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

Details

Serval ID
serval:BIB_C3E1143B2AA2
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Phase Ib Trial With Birabresib, a Small-Molecule Inhibitor of Bromodomain and Extraterminal Proteins, in Patients With Selected Advanced Solid Tumors.
Journal
Journal of clinical oncology
Author(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
Publication state
Published
Issued date
20/10/2018
Peer-reviewed
Oui
Volume
36
Number
30
Pages
3007-3014
Language
english
Notes
Publication types: Clinical Trial, Phase I ; Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
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.
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.
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.
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.
Keywords
Acetanilides/administration & dosage, Acetanilides/adverse effects, Acetanilides/pharmacokinetics, Adult, Aged, Antineoplastic Agents/administration & dosage, Antineoplastic Agents/adverse effects, Antineoplastic Agents/pharmacokinetics, Dose-Response Relationship, Drug, Female, Heterocyclic Compounds, 3-Ring/administration & dosage, Heterocyclic Compounds, 3-Ring/adverse effects, Heterocyclic Compounds, 3-Ring/pharmacokinetics, Humans, Male, Maximum Tolerated Dose, Middle Aged, Neoplasms/drug therapy, Young Adult
Pubmed
Web of science
Create date
12/05/2018 9:12
Last modification date
24/09/2019 5:11
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