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 .

• Authors: Asha Nayak-Kapoor, Zhonglin Hao, Ramses Sadek, Robin Dobbins, Lisa Marshall, Nicholas N Vahanian, W Jay Ramsey, Eugene Kennedy, Mario R Mautino, Charles J Link, Ray S Lin, Stephanie Royer-Joo, Xiaorong Liang, Laurent Salphati, Kari M Morrissey, Sami Mahrus, Bruce McCall, Andrea Pirzkall, David H Munn, John E Janik, Samir N Khleif
• Journal: Journal for immunotherapy of cancer (J Immunother Cancer) Vol. 6 Issue 1 Pg. 61 (06 20 2018) ISSN: 2051-1426 [Electronic] England
• PMID: 29921320 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• Enzyme Inhibitors
• Indoleamine-Pyrrole 2,3,-Dioxygenase

Topics

• Aged
• Aged, 80 and over
• Biomarkers, Tumor
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Female
• Humans
• Indoleamine-Pyrrole 2,3,-Dioxygenase (antagonists & inhibitors)
• Male
• Middle Aged
• Neoplasm Metastasis
• Neoplasm Staging
• Neoplasms (drug therapy, enzymology, pathology)
• Recurrence
• Treatment Outcome