Phase Ia study of the indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor navoximod (GDC-0919) in patients with recurrent advanced solid tumors

Abstract

<h3>Background</h3> Indoleamine-2,3-dioxygenase 1 (IDO1) catalyzes the oxidation of tryptophan into kynurenine and is partially responsible for acquired immune tolerance associated with cancer. The IDO1 small molecule inhibitor navoximod (GDC-0919, NLG-919) is active as a combination therapy in multiple tumor models. <h3>Methods</h3> This open-label Phase Ia study assessed safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary anti-tumor activity of navoximod in patients with recurrent/advanced solid tumors, administered as 50-800&nbsp;mg BID on a 21/28&nbsp;day and at 600&nbsp;mg on a 28/28&nbsp;day schedule. Plasma kynurenine and tryptophan were longitudinally evaluated and tumor assessments were performed. <h3>Results</h3> Patients (<i>n</i>&nbsp;= 22) received a median of 3&nbsp;cycles of navoximod. No maximum tolerated dose was reached. One dose-limiting toxicity of Grade 4 lower gastrointestinal hemorrhage was reported. Adverse events (AEs) regardless of causality in ≥20% of patients included fatigue (59%), cough, decreased appetite, and pruritus (41% each), nausea (36%), and vomiting (27%). Grade ≥ 3 AEs occurred in 14/22 patients (64%), and were related to navoximod in two patients (9%). Navoximod was rapidly absorbed (T_max ~ 1&nbsp;h) and exhibited dose-proportional increases in exposure, with a half-life (t_1/2 ~ 11&nbsp;h) supportive of BID dosing. Navoximod transiently decreased plasma kynurenine from baseline levels with kinetics consistent with its half-life. Of efficacy-evaluable patients, 8 (36%) had stable disease and 10 (46%) had progressive disease. <h3>Conclusions</h3> Navoximod was well-tolerated at doses up to 800&nbsp;mg BID decreasing plasma kynurenine levels consistent with its half-life. Stable disease responses were observed. <h3>Trial registration</h3> ClinicalTrials.gov identifier: NCT02048709.