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Ref Type Journal Article
PMID (30711772)
Authors Postel-Vinay S, Herbschleb K, Massard C, Woodcock V, Soria JC, Walter AO, Ewerton F, Poelman M, Benson N, Ocker M, Wilkinson G, Middleton M
Title First-in-human phase I study of the bromodomain and extraterminal motif inhibitor BAY 1238097: emerging pharmacokinetic/pharmacodynamic relationship and early termination due to unexpected toxicity.
Journal European journal of cancer (Oxford, England : 1990)
Vol 109
Date 2019 Jan 31
Abstract Text Bromodomain and extraterminal motif (BET) protein inhibition is a promising cancer treatment strategy, notably for targeting MYC- or BRD4-driven diseases. A first-in-human study investigated the safety, pharmacokinetics, maximum tolerated dose and recommended phase II dose of the BET inhibitor BAY 1238097 in patients with advanced malignancies.In this phase I, open-label, non-randomised, multicentre study, patients with cytologically or histologically confirmed advanced refractory malignancies received oral BAY 1238097 twice weekly in 21-day cycles using an adaptive dose-escalation design at a starting dose of 10 mg/week. Model-based dose-response analysis was performed to guide dose escalation. Safety, pharmacokinetics, pharmacodynamics and tumour response were evaluated.Eight patients were enrolled at three dose levels (10 mg/week, n = 3; 40 mg/week, n = 3; 80 mg/week, n = 2). Both patients receiving 80 mg/week had dose-limiting toxicities (DLTs) (grade 3 vomiting, grade 3 headache and grade 2/3 back pain). The most common adverse events were nausea, vomiting, headache, back pain and fatigue. Pharmacokinetic analysis indicated a linear dose response with increasing dose. Two patients displayed prolonged stable disease; no responses were observed. Biomarker evaluation of MYC and HEXIM1 expression demonstrated an emerging pharmacokinetic/pharmacodynamic relationship, with a trend towards decreased MYC and increased HEXIM1 expression in response to treatment.The study was prematurely terminated because of the occurrence of DLTs at a dose below targeted drug exposure. Pharmacokinetic modelling indicated that an alternate dosing schedule whereby DLTs could be avoided while reaching efficacious exposure was not feasible. Registration number: NCT02369029.


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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
BAY 1238097 BAY 1238097 3 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
BAY 1238097 BAY1238097|BAY-1238097 BET Inhibitor (Pan) 27 BAY 1238097 targets proteins of the bromodomain (BRD) and extraterminal (BET) family to prevent interaction with histones and subsequent expression of genes, such as MYC, to prevent cell growth and proliferation (PMID: 30711772).
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 BAY 1238097 Clinical Study Actionable In a Phase I trial, BAY 1238097 therapy resulted in zero objective responses and stable disease in 25% (2/8) of patients with refractory advanced solid tumors; due to high toxicity the trial was terminated prematurely (PMID: 30711772; NCT02369029). 30711772