This phase I trial is studying the side effects and best dose of GDC-0449 in treating young patients with medulloblastoma that is recurrent or did not respond to previous treatment. GDC-0449 may be effective in treating young patients with medulloblastoma.
PRIMARY OBJECTIVE: 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 medulloblastoma. SECONDARY OBJECTIVES: 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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
34
UCSF-Mount Zion
San Francisco, California, United States
Children's National Medical Center
Washington D.C., District of Columbia, United States
Lurie Children's Hospital-Chicago
Chicago, Illinois, United States
Mean steady-state total (protein bound and non-protein bound) GDC-0449 plasma concentrations (Css)
95% confidence interval estimates for 2 doses compared.
Time frame: 21 days
Pharmacokinetics of GDC-0449, including the elimination rate constant and terminal half life
We will study two BSA defined strata.
Time frame: Up to 3 months after completion of study treatment
Tumor responses
Descriptive statistics will be provided describing tumor responses.
Time frame: Up to 30 days after completion of study treatment
Progression-free survival
Kaplan-Meier estimates of the distribution of progression-free survival (PFS) will be constructed.
Time frame: Up to 30 days after completion of study treatment
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Duke University Medical Center
Durham, North Carolina, United States
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States
Children's Hospital of Pittsburgh of UPMC
Pittsburgh, Pennsylvania, United States
Pediatric Brain Tumor Consortium
Memphis, Tennessee, United States
St. Jude Children's Research Hospital
Memphis, Tennessee, United States
Texas Children's Hospital
Houston, Texas, United States