Brain Tumours

Phase I/II: Study Design

Phase I  Pediatric patients with recurrent/refractory MB, rhabdomyosarcoma, neuroblastoma, hepatoblastoma, high-grade glioma, or osteosarcoma

Dose escalation Oral, once-daily LDE225 in 28-day cycle Starting dose = 372 mg/m 2 Bayesian logistic regression model using overdose control* DLT evaluation at 6 weeks MB enrichment Enrollment to previously tested lower dose levels

Safety expansion (n = 12) Once-daily LDE225 at declared MTD

Declaration of MTD

Primary endpoint – MTD, DLTs Secondary endpoints – Safety, PK, ORR, PD/biomarkers (validation of Hh gene expression signature)

Phase II  Pediatric patients with recurrent or refractory MB Recommended Dose LDE225 Pediatric MB patients (n = 30)

Primary endpoint – ORR (regardless of Hh pathway status) Secondary endpoints – ORR and duration of response as a function of Hh pathway status, safety, PK

DLT, dose-limiting toxicity; Hh, hedgehog; MB, medulloblastoma; MTD, maximum tolerated dose; ORR, overall response rate; PD, pharmacodynamics; PK, pharmacokinetics; PR, partial response