Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
European journal of cancer (Oxford, England : 1990)	109		2019 Jan 31	103-110	Eur J Cancer

URL

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	0	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
BAY 1238097		BAY1238097\|BAY-1238097	BET Inhibitor (Pan) 32	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