A MULTICENTRIC PHASE I STUDY OF SUNITINIB WITH CONCOMITANT RADIATION THERAPY IN INOPERABLE SARCOMAS (GIST EXCLUDED) M.P. SUNYACH, D. PEROL, N. PENEL, P. CASSIER, X. LIEM, S. DUSSART, C. CROPET, E. BLANC, G. KANTOR

Local control with exclusive radiotherapy (RT) in sarcoma is infrequent even with higher doses. Preclinical data suggest potential synergy of RT when combined with an angiogenesis inhibitor. Based on these findings, a dose-finding, dose escalation study to assess the safety and feasibility of continuous dosing of sunitinib (S) with concomitant RT in inoperable non-GIST sarcomas patients was thus initiated. Background

Methods A 3+3 dose escalation design of sunitinib combined with constant dose of RT: 3 to 6 patients were sequentially enrolled in 2 steps to receive 1 of 3 escalated doses of sunitinib Extension cohort: 12 additional patients at maximal tolerated dose (MTD)

Determination of the MTD Assessed by the incidence rate of dose-limiting toxicity (DLT) defined as: -Musculo-skeletal or cutaneous grade ≥ 3 toxicity in the radiation field: oat dose < 30 Gy oat dose 30 Gy without return to a grade ≤ 2 in ≤ 4 weeks, -Any grade ≥ 4 toxicity. and observed during 14 weeks from the start of S+RT. Main objective

Treatment Radiotherapy (RT)  60 Gy in 30 fractions (2 Gy x 5 fractions per week) Sunitinib (S)  Dose level 1 (DL1): 25 mg/day during the 6-week RT  Dose level 2 (DL2): 37.5 mg/day during the 6-week RT  Dose level 3 (DL3): 50 mg/day during the 6-week RT

Study population Main inclusion criteria o Inoperable locally advanced or recurrent tumor without previous RT o Age ≥ 18 years o PS ≤ 2 o Number of metastatic sites ≤ 2 o ALT and AST ≤ 2.5 x ULN o Serum creatinine ≤ 1.5 mg/dL or creatinine clearance ≥ 50 mL/min Exclusion criteria o Prior sunitinib treatment o Brain metastases o Uncontrolled hypertension

10 patients were enrolled between May 2011 and June 2013 Patients characteristics CharacteristicsN = 10 Age (median/range)59 / Female8 TypeOsteosarcoma Pleomorphic undifferentiated Spindle cell Liposarcoma Epithelioid Chordoma Irradiation fieldLimb Face Pelvis Pleura

Patients characteristics CharacteristicsN = 10 Previous chemotherapy5 Previous surgery4 Previous targeted therapy1 No previous treatment4 Local relapse or progression4 Metastases2

* with grade 3 dyspnea and lymphopenia resolved with antibiotic therapy. DLT Dose levelSunitinibNDLT DL125 mg3No DLT 9 # patients evaluable for DLT DL237.5 mg31 DLT: grade 4 thrombopenia* # 1 non-evaluable patient (early stop of sunitinib at DL1) 3No DLT DL350 mgNot tested

Other toxicities No toxicities requiring discontinuation of RT were reported: 60 Gy were delivered to all patients (except for the patient with DLT: 40 Gy). No toxicities requiring interruption of sunitinib (≥ 9 days, consecutive or not) were reported.  Interruption ≤ 8 days for 2 patients (1 at DL1 and 1 at DL2): grade 1 thrombopenia and grade 3 sunitinib cutaneous allergy outside the irradiation field  Permanent discontinuation of sunitinib for 1 patient at DL1 (grade 2 hypertension – non compliance with antihypertensive therapy) = patient considered non-evaluable for DLT

Based on: Occurrence of grade 3 events at DL2 (4/6 patients) DL3 (sunitinib 50 mg/day during 6 weeks) higher than standard dose  Stop of dose escalation / formal MTD not reached  Extension cohort at DL2 Decision of independant Data Safety Monitoring Board – Sept 2013

Local progression within 12 months from inclusion: 3 patients  2 to 8 months Local control at the end of follow-up (12 months): 6 patients (5 at DL2)  1 complete response (CR) after surgery (inoperable patient at inclusion) – patient at DL1  Partial response: 2 patients  Stable disease: 2 patients  Suspicion of relapse at 12 months after CR: 1 patient (relapse (10 mm) confirmed at 15 months). 1 patient non evaluable for local control (early study withdrawal). Efficacy – Preliminary results

RT combined with sunitinib at 37.5 mg/day given continuously during 6-week radiotherapy appears safe and feasible. Enrolment of 12 additional patients at DL2 is ongoing to confirm these findings. Conclusions

Acknowledgements All patients who participated Investigators Lyon: M.P. Sunyach, J.Y. Blay, P. Cassier, P. Heudel Lille: N. Penel, X. Liem, A. Cordoba Largo, E. Lartigau Bordeaux: G. Kantor Villejuif: C. Le Péchoux, J. Domont, A. Le Cesne, O. Mir Marseille: F. Duffaud, D. Badinand, T. Duberge, T.K. Huynh, L. Padovani, S. Salas French Ministry of Health (PHRC) Pfizer for drug supply