994 / 1266
Phase I/II: Study Design
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
Declaration
of MTD
Safety expansion
(n = 12)
Once-daily LDE225 at declared
MTD
Primary endpoint
– ORR (regardless of Hh pathway status)
Secondary endpoints
– ORR and duration of response as a function of Hh pathway status, safety, PK
Phase I
Pediatric patients with recurrent/refractory MB, rhabdomyosarcoma, neuroblastoma,
hepatoblastoma, high-grade glioma, or osteosarcoma
Phase II
Pediatric patients with recurrent or refractory MB
Recommended Dose LDE225
Pediatric MB patients (n = 30)
Primary endpoint
– MTD, DLTs
Secondary endpoints
– Safety, PK, ORR, PD/biomarkers (validation of Hh gene expression signature)
DLT, dose-limiting toxicity; Hh, hedgehog; MB, medulloblastoma; MTD, maximum tolerated dose; ORR, overall response rate; PD, pharmacodynamics; PK,
pharmacokinetics; PR, partial response