Background: Immunotherapy with high dose IL-2 (HD-IL2) has been shown to induce long-term durable responses in a subset of patients (pts) with metastatic melanoma (MM). Combination immunotherapy, involving concomitant or sequential administration, may enhance the fraction of pts with long-term control. IL-2, an immune activating cytokine, and ipilimumab (IPI), a CTLA-4 immune checkpoint inhibitor, offer complementary mechanisms relating to efficacy in mm pts. We initiated a Phase IV open-label study to assess sequenced use of HD IL-2 and IPI in pts with MM. Methods: Between September 2013 and May 2015, twenty nine pts with Stage IV mm were randomized to receive treatment with 2 courses of HD IL-2 (600,000 IU/kg) followed by induction IPI 3 mg/kg for four doses, or vice-versa. The primary objective of the study was to compare 1-year OS with that of historical control (Hodi et al, NEJM 2010). The Evaluable Population (EP) was defined as pts who received at least 50% of planned treatment with each study drug. Results: 13 pts were randomized to receive HD IL-2 first, and 16 were randomized to receive IPI first. 20 pts were included in the EP: 7 in the HD IL-2 first arm, 13 in the IPI first arm. For the EP, 1-year OS was 77%, 1-year PFS was 26%, and the overall response rate (ORR) was 25%. The frequency of adverse events (AEs) was similar in both treatment arms. Of the 28 pts in the Safety Population, 12 reported occurrence of Grade 3 or higher AEs, including 3 who ended study as a result. There was one treatment-related death in a patient receiving cycle 1 of HD IL-2 who developed cerebral hemorrhage as a result of thrombocytopenia. Conclusions: HD IL-2 and IPI may be administered sequentially in pts with MM, with an acceptable toxicity profile that is consistent with known AEs for each agent. The primary efficacy endpoint of 1-year OS (77%) in this small sample size was superior to that of IPI alone (46%) from historical studies. The ORR of the combination appears to be higher than the additive anticipated response rate of each monotherapy. These data provide preliminary evidence for synergistic effects of coordinated administration of these two agents. Clinical trial information: NCT01856023