A Study to Investigate Efficacy and Safety of Cobimetinib Plus Atezolizumab and Atezolizumab Monotherapy Versus Regorafenib in Participants With Metastatic Colorectal Adenocarcinoma (COTEZO IMblaze370)
- Conditions
- Colorectal Cancer
- Interventions
- Registration Number
- NCT02788279
- Lead Sponsor
- Hoffmann-La Roche
- Brief Summary
This is a Phase III, multicenter, open-label, three-arm, randomized study in participants with unresectable locally advanced or metastatic colorectal cancer (CRC) who have received at least two prior regimens of cytotoxic chemotherapy for metastatic disease. The study compares regorafenib, a standard of care therapy in this setting, to cobimetinib plus atezolizumab and atezolizumab monotherapy.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 363
Disease-specific inclusion criteria:
- Histologically confirmed adenocarcinoma originating from the colon or rectum (Stage 4 American Joint Committee on Cancer [AJCC] 7th edition)
- Experienced disease progression or was intolerant to at least two systemic chemotherapy regimens for metastatic colorectal cancer that must have included fluroropyrimidines, irinotecan, and oxaliplatin; adjuvant regimen can be considered as one chemotherapy regimen for metastatic disease if the participant had disease recurrence within 6 months of completion; disease progression must have occurred within 3 months of the last systemic therapy administration
General inclusion criteria:
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Anticipated life expectancy greater than or equal to (>=) 3 months
- Adequate hematologic and end organ function
- Women of childbearing potential must agree to appropriately use an effective form of contraception (failure rate of less than [<] 1 percent [%] per year) during the treatment period, within 5 months after the last dose of atezolizumab, and within 3 months after the last dose of cobimetinib and regorafenib
- Men must agree not to donate sperm or have intercourse with a female partner without using appropriate barrier contraception during the treatment period and for 3 months after the last dose of either cobimetinib or regorafenib
- Provide an archival or newly obtained tumor tissue sample
- After the approximate 5% cap for microsatellite (MSI)-high participants is reached, only MSI-stable participants will be eligible
- Once the 50% cap for wild-type RAS has been reached, only extended RAS-mutant participants will be eligible
- Major surgery or radiotherapy within 21 days prior to Cycle 1 Day 1 or anticipation of needing such procedure while receiving study treatment
- Treatment with any anti-cancer agent within 14 days prior to Cycle 1 Day 1
- Uncontrolled tumor-related pain. Participants requiring narcotic pain medication must be on a stable regimen at study entry
- Uncontrolled pleural effusion, pericardial effusion or ascites requiring repeated drainage more than once every 28 days. Indwelling drainage catheters (e.g., PleurX®) are allowed
- Active or untreated central nervous system (CNS) metastases are excluded
- Prior therapy with any cancer immunotherapy, MEK inhibitor, or regorafenib
- Participants with active malignancy (other than CRC) or a prior malignancy within the past 3 years are excluded. Participants with completely resected cutaneous melanoma (early stage), basal cell carcinoma, cutaneous squamous cell carcinoma, cervical carcinoma in-situ, breast carcinoma in-situ, and localized prostate cancer are eligible
- Unstable angina, new onset angina within last 3 months, myocardial infarction within last 6 months and current congestive heart failure New York Heart Association Class II or higher
- Left ventricular ejection fraction (LVEF) below institutional lower limit of normal or below 50%, whichever is lower
- Poorly controlled hypertension, defined as a blood pressure consistently above 150/90 millimeters of Mercury (mmHg) despite optimal medical management
- Human immunodeficiency virus (HIV) infection
- Active tuberculosis infection
- Severe infections within 2 weeks prior to Cycle 1 Day 1
- Active or chronic viral hepatitis B or C infection
- History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for central serous retinopathy, retinal vein occlusion, or neovascular macular degeneration
- Participants will be excluded if they currently have any of the risk factors as defined in the study protocol for retinal vein occlusion
- History of autoimmune disease
- History of idiopathic pulmonary fibrosis, organizing pneumonia, bronchiolitis obliterans, drug-induced pneumonitis, or idiopathic pneumonitis
- History of organ transplantation including allogeneic bone marrow transplantation
- Inability to swallow medications
- Malabsorption condition that would alter the absorption of orally administered medications
- Pregnant, lactating, breastfeeding, or intending to become pregnant during the study
- Administration of a live, attenuated vaccine within 4 weeks before randomization or anticipation of a live attenuated vaccine will be required during the study
