Background: IDO is an enzyme that catalyzes tryptophan to kynurenine. Tryptophan depletion enhances the function of the suppressive Treg and inhibits the effector T cells. Kynurenine metabolites may augment the suppressive effect on the immune responses. The normal physiologic function of IDO is the regulation of acquired local and peripheral immune tolerance. In cancer, IDO can either be expressed directly by the tumor cells, or induced indirectly in host antigen presenting cells by the presence of tumor. In these settings, the IDO pathway mediates an acquired immune tolerance towards tumors, allowing tumors to thwart an immune response by the host. Therefore, IDO is an attractive target. Anti- CTLA-4 (ipilimumab) and anti-PD-1 (pembrolizumab and nivolumab) are monoclonal antibodies that block CTLA-4/ PD-1, enhancing immune responses against tumors. Tumor models have shown synergistic effect with anti-CTLA-4 and anti-PD-1 treatments in combination with indoximod providing a rationale for this trial. Methods: Metastatic melanoma patients were treated in a standard design (3+3) dose escalation of oral indoximod twice daily (BID) with ipilimumab (3mg/kg q3 weeks x 4 doses) in Phase 1b. In Phase 2, indoximod is given with provider choice of Ipilimumab, pembrolizumab or nivolumab. In the event of progression, the provider can change therapy from one checkpoint inhibitor (anti-CTLA-4 or anti-PD-1) to another while continuing indoximod. Primary objective is overall response rate, secondary objectives median progression free and overall survival. Results: To date, 45 patients of a planned 105 are enrolled of which 9 patients comprised the Phase 1b cohort without DLT. The recommended Phase 2 dose was 1200 mg BID. 1 patient in Phase 1 demonstrated an ongoing CR currently at 11 months and 6 out of 9 patients are still alive (9-14 month from enrollment) and receiving additional treatment after coming off study. No SAEs or changes in ipilimumab dose due to indoximod addition were documented. Conclusions: The Phase 1b part has been successfully concluded without significant toxicities. Phase 2 is ongoing. Updated data to be presented. Clinical trial information: NCT02073123