Background: Pts with advanced HCC have limited treatment options. Sorafenib, the current standard of care, achieves only modest overall survival improvements. There is a clear etiologic association between HCC and prior/concurrent hepatitis B (HBV) or C (HCV) infection. Programmed death-1 (PD-1) is an immune checkpoint receptor that inhibits T-cell activation when bound by ligands including PD-L1/L2. PD-L1 overexpression has been noted on HCC tumors, and PD-1/PD-L1 interaction may contribute to viral hepatitis induced T-cell exhaustion. Nivolumab, a PD-1 receptor blocking antibody, has shown efficacy against various solid tumor types in Ph 1 trials. We hypothesized that blockade of PD-1/PD-L1 interaction could enhance T-cell activation and mediate antitumor and/or antiviral activity in HCC pts. We describe a phase I, dose-escalation study of nivolumab in advanced HCC pts. Methods: Successive pt cohorts with histologically confirmed advanced HCC with/without HBV or HCV infection (N=72 max) will be treated on 3 distinct arms with IV nivolumab at 0.3, 1 and 3.0 mg/kg (uninfected or HCV-infected pts) or 0.1, 0.3, 1 and 3.0 mg/kg (HBV-infected pts) every 2 weeks using a 3+3 escalation scheme. Pts must have progressive disease or intolerance after ≥1 line of therapy or have refused sorafenib treatment, and a Child-Pugh class A. HBV-infected pts must be receiving antiviral therapy (viral DNA <100 IU/mL) for ≥3 months. Pts with brain metastasis, encephalopathy, prior/current ascites requiring paracentesis, history of recent variceal bleeding, active coinfection with HIV, or both HBV and HCV, or concurrent hepatitis D and HBV infection will be excluded. Primary endpoints include characterization of safety, tolerability, dose-limiting toxicities and maximum tolerated dose of nivolumab. Secondary endpoints include assessment of the preliminary antitumor activity (per modified RECIST for HCC), PK and immunogenicity. Exploratory endpoints include evaluation of the relationship between tumor PD-L1 expression and clinical outcome, and nivolumab’s antiviral and immunoregulatory activity in peripheral blood and/or tumor specimens. Clinical trial information: NCT01658878.