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

Abstract

Background: 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.

Methods: 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 mg BID on a 21/28 day and at 600 mg on a 28/28 day schedule. Plasma kynurenine and tryptophan were longitudinally evaluated and tumor assessments were performed.

Results: Patients (n = 22) received a median of 3 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 (Tmax ~ 1 h) and exhibited dose-proportional increases in exposure, with a half-life (t1/2 ~ 11 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.

Conclusions: Navoximod was well-tolerated at doses up to 800 mg BID decreasing plasma kynurenine levels consistent with its half-life. Stable disease responses were observed.

Trial registration: ClinicalTrials.gov identifier: NCT02048709 .

Keywords: IDO1; Kynurenine; Navoximod; Phase I; Tryptophan.

Conflict of interest statement

Ethics approval and consent to participate

The protocol was approved by Institutional Review Board at Georgia Cancer Center at Augusta University prior to patient recruitment and was conducted in accordance with the Declaration of Helsinki International Conference on Harmonization E6 Guidelines for Good Clinical Practice. Written informed consent was obtained for all patients prior to performing study-related procedures in accordance with federal and institutional guidelines. The study was registered on Competing interests

AN: None. ZH: None. RS: None. RD: None. LM: Employee of Georgia Cancer Center, no conflicts of interest. NNV: NewLink employee and shareholder. WJR: NewLink employee and shareholder. EK: NewLink employee and shareholder. MM: NewLink employee and shareholder. CL: NewLink employee and shareholder. RL: Employee of Genentech, Inc., shareholder of F. Hoffmann La Roche, Ltd. SRJ: Consultant of Genentech, Inc., shareholder of F. Hoffmann La Roche, Ltd. XL: Employee of Genentech, Inc., shareholder of F. Hoffmann La Roche, Ltd. LS: Employee of Genentech, Inc., shareholder of F. Hoffmann La Roche, Ltd. KM: Employee of Genentech, Inc., shareholder of F. Hoffmann La Roche, Ltd. SM: Employee of Genentech, Inc., shareholder of F. Hoffmann La Roche, Ltd. BM: Employee of Genentech, Inc., shareholder of F. Hoffmann La Roche, Ltd. AP: Employee of Genentech, Inc., shareholder of F. Hoffmann La Roche, Ltd. DHM: NewLink Genetics consultant, research support, shareholder. SNK: Member of NewLink SAB, Preclinical Research Agreement Genentech. JEJ: None.

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Figures

Fig. 1

Study design for ascending (BID) and continuous schedules

Fig. 2

a Mean (± SD) plasma concentrations of navoximod after multiple twice-daily doses on Cycle 1, Day 21. The 600 mg BID cohort includes patients from both the 21/28 and continuous dosing schedules. b Single dose and multiple dose pharmacokinetic parameters for navoximod

Fig. 3

Time on study treatment (navoximod dose BID), reason for treatment discontinuation, and best response by RECIST/change in sum of longest diameters for individual patients. PD: Progressive disease

Fig. 4

Mean (± 95% CI) fold changes in plasma Kyn at (a) Cycle 1, Day 1 and (b) Cycle 1, Day 21, relative to Day 1 predose levels after a single oral dose of navoximod. Gray ribbons represent 95% confidence intervals, and dashed horizontal lines represent no change from baseline. The significance of the Kyn changes from baseline is indicated by the 95% confidence intervals relative to the horizontal lines representing no change. If the confidence interval does not overlap with the no change reference line, then the change is significant in the context of a 95% confidence interval