Background: Nivolumab, a fully human IgG4 programmed death-1 (PD-1) immune checkpoint inhibitor antibody, and ipilimumab, a fully human IgG1 cytotoxic T-lymphocyte antigen-4 receptor (CTLA-4) blocking antibody, have shown antitumor activity and durable responses in patients (pts) with solid tumors including melanoma, renal cell cancer and non-small cell lung cancer. Preclinical and clinical data indicate that combined PD-1 and CTLA-4 blockade may improve antitumor activity. We hypothesize that nivolumab alone or combined with ipilimumab may have activity in additional solid tumor types. We describe a phase I/II signal detection, open-label study to analyze the safety and efficacy of these agents in locally advanced or metastatic triple-negative breast, small-cell lung, gastric or pancreatic cancer—areas of significant unmet medical need. Methods: The primary and secondary objectives of this study are objective response (OR) rate and safety, respectively. Exploratory objectives include progression-free survival, overall survival, immunogenicity, pt-reported global health outcomes, and analysis of pharmacodynamic activity of nivolumab alone or combined with ipilimumab in peripheral blood and tumor tissue. Additionally, evaluation of putative biomarkers such as PD-1 ligand (PD-L1) expression will be performed. The study uses a modified Simon 2-stage design. In stage 1, 36 pts for each tumor type will be assigned 1:1 to treatment with either nivolumab 3 mg/kg IV Q2W (arm N), or nivolumab 1 mg/kg + ipilimumab 3 mg/kg IV Q3W for 4 doses then nivolumab 3 mg/kg IV Q2W (arm N+I), until progression or toxicity. Responses will be assessed using RECIST criteria at wks 6, 12, 18, 24 and then Q12W. Treatment arms will proceed independently into stage 2 if ≥2 pts in a given arm for each tumor type have an OR. In stage 2, an additional 22 pts per tumor type will be assigned to each arm (N or N+I) and receive the stage 1 dosing regimen. Key eligibility criteria include ECOG status ≤1, available fresh or archival tumor tissue, measurable disease by CT or MRI (RECIST 1.1), and adequate bone marrow, liver and renal function. Clinical trial information: NCT01928394.