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Atezolizumab Atezolizumab (MPDL3280A), an Engineered Anti-PDL1 Antibody Participants will receive atezolizumab monotherapy 1200 milligrams (mg) intravenous (IV) on Day 1 in a 21-day cycle until disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1, unacceptable toxicity, death, participant's or physician decision to withdraw, or pregnancy, whichever occurs first. Cobimetinib + Atezolizumab Atezolizumab (MPDL3280A), an Engineered Anti-PDL1 Antibody Participants will receive cobimetinib 60 mg orally on Days 1 to 21 plus atezolizumab 840 mg IV on Day 1 and Day 15 in a 28-day cycle until disease progression according to RECIST Version 1.1, unacceptable toxicity, death, participant's or physician decision to withdraw, or pregnancy, whichever occurs first. Cobimetinib + Atezolizumab Cobimetinib Participants will receive cobimetinib 60 mg orally on Days 1 to 21 plus atezolizumab 840 mg IV on Day 1 and Day 15 in a 28-day cycle until disease progression according to RECIST Version 1.1, unacceptable toxicity, death, participant's or physician decision to withdraw, or pregnancy, whichever occurs first. Regorafenib Regorafenib Participants will receive regorafenib 160 mg orally on Days 1 to 21 in a 28-day cycle until disease progression according to RECIST Version 1.1, unacceptable toxicity, death, participant's or physician decision to withdraw, or pregnancy, whichever occurs first.
- Primary Outcome Measures
Name Time Method Overall Survival (OS) From randomization up to death due to any cause (up to approximately 20 months) Overall survival is defined as the time (in months) between the date of randomization and the date of death due to any cause. Participants who were not reported as having died at the date of analysis were censored at the date when they were last known to be alive. Participants who did not have post-baseline information were censored at the date of randomization + 1 day. Median OS was estimated by Kaplan-Meier method and 95% CI was assessed using the method of Brookmeyer and Crowley.
- Secondary Outcome Measures
Name Time Method Progression-Free Survival (PFS) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) From randomization up to disease progression or death due to any cause (up to approximately 20 months) PFS was defined as the time from randomization to disease progression as determined by the investigator with the use of RECIST v1.1 or death due to any cause, whichever occurred earlier. Disease progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeters (mm). For non-target lesions, disease progression was defined as unequivocal progression of existing lesions. The appearance of one or more new lesions was also considered progression. Participants who did not have post-baseline information were censored at the date of randomization + 1 day. Median OS was estimated by Kaplan-Meier method and 95% CI was assessed using the method of Brookmeyer and Crowley.
Percentage of Participants With Investigator-Assessed Objective Response of Complete Response (CR) or Partial Response (PR) According to RECIST Version 1.1 From randomization up to death due to any cause (up to approximately 20 months) PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. CR was defined as disappearance of all target and non-target lesions and normalization of tumor marker levels (as applicable to non-target lesions). Objective response and its 95% CI were calculated using the Clopper-Pearson method.
Duration of Response (DOR) According to RECIST Version 1.1 From first occurrence of CR or PR up to disease progression or death due to any cause (up to approximately 20 months) DOR is defined as the period measured from the date of the first occurrence of a CR or PR (whichever status is recorded first) until the first date that progressive disease or death is documented. Disease progression was determined on the basis of investigator assessment with use of RECIST v1.1. Median DOR was estimated using the Kaplan-Meier method, and the 95% CI was calculated using the method of Brookmeyer and Crowley.
Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life-C30 Questionnaire (EORTC QLQ-C30) Physical Functioning Sub-scale Score Baseline, end of the study (up to approximately 2.5 years) The EORTC QLQ-C30 questionnaire consisted of 30 questions generating five functional scores (physical, role, cognitive, emotional, and social); a global health status/global quality of life scale score; three symptom scale scores (fatigue, pain, and nausea and vomiting); and six stand alone one-item scores that capture additional symptoms (dyspnea, appetite loss, sleep disturbance, constipation, and diarrhea) and perceived financial burden. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning.
Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life-C30 Questionnaire (EORTC QLQ-C30) Global Quality of Life Sub-scale Score at the End of the Study Baseline, end of the study (up to approximately 2.5 years) The EORTC QLQ-C30 questionnaire consisted of 30 questions generating five functional scores (physical, role, cognitive, emotional, and social); a global health status/global quality of life scale score; three symptom scale scores (fatigue, pain, and nausea and vomiting); and six stand alone one-item scores that capture additional symptoms (dyspnea, appetite loss, sleep disturbance, constipation, and diarrhea) and perceived financial burden. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning.
