A Phase Ib Open-Label Study Evaluating the Safety, Tolerability and Pharmacokinetics of Cobimetinib in Combination With Bevacizumab and Immunotherapy When Administered in Patients With Gastrointestinal and Other Tumors
Overview
- Phase
- Phase 1
- Intervention
- Atezolizumab
- Conditions
- Colorectal Cancer
- Sponsor
- Hoffmann-La Roche
- Enrollment
- 51
- Locations
- 6
- Primary Endpoint
- Percentage of Participants with Adverse Events
- Status
- Completed
- Last Updated
- 6 years ago
Overview
Brief Summary
This is an open-label, multicenter, single-arm, two-stage, Phase Ib study designed to assess the safety, tolerability, and pharmacokinetics of oral cobimetinib with intravenous (IV) atezolizumab and bevacizumab in participants with metastatic colorectal cancer (mCRC) who have received and progressed on at least one prior line of therapy that contained a fluoropyrimidine and oxaliplatin or irinotecan. There are two stages in this study: Stage 1 (safety run-in phase) and Stage 2 (dose expansion phase with two cohorts, an expansion cohort and a biopsy cohort).
Investigators
Eligibility Criteria
Inclusion Criteria
- •Eastern Cooperative Oncology Group performance status of 0 or 1
- •Histologically confirmed unresectable metastatic colorectal adenocarcinoma
- •Life expectancy at least 12 weeks
- •Progression on a prior line of therapy that contained a fluoropyrimidine and oxaliplatin or irinotecan for unresectable metastatic colorectal adenocarcinoma
- •Measurable disease per RECIST v1.1
- •Adequate hematologic and end organ function
- •Creatinine clearance greater than or equal to (\>=) 30 milliliters per minute (mL/min)
- •For biopsy cohort, participants must be bevacizumab naive or received the last bevacizumab treatment at least 12 months prior to Cycle 1 Day 1 and according to the investigator's judgment the planned biopsies would not expose participants to substantially increased risk of complications
- •For women of childbearing potential, agreement to remain abstinent (refrain from heterosexual intercourse) or use of contraceptive methods that result in a failure rate of less than (\<) 1 percent (%) per year during the treatment period and for at least 180 days after the last study treatment
- •For men, agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm
Exclusion Criteria
- •More than one prior line of systemic therapy for advanced CRC
- •Participants with known microsatellite (MSI)-high status
- •Major surgery or significant traumatic injury within 60 days prior to enrollment
- •Minor surgical procedure within 15 days of study Cycle 1 Day 1
- •Untreated central nervous system (CNS) metastases
- •Treatment with any investigational agent or approved therapy within 28 days
- •Malignancies other than colorectal cancer within 5 years prior to Cycle 1 Day 1
- •Prior radiation therapy within 30 days prior to study Cycle 1 Day 1 and/or persistence of radiation-related adverse effects
- •Prior allogeneic bone marrow transplantation or solid organ transplant for another malignancy in the past
- •Spinal cord compression not definitively treated with surgery and/or radiation
Arms & Interventions
Cobimetinib + Bevacizumab + Atezolizumab (Stage 1: SRP)
Stage 1 Safety Run-in Phase (SRP): Approximately 12 participants will receive cobimetinib 60 milligrams (mg) orally once daily for Days 1-21 with atezolizumab 840 mg and bevacizumab 5 milligrams per kilogram (mg/kg) administered by IV infusion on Days 1 and 15 of each 28-day cycle. Atezolizumab will be administered first, followed by bevacizumab, with a minimum of 60 minutes between dosing. Upon determination of the safety and tolerability of the treatment regimen, the study will proceed to Stage 2: dose expansion phase. If the results from the safety run-in phase require dose reduction in cobimetinib, then an additional Stage 1 cohort will be opened. Treatment will continue until the participant has disease progression according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1), unacceptable toxicity, death, participant or physician decision to withdraw, or pregnancy, whichever occurs first.
Intervention: Atezolizumab
Cobimetinib + Bevacizumab + Atezolizumab (Stage 1: SRP)
Stage 1 Safety Run-in Phase (SRP): Approximately 12 participants will receive cobimetinib 60 milligrams (mg) orally once daily for Days 1-21 with atezolizumab 840 mg and bevacizumab 5 milligrams per kilogram (mg/kg) administered by IV infusion on Days 1 and 15 of each 28-day cycle. Atezolizumab will be administered first, followed by bevacizumab, with a minimum of 60 minutes between dosing. Upon determination of the safety and tolerability of the treatment regimen, the study will proceed to Stage 2: dose expansion phase. If the results from the safety run-in phase require dose reduction in cobimetinib, then an additional Stage 1 cohort will be opened. Treatment will continue until the participant has disease progression according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1), unacceptable toxicity, death, participant or physician decision to withdraw, or pregnancy, whichever occurs first.
