Indication Title Glioblastome multiforme récidivant Protocol ID CL1-49076-002 Phase Phase I/II Sponsor SERVIER Principal Investigator Dr. A. Hottinger Primary Objective Phase I: dose-finding part Phase I/II study of S 49076, a multi-target inhibitor of c-MET, AXL, FGFR in combination with bevacizumab in patients with recurrent glioblastoma multiform   Determine the safety profile and tolerability of S 49076 given in combination with a fixed dose of bevacizumab in patients with recurrent GBM in term of Maximum Tolerated Dose and Dose Limiting Toxicities (DLT, assessed during cycle 1). Establish the Recommended Phase II dose (RPIID) of S 49076 given in combination with a fixed dose of bevacizumab. Phase II : efficacy part  Inclusion/exclusion criteria Determine the progression-free survival rate at 6 months in patients with recurrent GBM and treated with S 49076 and bevacizumab according to RANO criteria. Inclusion Criteria Demographic characteristics  Male or female patient aged 18 years old. Disease characteristics  Histologically confirmed diagnosis of glioblastoma multiform (WHO grade IV). Patients will be eligible if original histology was low-grade glioma and a subsequent diagnosis of glioblastoma was made.  Unequivocal evidence of first progression/recurrence after standard treatment with combined chemo-irradiation with temozolomide (including a possible combination of temozolomide with an investigational agent) performed by MRI within 2 weeks before the first test drug administration.  No more than one prior line of treatment.  Patients must have measurable tumour disease as defined by RANO.  Stable or decreasing dose of corticosteroids within 10 days prior to the first test drug administration.  Availability of formalin fixed paraffin embedded tumour tissue samples representative of glioblastoma at first diagnosis and if available at recurrence. Medical and therapeutic criteria  Ability to swallow oral capsules.  Ability to undergo brain MRI with intravenous gadolinium.  Estimated life expectancy > 12 weeks.  Karnofsky Performance Status ≥ 70%.  Adequate haematological, renal and hepatic functions within 7 days prior to the first test drug administration, defined as: o Absolute neutrophil count (ANC) ≥ 1.5 x 109/L. o Haemoglobin ≥ 9g/dL. o Platelets ≥ 100 x 109/L. o Creatinine clearance ≥ 60 mL/min (assessed with CockcroftGault formula). o ASAT and ALAT < 2.5 x local UNL. o Total bilirubin < 1.5 x local UNL (except Gilbert disease confirmed by the UGT1A1 polymorphism analysis). o Kaliemia within the local normal range (with or without potassium supply). o Magnesemia within the local normal range (with or without magnesium supply). o Urine dipstick test for proteinuria < 2+. Patients found with ≥ 2+ on dipstick proteinuria urinalysis at baseline should undergo 24 hours urine collection and demonstrate < 1g of protein/24 hours.  Coagulation parameters in normal limit: prothrombine ratio (PR) and activated partial thromboplastin time (aPTT), international normalized ratio (INR).  Patients must use effective contraception: o In case patient is a woman of childbearing potential: woman must have been tested negative in a serum pregnancy test within 7 days prior to the first day of test drug administration and must use highly effective methods of birth control defined as those alone or in combination that result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly such as implants, injectable, combined oral contraceptives, some intra-uterine devices, sexual abstinence or vasectomized partner during the study, starting at least 1 month prior to the first test drug administration and lasting at least 6 months after the last dose of test drug. o In case patient is a man whose partner is a woman of childbearing potential: man must be either vasectomized or the partner must use highly effective methods of birth control defined as those alone or in combination that result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly, starting at least 1 month prior to the first test drug administration and lasting at least 6 months after the last dose of test drug for both sexes.  Obtained Informed consent Non-inclusion criteria General criteria  Foreseeable poor compliance to the study procedures.  Legally incapacitated person under guardianship or trusteeship.  Pregnant or breast-feeding women.  Involvement in another therapeutic interventional trial at the same time or within 3 weeks prior to the first day of test drug administration. Medical and therapeutic criteria  Major surgery (including craniotomy) within 4 weeks prior to the first day of test drug administration or minor surgical procedures (e.g core biopsy or fine needle aspiration) within 14 days.  Chemotherapy within 4 weeks (6 weeks for nitroso-ureas) prior to the first day of test drug administration.  Any other prior therapy involving an agent for treating GBM (including investigational drugs, biologic/targeted therapy or immunologic agents) within less than 5 times of the halflife of said agent or within 3 weeks (whichever is the shorter), prior to the first day of test drug administration.  Radiotherapy within 3 months prior the diagnosis of progression.  Prior treatment with bevacizumab or other VEGF-receptor targeted agent.  Prior treatment with a PI3K inhibitor, HGF or Met pathways for phase II part.  Prior treatment with carmustine wafer.  Patients who are receiving concurrent valproic acid or EnzymeInducing Anti-Epileptics Drugs (EIAEDs) (e.g., carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, primidone and midazolam or who received EIAEDs within 2 weeks, 5 days for valproic acid prior to the first day of test drug administration.  Concomitant uncontrolled infection or severe systemic disease (at the discretion of the investigator).  Known organ dysfunction which would either compromise the patient’s safety or interfere with the evaluation of the test drug(s) safety.  In the investigator’s opinion, significant malabsorption syndrome, significant chronic digestive or gastrointestinal inflammatory syndrome, history of bleeding ulcer within 4 weeks prior to the first day of test drug administration.  Known coagulopathy that increases risk of bleeding or a history of clinically significant haemorrhages in the past.  Evidence of Central Nervous System (CNS) haemorrhage on the baseline MRI.  Deep venous/arterial thromboembolic complication or bleeding diathesis or any other hemorrhage/bleeding event CTCAE grade > 3 within 30 days prior the first day of test drug administration.  History of abdominal fistula, gastrointestinal perforation, or intraabdominal abscess within 6 months prior the first day of test drug administration.  History of non-healing wounds or ulcers, or bone fractures within 3 months of fracture.  Uncontrolled diabetes mellitus even under treatment.  Known positive test for HIV.  Impaired cardiac function, including any of the following :  o Uncontrolled high blood pressure even under treatment (SBP ≥ 150 or DBP ≥ 100 mm Hg). o Prior history of encephalopathy. o Within 6 months prior to the first day of test drug administration, history of: New York Heart Association (NYHA) grade 2 or greater congestive heart failure, acute coronary syndromes (including unstable angina), coronary angioplasty, and/or stenting, ischemic/haemorrhagic stroke, atrial fibrillation, myocardial infarction. o LVEF < 55% as assessed by echocardiogram or MUGA performed within 14 days of inclusion. o QTc prolongation (defined as a QTc interval > 450 ms according to Fridericia’s correction after central reading) or other significant ECG abnormalities including, atrial fibrillation, 2nd degree AV block type II, 3rd degree AV block, or bradycardia (HR < 50 bpm), or any history of 2nd or 3rd degree block, using the analysis of an ECG performed within 14 days of inclusion. o Patients who are receiving medications known to prolong QTc interval and that may be associated with Torsades de Pointes within 4 weeks prior to the first day of test drug administration. o Cardiac Troponin (cTn) I or T (if cTnI is not available) > 2 x local UNL. hypertension crisis or hypertensive Patients who are receiving anticoagulant oral drugs (Vitamin K antagonist), aspirin > 325 mg/day, aspirin associated with clopidogrel, aspirin associated with prasugrel. Patients receiving rivaroxaban or dabigatran. Low-molecular-weight heparin as well as clopidogrel or prasugrel alone are permitted.