Title |
Phase Ia study of the indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor navoximod (GDC-0919) in patients with recurrent advanced solid tumors
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Published in |
Journal for Immunotherapy of Cancer, June 2018
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DOI | 10.1186/s40425-018-0351-9 |
Pubmed ID | |
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 |
Abstract |
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. 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. 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. 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. ClinicalTrials.gov identifier: NCT02048709 . |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 2 | 29% |
Turkey | 1 | 14% |
Spain | 1 | 14% |
Canada | 1 | 14% |
Unknown | 2 | 29% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 3 | 43% |
Practitioners (doctors, other healthcare professionals) | 2 | 29% |
Scientists | 1 | 14% |
Science communicators (journalists, bloggers, editors) | 1 | 14% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 92 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Bachelor | 13 | 14% |
Student > Ph. D. Student | 11 | 12% |
Researcher | 10 | 11% |
Student > Master | 9 | 10% |
Other | 6 | 7% |
Other | 15 | 16% |
Unknown | 28 | 30% |
Readers by discipline | Count | As % |
---|---|---|
Medicine and Dentistry | 16 | 17% |
Pharmacology, Toxicology and Pharmaceutical Science | 11 | 12% |
Biochemistry, Genetics and Molecular Biology | 10 | 11% |
Chemistry | 6 | 7% |
Nursing and Health Professions | 5 | 5% |
Other | 13 | 14% |
Unknown | 31 | 34% |