S 49076 is a novel oral inhibitor of MET, AXL and FGFR, three receptors which have been implicated in drug resistance following chemotherapy or various targeted therapies. S 49076 demonstrated to be effective in MET and FGFR-2 driven tumors in preclinical models. A Phase I open label multicenter study was undertaken to establish the recommended dose (RD) for further studies.
Patients (pts) with advanced solid tumors received S 49076 orally given once (QD) or twice (BID) daily during a continuous 21-day cycle at escalating doses guided by a standard 3 + 3 design and followed by an extension part. Pharmacokinetic (PK) parameters were assessed and pre- and post-treatment tumor biopsies were analyzed. Efficacy evaluation was performed as per RECIST 1.1 criteria.
As of July 2nd 2015, 100 pts (42% female, 58% male; median age of 60 years) have been treated. Doses from 15 mg to 900 mg were evaluated. Dose Limiting Toxicities (DLTs) were reported in 9 pts and occurred at 30, 760 and 900 mg in QD arm and at 180, 225, 285 mg in BID arm. The RD was defined at 600 mg QD. Adverse events (AEs) occurred with similar frequency for QD and BID dosing regimens at an equivalent total daily dose. Overall, 77 pts (77%) had drug-related AEs. Treatment related AEs occurring in >15% of pts were peripheral edema (30%), hypoalbuminemia (28%), yellow skin pigmentation (21%), dysaesthesia (21%) and asthenia (17%). The majority of these events were Grade 1-2 (NCI CTCAE v4.0) and did not lead to S 49076 discontinuation. At data cut-off, the mean duration of exposure was 10 weeks (range 0-91) with long-term stable disease > 6 months. To date, the expansion part is completed with 24 pts and 5 pts are still ongoing. PK data showed dose proportional increases in Cmax and AUC. Based on trough concentrations (Cmin) assessed at each cycle, no accumulation of S 49076 was found. Mean Cmax reached 1 ÂµM at the RD suggesting hitting of MET, AXL and FGFR according to PK/PD preclinical studies. Updated safety PK and efficacy data will be presented.
S 49076 demonstrated a good safety profile at the doses tested in monotherapy. Pharmacology and toxicity profiles of S 49076 warrant further investigations in combination therapies in solid tumors.
Clinical trial identification
EudraCT number: 2011-001127-20
S. Postel-Vinay, A. Hollebecque, J.-C. Soria, S. Balandraud, K. Brendel, V. Cattan, A. Jacquet-Bescond, N. Lopez Busto, S. Malasse, L. Marfai, J. Pauly, L. Prudkin, A. Azaro, J. Rodon: S49076 was discovered by SERVIER Study supported by SERVIER.