This randomized phase II trial studies how well capecitabine and bevacizumab with or without atezolizumab work in treating patients with colorectal cancer that is not responding to treatment and has spread to other places. Immunotherapy with monoclonal antibodies, such as atezolizumab and bevacizumab, may help the body?s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving atezolizumab with capecitabine and bevacizumab may be a better way in treating colorectal cancer.
PRIMARY OBJECTIVE: I. To estimate the efficacy of capecitabine/bevacizumab + atezolizumab, as compared with capecitabine/bevacizumab + placebo in refractory metastatic colorectal cancer (mCRC) as measured by progression-free survival (defined as the time of randomization to the first occurrence of progression based on Response Evaluation Criteria in Solid Tumors version 1.1, clinical progression, or death from any cause on study as determined by the investigator). SECONDARY OBJECTIVES: I. To estimate the efficacy of capecitabine/bevacizumab + atezolizumab, as compared with capecitabine/bevacizumab + placebo in refractory mCRC as measured by objective response rate (defined as partial response plus complete response) as determined by the investigator using Response Evaluation Criteria in Solid Tumors version 1.1 and immune-related response criteria (irRC). II. To estimate the efficacy of capecitabine/bevacizumab + atezolizumab as compared with capecitabine/bevacizumab + placebo in refractory mCRC as measured by overall survival (defined as death from any cause from the time of randomization until study completion). III. To evaluate the safety and tolerability of atezolizumab in combination with bevacizumab and capecitabine in refractory mCRC as measured by the serious adverse events and adverse events \>= grade 3 according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. CORRELATIVE OBJECTIVE: I. To explore any correlation between tissue and blood based biomarkers and clinical outcomes. OUTLINE: Patients are randomized 2:1 to Arm I:Arm II. ARM I (ATEZOLIZUMAB, BEVACIZUMAB, CAPECITABINE): Patients receive atezolizumab intravenously (IV) over 30-60 minutes on day 1, bevacizumab IV over 30-90 minutes on day 1, and capecitabine orally (PO) twice daily (BID) on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. ARM II (PLACEBO, BEVACIZUMAB, CAPECITABINE): Patients receive placebo IV over 30-60 minutes on day 1, bevacizumab IV over 30-90 minutes on day 1, and capecitabine PO BID on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days, every 3 months until progressive disease, then every 6 months thereafter.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
133
Given IV
Given IV
Given PO
Correlative studies
Given IV
Mayo Clinic Hospital
Phoenix, Arizona, United States
Mayo Clinic in Arizona
Scottsdale, Arizona, United States
City of Hope Comprehensive Cancer Center
Duarte, California, United States
USC / Norris Comprehensive Cancer Center
Los Angeles, California, United States
Emory University Hospital/Winship Cancer Institute
Atlanta, Georgia, United States
University of Michigan Comprehensive Cancer Center
Ann Arbor, Michigan, United States
Mayo Clinic
Rochester, Minnesota, United States
Roswell Park Cancer Institute
Buffalo, New York, United States
Duke University Medical Center
Durham, North Carolina, United States
Rhode Island Hospital
Providence, Rhode Island, United States
Progression Free Survival (PFS)
Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. The primary comparisons will be superiority of the active treatment for PFS of atezolizumab versus placebo. PFS will be compared between treatment arms using the un-stratified log-rank test at one-sided level of 0.10 and the p-value will be used for decision making. The hazard ratio (HR) for PFS will be estimated using a Cox proportional hazards model and the 95% confidence interval (CI) for the HR will be provided. Kaplan-Meier methodology will be used to estimate the median PFS for each treatment arm, and Kaplan-Meier curves will be produced. Progression is defined as any new lesion or increase by ≥20% of previously involved sites from nadir based on RECIST criteria.
Time frame: From randomization to first documentation of disease progression by RECIST v1.1, or death from any cause, assessed up to 20 months
Overall Survival (OS)
The distribution of survival time will be estimated using the method of Kaplan-Meier. OS will be compared between treatment arms using the unstratified log-rank test. OS medians, survival rates and HR will be estimated along with 95% confidence intervals.
Time frame: From randomization to death due to any cause, assessed up to 20 months
Objective Response Rate
The objective response rate is defined as the percentage of participants who achieve a partial response or compete response as assessed (partial response \[PR\] or complete response \[CR\] per RECIST v1.1) during treatment with study therapy. Rates of response will be compared across arms using a fisher's exact test for proportion. Point estimates will be generated for objective response rates within each arm along with 95% binomial confidence intervals. Complete response (CR): Disappearance of all evidence of disease, Partial response (PR): Regression of measurable disease and no new sites
Time frame: Up to 20 months
The Number of Participants Who Experienced at Least One Grade 3 or Higher Adverse Event Deemed at Least Possibly Related to Treatment (Toxicity)
The number of participants who experienced at least one grade 3 or higher adverse event deemed at least possibly related to treatment (toxicity) is reported below. Graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Toxicities will be evaluated via the ordinal CTCAE standard toxicity grading.
Time frame: Up to 20 months
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