Percentage of Participants With Adverse Events (AEs) Baseline, end of the study (up to approximately 2.5 years) Plasma Concentration of Cobimetinib Predose (0 hours) and 3 to 6 hours after dose on Day 15 of Cycles 1 and 4 (1 cycle = 28 days) (up to approximately 2.5 years). Serum Concentration of Atezolizumab Pre-infusion (0 hours) on Day 1 of Cycle 1 up to approximately 2.5 years. Detailed time frame is explained in the outcome measure description field. Pre-infusion (0 hours) on Day 1 of Cycles 1 to 4; 30 minutes post-infusion on Day 1 of Cycles 1 and 4; pre-infusion (0 hours) on Day 1 of Cycle 8 and every 8 cycles thereafter; at treatment discontinuation; 120 days after treatment discontinuation (up to approximately 2.5 years) (1 cycle = 28 days)
Percentage of Participants With Anti-Therapeutic Antibodies (ATAs) to Atezolizumab Pre-infusion (0 hours) on Day 1 of Cycles 1 to 4, 8, and every 8 cycles thereafter; at treatment discontinuation; 120 days after treatment discontinuation (up to approximately 2.5 years) (1 cycle = 28 days)
Trial Locations
- Locations (73)
Yale Cancer Center; Medical Oncology
🇺🇸New Haven, Connecticut, United States
Florida Cancer Specialists; SCRI
🇺🇸Fort Myers, Florida, United States
Cancer Specialists; North Florida ;Jacksonville (AC Skinner Pkwy)
🇺🇸Jacksonville, Florida, United States
Georgetown University
🇺🇸Washington, District of Columbia, United States
Florida Cancer Specialists.
🇺🇸Saint Petersburg, Florida, United States
Cross Cancer Institute; Clinical Trials
🇨🇦Edmonton, Alberta, Canada
BCCA-Vancouver Cancer Centre
🇨🇦Vancouver, British Columbia, Canada
Cliniques Universitaires St-Luc
🇧🇪Bruxelles, Belgium
AZ Groeninge
🇧🇪Kortrijk, Belgium
Tuen Mun Hospital; Clinical Oncology
🇭🇰Hong Kong, Hong Kong
National Cancer Center
🇰🇷Gyeonggi-do, Korea, Republic of
MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
City of Hope Comprehensive Cancer Center
🇺🇸Duarte, California, United States
Ingalls Cancer Research Center
🇺🇸Harvey, Illinois, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
North Shore Hem Onc Associates
🇺🇸East Setauket, New York, United States
Medical Oncology Associates
🇺🇸Spokane, Washington, United States
Northern Cancer Institute
🇦🇺St Leonards, New South Wales, Australia
Sydney Adventist Hospital; Clinical Trial Unit
🇦🇺Sydney, New South Wales, Australia
Monash Medical Centre; Oncology
🇦🇺Clayton, Victoria, Australia
Austin Health; Cancer Clinical Trial Centre
🇦🇺Heidelberg, Victoria, Australia
Peninsula and South Eastern Haematology and Oncology Group
🇦🇺Frankston, Victoria, Australia
Imeldaziekenhuis
🇧🇪Bonheiden, Belgium
GHdC Site Notre Dame
🇧🇪Charleroi, Belgium
Tom Baker Cancer Centre-Calgary
🇨🇦Calgary, Alberta, Canada
The Ottawa Hospital
🇨🇦Ottawa, Ontario, Canada
Sunnybrook Health Sciences Centre
🇨🇦Toronto, Ontario, Canada
Hopital du Sacre-Coeur
🇨🇦Montreal, Quebec, Canada
McGill University Health Center, Cedar Cancer Center
🇨🇦Montreal, Quebec, Canada
CHU de Québec
🇨🇦Quebec City, Quebec, Canada
Queen Mary Hospital; Dept. of Clinical Oncology
🇭🇰Hong Kong, Hong Kong
Azienda Osp Uni Seconda Università Degli Studi Di Napoli; Unità Operativa Oncologia Medica
🇮🇹Napoli, Campania, Italy
IRCCS Ospedale Casa Sollievo Della Sofferenza; Oncologia
🇮🇹San Giovanni Rotondo, Puglia, Italy
Asst Grande Ospedale Metropolitano Niguarda; Dipartimento Di Ematologia Ed Oncologia
🇮🇹Milano, Lombardia, Italy
Asan Medical Center - Oncology
🇰🇷Seoul, Korea, Republic of
Centrum Onkologii im. Prof. F. Lukaszczyka w Bydgoszczy
🇵🇱Bydgoszcz, Poland
Hospital Univ Vall d'Hebron; Servicio de Oncologia
🇪🇸Barcelona, Spain
Queen's Hospital
🇬🇧Romford, United Kingdom
Weston Park Hospital; Cancer Clinical Trials Centre
🇬🇧Sheffield, United Kingdom
Southdale Cancer Clinic U of M Medical Center, Fairview- Edina
🇺🇸Edina, Minnesota, United States
INTEGRIS Cancer Inst of OK
🇺🇸Oklahoma City, Oklahoma, United States
Sarah Cannon Research Inst.
