A Phase I Pharmacokinetic and Safety Study in Children With Recurrent or Refractory Medulloblastoma to Identify a Pharmacokinetic Based Dose for GDC-0449
I. To investigate the safety and pharmacokinetics of a daily dose of hedgehog antagonist
GDC-0449 using the available formulation in pediatric patients with recurrent or refractory
I. To document and describe toxicities associated with this drug in these patients.
II. To characterize the pharmacokinetics of this drug in these patients. III. To document
preliminary antitumor activity of this drug in these patients. IV. To document pathologic
and genomic methods to identify CNS tumors with activation of the PTCH/SHH pathway.
OUTLINE: This is a multicenter study.
Patients receive oral hedgehog antagonist GDC-0449 once daily on days 1 and 4-28 in course 1
and on days 1-28 in all subsequent courses. Treatment repeats every 28 days for up to 26
courses in the absence of disease progression or unacceptable toxicity.
Blood samples are collected periodically for pharmacokinetic studies. Archival tumor tissue
samples are collected and analyzed for the expression of genes that activate the SHH (e.g.,
Gli1, Gli2, SFRP1, ATOH1, and PTCH2) or WNT (e.g., DKK2 and DKK4) cell signal pathways by in
situ hybridization and reverse transcriptase real time-PCR.
After completion of study therapy, patients are followed for 90 days.
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Mean steady-state total (protein bound and non-protein bound) GDC-0449 plasma concentrations (Css)
95% confidence interval estimates for 2 doses compared.
Pediatric Brain Tumor Consortium
United States: Food and Drug Administration
|Duke University Medical Center||Durham, North Carolina 27710|
|Pediatric Brain Tumor Consortium||Memphis, Tennessee 38105|