Study of Vismodegib in Combination With Temozolomide Versus Temozolomide Alone in Patients With Medulloblastomas With an Activation of the Sonic Hedgehog Pathway

Inclusion Criteria: * Age ≥ 18 years * Patients must have histologically confirmed medulloblastoma (including posterior fossa primitive neuroectodermal tumor) for which no known curative therapy exists * Patients must have recurrent or refractory disease * Patients must have evidence of measurable disease or lesion in pre-inclusion MRI. Patients with measurable spinal disease are eligible. NB: Patients with complete resection for recurrence are not eligible. * Activation of the SHH pathway validated by IHC. * ECOG performance status 0, 1 or 2 * Life expectancy ≥ 12 weeks * Patients must have normal organ and marrow function as defined below: Neutrophils ≥ 1. 5 G/L Platelets ≥ 100 G /L Hemoglobin ≥ 10g/dL Creatinine clearance ≥ 50 mL/min (calculated by Cockcroft-Gault formula or MDRD formula for patients older than 65 years ) or serum creatinine within normal limits or less than 1.5 x upper limit of normal (ULN) Total bilirubin ≤ 1.5 ULN ALAT and ASAT ≤ 2.5 ULN Serum albumin ≥ 25 g/L. * Patients recovered from prior treatment-related toxicity (persistent treatment related toxicity \<Grade 2 are allowed (NCI-CTCAE v4.0). * Prior therapy: No prior hedgehog antagonist vismodegib or other antagonists of the hedgehog pathway, and no prior temozolomide treatment for patients to be randomized in Arm A or B. Patients previously treated with temozolomide are eligible for enrollment in study arm C on a case by case basis and following sponsor agreement More than 4 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosoureas, 6 months after high dose therapy) or immunotherapy At least 3 months since prior craniospinal irradiation (≥ 23 Gy) At least 8 weeks since prior local irradiation to primary tumor At least 2 weeks since prior focal irradiation for symptomatic metastatic sites. At least 1 week since prior colony-stimulating factors (e.g., G-CSF, GM-CSF, or erythropoietin) * Women of childbearing potential\* are required to have a negative serum pregnancy test within 72 hours prior to study treatment initiation (i.e. Cycle 1 Day 1). \*: Female patients who meet at least one of the following criteria are defined as women of non-childbearing potential: ≥50 years old and naturally amenorrheic for ≥ 1 year Permanent premature ovarian failure confirmed by a specialist gynaecologist Previous bilateral salpingo-oophorectomy XY genotype, Turner's syndrome, or uterine agenesis Female patient who do not meet at least of the above criteria are defined as women of childbearing potential. * An embryo-fetal development study in rats has confirmed the teratogenic potential of vismodegib. Therefore, women of child-bearing potential and men must use two forms of effective contraception (including one barrier method- refer to Appendix 4 for acceptable method of contraception) at least 4 weeks prior to study entry, during the study period and for at least 24 months post-treatment for women and 2 months post-treatment for men. Prior to dispensing vismodegib, the investigator must confirm and document the patient's use of two contraceptive methods, dates of negative pregnancy test, and confirm the patient's understanding of the teratogenic potential of vismodegib. * Ability to understand and willingness to comply to follow-up visits. * Covered by a medical insurance (in countries where applicable) Exclusion Criteria: * Tumor tissue sample not available for biological studies (from the initial diagnosis and/or relapse) * Pregnant or breastfeeding women are not eligible. * History of allergic reactions attributed to compounds of similar chemical composition to vismodegib. * Any contraindications to temozolomide treatment as per Temodal® SPC (see Appendix 5). * Patients with malabsorption syndrome or other condition that would interfere with intestinal absorption. Patients must be able to swallow capsules. * Uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, or hypokalemia, defined as less than the lower limit of normal despite adequate electrolyte supplementation. * History of congestive heart failure. * History of ventricular arrhythmia requiring medication. * Congenital long QT syndrome. * Clinically significant unrelated systemic illness (e.g., serious infection or significant cardiac, pulmonary, hepatic, or other organ dysfunction) that would compromise the patient's ability to tolerate study treatment or would likely interfere with study procedures or results. * Patients using prohibited concomitant and/or concurrent medications (see section "Prohibited concomitant/concurrent treatments.)