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
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 363
- 试验地点
- 73
- 主要终点
- Overall Survival (OS)
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
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.
干预措施: Atezolizumab (MPDL3280A), an Engineered Anti-PDL1 Antibody (Drug)
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.
干预措施: Atezolizumab (MPDL3280A), an Engineered Anti-PDL1 Antibody (Drug)
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.
干预措施: Cobimetinib (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.
干预措施: Regorafenib (Drug)
结局指标
主要结局
Overall Survival (OS)
时间窗: 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.
次要结局
- 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))
- 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))
- 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))
- 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))
- 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))
- 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.)
- 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))