An international, randomized, open-label Phase I/II study of vismodegib in combination with temozolomide versus temozolomide alone in adult patients with recurrent or refractory medulloblastoma presenting an activation of the Sonic Hedgehog pathway

INTERVENTION: Product Name: GDC‐0449 Pharmaceutical Form: Capsule CONDITION: Recurrent, progressive or refractory medulloblastoma with activation of the SHH pathway ; MedDRA version: 14.1 Level: PT Classification code 10066594 Term: Medulloblastoma recurrent System Organ Class: 10029104 ‐ Neoplasms benign, malignant and unspecified (incl cysts and polyps) Therapeutic area: Diseases [C] ‐ Cancer [C04] PRIMARY OUTCOME: Main Objective: Phase I: to evaluate the safety of a fixed dose of vismodegib in combination with temozolomide in adult patients with recurrent, progressive, or refractory to standard therapy medulloblastoma.; ; Phase II: to estimate the efficacy of vismodegib in combination with concomitant temozolomide in adult patients with recurrent, progressive, or refractory to standard therapy medulloblastoma. Primary end point(s): Phase I: number of adverse events; Phase II: progression‐free rate Secondary Objective: Phase I:; ‐ to determine the pharmacokinetic profile of the vismodegib in combination with temozolomide; ‐ to collect preliminary results on 6‐month progression‐free rate of the combination vismodegib + temozolomide; ; Phase II: to estimate in the 2 study arms:; ‐ the objective tumor response rate (complete response + partial response + stable disease); ‐ the duration of treatment response; ‐ the best overall response obtained during the study; ‐ the progression‐free survival; ‐ the time to progression; In the combination arm: to further evaluate the safety of the combination. Timepoint(s) of evaluation of this end point: Phase I: 3 months; Phase II: 6 months SECONDARY OUTCOME: Secondary end point(s): ‐ objective response rate ; ‐ duration of treatment response ; ‐ best overall response ; ‐ progression‐free survival ; ‐ time to progression ; ‐ time to treatment failure Timepoint(s) of evaluation of this end point: ‐ progression‐free rate preliminary results: 6 months ; ‐ all the endpoints will be assessed 1 year after the last patient enrollment. INCLUSION CRITERIA: I1. Age = 18 years. I2. Patients must have histologically confirmed medulloblastoma (including posterior fossa primitive neuroectodermal tumor) for which no known curative therapy exists. I3. Patients must have recurrent or refractory disease I4. 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. I5. The activation of the SHH pathway must be validated by IHC before initiation of treatment. I6. ECOG performance status 0, 1 or 2 (Appendix 4). I7. Life expectancy = 12 weeks (as determined by treating physician). I8. Patients must have normal organ and marrow function as defined below: ? Neutrophils = 1. 5 G/L ? Platelets = 100 G /L (transfusion‐independent) ? Hemoglobin = 10g/dL (RBC transfusions allowed) ? Creatinine clearance = 50 mL/min (calculated by Cockcroft‐Gaul