A phase I pharmacokinetic trial of sonic hedgehog (SHH) antagonist GDC-0449 in pediatric patients with recurrent or refractory medulloblastoma: A Pediatric Brain Tumor Consortium study (PBTC 25).

CRA9501 Background:Aberrant signaling in SHH pathway is implicated in causing medulloblastoma in approximately 20% of children with this disease. GDC-0449 is an orally active agent that binds to the SMO receptor and prevents downstream signaling through GLI. Preclinical murine models predict efficacy of an SMO antagonist to treat tumors dependent on the SHH pathway. Adult studies have documented the efficacy of this compound against recurrent medulloblastoma and basal cell carcinoma. A phase I pharmacokinetic trial of GDC 0449 was conducted in children with recurrent or refractory medulloblastoma to select, based on safety and pharmacokinetics, one of two dosages to recommend for a pediatric phase II trial. We also used immunonistochemistry (IHC) and in situ hybridization (ISH) on paraffin-embedded tissue to determine which tumors belonged to the SHH subtype. Methods: GDC 0449 was administered once daily for 28 days dose levels of (1) 85 mg/m2/dose and (2) 170 mg/m2/dose. A course was defined as 28 days i...