Abstract C65: First-in-human Phase I dose-escalation study of a MET/AXL/FGFR inhibitor, S 49076, in patients with advanced solid tumors.
Authors: Hollebecque Antoine , Soria Jean-Charles , Bahleda Ratislav , Lopez-Busto Natividad , Jacquet-Bescond Anne , Burbridge Mike F. , Valérie Cattan , Pauly Jeanne , Herranz Maria , Azaro Analia , Depil Stéphane , Rodon Jordi 
Published: August 2014

Abstract
Background: S 49076 is a novel ATP-competitive tyrosine kinase inhibitor which displays a unique profile targeting MET, AXL and FGFR-1/2/3 (IC50 for inhibition of pathway activation was &lt;200nM) but not VEGFR-2. Considering the strong implication of these kinases in tumor progression and metastasis formation combined to the ability of S 49076 to inhibit known MET and FGFR mutated variants, efficacy is expected in treatment of patients (pts) with primary cancer and metastasis. Based on the non-clinical studies showing a favorable and novel pharmacological profile, an oral formulation of S 49076 is evaluated in a phase I dose-escalation study in pts with advanced solid tumors. This first-in-human study aims to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics (PK), pharmacodynamics (PD) and potential efficacy of S 49076.
Methods: Pts are enrolled on dose-escalation cohorts, using a “3+3” design. Two dosing regimens of S 49076 administration (once a day, QD, or twice a day, BID) are tested in this study, in which pts receive oral capsule(s) of S 49076 during a continuous 21-day cycle. The PK measurements are performed at D1 and at steady state. Tumor biopsies for genomic and proteomic analyses are taken predose and on treatment. Tumor response is measured once every 2 cycles.
Results: To date 49 pts have been treated at doses ranging from 15 to 270 mg QD or 7.5 to 225 mg BID. Median age is 59 years, and the most common tumor types are colorectal, NSCLC and uveal melanoma. The most frequent adverse events reported as treatment-related by the investigator have been hypomagnesemia, peripheral edema and hypoalbuminemia mostly grade (G) 1-2. Three DLTs were observed, including failure to restart S 49076 within 1 week due to G2 asymptomatic ejection fraction decrease in 30 mg QD and 225 mg BID cohorts and G3 hypotension in the 180 mg BID cohort. MTD has not been reached and the dose escalation is ongoing. Among 37 evaluable pts, 20 pts had stable disease (SD) ranging from 6 to 36 weeks of whom 3 pts with uveal melanoma had prolonged SD from 12 to 24 weeks. Preliminary PK analyses showed that the maximal plasma concentration (Cmax) occurred between 2h and 6h after oral administration. The bioavailability was estimated to be around 30% and the effective half-life around 15h. There was no evidence of non-linearity since Cmax and AUC24h increased proportionally over the range of doses tested and no evidence of time dependent PK. Based on PK data, the plasma concentrations reached in human at the higher doses are consistent with inhibition of the S 49076 targets MET, AXL and FGFR.
Conclusions: The general safety profile of oral treatment with S 49076 is good at the doses tested. PK data suggest dose proportionality in exposure without marked drug accumulation. S 49076 has demonstrated preliminary anti-tumor activity, especially in uveal melanoma.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C65.
Citation Format: Antoine Hollebecque, Jean-Charles Soria, Ratislav Bahleda, Natividad Lopez-Busto, Anne Jacquet-Bescond, Mike F. Burbridge, Cattan Valérie, Jeanne Pauly, Maria Herranz, Analia Azaro, Stéphane Depil, Jordi Rodon. First-in-human Phase I dose-escalation study of a MET/AXL/FGFR inhibitor, S 49076, in patients with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C65.