First-in-human Phase 1 open label study of the BET inhibitor ODM-207 in patients with selected solid tumours
Open Access
- 8 December 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in British Journal of Cancer
- Vol. 123 (12), 1730-1736
- https://doi.org/10.1038/s41416-020-01077-z
Abstract
Background Bromodomain and extra-terminal domain (BET) proteins are reported to be epigenetic anti-cancer drug targets. This first-in-human study evaluated the safety, pharmacokinetics and preliminary anti-tumour activity of the BET inhibitor ODM-207 in patients with selected solid tumours. Methods This was an open-label Phase 1 study comprised of a dose escalation part, and evaluation of the effect of food on pharmacokinetics. ODM-207 was administered orally once daily. The dose escalation part was initiated with a dose titration in the initial cohort, followed by a 3 + 3 design. Results Thirty-five patients were treated with ODM-207, of whom 12 (34%) had castrate-resistant prostate cancer. One dose-limiting toxicity of intolerable fatigue was observed. The highest studied dose achieved was 2 mg/kg due to cumulative toxicity observed beyond the dose-limiting toxicity (DLT) treatment window. Common AEs included thrombocytopenia, asthenia, nausea, anorexia, diarrhoea, fatigue, and vomiting. Platelet count decreased proportionally to exposure with rapid recovery upon treatment discontinuation. No partial or complete responses were observed. Conclusions ODM-207 shows increasing exposure in dose escalation and was safe at doses up to 2 mg/kg but had a narrow therapeutic window.This publication has 31 references indexed in Scilit:
- Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3Journal of Clinical Oncology, 2016
- BET Bromodomain Inhibition as a Therapeutic Strategy in Ovarian Cancer by Downregulating FoxM1Theranostics, 2016
- Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano ClassificationJournal of Clinical Oncology, 2014
- The Mechanisms behind the Therapeutic Activity of BET Bromodomain InhibitionMolecular Cell, 2014
- NUT midline carcinomaCancer Genetics and Cytogenetics, 2010
- Selective inhibition of BET bromodomainsNature, 2010
- New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1)European Journal of Cancer, 2009
- Recruitment of P-TEFb for Stimulation of Transcriptional Elongation by the Bromodomain Protein Brd4Molecular Cell, 2005
- The Bromodomain Protein Brd4 Is a Positive Regulatory Component of P-TEFb and Stimulates RNA Polymerase II-Dependent TranscriptionMolecular Cell, 2005
- Activation of chromatin by acetylation of histone side chains.Proceedings of the National Academy of Sciences of the United States of America, 1976