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

Postel-Vinay, S; Herbschleb, K; Massard, C; Woodcock, V; Soria, J-C; Walter, AO; Ewerton, F; Poelman, M; Benson, N; Ocker, M; Wilkinson, G; Middleton, MR

Journal article

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

Abstract:: Background: 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. Material and methods: 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. Results: 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. Conclusion: 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.

Publication status:: Published

Peer review status:: Peer reviewed

Actions

Email

Email this record

Send the bibliographic details of this record to your email address.

Your Email
Please enter the email address that the record information will be sent to.

-
Your message (optional)
Please add any additional information to be included within the email.
Cite

Cite this record

APA Style

Postel-Vinay, S., Herbschleb, K., Massard, C., Woodcock, V., Soria, J.-C., Walter, A. O., Ewerton, F., Poelman, M., Benson, N., Ocker, M., Wilkinson, G., & Middleton, M. R. (2019). 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. European Journal of Cancer, 109, 103–110.

MLA Style

Postel-Vinay, S., et al. “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.” European Journal of Cancer, vol. 109, Elsevier, 2019, pp. 103–10.

Chicago Style

Postel-Vinay, S, K Herbschleb, C Massard, V Woodcock, J-C Soria, AO Walter, F Ewerton, et al. 2019. “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.” European Journal of Cancer 109: 103–10.
Share
Print