Background: There is no standard of care for the treatment of recurrent GBM (rGBM) and more effective treatments are clearly needed. S49076 is an orally bioavailable multikinase inhibitor of MET, AXL, FGFR1, 2, 3. The ability of S49076 to inhibit tumor growth in vivo was showed in a xenograft mouse model resistant to bevacizumab (BEV). Here, we report data from an ongoing Phase I study of S49076 in combination with BEV at first recurrence. Methods: Patients (pts) received escalating doses from 400 to 600 mg of S49076 orally, on a continuous once daily schedule of 28-day cycle, with BEV 10mg/kg on days 1 and 15. Primary objectives were to determine the Maximum Tolerated Dose (MTD), the Dose Limiting Toxicities (DLT) and to establish the Recommended Phase II Dose (RP2D) of S49076+BEV. Secondary objectives included pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity (assessed every each cycle using RANO criteria). Results: Thirteen rGBM pts were included. Overall 75% (9/12) were male, median age was 56 years (range 34-70), and median KPS was 90 (range 70-100). Three pts were respectively treated at the dose levels 400 mg and 500 mg and 6 patients at 600 mg (due to 1 DLT observed; G3 asymptomatic ejection fraction decrease). This dose level was considered as the RP2D. The reported adverse events (AE) related to S49076 were mainly of G1 or G2 (2 AE ≥ G3). No grade 5 S49076 and/or BEV related AE has been observed. Best responses for the 12 evaluable pts were: 4 partial responses (PR) confirmed and 2 unconfirmed, 5 stable disease (SD) including 2 SD ≥ 3 months, and 1 progressive disease. Similar S49076 PK profile in combination to BEV has been observed in the first-in-human study where S49076 was used in monotherapy. PD results showed high and moderate MET amplification assessed by FISH in 2 pts which were not predictive of clinical response. No expression of MET and AXL were observed by immunohistochemistry (IHC) in any of the pts. Conclusions: The combination of BEV and S49076 has been well tolerated at the dose levels tested. These preliminary data does not suggest an increase of activity by adding S49076 to BEV. Clinical trial information: 2013-003079-37.