Phase lB Portion:~The phase 1 portion of this study will be a standard 3+3 design.~Pembrolizumab will be administered at 200 mg intravenously (IV) on day 1 of each cycle, every 21 days.~Azacitidine will be administered at 100 mg subcutaneous injection (SQ) daily on days 1-5 of each cycle, every 21 days~Three dose levels of epacadostat (INCB024360) will be explored: dose levels -1, 1 and 2.~The dose level 1 will be the starting dose level.~If the dose level 2 is tolerable without dose limiting toxicities (DLTs), the dose level 2 will be considered the RP2D, and the phase II part will be initiated.~DLT will be monitored during the first 21 days (cycles 1) and will be used for purposes of dose escalation and determination of RP2D.~Definition of DLT:~Hematologic Toxicities:~Any Grade 4 thrombocytopenia or neutropenia lasting > 7 days~Any Grade 3 thrombocytopenia with severe bleeding~Nonhematologic Toxicities:~o Any Grade 4 toxicity EXCLUDING: Grade 4 abnormal laboratory values with a clear alternative explanation or transient (≤ 72 hours), or without associated clinically significant signs or symptoms based on investigator determination.~Any Grade 3 or 4 AST, ALT, or total bilirubin elevation~Any other Grade 3 toxicity EXCLUDING:~Nausea/vomiting controlled by medical intervention within 72 hours~Grade 3 rash in the absence of desquamation, no mucosal involvement, does not require systemic steroids, and resolves to Grade 1 within 14 days.~Grade 3 abnormal laboratory values with a clear alternative explanation or transient (≤ 72 hours), or without associated clinically significant signs or symptoms based on investigator determination.~Phase ll portion:~The phase 2 portion of this study is a non-randomized, open-label, single-arm phase II study. The primary objective of this study is to evaluate objective response rate (ORR) using RECIST1.1.~Study Procedure~One cycle of therapy is defined as 21 days.~Subjects may continue treatment up to 35 cycles of the study therapy (the combination of azacitidine, pembrolizumab and epacadostat [INCB024360] for the first 18 cycles [Cycle 1 to Cycle 18], and the combination of pembrolizumab and epacadostat (INCB024360) for the remaining 17 cycles [Cycle 19 to Cycle 35]) until evidence of progression of disease (PD) or unacceptable toxicity.~Dose-limiting toxicity (DLT) will be assessed during the first 21 days (cycle 1).~Tumor response will be determined by radiologic measurements by CT and by using RECIST. Assessment of tumor response will be performed every 3 cycles (approximately 9 weeks).~All patients will be evaluated and graded for adverse events according to the NCI Common Terminology for Adverse Events, version 4.0 (NCI-CTCAE).~Study Treatment~Pembrolizumab 200 mg will be administered intravenously over 30 minutes on days 1 of each cycle every 21 days.~Azacitidine 100 mg will be administered as subcutaneous injection on days 1-5 of each cycle every 21 days.~Epacadostat (INCB024360) will be administered orally twice a day continuously on days 1-21 of each cycle every 21 days. Two dose levels of epacadostat (INCB024360) will be explored: 100 mg BID and 300 mg BID.
Trial Design This is an open label, single-arm, phase IB/II trial to evaluate the safety, tolerability and anti-tumor efficacy of epacadostat (INCB024360) in combination with pembrolizumab (MK-3475) plus azacitidine in patients with chemo-refractory MSS mCRC.~The phase 1B portion of the study will evaluate the safety, tolerability and RP2D of epacadostat (INCB024360) in combination with pembrolizumab plus azacitidine in subjects with chemo-refractory MSS mCRC without any further standard treatment options.~The phase 2 portion of the study will evaluate the efficacy and safety of epacadostat (INCB024360) in combination with pembrolizumab plus azacitidine in subjects with chemo-refractory MSS mCRC without any further standard treatment options.~In both phase IB and phase 2 portions, patients will receive the combination of azacitidine, pembrolizumab and epacadostat (INCB024360) for the first 18 cycles (Cycles 1-18). Beginning with Cycle 19 through Cycle 35, patients will receive the combination of pembrolizumab and epacadostat (INCB024360).