Colorectal Cancer
Conditions
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).
Interventions
DRUGAtezolizumab
Atezolizumab 840 mg will be administered by IV infusion on Days 1 and 15 of each 28-day cycle.
DRUGBevacizumab
Bevacizumab 5 mg/kg will be administered by IV infusion on Days 1 and 15 of each 28-day cycle.
DRUGCobimetinib
Cobimetinib 60 mg or at dose determined during safety run-in phase will be administered orally once daily for 21 days of each 28-day cycle as specified in the arm descriptions.
Sponsors
Hoffmann-La Roche
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 * Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures * Current or recent use of therapeutic oral or parenteral anticoagulants or thrombolytic agents * Intake of St. John's wort or hyperforin (potent cytochrome P450 \[CYP\] 3A4 enzyme inducer) or grapefruit juice (potent CYP3A4 enzyme inhibitor) within 7 days prior to initiation of study treatment * History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins * Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any components of cobimetinib, atezolizumab, or bevacizumab formulations * Prior treatment with clusters of differentiation (CD) 137 (CD137) agonists or immune checkpoint blockage therapies, anti-programmed death protein-1, anti-program death-ligand 1, mitogen-activated protein kinase (MEK) inhibitor * Proteinuria value \> 1.0 g at screening * Uncontrolled glaucoma with intraocular pressure ≥ 21 mmHg * Hyperglycemia (fasting) ≥ Grade 2 * Human Immunodeficiency Virus (HIV) infection * Active hepatitis B or hepatitis C * History of autoimmune disease, clinically significant cardiac or pulmonary dysfunction * Administration of a live, attenuated vaccine within 4 weeks prior to Cycle 1 Day 1 or at any time during the study and for at least 5 months after the last dose of study drug * History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment/central serous chorioretinopathy, retinal vein occlusion, or neovascular macular degeneration * History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis * Uncontrolled tumor pain
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percentage of Participants with Adverse Events | Baseline up to approximately 12 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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) | Safety run-in phase and expansion cohort: Prior to the infusion (0 hours) on Day 1 of Cycles 1, 2, 4, 8, every 8 cycles thereafter (maximum up to 12 months) and on Day 15 of Cycle 3; 30 minutes after end of infusion (infusion duration 30-60 minutes) on Cycle 1 Day 1 and Cycle 3 Day 15; at treatment discontinuation visit (up to 12 months). Biopsy cohort: prior to the infusion (0 hours) on Day 1 of Cycles 3, 5, 9, every 8 cycles thereafter (maximum up to 12 months) and on Day 15 of Cycle 4; 30 minutes after end of infusion on Day 15 of Cycle 4; at treatment discontinuation visit (up to 12 months). Each cycle is 28 days. |
| 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. | — |
| 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. | — |
| 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) | Safety run-in phase and expansion cohort: Prior to the infusion (0 hours) on Day 1 of Cycle 1, 2, 4, 8, and every 8 cycles thereafter (maximum up to 12 months) and on Day 15 of Cycle 3; 30 minutes after end of infusion (infusion duration 30-60 minutes) on Cycle 3 Day 15; at treatment discontinuation visit (up to 12 months). Biopsy cohort: prior to the infusion (0 hours) on Day 1 of Cycles 3, 5, 9, every 8 cycles thereafter (maximum up to 12 months) and on Day 15 of Cycle 4; 30 minutes after end of infusion on Day 15 of Cycle 4; at treatment discontinuation visit (up to 12 months). Each cycle is 28 days. |
| Serum Cmin of Atezolizumab | Baseline up to approximately 12 months (detailed sample collection timepoints are provided in outcome measure description field) | Safety run-in phase and expansion cohort: Prior to the infusion (0 hours) on Day 1 of Cycles 1, 2, 4, 8, every 8 cycles thereafter (maximum up to 12 months) and on Day 15 of Cycle 3; 30 minutes after end of infusion (infusion duration 30-60 minutes) on Cycle 1 Day 1 and Cycle 3 Day 15; at treatment discontinuation visit (up to 12 months). Biopsy cohort: prior to the infusion (0 hours) on Day 1 of Cycles 3, 5, 9, every 8 cycles thereafter (maximum up to 12 months) and on Day 15 of Cycle 4; 30 minutes after end of infusion on Day 15 of Cycle 4; at treatment discontinuation visit (up to 12 months). Each cycle is 28 days. |
Countries
Spain, United States
Outcome results
None listed