A phase 1 study of PF-06840003, an oral indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor in patients with recurrent malignant glioma.
Adolescent
Adult
Aged
Antineoplastic Agents
/ administration & dosage
Central Nervous System Neoplasms
/ drug therapy
Female
Glioma
/ drug therapy
Humans
Indoleamine-Pyrrole 2,3,-Dioxygenase
/ antagonists & inhibitors
Indoles
/ administration & dosage
Kynurenine
/ metabolism
Male
Middle Aged
Neoplasm Recurrence, Local
/ drug therapy
Succinimides
/ administration & dosage
Treatment Outcome
Tryptophan
/ metabolism
Young Adult
Glioblastoma
IDO1
Immuno-oncology
Kynurenine
Malignant glioma, tryptophan catabolism
Journal
Investigational new drugs
ISSN: 1573-0646
Titre abrégé: Invest New Drugs
Pays: United States
ID NLM: 8309330
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
07
04
2020
accepted:
10
05
2020
pubmed:
22
5
2020
medline:
11
9
2021
entrez:
22
5
2020
Statut:
ppublish
Résumé
Background PF-06840003 is a highly selective indoleamine 2, 3-dioxygenase (IDO1) inhibitor with antitumor effects in preclinical models. This first-in-human phase 1 study evaluated safety, pharmacokinetics/pharmacodynamics, and preliminary efficacy in recurrent malignant glioma to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Methods Patients (N = 17) received oral PF-06840003 in four dose-escalation groups: 125 mg once-daily (QD; n = 2); 250 mg QD (n = 4); 250 mg twice-daily (BID; n = 3); 500 mg BID (n = 8). A modified toxicity probability interval method determined the MTD. Results Four patients experienced serious adverse events (SAEs); one with treatment-related SAEs (grade 4 alanine and aspartate aminotransferase elevations). The dose-limiting toxicity (DLT) rate at 500 mg BID was 12.5% (n = 1/8); the MTD was not reached. Following PF-06840003 dosing, median time to maximum plasma concentration for the active enantiomer PF-06840002 was 1.5-3.0 hr and mean elimination half-life was 2 to 4 hr (Cycle 1 Day 1). Urinary recovery of PF-06840002 was low (< 1%). At 500 mg BID, maximum mean percentage inhibition of
Identifiants
pubmed: 32436060
doi: 10.1007/s10637-020-00950-1
pii: 10.1007/s10637-020-00950-1
doi:
Substances chimiques
Antineoplastic Agents
0
Indoleamine-Pyrrole 2,3,-Dioxygenase
0
Indoles
0
PF-06840003
0
Succinimides
0
Kynurenine
343-65-7
Tryptophan
8DUH1N11BX
Banques de données
ClinicalTrials.gov
['NCT02764151']
Types de publication
Clinical Trial, Phase I
Journal Article
Multicenter Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1784-1795Subventions
Organisme : NCI NIH HHS
ID : UG1 CA189960
Pays : United States
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