Standard of Care Alone or in Combination With Ad-CEA Vaccine and Avelumab in People With Previously Untreated Metastatic Colorectal Cancer QUILT-2.004

Summary

Participation Requirements

Description

Background Colorectal cancer (CRC) is the fourth most common cancer diagnosis in the United States and accounts for the second most cancer-related deaths. Programmed death ligand 1 (PD-L1) is a transmembrane protein that was first identified for its role in the maintenance of self-tolerance and prev...

Background Colorectal cancer (CRC) is the fourth most common cancer diagnosis in the United States and accounts for the second most cancer-related deaths. Programmed death ligand 1 (PD-L1) is a transmembrane protein that was first identified for its role in the maintenance of self-tolerance and prevention of autoimmunity. Blockade of the interaction between PD-L1 on tumor cells and PD-1 on T cells is expected to reverse T cell suppression within tumors. These agents are dependent on underlying T cell activation against the tumor cell to be effective. Avelumab is a fully human IgG1 anti-PDL1 antibody that selectively binds to PD-L1 and competitively blocks its interaction with PD-1. In ongoing phase 1 trials of avelumab, the agent has been well tolerated and has shown clinical activity. Clinical trials with anti-PD-1/L1 agents in colorectal cancer have resulted in minimal activity in patients who do not have mismatch repair deficiency (MMR-D). Therapeutic cancer vaccines targeting overexpressed proteins offer a potential method to activate T cells against tumors. A novel adenovirus based, CEA-targeting vaccine has demonstrated cytolytic T cell responses in patients with metastatic colorectal cancer. Standard of care agents in first line metastatic CRC have properties been associated with improved immune response via immunologic cell death and immunogenic modulation. Primary Objective -To determine if there is an improvement progression free survival among patients with metastatic colorectal cancer lacking a mismatch repair deficiency who are treated with standard of care + anti- PDL1 monoclonal antibody + Ad-CEA therapeutic cancer vaccine compared with standard of care alone. Eligibility Subjects age 18 and older with previously untreated pathologically confirmed metastatic or unresectable colorectal cancer; prior adjuvant therapy is acceptable. ECOG performance status less than or equal to 2. Normal organ and bone marrow function. Subjects with active autoimmune diseases requiring treatment and subjects requiring system steroids (except for physiologic doses for steroid replacement) are not allowed. Tumor sample and whole blood sample must be available for proteomics, genomics and transcriptomics analyses. Subjects with metastatic or unresectable colorectal cancer with mismatch repair deficiency (MMR-D or MSI-High) will not be eligible. Design This is a randomized, multicenter phase II clinical trial designed to evaluate the potential improvement in progression free survival (PFS) when Avelumab and Ad-CEA vaccine are used in combination with standard of care therapy in metastatic or unresectable colorectal cancer when compared with standard of care alone (FOLFOX-A). A lead in cohort, comprising the first 6 evaluable subjects enrolled, will be treated with avelumab + Ad- CEA vaccine + standard of care in order to assess the safety of the combination. If no more than 1 subject in the lead in cohort experiences a dose limiting toxicity attributable to the IND agents, 70 evaluable subjects will be randomized on a 1:1 basis to receive either Avelumab + Ad-CEA vaccine + standard of care (Arm B) or standard of care alone (Arm A). Standard of care therapy consists of 6 - 12 two week cycles of bevacizumab + FOLFOX (5-FU, leucovorin, oxaliplatin) followed by two week cycles of bevacizumab + capecitabine until disease progression. Subjects assigned to Arm A that have progressive disease will be offered Avelumab + Ad-CEA vaccine in combination with a standard chemotherapy regimen. Kaplan-Meier curves and a two-tailed log-rank test will be the primary analysis methods. The accrual ceiling for the study is set at 97.

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