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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Le résumé fourni par la source
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.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Phase Ia study of the indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor navoximod (GDC-0919) in patients with recurrent advanced solid tumors
- Date Crossref
- 20/06/2018
- Éditeur
- BMJ
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Augusta University Health pays non établi dans la noticeÉtablissement de santé
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NewLink Genetics (United States) pays non établi dans la noticeEntreprise
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Georgetown University Present Address: Lombardi Comprehensive Cancer Center pays non établi dans la noticeUniversité ou école supérieure
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Georgetown University Medical Center pays non établi dans la noticeÉtablissement de santé
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Vince Lombardi Cancer Clinic Genentech pays non établi dans la noticeÉtablissement de santé
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U-M Rogel Cancer Center pays non établi dans la noticeÉtablissement de santé
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Georgia Cancer Center at Augusta University pays non établi dans la noticeUniversité ou école supérieure
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Inc. Genentech pays non établi dans la noticeEntreprise
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Present Address: Lombardi Comprehensive Cancer Center pays non établi dans la noticeInstitution
Augusta University Health, NewLink Genetics (United States) et Present Address: Lombardi Comprehensive Cancer Center — Georgetown University, avec 6 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.