Highlights
- •BET inhibition may be a promising therapeutic strategy for MYC-driven tumours.
- •BAY 1238097 is a highly selective BET inhibitor known to suppress MYC expression.
- •Severe toxicities at dose escalation led to phase I study termination.
- •Pharmacokinetic simulations of a feasible alternate schedule were unsuccessful.
- •Trends towards modulation of pharmacodynamic BET-inhibition biomarkers were observed.
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.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to European Journal of CancerAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Preclinical evaluation of the BET bromodomain inhibitor BAY 1238097 for the treatment of lymphoma.Br J Haematol. 2017; 178: 936-948
- Inhibition of bromodomain and extra-terminal proteins (BET) as a potential therapeutic approach in haematological malignancies: emerging preclinical and clinical evidence.Ther Adv Hematol. 2015; 6: 128-141
- Selective inhibition of BET bromodomains.Nature. 2010; 468: 1067-1073
- The landscape of somatic copy-number alteration across human cancers.Nature. 2010; 463: 899-905
- BET bromodomain inhibition as a therapeutic strategy to target c-Myc.Cell. 2011; 146: 904-917
- X-ray structures of Myc-Max and Mad-Max recognizing DNA: molecular bases of regulation by proto-oncogenic transcription factors.Cell. 2003; 112: 193-205
- Efficacy of BET bromodomain inhibition in Kras-mutant non-small cell lung cancer.Clin Cancer Res. 2013; 19: 6183-6192
- Discovery and characterization of super-enhancer-associated dependencies in diffuse large B cell lymphoma.Cancer Cell. 2013; 24: 777-790
- Phase I trial of bortezomib (PS-341; NSC 681239) and "nonhybrid" (bolus) infusion schedule of Alvocidib (flavopiridol; NSC 649890) in patients with recurrent or refractory indolent B-cell neoplasms.Clin Cancer Res. 2014; 20: 5652-5662
- Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer.Nature. 2014; 510: 278-282
- Bromodomain inhibition shows antitumoral activity in mice and human luminal breast cancer.Oncotarget. 2017; 8: 51621-51629
- Targeting BET bromodomain proteins in solid tumors.Oncotarget. 2016; 7: 53997-54009
- Inhibition of BET bromodomain proteins as a therapeutic approach in prostate cancer.Oncotarget. 2014; 4: 2419-2429
- Super-enhancers define a proliferative PGC-1α-expressing melanoma subgroup sensitive to BET inhibition.Oncogene. 2018; 37: 512-521
- Predictive pharmacokinetic-pharmacodynamic modeling of tumor growth kinetics in xenograft models after administration of anticancer agents.Cancer Res. 2004; 64: 1094-1101
Haendler B, Gelato K, Schoeckel L, Sugawara T, Lejeune P, Ellinger-Ziegelbauer H, et al. The BET inhibitor BAY 1238097 shows efficacy in BRAF wild-type and mutant melanoma models. American Association for Cancer Research Annual Meeting 2016, New Orleans, Louisiana, USA, April 16–20 2016:4703.
Klingbeil O, Haendler B, Stresemann A, Merz C, Walter A, Fernández-Montalván AE, et al. In vivo efficacy of BET inhibitor BAY 1238097 in preclinical models of melanoma and lung cancer. American Association for Cancer Research Annual Meeting 2016, New Orleans, Louisiana, USA, April 16–20 2016:4714.
- Rendering the 3 + 3 design to rest: more efficient approaches to oncology dose-finding trials in the era of targeted therapy.Clin Cancer Res. 2016; 22: 2623-2629
- Adaptive design methods in clinical trials – a review.Orphanet J Rare Dis. 2008; 3: 11
- Clinical trials for BET inhibitors run ahead of the science.Drug Discov Today Technol. 2016; 19: 45-50
- BET inhibitors: a novel epigenetic approach.Ann Oncol. 2017; 28: 1776-1787
- Clinical response of carcinomas harboring the BRD4-NUT oncoprotein to the targeted bromodomain inhibitor OTX015/MK-8628.Cancer Discov. 2016; 6: 492-500
- The circadian expression of c-MYC is modulated by the histone deacetylase inhibitor trichostatin A in synchronized murine neuroblastoma cells.Chronobiol Int. 2010; 27: 722-741
- The mechanisms behind the therapeutic activity of BET bromodomain inhibition.Mol Cell. 2014; 54: 728-736
- Drug discovery targeting bromodomain-containing protein 4.J Med Chem. 2017; 60: 4533-4558
Article info
Publication history
Published online: January 31, 2019
Accepted:
December 18,
2018
Received in revised form:
December 13,
2018
Received:
September 17,
2018
Identification
Copyright
© 2018 Published by Elsevier Ltd.
