A Phase I Pharmacokinetic and Safety Study in Children With Recurrent or Refractory Medulloblastoma to Identify a Pharmacokinetic Based Dose for GDC-0449
Overview
- Phase
- Phase 1
- Intervention
- vismodegib
- Conditions
- Recurrent Childhood Medulloblastoma
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 34
- Locations
- 9
- Primary Endpoint
- Mean steady-state total (protein bound and non-protein bound) GDC-0449 plasma concentrations (Css)
- Status
- Completed
- Last Updated
- 12 years ago
Overview
Brief Summary
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.
Detailed Description
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Histologically confirmed medulloblastoma, including posterior fossa primitive neuroectodermal tumor (PNET)
- •Recurrent, progressive, or refractory to standard therapy
- •No known curative therapy exists
- •Neurological deficits allowed provided they are stable for ≥ 1 week prior to study entry
- •No atypical teratoid/rhabdoid tumor or supratentorial PNET
- •Karnofsky performance status (PS) 60-100% (for patients \> 16 years of age) OR Lansky PS 60-100% (for patients ≤ 16 years of age)
- •ANC ≥ 1,000/μL\*
- •Platelet count ≥ 100,000/μL (transfusion independent)\*
- •Hemoglobin ≥ 8.0 g/dL (RBC transfusion allowed)\*
- •Creatinine clearance or radioisotope GFR ≥ 70 mL/min OR serum creatinine based on age as follows:
Exclusion Criteria
- Not provided
Arms & Interventions
Arm I
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.
Intervention: vismodegib
Arm I
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.
Intervention: laboratory biomarker analysis
Arm I
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.
Intervention: pharmacological study
Outcomes
Primary Outcomes
Mean steady-state total (protein bound and non-protein bound) GDC-0449 plasma concentrations (Css)
Time Frame: 21 days
95% confidence interval estimates for 2 doses compared.
Pharmacokinetics of GDC-0449, including the elimination rate constant and terminal half life
Time Frame: Up to 3 months after completion of study treatment
We will study two BSA defined strata.
Secondary Outcomes
- Tumor responses(Up to 30 days after completion of study treatment)
- Progression-free survival(Up to 30 days after completion of study treatment)