Study of Cobimetinib in Combination With Atezolizumab and Bevacizumab in Participants With Gastrointestinal and Other Tumors

NCT02876224 | Completed Phase 1

• 2 other identifiers: CO390832016-000584-16
• Study Type: interventional
• Target: 51
• Locations: 2 countries
• Sites: 6

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).

Conditions

Colorectal Cancer

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants with Adverse Events

  Baseline up to approximately 12 months

Secondary Outcomes (6)

• 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)

• 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.

Study Arms (3)

Cobimetinib + Bevacizumab + Atezolizumab (Stage 1: SRP)

EXPERIMENTAL

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.

Drug: Atezolizumab; Drug: Bevacizumab; Drug: Cobimetinib

Cobimetinib + Bevacizumab + Atezolizumab (Stage 2: BC)

EXPERIMENTAL

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.

Drug: Atezolizumab; Drug: Bevacizumab; Drug: Cobimetinib

Cobimetinib + Bevacizumab + Atezolizumab (Stage 2: EC)

EXPERIMENTAL

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.

Drug: Atezolizumab; Drug: Bevacizumab; Drug: Cobimetinib

Interventions

Atezolizumab DRUG

Atezolizumab 840 mg will be administered by IV infusion on Days 1 and 15 of each 28-day cycle.

Also known as: RO5541267

Cobimetinib + Bevacizumab + Atezolizumab (Stage 1: SRP); Cobimetinib + Bevacizumab + Atezolizumab (Stage 2: BC); Cobimetinib + Bevacizumab + Atezolizumab (Stage 2: EC)

Bevacizumab DRUG

Bevacizumab 5 mg/kg will be administered by IV infusion on Days 1 and 15 of each 28-day cycle.

Also known as: RO4876646

Cobimetinib + Bevacizumab + Atezolizumab (Stage 1: SRP); Cobimetinib + Bevacizumab + Atezolizumab (Stage 2: BC); Cobimetinib + Bevacizumab + Atezolizumab (Stage 2: EC)

Cobimetinib DRUG

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.

Also known as: RO5514041

Cobimetinib + Bevacizumab + Atezolizumab (Stage 1: SRP); Cobimetinib + Bevacizumab + Atezolizumab (Stage 2: BC); Cobimetinib + Bevacizumab + Atezolizumab (Stage 2: EC)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (6)

University Of Colorado

Aurora, Colorado, 80045, United States

Location

Memorial Sloan-Kettering Cancer Center

New York, New York, 10065, United States

Location

Sarah Cannon Research Inst.

Nashville, Tennessee, 37203, United States

Location

The University of Texas MD Anderson Cancer Center

Houston, Texas, 77030-4009, United States

Location

Hospital Universitario Vall d'Hebron

Barcelona, 08035, Spain

Location

START Madrid. Centro Integral Oncologico Clara Campal; CIOCC

Madrid, 28050, Spain

Location

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

atezolizumab; Bevacizumab; cobimetinib

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 18, 2016
• First Posted: August 23, 2016
• Study Start: September 30, 2016
• Primary Completion: June 25, 2019
• Study Completion: June 25, 2019
• Last Updated: August 13, 2019

Record last verified: 2019-08

Locations

ES (2); US (4)