molecularly defined subgroups by LOH status.
Time frame: From baseline up to 48 months
Plasma concentration of cobimetinib and niraparib
The Pharmacokinetic (PK) profile of cobimetinib plus niraparib is evaluated in terms of Plasma concentration at specified timepoints.
Time frame: Arm A: Day 15 of Cycle 1 and 2 - Arm B: Day 15 of Cycle 1
Serum concentration of atezolizumab
The PK profile of cobimetinib plus niraparib plus atezolizumab will be evaluated in terms of Serum concentration of atezolizumab at specified timepoints (Arm B only).
Time frame: Day 1 of Cycle 1, 2 and 3 and at treatment discontinuation visit, up to 48 months
Number of patients with Anti-Drug Antibodies (ADA)
The immunogenicity profile of Atezolizumab is evaluated in terms of number of patients with ADA at baseline and during the study.
Time frame: Day 1 of Cycle 1, 2 and 3 and at treatment discontinuation visit, up to 48 months
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