First-in-Human Phase I Study of the Oral Inhibitor of Indoleamine 2,3-Dioxygenase-1 Epacadostat (INCB024360) in Patients with Advanced Solid Malignancies - PubMed (original) (raw)
Clinical Trial
First-in-Human Phase I Study of the Oral Inhibitor of Indoleamine 2,3-Dioxygenase-1 Epacadostat (INCB024360) in Patients with Advanced Solid Malignancies
Gregory L Beatty et al. Clin Cancer Res. 2017.
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.
©2017 American Association for Cancer Research.
Conflict of interest statement
Conflict of interest statement:
Incyte Corporation provided research funding to the institutions of G. L. Beatty, P. J. O’Dwyer, and T. F. Gajewski for conduct of the study. J. Clark, K. J. Bowman, P. A. Scherle, J. G. Shi, R. C. Newton, R. Schaub, J. Maleski, and L. Leopold are employees of Incyte Corporation.
Figures
Figure 1
Pharmacodynamic effects of epacadostat BID dosing in vivo. (A) Kyn levels by dose group at baseline and day 15. The dashed line represents the median Kyn value observed in normal, healthy volunteers (1499 nM). (B) Percentage decrease in Kyn levels from baseline by dose. (C) Average Kyn inhibition over time by dose on day 15 (relative to day 1) following IDO1 induction with IFN-γ and LPS. Time 0 represents the trough levels before the next dose of epacadostat treatment. (D) Epacadostat plasma concentrations relative to percentage Kyn inhibition. BID=twice daily; IDO1=indoleamine 2,3-dioxygenase-1; IFN-γ=interferon gamma; Kyn=kynurenine; LPS=lipopolysaccharide.
Figure 2
Prolonged stable disease compared with last prior therapy was achieved in a subset of patients (n=11). Two patients with melanoma refractory to ipilimumab achieved stable disease with epacadostat. The dashed line represents at least 16 weeks (112 days) on epacadostat therapy.
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References
- Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372:320–30. - PubMed
- Robert C, Thomas L, Bondarenko I, O’Day S, Weber J, Garbe C, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517–26. - PubMed
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