🇺🇸Nashville, Tennessee, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
Port Macquarie Base Hospital;North Coast Cancer Institute
🇦🇺Port Macquarie, New South Wales, Australia
University of Pittsburgh Cancer Institute; Division of Medical Oncology
🇺🇸Pittsburgh, Pennsylvania, United States
UZ Leuven Gasthuisberg
🇧🇪Leuven, Belgium
Irccs Istituto Nazionale Dei Tumori (Int);S.C. Medicina Oncologica 1
🇮🇹Milano, Lombardia, Italy
A.O. Universitaria Pisana; Oncologia
🇮🇹Pisa, Toscana, Italy
SCRI Tennessee Oncology Chattanooga
🇺🇸Chattanooga, Tennessee, United States
A.O. Universitaria Policlinico Di Modena; Oncologia
🇮🇹Modena, Emilia-Romagna, Italy
Istit. Naz. per la Ricerca sul Cancro - Az. Osped. S. Martino
🇮🇹Genova, Liguria, Italy
Chonnam National University Hwasun Hospital
🇰🇷Jeollanam-do, Korea, Republic of
Uniwersyteckie Centrum Kliniczne; Klinika Onkologii i Radioterapii
🇵🇱Gdańsk, Poland
Arkhangelsk Regional Clinical Oncology Dispensary
🇷🇺Arkhangelsk, Russian Federation
BHI of Omsk region Clinical Oncology Dispensary
🇷🇺Omsk, Russian Federation
Seoul National University Hospital
🇰🇷Seoul, Korea, Republic of
Samsung Medical Center
🇰🇷Seoul, Korea, Republic of
Szpitale Pomorskie Sp. z o. o.
🇵🇱Gdynia, Poland
Szpital Uniwersytecki w Krakowie, Oddział Kliniczny Kliniki Onkologii
🇵🇱Krakow, Poland
Woj.Wielospecjalistyczne Centrum Onkologii i Traumatologii; Oddz.Hematologii Pododz.Chemioterapii
🇵🇱Lodz, Poland
Yonsei University Health System/Severance Hospital
🇰🇷Seoul, Korea, Republic of
N.N.Burdenko Main Military Clinical Hospital; Oncology Dept
🇷🇺Moscow, Russian Federation
Hospital Ramon y Cajal; Servicio de Oncologia
🇪🇸Madrid, Spain
Royal Marsden Hospital; Dept of Medical Oncology
🇬🇧Sutton, United Kingdom
Royal Marsden Hospital - Fulham; Oncology Department
🇬🇧London, United Kingdom
Hospital de Navarra; Servicio de Oncologia
🇪🇸Navarra, Spain
The Christie; GI Research Office
🇬🇧Manchester, United Kingdom
Hospital Clínico Universitario de Valencia; Servicio de Oncología
🇪🇸Valencia, Spain
Hospital Clinico San Carlos; Servicio de Oncologia
🇪🇸Madrid, Spain
Hospital Universitario 12 de Octubre; Servicio de Oncologia
🇪🇸Madrid, Spain
Birmingham Heartlands Hospital; Dept of Oncology
🇬🇧Birmingham, United Kingdom
Churchill Hospital; Department of Oncology
🇬🇧Oxford, United Kingdom
Prince of Wales Hosp; Dept. Of Clinical Onc
🇭🇰Shatin, Hong Kong