Phase I/IIa, open-label, multicentre study to evaluate the optimal dosing and safety of ODM-203 in patients with advanced or metastatic solid tumours

Abstract

Background: Genetic alterations in fibroblast growth factor receptor (FGFR) and vascular endothelial growth factor receptor (VEGFR) signalling are observed in various tumours. We report a first-in-human phase I/IIa trial evaluating tolerability, pharmacokinetics and preliminary antitumour activity of ODM-203, a novel FGFR and VEGFR inhibitor.

Methods: Open-label, non-randomised, multicentre, phase I/IIa dose escalation and expansion study in patients with advanced or metastatic solid tumours.

Results: Overall, 84 patients received treatment; optimal tablet dose was found to be 400 mg/day with food. All patients experienced at least one adverse event; the majority (89.2%) were grade 1 or 2% and 70.4% were considered treatment related. The most commonly reported events were bilirubin increase-related events (75%) and diarrhoea (50%).Overall response rate was 9.2% and median progression-free survival was 16.1 and 12.4 weeks for patients with aberrant or non-aberrant FGFR tumours. Median time on treatment was 10.1 weeks for all patients and 14.5 weeks for patients who received 400 mg tablets.

Conclusion: This study suggests ODM-203 400 mg/day results in sufficient plasma concentrations and acceptable tolerability in most patients. Preliminary signs of therapeutic activity of ODM-203 in patients with solid tumours was observed.

Trial registration number: NCT02264418.

Keywords: FGFR and VEGFR inhibitor; ODM-203; dose escalation study; phase I; solid tumours.

Conflict of interest statement

Competing interests: PB reports personal fees from Orion Pharma, during the conduct of the study, personal fees from Bristol-Myers Squibb, MSD, Pfizer, Novartis, EUSA, Oncorena, TILT Biotherapeutics, Faron Pharmaceuticals, Ipsen and Herantis Pharma, outside the submitted work, and stock ownership: TILT Biotherapeutics and Terveystalo. At the time of the study PB was employed by Helsinki University Hospital. CM reports consultant/advisory fees from Amgen, Astellas, Astra Zeneca, Bayer, BeiGene, BMS, Celgene, Debiopharm, Genentech, Ipsen, Janssen, Lilly, MedImmune, MSD, Novartis, Pfizer, Roche, Sanofi, Orion, outside the submitted work, he is also principal/sub-Investigator of clinical trials for Abbvie, Aduro, Agios, Amgen, Argen-x, Astex, AstraZeneca, Aveo pharmaceuticals, Bayer, Beigene, Blueprint, BMS, Boeringer Ingelheim, Celgene, Chugai, Clovis, Daiichi Sankyo, Debiopharm, Eisai, Eos, Exelixis, Forma, Gamamabs, Genentech, Gortec, GSK, H3 biomedecine, Incyte, Innate Pharma, Janssen, Kura Oncology, Kyowa, Lilly, Loxo, Lysarc, Lytix Biopharma, Medimmune, Menarini, Merus, MSD, Nanobiotix, Nektar Therapeutics, Novartis, Octimet, Oncoethix, Oncopeptides AB, Orion, Pfizer, Pharmamar, Pierre Fabre, Roche, Sanofi, Servier, Sierra Oncology, Taiho, Takeda, Tesaro, Xencor. KJP reports personal fees from MSD, BMS, Roche Pfizer, Varian and Ipsen, outside the submitted work, and stock ownership: Faron Pharmaceuticals. At the time of the study KJP was employed part time (6 months) by Orion Pharma. AA reports personal fees from Orion Pharma and Amcure, outside the submitted work. AI reports research grants and personal fees from Ipsen, Novartis, Bayer, Bristol-Myers Squibb, Epizyme, Immune Design, Daiichi Sankyo and MSD outside the submitted work. GC reports personal fees from Roche, Seattle Genetics, Daichii Sankyo, AstraZeneca and Lilly, and other from Roche and Pfizer outside the submitted work. UL reports personal fee from Bayer and Pfizer outside the submitted work, and research grants from Roche, BMS, Pfizer and GSK. H-TA is an employee of HCAHealthcare UK/Sarah Cannon and reports receiving speaker bureau honoraria from Pierre Fabre, Guardant, BeiGene, and Roche outside the submitted work. PH, CG, TI and MVJM were employed by Orion. JAR reports personal fees and other from Novartis, Kelun Pharmaceuticals/Klus Pharma, Spectrum Pharmaceuticals Inc., Pfizer and Bayer, personal fees from Eli Lilly, Orion Pharmaceuticals, Peptomyc, Roche Pharmceuticals, Ellipses Pharma, Certera, and Ionctura SA, and other from European Journal of Cancer, VHIO/ Ministero De Empleo Y Seguridad Social, Chinese University of Hong Kong, SOLTI, Elsevier, GlaxoSmithKline, ESMO, Department of Defense, Merck Sharp & Dohme, Lousiania State University, Huntsman Cancer Institute, Cancer Core Europe, Karolinska Cancer Institute, King Abdullah International Medical Research Center, WIN Consortium, Janssen, Tocagen, Symphogen, BioAlta, GenMab, CytomX, Kelun-Biotech, Takea-Millenium, and Ipsen outside the submitted work.

© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.

Figures

Figure 1

ODM-203 exposure versus total bilirubin.

Figure 2

The average (±SEM) plasma concentrations of ODM-203 after single (A) and repeated (B) dosing of ODM-203 tablet formulation (once daily dosing). Solid line at 2500 ng/mL represents the anticipated lower limit for target concentration range. SEM, Standard error of the mean.

Figure 3

ODM-203 best tumour response (RECIST) for FGFR patients (A) and non-FGFR patients (B). ITT 76 patients, 4 patients with low exposure (100–200 mg) and one patient with non-evaluable non-target lesions (600 mg) are not included. Unscheduled visits are included in the data. Transcript of abbreviations: CUP, cancer of unknown primary; FGFR, fibroblast growth factor receptor; GIST, gastrointestinal stromal tumour; H&N, head and neck; mBC, metastatic breast cancer; mCRC, metastatic colorectal cancer; mHCC, metastatic hepatocellular carcinoma; NSCLC, non-small cell lung cancer; RECIST, Response Evaluation Criteria in Solid Tumours; SCC, squamous cell carcinoma; STS, soft-tissue sarcoma.