First-in-human Phase 1 open label study of the BET inhibitor ODM-207 in patients with selected solid tumours

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.

Clinical trial registration: The clinical trial registration number is NCT03035591.

Conflict of interest statement

All authors have completed the Unified Competing Interest form (http://www.icmje.org/coi_disclosure.pdf) and declare: I.B. reports scientific consultancy role for Orion Pharma. P.B. reports personal fees from Orion Pharma, during the conduct of the study; personal fees from BMS, MSD, Pfizer, Novartis, Oncorena, TILT Biotherapeutics, Faron Pharmaceuticals, Ipsen, Herantis Pharma, outside the submitted work; and stock ownership: TILT Biotherapeutics and Terveystalo. S.P-V. has received research funding from Merck KGaA, Boehringer Ingelheim and Institut Roche for unrelated research projects. SPV has participated to advisory boards for Merck KGaA. As part of the Drug Development Department (DITEP), SPV is principal investigator or sub-investigator of clinical trials from Abbvie, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, Astra Zeneca, Aveo, Bayer Healthcare Ag, Bbb Technologies Bv, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corporation, Chugai Pharmaceutical Co., Clovis Oncology, Daiichi Sankyo, Debiopharm S.A., Eisai, Eli Lilly, Exelixis, Forma, Gamamabs, Genentech, Inc., Glaxosmithkline, H3 Biomedicine, Inc, Hoffmann La Roche Ag, Innate Pharma, Iris Servier, Janssen Cilag, Kyowa Kirin Pharm. Dev., Inc., Loxo Oncology, Lytix Biopharma As, Medimmune, Menarini Ricerche, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus, Millennium Pharmaceuticals, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Octimet Oncology Nv, Oncoethix, Onyx Therapeutics, Orion Pharma, Oryzon Genomics, Pfizer, Pharma Mar, Pierre Fabre, Roche, Sanofi Aventis, Taiho Pharma, Tesaro Inc, and Xencor. R.P. reports other from Celgene, during the conduct of the study. J.A., T.K. and A.S. are employees of Orion Corporation Orion Pharma. J.DB. has served on advisory boards and received fees from many companies including Astra Zeneca, Astellas, Bayer, Boehringer Ingelheim, Cellcentric, Daiichi, Genentech/Roche, Genmab, GSK, Janssen, Merck Serono, Merck Sharp & Dohme, Menarini/Silicon Biosystems, Orion, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Vertex Pharmaceuticals. He is an employee of The ICR, which have received funding or other support for his research work from AZ, Astellas, Bayer, Cellcentric, Daiichi, Genentech, Genmab, GSK, Janssen, Merck Serono, MSD, Menarini/Silicon Biosystems, Orion, Sanofi Aventis, Sierra Oncology, Taiho, Pfizer, Vertex, and which has a commercial interest in abiraterone, PARP inhibition in DNA repair defective cancers and PI3K/AKT pathway inhibitors (no personal income). He was named as an inventor, with no financial interest, for patent 8,822,438. He has been the CI/PI of many industry sponsored clinical trials. JDB is a National Institute for Health Research (NIHR) Senior Investigator. The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. The remaining authors declare no competing interests.

Figures

Fig. 1. Pharmacokinetics of ODM-207.

Cohort mean concentrations in fed-state on day 1 and day 15 (a), and in fed/fasted state in one cohort (b). a Cohorts 1A-1 0.6 mg/kg (blue square), Cohort 1A-2 1.3 mg/kg (green circle), Cohort 1A-3 1.5 mg/kg (orange diamond), and Cohort 1A-4 2.0 mg/kg (pink triangle). b Fasted state (blue square) and fed state (green circle).

Fig. 2. Platelet count change over time.

Mean platelet change from baseline (%) by pre-dose ODM-207 exposure (a) and examples of recovery of platelets upon dosing interruption (b). a Pre-dose concentration (ng/mL) <3500 (blue triangle), 3500–5000 (orange circle), and ≥5000 (green diamond). b Dosing interruption (orange circle) and resumption (green triangle).

Fig. 3. Duration of treatment and reason for discontinuation by cancer type.

CRPC castration-resistant prostate cancer, ER + mBC oestrogen receptor positive metastatic breast cancer, NMC NUT midline carcinoma, NSCLC non-small cell lung cancer, RSCDS round small cells desmoplastic sarcoma, CRC colorectal carcinoma, SCLC small cell lung cancer, NHL non-Hodgkin’s lymphoma, SD stable disease, PD progressive disease, CR complete response, EOS end of study.