Phase Ib Trial With Birabresib, a Small-Molecule Inhibitor of Bromodomain and Extraterminal Proteins, in Patients With Selected Advanced Solid Tumors.

Détails

ID Serval
serval:BIB_C3E1143B2AA2
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Phase Ib Trial With Birabresib, a Small-Molecule Inhibitor of Bromodomain and Extraterminal Proteins, in Patients With Selected Advanced Solid Tumors.
Périodique
Journal of clinical oncology
Auteur(s)
Lewin J., Soria J.C., Stathis A., Delord J.P., Peters S., Awada A., Aftimos P.G., Bekradda M., Rezai K., Zeng Z., Hussain A., Perez S., Siu L.L., Massard C.
ISSN
1527-7755 (Electronic)
ISSN-L
0732-183X
Statut éditorial
Publié
Date de publication
2018
Peer-reviewed
Oui
Volume
36
Numéro
30
Pages
3007-3014
Langue
anglais
Notes
Publication types: Journal Article

Résumé
Purpose Birabresib (MK-8628/OTX015) is a first-in-class bromodomain inhibitor with activity in select hematologic tumors. Safety, efficacy, and pharmacokinetics of birabresib were evaluated in patients with castrate-resistant prostate cancer, nuclear protein in testis midline carcinoma (NMC), and non-small-cell lung cancer in this phase Ib study. Patients and Methods Forty-seven patients were enrolled to receive birabresib once daily at starting doses of 80 mg continuously (cohort A) or 100 mg for 7 consecutive days (cohort B) in 21-day cycles using a parallel dose escalation 3 + 3 design. The primary objective was occurrence of dose-limiting toxicities (DLTs) and determination of the recommended phase II dose. Results Of 46 treated patients, 26 had castrate-resistant prostate cancer, 10 NMC, and 10 non-small-cell lung cancer. For cohort A, four of 19 (21%) evaluable patients had DLTs at 80 mg once daily (grade 3 thrombocytopenia [n = 3], ALT/hyperbilirubinemia [n = 1]) and two of three had DLTs at 100 mg once daily (grade 2 anorexia and nausea with treatment delay > 7 days [n = 1], grade 4 thrombocytopenia [n = 1]). No DLTs occurred in cohort B. Of 46 patients, 38 (83%) had treatment-related adverse events (diarrhea, 17 [37%]; nausea, 17 [37%]; anorexia, 14 [30%]; vomiting, 12 [26%]; thrombocytopenia 10 [22%]). Three patients with NMC (80 mg once daily) had a partial response (Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) with duration of 1.4 to 8.4 months. Pharmacokinetic analysis indicated a dose-proportional increase in birabresib exposure and rapid absorption. Conclusion The recommended phase II dose of birabresib in patients with select solid tumors is 80 mg once daily with continuous dosing. Birabresib has dose-proportional exposure and a favorable safety profile, with clinical activity observed in NMC. Future studies of birabresib must consider intermittent scheduling to possibly mitigate the toxicities of chronic dosing.
Pubmed
Web of science
Création de la notice
12/05/2018 10:12
Dernière modification de la notice
11/04/2019 13:36
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