Background: High-dose (HD) IL-2 (600,000 IU.kg) and ipilimumab (3 mg/kg) are approved immunotherapy agents for selected patients with advanced melanoma and both are associated with durable responses in a small number of patients. Previous studies in a pre-clinical melanoma tumor models and in a small phase I/II dose escalation clinical trial suggested that concurrent combination treatment was associated with improved response rates, including a 17% complete response rate in the clinical trial, without an increase in toxicity. Data has also suggested that higher doses of ipilimumab may improve response rates as shown in clinical trials comparing 3 to 10 mg/kg dosing. To better define the potential benefit of this combination in patients with melanoma, this phase II multicenter, open-label, single arm trial, is being conducted (NCT02203604). Methods: The primary goal of this trial is to determine the clinical OR rate within the first 24 weeks. Secondary end points include safety, feasibility, overall survival, one- and two-year survival, progression-free survival, best overall response, and frequency of effector CD8+ T cells and CD4+FoxP3+ regulatory T cells in peripheral blood, and when possible in the tumor microenvironment. Adults with advanced unresectable stage III and IV melanoma and who meet criteria for high-dose IL-2 therapy are eligible. Main exclusion criteria are active brain metastases, active autoimmune diseases, concurrent systemic immunosuppressive therapy as well as prior immunotherapy with IL-2 or impilimumab. Up to 82 patients will be enrolled and receive ipilumimab (10 mg/kg) for 4 cycles (Days 1, 22, 43, 64) and high-dose IL-2 (600,000 IU/kg) for 2 cycles (Days 22-26, 43-47) followed by maintenance ipilimumab. Preliminary safety assessment will be performed on the first 6 patients before other patients are allowed to enter the study. If significant toxicity occurs in the first 6 patients ipilimumab will be dose reduced to 3 mg/kg. As of Feb 4, 2015 3 patients have been enrolled. Clinical trial information: NCT02203604