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

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ClinicalTrials.gov Identifier: NCT02876224
Recruitment Status : Completed
First Posted : August 23, 2016
Last Update Posted : August 13, 2019
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

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).

Condition or disease Intervention/treatment Phase
Colorectal Cancer Drug: Atezolizumab Drug: Bevacizumab Drug: Cobimetinib Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 51 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : September 30, 2016
Actual Primary Completion Date : June 25, 2019
Actual Study Completion Date : June 25, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 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.
Drug: Atezolizumab
Atezolizumab 840 mg will be administered by IV infusion on Days 1 and 15 of each 28-day cycle.
Other Name: RO5541267

Drug: Bevacizumab
Bevacizumab 5 mg/kg will be administered by IV infusion on Days 1 and 15 of each 28-day cycle.
Other Name: RO4876646

Drug: Cobimetinib
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.
Other Name: RO5514041

Experimental: 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.
Drug: Atezolizumab
Atezolizumab 840 mg will be administered by IV infusion on Days 1 and 15 of each 28-day cycle.
Other Name: RO5541267

Drug: Bevacizumab
Bevacizumab 5 mg/kg will be administered by IV infusion on Days 1 and 15 of each 28-day cycle.
Other Name: RO4876646

Drug: Cobimetinib
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.
Other Name: RO5514041

Experimental: 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.
Drug: Atezolizumab
Atezolizumab 840 mg will be administered by IV infusion on Days 1 and 15 of each 28-day cycle.
Other Name: RO5541267

Drug: Bevacizumab
Bevacizumab 5 mg/kg will be administered by IV infusion on Days 1 and 15 of each 28-day cycle.
Other Name: RO4876646

Drug: Cobimetinib
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.
Other Name: RO5514041




Primary Outcome Measures :
  1. Percentage of Participants with Adverse Events [ Time Frame: Baseline up to approximately 12 months ]

Secondary Outcome Measures :
  1. Plasma Maximum Concentration (Cmax) of Cobimetinib [ Time Frame: 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. ]
  2. Plasma Minimum Concentration (Cmin) of Cobimetinib [ Time Frame: 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. ]
  3. Serum Cmax of Atezolizumab [ Time Frame: 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.

  4. Serum Cmin of Atezolizumab [ Time Frame: 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.

  5. Serum Cmin of Bevacizumab [ Time Frame: 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. ]
  6. Percentage of Participants with Anti-therapeutic Antibodies (ATAs) Response to Atezolizumab [ Time Frame: 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02876224


Locations
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United States, Colorado
University Of Colorado
Aurora, Colorado, United States, 80045
United States, New York
Memorial Sloan-Kettering Cancer Center
New York, New York, United States, 10065
United States, Tennessee
Sarah Cannon Research Inst.
Nashville, Tennessee, United States, 37203
United States, Texas
The University of Texas MD Anderson Cancer Center
Houston, Texas, United States, 77030-4009
Spain
Hospital Universitario Vall d'Hebron
Barcelona, Spain, 08035
START Madrid. Centro Integral Oncologico Clara Campal; CIOCC
Madrid, Spain, 28050
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
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Study Director: Clinical Trials Hoffmann-La Roche

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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT02876224     History of Changes
Other Study ID Numbers: CO39083
2016-000584-16 ( EudraCT Number )
First Posted: August 23, 2016    Key Record Dates
Last Update Posted: August 13, 2019
Last Verified: August 2019
Additional relevant MeSH terms:
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Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Colonic Diseases
Antineoplastic Agents, Immunological
Antineoplastic Agents
Angiogenesis Modulating Agents
Physiological Effects of Drugs
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Rectal Diseases
Bevacizumab
Atezolizumab
Antibodies, Monoclonal
Angiogenesis Inhibitors
Growth Substances
Growth Inhibitors
Immunologic Factors