Background: The PD-1/PD-L1 pathway plays a key role in controlling T-cell activation and may be utilized by tumor cells to evade antitumor responses. Anti-PD-1 and anti-PD-L1 antibodies have shown acceptable safety profiles and clinical activity across a range of tumor types. MEDI0680 is a humanized IgG4κ mAb specific for human PD-1 that blocks PD-L1 and programmed cell death ligand-2 (PD-L2). Blocking both PD-L1 and PD-L2 may have more efficient blockade and may be more specific for different tumor groups in comparison to blocking either one alone. MEDI4736 is a human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80 with high affinity and selectivity. Anti-PD-1 and PD-L1 agents block distinct interactions contributing to immunosuppression, suggesting potential additive or synergistic effects. Preclinical data, including mouse models, support potential benefit for anti-PD-L1 and anti-PD-1 in combination. Methods: This phase I, multicenter, open-label study evaluates the safety of MEDI0680 in combination with MEDI4736 in patients with advanced malignancies (NCT02118337). Eligible patients ( ≥ 18 years) will have an Eastern Cooperative Oncology Group performance status of 0-1. The primary objectives are to assess safety and tolerability, and determine the maximum tolerated dose of MEDI0680 in combination with MEDI4736. Secondary objectives include assessment of antitumor activity (including objective response rate, disease control rate, duration of response, progression-free survival, and overall survival), pharmacokinetics, and immunogenicity of the combination. Exploratory objectives include an evaluation of biomarkers within the tumor microenvironment and their relationship to tumor response, identification of genetic predictors of response or resistance, and an assessment of patient-reported outcomes. Recruitment is ongoing, with a target enrollment of approximately 150 patients across 3 centers in the United States. Clinical trial information: NCT02118337