Background: Programmed death-1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) are immune checkpoint receptors that attenuate T-cell responses and contribute to immune evasion by tumor cells. Nivolumab is a PD-1 receptor blocking monoclonal antibody that has shown clinical activity in phase 1 trials with various tumor types including MEL. Ipilimumab is an anti-CTLA-4 monoclonal antibody approved for advanced or metastatic MEL. Preclinical data suggest that combined PD-1 and CTLA-4 receptor blockade may improve antitumor activity in MEL, with PD-1 blockade upregulating CTLA-4 expression and CTLA-4 blockade upregulating PD-1 expression on tumor-infiltrating T cells. We describe a phase II study evaluating nivolumab administered sequentially with ipilimumab in pts with advanced (unresectable stage III) or metastatic (stage IV) MEL. Methods: This open-label, phase II study will enroll approximately 80 pts. During the induction period, pts will be randomized 1:1 to either nivolumab (3 mg/kg, q2w) from Weeks (Wk) 1-13 followed by ipilimumab (3 mg/kg, q3w) from Wks 14-25, or ipilimumab followed by nivolumab at the same doses and schedules. All pts will then receive nivolumab (3 mg/kg, q2wk) during the continuation period until disease progression or unacceptable toxicity, for ≤2 years from initial study treatment. Pts may be treatment-naive or have disease recurrence or progression after one prior systemic therapy, excluding prior anti-PD-1, anti-CTLA-4, or a BRAF inhibitor. The primary endpoint is the incidence of treatment-related Grade 3–5 adverse events (AEs) during the induction period. Secondary endpoints are response rate at Wk 25 and progression rates at Wks 13 and 25. Exploratory endpoints include safety and tolerability; overall survival; pt-level time course of treatment-related grade 3–5 AEs, response, progression, treatment discontinuation, and death; the association of changes in pharmacodynamic immune markers from baseline to Wk 13 and Wk 25 and clinical response; the association between baseline immunological parameters and clinical response; and immune-related single nucleotide polymorphisms. Clinical trial information: NCT01783938.