Intervention: Bevacizumab
Cobimetinib + Bevacizumab + Atezolizumab (Stage 1: SRP)
Stage 1 Safety Run-in Phase (SRP): Approximately 12 participants will receive cobimetinib 60 milligrams (mg) orally once daily for Days 1-21 with atezolizumab 840 mg and bevacizumab 5 milligrams per kilogram (mg/kg) administered by IV infusion on Days 1 and 15 of each 28-day cycle. Atezolizumab will be administered first, followed by bevacizumab, with a minimum of 60 minutes between dosing. Upon determination of the safety and tolerability of the treatment regimen, the study will proceed to Stage 2: dose expansion phase. If the results from the safety run-in phase require dose reduction in cobimetinib, then an additional Stage 1 cohort will be opened. Treatment will continue until the participant has disease progression according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1), unacceptable toxicity, death, participant or physician decision to withdraw, or pregnancy, whichever occurs first.
Intervention: Cobimetinib
Cobimetinib + Bevacizumab + Atezolizumab (Stage 2: BC)
Stage 2 Biopsy Cohort (BC): Approximately 7 evaluable participants in the biopsy cohort in expansion phase will receive bevacizumab 5 mg/kg IV on Cycle 1 Days 1 and 15 (tumor biopsy on Cycle 1 Day 8) and cobimetinib (at dose determined during safety run-in phase) orally on Cycle 1 Day 15 to Cycle 2 Day 14 (tumor biopsy on Cycle 1 Day 22). From Cycle 2 onwards, participants will follow the same treatment regimen for bevacizumab and atezolizumab (optional tumor biopsy on Cycle 2 Day 22) as those in the safety run-in phase and expansion cohort, and for cobimetinib cycles start at Day 15 and will continue 21 days to Day 7 of next cycle. Atezolizumab will be administered first, followed by bevacizumab, with a minimum of 60 minutes between dosing. Biopsies must be collected before the initiation of cobimetinib and atezolizumab. Treatment will continue until disease progression according to RECIST v1.1, unacceptable toxicity, death, decision to withdraw, or pregnancy, whichever occurs first.
Intervention: Atezolizumab
Cobimetinib + Bevacizumab + Atezolizumab (Stage 2: BC)
Stage 2 Biopsy Cohort (BC): Approximately 7 evaluable participants in the biopsy cohort in expansion phase will receive bevacizumab 5 mg/kg IV on Cycle 1 Days 1 and 15 (tumor biopsy on Cycle 1 Day 8) and cobimetinib (at dose determined during safety run-in phase) orally on Cycle 1 Day 15 to Cycle 2 Day 14 (tumor biopsy on Cycle 1 Day 22). From Cycle 2 onwards, participants will follow the same treatment regimen for bevacizumab and atezolizumab (optional tumor biopsy on Cycle 2 Day 22) as those in the safety run-in phase and expansion cohort, and for cobimetinib cycles start at Day 15 and will continue 21 days to Day 7 of next cycle. Atezolizumab will be administered first, followed by bevacizumab, with a minimum of 60 minutes between dosing. Biopsies must be collected before the initiation of cobimetinib and atezolizumab. Treatment will continue until disease progression according to RECIST v1.1, unacceptable toxicity, death, decision to withdraw, or pregnancy, whichever occurs first.
Intervention: Bevacizumab
Cobimetinib + Bevacizumab + Atezolizumab (Stage 2: BC)
Stage 2 Biopsy Cohort (BC): Approximately 7 evaluable participants in the biopsy cohort in expansion phase will receive bevacizumab 5 mg/kg IV on Cycle 1 Days 1 and 15 (tumor biopsy on Cycle 1 Day 8) and cobimetinib (at dose determined during safety run-in phase) orally on Cycle 1 Day 15 to Cycle 2 Day 14 (tumor biopsy on Cycle 1 Day 22). From Cycle 2 onwards, participants will follow the same treatment regimen for bevacizumab and atezolizumab (optional tumor biopsy on Cycle 2 Day 22) as those in the safety run-in phase and expansion cohort, and for cobimetinib cycles start at Day 15 and will continue 21 days to Day 7 of next cycle. Atezolizumab will be administered first, followed by bevacizumab, with a minimum of 60 minutes between dosing. Biopsies must be collected before the initiation of cobimetinib and atezolizumab. Treatment will continue until disease progression according to RECIST v1.1, unacceptable toxicity, death, decision to withdraw, or pregnancy, whichever occurs first.
