title: First-in-Human Phase I Study of the Oral Inhibitor of Indoleamine 2,3-Dioxygenase-1 Epacadostat (INCB024360) in Patients with Advanced Solid Malignancies.
abstract: Purpose:Indoleamine 2,3-dioxygenase-1 (IDO1) catalyzes the degradation of tryptophan to N-formyl-kynurenine. Overexpressed in many solid malignancies, IDO1 can promote tumor escape from host immunosurveillance. This first-in-human phase I study investigated the maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics, and antitumor activity of epacadostat (INCB024360), a potent and selective inhibitor of IDO1.Experimental Design:Fifty-two patients with advanced solid malignancies were treated with epacadostat [50 mg once daily or 50, 100, 300, 400, 500, 600, or 700 mg twice daily (BID)] in a dose-escalation 3 + 3 design and evaluated in 28-day cycles. Treatment was continued until disease progression or unacceptable toxicity.Results:One dose-limiting toxicity (DLT) occurred at the dose of 300 mg BID (grade 3, radiation pneumonitis); another DLT occurred at 400 mg BID (grade 3, fatigue). The most common adverse events in >20% of patients overall were fatigue, nausea, decreased appetite, vomiting, constipation, abdominal pain, diarrhea, dyspnea, back pain, and cough. Treatment produced significant dose-dependent reductions in plasma kynurenine levels and in the plasma kynurenine/tryptophan ratio at all doses and in all patients. Near maximal changes were observed at doses of ≥100 mg BID with >80% to 90% inhibition of IDO1 achieved throughout the dosing period. Although no objective responses were detected, stable disease lasting ≥16 weeks was observed in 7 of 52 patients.Conclusions:Epacadostat was generally well tolerated, effectively normalized kynurenine levels, and produced maximal inhibition of IDO1 activity at doses of ≥100 mg BID. Studies investigating epacadostat in combination with other immunomodulatory drugs are ongoing.Clin Cancer Res; 23(13); 3269-76. ©2017 AACR.
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. gregory.beatty@uphs.upenn.edu.|Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Beatty
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.|Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: O'Dwyer
authors.affiliation: Incyte Corporation, Wilmington, Delaware.
authors.forename: Jason
authors.initials: J
authors.lastname: Clark
authors.affiliation: Incyte Corporation, Wilmington, Delaware.
authors.forename: Jack G
authors.initials: JG
authors.lastname: Shi
authors.affiliation: Incyte Corporation, Wilmington, Delaware.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Bowman
authors.affiliation: Incyte Corporation, Wilmington, Delaware.
authors.forename: Peggy A
authors.initials: PA
authors.lastname: Scherle
authors.affiliation: Incyte Corporation, Wilmington, Delaware.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Newton
authors.affiliation: Incyte Corporation, Wilmington, Delaware.
authors.forename: Richard
authors.initials: R
authors.lastname: Schaub
authors.affiliation: Incyte Corporation, Wilmington, Delaware.
authors.forename: Janet
authors.initials: J
authors.lastname: Maleski
authors.affiliation: Incyte Corporation, Wilmington, Delaware.
authors.forename: Lance
authors.initials: L
authors.lastname: Leopold
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Gajewski
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D064420:Drug-Related Side Effects and Adverse Reactions / Q000145:classification / Q000473:pathology*; D005260:Female; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010091:Oximes / Q000008:administration & dosage*; D013449:Sulfonamides / Q000008:administration & dosage*
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D010091:Oximes; D013449:Sulfonamides; C000613752:epacadostat