Background: EnAd is a tumor-selective chimeric Ad11/Ad3 group B oncolytic adenovirus developed using directed evolution. Phase I clinical studies have identified a well-tolerated systemic dose and regimen for EnAd monotherapy. EnAd shows a high level of selective replication and cell killing for a broad range of carcinoma cell lines with little replication in normal and non-carcinoma cells. Previous studies have shown that after systemic administration there is significant uptake and replication of EnAd in various carcinomas associated with improved CD8+ T-cell tumor infiltration. These data provide the rationale for combination of EnAd with the checkpoint inhibitor (CPI), nivolumab (anti-PD-1 antibody) to potentially enhance the response to nivolumab. This is a phase I study in subjects with metastatic or advanced carcinoma. The study design has a dose escalation stage, followed by a dose expansion stage which will evaluate the ability to improve responses in tumors normally non-responsive to CPI and also to evaluate the ability to detect meaningful responses in PDL1 negative tumors that are less responsive to CPI. Methods: The dose escalation phase consists of 5 cohorts of patients with metastatic or advanced epithelial tumors in a standard "3 + 3" design. Subjects will receive increasing dose levels and/or cycles of EnAd followed by a q3w regimen of nivolumab (360mg). EnAd treatment cycles comprise 3 intravenous (IV) infusions on Days 1, 3 and 5. Nivolumab is administered as an IV infusion given every 3 weeks starting on Day 15 and continuing for up to 8 treatment cycles. The Dose Expansion phase will investigate the combination of EnAd and nivolumab in expanded cohorts of colorectal cancer, urothelial cell carcinoma, squamous cell carcinoma of the head & neck, and non-small cell lung cancer patients. The primary objectives are to establish the MTD of EnAd and nivolumab combination, to evaluate the safety and to recommend doses for future studies. Secondary endpoints include overall response, duration of response and progression free survival, assessed according to RECIST Version 1.1 and irRECIST Version 1. Enrollment to cohorts 3 & 4 began in January 2017. Clinical trial information: NCT02636036