Phase 1 study of ODM-203, a selective dual FGFR/VEGFR inhibitor, in patients with advanced solid tumours

Abstract

Background: Inhibitors of fibroblast growth factor receptors (FGFR) are being developed for treatment of solid tumours with FGFR genetic alterations. ODM‐203 is a small molecule with balanced inhibitory effects on both FGFR 1‐4 and VEGFR 1‐3 subtypes. We present updated results from the first‐in‐man study. Methods: ODM‐203 was evaluated in an open 3 + 3 dose escalation design to identify the maximum tolerated dose (MTD), dosed daily in a 4 week cycle. Subsequent cohorts are evaluating the optimal dose and alternative dosing schedules. Pharmacokinetics and safety variables were closely monitored during the first 4 weeks with tumour response according to RECIST recorded every 8 weeks on treatment. Patients continued ODM‐203 treatment until disease progression or dose limiting toxicity (DLT). Results: 31 patients (median age 54, range 28‐80 years) with advanced solid tumours received ODM‐203 treatment in doses between 50‐800mg once/day during the dose escalation phase. Patients had various primary tumours, some having FGFR alterations. One cholangiocarcinoma patient with FGFR2 fusion has been treated for more than 1 year. One DLT (corneal keratopathy) was recorded at 800mg/day but MTD was not identified. A single grade 4 AE (lipase increase) was reported. Most AE's reported were grade 1‐2, the most common ones being increased bilirubin (61%), diarrhoea (36%), alopecia (29%), jaundice (26%), increased phosphate (26%), stomatitis (23%) and epistaxis (19%). Increased bilirubin was due to UGT1A1 inhibition by ODM‐203 and resolved in all cases upon dose reduction/interruption. Plasma ODM‐203 exposure was variable. There were 3 partial responses (RCC, ovarian and FGFR mutated salivary gland cancer) and 5 further patients achieved target lesion reduction. In addition, 4 patients had disease stabilisation of at least 24wk. Further follow‐up and results of ongoing dose schedule evaluation will also be presented. Conclusions: In ODM‐203 treated patients there was preliminary evidence of promising anti‐tumour activity although FGFR‐aberrant tumours were not preselected. ODM‐203 elicited on‐target adverse effects in addition to bilirubin changes. An expansion study in patients with FGFR‐aberrant or VEGFR sensitive tumours is ongoing.