Background: Epacadostat (E) is an inhibitor of Indoleamine 2,3 dioxygenase-1 (IDO1) which is a rate-limiting enzyme in the catabolism of tryptophan to kynurenine. The inhibition of IDO1 leads to increase tryptophan and reversal of immunosuppression by increasing the proliferation of T cells, suppression of regulatory T cells (Tregs) and activation of mTOR which suppresses autophagy. Sirolimus (S) can reverse the mTOR activation induced by E, suppress the expression of PD-L1 and function of Tregs. We initiated a phase I trial to test the safety and tolerability of SE combination in patients (pts) with advanced solid tumors and performed PK studies. Methods: The phase I trial portion of the study used a modified 3+3 design in which the dose transition rule was similar to standard 3+3 design with the modification based on sirolimus PK data. S had a lead-in of 3mg/day(d) at d -7 followed by 1mg/d with E added on d1 of Cycle(C) 1 starting at 100mg bid in a 28d C at dose level 1; then S is escalated to 6mg/d followed by 2mg/d maintenance with E at 300mg bid at level 2. An additional level 3 was added with S at 6mg/d followed by 2mg/day with E at 400mg bid based on results of E at 400-600 mg bid in combination with a checkpoint inhibitor with improved control of peripheral kynurenine and intra-tumoral kynurenine reductions. PK samples from plasma samples for determination of plasma E concentrations were obtained on C1d1, prior to administration of the first E dose. Plasma samples were also obtained on C1d1 at two hours post-dose, coinciding with the previously reported Tmax for E. For pts continuing E treatment, plasma samples were obtained on C2d1, prior to dosing (representing trough drug concentrations) as well as at two hours (representing Cssmax). Results: The phase I study enrolled 15 pts. The types of cancers were non-small cell lung ca (1), colorectal (5), esophagus (1), gallbladder (1) and sarcoma (1). Mean values as well as the range of plasma E concentrations observed in the three dose cohorts at each collection time are summarized. Conclusions: The combination of SE showed results consistent with reports that E accumulates upon repeat administration in a dose-proportional fashion. Plasma concentrations of E observed across the three dose cohorts are also consistent with those previously reported. Due the small number of pts studied, and moderate variability in PK reported for this drug, it is not possible to draw definitive conclusions regarding dose-proportionality. Mean (range) plasma E concentrations (ng/mL) determined in samples obtained from pts at trough and two hours post-dose during treatment C1 and C2. Clinical trial information: NCT03217669.

< LLOQ = less than lower assay limit of quantitation.