Background: We hypothesize that patients with advanced melanoma who progress on anti-PD-1 therapy upfront may respond to the addition of the CTLA-4 inhibitor ipi to continue PD-1 inhibition (with nivo), and that responses would occur at a rate higher than would be expected from switching to ipi alone. We surmise that this would occur because melanomas primarily refractory to PD-1 antibodies may not have a sufficient pre-existing T cell infiltrate, which can be corrected by adding treatment with ipi, as CTLA-4 blockade increases new intratumoral T cell infiltration. Methods: This is a Phase 2, prospective open-label study of ipi +/- nivo in patients with advanced melanoma refractory to a PD-1 inhibitor. The primary endpoint of the study is progression free survival. Secondary objectives include the difference in T-cell infiltrate in biopsies of patients with response and no-response to therapy; objective response rate; overall survival; and toxicity. Key eligibility criteria include unresectable melanoma; disease progression while on prior PD-1 agents or after stopping with no intervening therapy; no confirmed partial or complete response to prior anti-PD1 agents; no prior receipt of CTLA-4 inhibitor; Zubrod performance status 0-2; no active brain metastases; no history of autoimmune pneumonitis or colitis requiring steroids or interruption of therapy; and adequate organ function. Prior receipt of BRAF/MEK inhibitors is permitted. Subjects are randomized 1:3 to ipi 3mg/kg q3wk x4 doses or ipi with nivo 1mg/kg q3wk x4 doses followed by nivo 240mg q2wk (21 planned on ipi; 63 on ipi+nivo). Tumor biopsy and blood for correlative studies are taken prior to enrollment and at Day 28-35 on study. Tumor assessments are performed every 12 weeks for 1 year and treatment is continued while clinical benefit persists with a final survival follow-up at 2 years. The combination will be considered superior to single-agent ipi if PFS is doubled from 3 to 6 months with one-sided alpha of 0.1 and power of 0.9. As of January 2018, 5 of 84 planned subjects have enrolled. Clinical trial information: NCT03033576