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 with advanced solid tumors, with plans for an expansion phase II study in patients with advanced recurrent lung cancer once maximum tolerated dose (MTD) was defined. 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 day -7 followed by 1mg/d with E added on day 1 of Cycle 1 starting at 300mg bid in a 28d cycle 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 400 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. Enrollment continued until Dose limiting toxicity (DLT) which was defined as grade 3 hematologic toxicities or grade 3 or 4 non-hematologic toxicities up to Cycle 2 day 1. MTD was defined as DLT not exceeding 33% of subjects. Results: The phase I study enrolled 15 patients, with 9 patients evaluable. The types of cancers were non-small cell lung ca (1), colorectal (5), esophagus (1), gallbladder (1) and sarcoma (1). DLT was not observed up to level 3. Adverse events attributed to SE were Grade 1 Diarrhea (2), stomach pain (1); elevated liver enzymes (ELE) (1), decreased white blood cell (1), anorexia (1), hypokalemia (1), dizziness (1), skin rash (1); Grade 2 ELE (1), Anemia (1), Vertigo (1), Constipation (1), Nausea (2); Grade 3: Diarrhea (1), serotonin syndrome (1), dyspnea (1). The best response observed was stable disease in 3 patients, 5 patients had disease progression and 1 patient was not assessable for response due treatment discontinuation related to side effect of serotonin syndrome. The Expansion Cohort (Part 2) did not proceed since the sponsor decided to discontinue further development of E. Conclusions: The combination of SE is feasible, tolerable with mostly grade 1 and 2 toxicities. There were few grades 3 toxicities. SE produced stable disease as best response in 33% of patients. Research using the combination of SE as an immunomodulatory therapy in patients with lung cancer resistant to checkpoint inhibitor is worth additional exploration. Clinical trial information: NCT03217669.