This randomized phase II trial studies how well atezolizumab with or without cobimetinib works in treating patients with bile duct cancer that has spread to other places in the body (metastatic) and cannot be removed by surgery (unresectable) or gallbladder cancer. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Cobimetinib is used in patients whose cancer has a mutated (changed) form of a gene called BRAF. It is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals cancer cells to multiply. This helps slow or stop the spread of cancer cells. Giving atezolizumab with cobimetinib may work better at treating patients with bile duct and gallbladder cancer.
PRIMARY OBJECTIVE: I. To assess the progression free survival (PFS) of patients receiving atezolizumab monotherapy and cobimetinib in combination with atezolizumab for unresectable cholangiocarcinoma. SECONDARY OBJECTIVES: I. To assess the overall survival (OS) of patients receiving cobimetinib in combination with atezolizumab and atezolizumab monotherapy for unresectable cholangiocarcinoma. II. To determine the objective response rate (ORR), defined as complete plus partial response, of cobimetinib in combination with atezolizumab and atezolizumab monotherapy in patients with unresectable cholangiocarcinoma. III. To assess the safety and tolerability of cobimetinib in combination with atezolizumab and atezolizumab monotherapy in patients with unresectable cholangiocarcinoma. IV. To determine the relationship between PD-L1 expression in tumor at baseline and on treatment, and response to treatment. CORRELATIVE OBJECTIVES: I. To determine the effect of cobimetinib on CD8+ T cell infiltration in tumor. II. To determine the effect of cobimetinib on T cell subpopulations systemically and in tumor, PD-1/PD-L1 expression on tumor, and MHC 1/2 expression. III. To determine the effect of cobimetinib on markers of immune exhaustion and pro-apoptotic factors in CD8+ effector T cells. IV. To explore the effect of cobimetinib on local and systemic immune activation pathways and immune suppressive pathways through expression profiling. OUTLINE: Patients are randomized to 1 of 2 arms. ARM A: Patients receive atezolizumab intravenously (IV) over 30-60 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) or magnetic resonance imaging (MRI) and collection of blood samples throughout the trial and undergo tumor biopsy on study. ARM B: Patients receive atezolizumab IV over 30-60 minutes on days 1 and 15 and cobimetinib orally (PO) once daily (QD) on days 1-21. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI and collection of blood samples throughout the trial and undergo tumor biopsy on study. After completion of study treatment, patients are followed up every 3 months until death, withdrawal of consent, or study closure, whichever occurs first.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
86
Given IV
Undergo tumor biopsy
Undergo collection of blood samples
Given PO
Undergo CT
Undergo MRI
City of Hope Comprehensive Cancer Center
Duarte, California, United States
University of California Davis Comprehensive Cancer Center
Sacramento, California, United States
City of Hope South Pasadena
South Pasadena, California, United States
UCHealth University of Colorado Hospital
Aurora, Colorado, United States
Smilow Cancer Hospital-Derby Care Center
Derby, Connecticut, United States
Progression Free Survival (PFS)
PFS within each treatment arm will be summarized descriptively and compared between groups, under the assumption of Cox proportional hazards, using the stratified log-rank test to account for tumor site. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: From date of randomization to time of progression or death, assessed up to 1 year
Number of Participants With Adverse Events
Will be assessed using National Cancer Institute's Common Terminology Criteria for Adverse Events version 5.0. The incidence of AEs will be tabulated by subgroups of interest (e.g. grade 3 or higher, organ class, relationship to study drug). For analyses at the individual level, the highest grade and relationship to study drug will be assumed if multiple events have occurred. Toxicity will be tabulated by type and grade and will be summarized with descriptive statistics.
Time frame: Up to 1 year
Objective Response Rate
Defined as the proportion of response evaluable subjects who have a complete response or partial response and will be assessed by Response Evaluation Criteria in Solid Tumors version 1.1. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: Up to 1 year
Overall Survival
Results will be summarized descriptively and compared between groups, under the assumption of proportional hazards, using the stratified log-rank test to account for tumor site.
Time frame: From date of randomization to time of death, assessed up to 1 year
Change in CD8+ Density Within the Tumor
Change between the pre-treatment tumor biopsy to the on-treatment biopsy collected on day 21.
Time frame: Day 21
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Smilow Cancer Hospital Care Center-Fairfield
Fairfield, Connecticut, United States
Smilow Cancer Hospital Care Center - Guilford
Guilford, Connecticut, United States
Smilow Cancer Hospital Care Center at Saint Francis
Hartford, Connecticut, United States
Smilow Cancer Center/Yale-New Haven Hospital
New Haven, Connecticut, United States
Yale University
New Haven, Connecticut, United States
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