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 1 study investigated the maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics, and antitumor activity of epacadostat (INCB024360), a potent and selective inhibitor of IDO1. PATIENTS AND METHODS 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.

Indoleamine 2,3‐dioxygenase 1 in coronary atherosclerotic plaque enhances tissue factor expression in activated macrophages

“…Many solid malignancies express IDO1, which can promote tumor escape from host immunosurveillance. Clinical trials of epacadostat combined with other immunomodulatory drugs against several malignancies are ongoing 42. The present findings showed that epacadostat not only reduced IDO1 activity, but also suppressed TF expression via NFκB (p65) binding activity and Kyn production.…”

Indoleamine 2,3-Dioxygenase and Its Therapeutic Inhibition in Cancer

“…Clinical evaluation of epacadstat opened with a first-in-human Phase I study to investigate safety and maximum-tolerated dose, pharmacokinetics, pharmacodynamics and antitumor activity (Beatty et al , 2017). In this study, epacadostat was generally well tolerated, effectively normalized plasma kynurenine levels and was maximally inhibitory to IDO1 activity at doses of >100 mg BID.…”

“…In this study, epacadostat was generally well tolerated, effectively normalized plasma kynurenine levels and was maximally inhibitory to IDO1 activity at doses of >100 mg BID. While no objective responses were detected, stable disease lasting ≥16 weeks was observed in 7/52 patients (Beatty et al, 2017). A study co-administering epacadostat in combination with ipilimumab was conducted in patients with advanced melanoma (Gibney et al , 2015).…”

Immunotherapy against endocrine malignancies: immune checkpoint inhibitors lead the way

“…Inspired by the success of checkpoint inhibitors, several other checkpoints are now under investigation as targets for monotherapy or as combination therapy, including lymphocyte activation gene-3 (LAG-3), T-cell immunoglobulin mucin-3 (TIM-3) and indoleamine-2,3-dioxygenase (IDO) (Brignone et al 2010, Wang-Gillam et al 2013, Beatty et al 2017). (Grosso et al 2007, Assal et al 2015.…”