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

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 immunoglobulin G 1 (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, carcinoembryonic antigen (CEA)-targeting vaccine has demonstrated cytolytic T cell responses in patients with metastatic colorectal cancer. * Standard of care agents in first line metastatic colorectal cancer (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 * Subject's age 18 and older with previously untreated pathologically confirmed metastatic or unresectable colorectal cancer; prior adjuvant therapy is acceptable. * Eastern Cooperative Oncology Group (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 microsatellite instability (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 investigational new drug (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.