Abstract / Summary
Indoleamine 2,3-dioxygenase-1 (IDO1) can mediate immune dysfunction by reducing tryptophan (Trp) and increasing kynurenine (Kyn). The CITN-04 clinical trial (NCT01961115) tested the safety and clinical activity of combination therapy with IDO1 inhibitor epacadostat (INCB024360) plus a multipeptide vaccine for melanoma, and tested whether epacadostat or the combination reduces Kyn/Trp ratios and enhances CD8 + tumor-infiltrating lymphocytes (TIL). Eligible subjects with measurable regional or distant melanoma metastases were treated with epacadostat (300 mg po bid) beginning day (D)0 plus a multipeptide melanoma vaccine (MELITAC 12.1) beginning D21. Tumor biopsies were obtained pretreatment, D21, and D42. Resection of all clinically evident disease by D42 was allowed. Safety was assessed by CTCAE v4.0. The primary immunologic endpoint was tumor infiltration with CD8 + T cells by immunohistochemistry (IHC). Circulating T cell responses were assessed by IFN-gamma ELIspot assay. Inhibition of IDO1 was assessed by Kyn/Trp ratios in serum and tumor. Clinical outcomes were recorded. Eleven eligible subjects were enrolled and treated. Transient DLTs were observed in 2 subjects (18%) but treatment was otherwise well-tolerated. Epacadostat normalized serum Kyn/Trp ratios in 91% of subjects. Intratumoral Kyn/Trp ratios varied widely pretreatment, but treatment also reduced Kyn/Trp intratumorally. The prespecified primary endpoint for increased intratumoral CD8 + T cell infiltrates by IHC was not met. From one subject, a D42 tumor contained T cells reactive to peptides in the vaccine, but baseline tumor was not available. Among 5 evaluable for clinical response, the best responses were PR in 1 subject, SD in 3, PD in one. Treatment with epacadostat (300 mg bid) + vaccine was safe, and it reduced serum and intratumoral Kyn/Trp ratios. The findings do not support the hypothesis that epacadostat alone or with vaccine would increase total CD8 + TIL. Circulating T cell responses were lower than in prior studies with vaccine alone. Transient clinical activity was observed in 1 patient. The findings of this study do not support routine combination of this vaccine with epacadostat, but there may be value in targeted study of IDO1 inhibitors for tumors with highest Kyn/Trp levels.