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.,GDC 0449 was administered once daily for 28 days dose levels of (1) 85 mg/m/dose and (2) 170 mg/m/dose. A course was defined as 28 days in duration. PK analysis was performed during the first course and steady-state concentrations were obtained prior to each subsequent course (day 21). MRI scans of the knees were obtained at baseline and 3 mos to assess abnormalities in bone development.,To date 11 eligible patients have been enrolled on the trial (10 males, median age 11.6 years (range 4.4-20.9). All patients were fully evaluable for toxicity. 1 DLT, grade 3 gamma-Glutamyl transpeptidase, occurred in a patient enrolled at 170 mg/m/dose. There were no grade 4 toxicities. The median (range) steady-state day 21 concentration at 85 mg/m (n=5) is 10.15 μ M (9.10-18.99 μ M) and at 170 mg/m (n=2) is 14.50 μ M (14.43-14.57 μ M). The steady-state GDC-0449 clearance (n=7) is 0.86 (0.44 - 1.17 L/h/m). At steady state (day 21), the ratio of GDC-0449 CSF to plasma is 1.3%, which is an estimate of the CSF penetration of GDC-0449.,GDC 0449 is well-tolerated in children with recurrent or refractory medulloblastoma. The phase I study estimating the recommended phase II dose of GDC 0449 is ongoing; final results including medulloblastoma subgroup data will be presented. [Table: see text].