Intervention: Cobimetinib
Cobimetinib + Bevacizumab + Atezolizumab (Stage 2: EC)
Stage 2 Expansion Cohort (EC): Approximately 14 participants will receive cobimetinib (at dose determined during safety run-in phase) orally once daily for Days 1-21 with atezolizumab 840 mg and bevacizumab 5 mg/kg administered by IV infusion on Days 1 and 15 of each 28-day cycle. Atezolizumab will be administered first, followed by bevacizumab, with a minimum of 60 minutes between dosing. Treatment will continue until the participant has disease progression according to RECIST v1.1, unacceptable toxicity, death, participant or physician decision to withdraw, or pregnancy, whichever occurs first.
Intervention: Atezolizumab
Cobimetinib + Bevacizumab + Atezolizumab (Stage 2: EC)
Stage 2 Expansion Cohort (EC): Approximately 14 participants will receive cobimetinib (at dose determined during safety run-in phase) orally once daily for Days 1-21 with atezolizumab 840 mg and bevacizumab 5 mg/kg administered by IV infusion on Days 1 and 15 of each 28-day cycle. Atezolizumab will be administered first, followed by bevacizumab, with a minimum of 60 minutes between dosing. Treatment will continue until the participant has disease progression according to RECIST v1.1, unacceptable toxicity, death, participant or physician decision to withdraw, or pregnancy, whichever occurs first.
Intervention: Bevacizumab
Cobimetinib + Bevacizumab + Atezolizumab (Stage 2: EC)
Stage 2 Expansion Cohort (EC): Approximately 14 participants will receive cobimetinib (at dose determined during safety run-in phase) orally once daily for Days 1-21 with atezolizumab 840 mg and bevacizumab 5 mg/kg administered by IV infusion on Days 1 and 15 of each 28-day cycle. Atezolizumab will be administered first, followed by bevacizumab, with a minimum of 60 minutes between dosing. Treatment will continue until the participant has disease progression according to RECIST v1.1, unacceptable toxicity, death, participant or physician decision to withdraw, or pregnancy, whichever occurs first.
Intervention: Cobimetinib
Outcomes
Primary Outcomes
Percentage of Participants with Adverse Events
Time Frame: Baseline up to approximately 12 months
Secondary Outcomes
- Plasma Maximum Concentration (Cmax) of Cobimetinib(Safety run-in phase and expansion cohort: Predose (0 hours) on Cycle 1 Day 15 and Cycle 3 Day 15; 2 to 4 hours postdose on Cycle 1 Day 1 and Cycle 3 Day 15. Biopsy cohort: 0-2 hours predose and 2-4 hours postdose on Cycle 2 Day 1. Each cycle is 28 days.)
- Plasma Minimum Concentration (Cmin) of Cobimetinib(Safety run-in phase and expansion cohort: Predose (0 hours) on Cycle 1 Day 15 and Cycle 3 Day 15; 2 to 4 hours postdose on Cycle 1 Day 1 and Cycle 3 Day 15. Biopsy cohort: 0-2 hours predose and 2-4 hours postdose on Cycle 2 Day 1. Each cycle is 28 days.)
- Serum Cmax of Atezolizumab(Baseline up to approximately 12 months (detailed sample collection timepoints are provided in outcome measure description field))
- Serum Cmin of Atezolizumab(Baseline up to approximately 12 months (detailed sample collection timepoints are provided in outcome measure description field))
- Percentage of Participants with Anti-therapeutic Antibodies (ATAs) Response to Atezolizumab(Baseline up to approximately 12 months (detailed sample collection timepoints are provided in outcome measure description field))
- Serum Cmin of Bevacizumab(Safety run-in phase and expansion cohort: prior to the infusion (0 hours) on Cycle 3 Day 15. Biopsy cohort: prior to the infusion (0 hours) on Cycle 3 Day 1. Each cycle is 28 days.)