A Study to Investigate Efficacy and Safety of Cobimetinib Plus Atezolizumab and Atezolizumab Monotherapy Versus Regorafenib in Participants With Metastatic Colorectal Adenocarcinoma (COTEZO IMblaze370)

• ClinicalTrials.gov Identifier: NCT02788279
• Recruitment Status: Completed
• First Posted: June 2, 2016
• Results First Posted: June 18, 2019
• Last Update Posted: December 11, 2019
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: May 27, 2016
• First Posted Date: June 2, 2016
• Results First Submitted Date: March 8, 2019
• Results First Posted Date: June 18, 2019
• Last Update Posted Date: December 11, 2019
• Actual Study Start Date: July 5, 2016
• Actual Primary Completion Date: March 9, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 24, 2019)

Overall Survival (OS) [ Time Frame: 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.

• Original Primary Outcome Measures (submitted: June 1, 2016): Overall Survival (OS) [ Time Frame: Baseline up to death (up to 3 years) ]

Current Secondary Outcome Measures (submitted: December 3, 2019)

• Progression-Free Survival (PFS) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: Baseline, end of the study (up to approximately 2.5 years) ]
• Plasma Concentration of Cobimetinib [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) ]

Original Secondary Outcome Measures (submitted: June 1, 2016)

• Progression-free Survival (PFS) according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 [ Time Frame: Baseline up to 3 years ]
• Percentage of Participants with Investigator-assessed Objective Response of Complete Response (CR) or Partial Response (PR) per RECIST Version 1.1 [ Time Frame: Baseline up to 3 years ]
• Duration of Response (DOR) based on RECIST Version 1.1 [ Time Frame: Baseline up to 3 years ]
• Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life-C30 questionnaire (EORTC QLQ-C30) score [ Time Frame: Baseline, 6-month survival follow-up (assessed up to 3 years) ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study to Investigate Efficacy and Safety of Cobimetinib Plus Atezolizumab and Atezolizumab Monotherapy Versus Regorafenib in Participants With Metastatic Colorectal Adenocarcinoma (COTEZO IMblaze370)
• Official Title: A Phase III, Open-Label, Multicenter, Three-Arm, Randomized Study to Investigate the Efficacy and Safety of Cobimetinib Plus Atezolizumab and Atezolizumab Monotherapy vs. Regorafenib in Patients With Previously Treated Unresectable Locally Advanced or Metastatic Colorectal Adenocarcinoma
• 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 Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Colorectal Cancer

Intervention

• Drug: Atezolizumab (MPDL3280A), an Engineered Anti-PDL1 Antibody
  Participants will receive atezolizumab IV at 840 mg on Day 1 and Day 15 in a 28-day cycle as a combination therapy or at 1200 mg on Day 1 in a 21-day cycle as a monotherapy until disease progression according to RECIST Version 1.1, unacceptable toxicity, death, participant's or physician decision to withdraw, or pregnancy, whichever occurs first.
• Drug: Cobimetinib
  Participants will receive cobimetinib 60 mg orally on Days 1 to 21 in a 28-day cycle as a combination therapy until disease progression according to RECIST Version 1.1, unacceptable toxicity, death, participant's or physician decision to withdraw, or pregnancy, whichever occurs first.
• Drug: 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.

Study Arms

• Experimental: Atezolizumab
  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.
  Intervention: Drug: Atezolizumab (MPDL3280A), an Engineered Anti-PDL1 Antibody
• Experimental: Cobimetinib + Atezolizumab
  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.
  Interventions:

  • Drug: Atezolizumab (MPDL3280A), an Engineered Anti-PDL1 Antibody
  • Drug: Cobimetinib
• Active Comparator: 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.
  Intervention: Drug: Regorafenib

Publications *

• Barteselli G, Goodman GR, Patel Y, Caro I, Xue C, McCallum S. Characterization of Serous Retinopathy Associated with Cobimetinib: Integrated Safety Analysis of Four Studies. Drug Saf. 2022 Dec;45(12):1491-1499. doi: 10.1007/s40264-022-01248-2. Epub 2022 Oct 30.
• Eng C, Kim TW, Bendell J, Argiles G, Tebbutt NC, Di Bartolomeo M, Falcone A, Fakih M, Kozloff M, Segal NH, Sobrero A, Yan Y, Chang I, Uyei A, Roberts L, Ciardiello F; IMblaze370 Investigators. Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol. 2019 Jun;20(6):849-861. doi: 10.1016/S1470-2045(19)30027-0. Epub 2019 Apr 16. Erratum In: Lancet Oncol. 2019 Jun;20(6):e293.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 7, 2018): 363
• Original Estimated Enrollment (submitted: June 1, 2016): 360
• Actual Study Completion Date: December 26, 2018
• Actual Primary Completion Date: March 9, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

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

Exclusion Criteria:

• 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Belgium, Canada, Hong Kong, Italy, Korea, Republic of, Poland, Russian Federation, Spain, United Kingdom, United States
• Removed Location Countries: France, Germany

Administrative Information

• NCT Number: NCT02788279
• Other Study ID Numbers: GO30182; 2016-000202-11 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Hoffmann-La Roche
• Original Responsible Party: Same as current
• Current Study Sponsor: Hoffmann-La Roche
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

• PRS Account: Hoffmann-La Roche
• Verification Date: November 2019