Background: Melanoma metastases limit infiltration and function of antitumor T cells in part by immunosuppression with IDO1. INCB024360 (epacadostat) is an IDO1 inhibitor that normalizes serum kynurenine/tryptophan (Kyn/Trp) ratios. MELITAC 12.1 multipeptide vaccine induces CD8 T cell responses to melanoma antigens. A clinical trial was designed to test hypotheses that IDO1 inhibition (IDO1i) plus vaccine will be safe, that IDO1i will increase CD8 T cell infiltration into metastases and will enhance immune signatures in tumor, which will be further increased by the vaccine. Methods: Patients (pts) with stage IIIB-IV melanoma were treated with INCB024360 days(d) 1-98 (300 mg po bid), and with MELITAC 12.1 emulsified in incomplete Freund’s adjuvant d21, 28, 35, 56, 77, 98. Prior checkpoint blockade therapy was allowed. Tumors were biopsied pretreatment, d21, and d42, when feasible. Safety was assessed by CTCAE v4. The primary immunologic endpoint was tumor infiltration with CD8+ T cells. The biologic effect of INCB024360 on IDO1 function was assessed by serum Kyn/Trp ratio. Clinical outcomes were assessed by RECIST 1.1. Results: Eleven eligible pts were enrolled and treated. There were dose-limiting toxicities (DLTs) in 2 pts: grade 3 transaminase elevation, grade 3 syncope, both of which resolved. Six pts had all evident sites of disease resected in protocol biopsies and 1 had non-measurable disease. Of 4 pts with measurable disease beyond d42, best overall responses were PR (1), SD (3). INCB024360 reduced serum Kyn/Trp ratios 44% (mean) by d21 (normalized in 10/11 pts). In 5 pts with evaluable biopsies d0 and d42, with multispectral immunofluorescence histology, CD8 T cell infiltrates increased significantly to d42. Conclusions: Combination therapy with INCB024360 and multipeptide vaccine was considered safe with transient DLTs in only 2 patients (18%). INCB024360 normalized serum Kyn/Trp ratios in 91% of patients at 300 mg bid. Clinical activity was observed. There is evidence of enhanced CD8 T cell infiltration with the combination. Ongoing studies will assess the impact of INCB024360 on immune signatures and tumor infiltrating T cell function. Clinical trial information: NCT01961115