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Ref Type Journal Article
PMID (29733771)
Authors Lewin J, Soria JC, Stathis A, Delord JP, Peters S, Awada A, Aftimos PG, Bekradda M, Rezai K, Zeng Z, Hussain A, Perez S, Siu LL, Massard C
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 : official journal of the American Society of Clinical Oncology
Vol 36
Issue 30
Date 2018 Oct 20
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Birabresib Y-803|MK-8628|OTX015 BET Inhibitor (Pan) 27 Birabresib (OTX015) is an inhibitor of the BET bromodomain proteins BRD3, BRD4, and BRD5, which inhibits interaction with acetylated histone H4, potentially resulting in decreased tumor cell proliferation (Mol Cancer Ther Nov 2013 12:C244, PMID: 29733771, PMID: 31204545).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown Advanced Solid Tumor not applicable Birabresib Phase Ib/II Actionable In a Phase Ib trial, Birabresib (OTX015) demonstrated favorable safety and resulted in partial response in 7% (3/42) and stable disease in 60% (25/42) of patients with non-small cell lung cancer, prostate cancer, or NUT midline carcinoma, with all of the responses occurring in NUT midline carcinoma patients (PMID: 29733771; NCT02259114). 29733771
Unknown unknown NUT midline carcinoma not applicable Birabresib Phase Ib/II Actionable In a Phase Ib trial, Birabresib (OTX015) demonstrated favorable safety and resulted in partial response in 33% (3/9) and stable disease in 33% (3/9) patients with NUT midline carcinoma (PMID: 29733771; NCT02259114). 29733771