This phase II trial studies how well vismodegib works in treating younger patients with recurrent or refractory medulloblastoma. Vismodegib may slow the growth of tumor cells.
PRIMARY OBJECTIVES: I. Estimate the efficacy of GDC-0449 (vismodegib) treatment for pediatric patients with recurrent or refractory medulloblastoma, as measured by the sustained objective response rates for patients without (stratum A) and with (stratum B) evidence of activation of Hedgehog (Hh) signaling pathway in their tumors. II. Characterize the pharmacokinetics (plasma) of GDC-0449 in children/adolescents with refractory medulloblastoma. III. To document pathologic and genomic methods to identify medulloblastomas with activation of the Hh signaling pathway. SECONDARY OBJECTIVES: I. Document and describe toxicities associated with GDC-0449 administered on a daily schedule. II. Estimate the duration of objective response and progression-free survival (PFS). III. Characterize the pharmacokinetics (cerebrospinal fluid) of GDC-0449 in children/adolescents with refractory medulloblastoma. OUTLINE: This is a multicenter study. Patients are stratified according to evidence of activation of Hedgehog signaling pathway in their tumors (without vs with vs unknown). Patients receive vismodegib orally (PO) once daily (QD) on days 1-28. Treatment repeats every 28 days for up to 26 courses in the absence of disease progression or unacceptable toxicity. Plasma and cerebrospinal fluid samples are collected periodically for pharmacokinetic and other correlative studies. After completion of study treatment, patients are followed up every other month for up to 12 months.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
12
Children's Hospital Los Angeles
Los Angeles, California, United States
Lucile Packard Children's Hospital Stanford University
Palo Alto, California, United States
Children's National Medical Center
Washington D.C., District of Columbia, United States
Objective Response (CR+PR) Sustained for ≥ 8 Weeks
Objective response is either a complete response or a partial response sustained for 8 weeks in a patient. The objective response rate will be reported separately for patients of each stratum. CR is complete disappearance of all enhancing tumor. PR is \>= 50% reduction in tumor size.
Time frame: Up to 12 months
Pharmacokinetics (Plasma) of GDC-0449
plasma GDC-0449 concentration of day 21 in first course
Time frame: up to 12 month
Progression-free Survival
Progression-free survival (PFS) is measured from the date of initial treatment with GDC-0449 until the earliest of progression or death on study. PFS is censored at the last tumor assessment date for patients without disease progression who have not died within 30 days of last exposure to study treatment. Kaplan-Meier method is used to estimate the progression-free survival.
Time frame: From start of treatment up to 2 years
Duration of Objective Response
The duration of objective response is measured from the initial scan documenting complete or partial response that was subsequently confirmed until the earlier of documented progression or death on study. Duration of objective response is censored at the last tumor assessment date for patients without disease progression who have not died within 30 days of last exposure to study treatment.
Time frame: From start of treatment up to 2 years
Pharmacokinetic Parameters of Vismodegib, CSF Penetration
The estimated median of cerebrospinal fluid (CSF) drug penetration is reported when expressed as an AUC ratio of CSF vismodegib to that of unbound drug in plasma.
Time frame: up to 12 month
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Lurie Children's Hospital-Chicago
Chicago, Illinois, United States
National Cancer Institute Pediatric Oncology Branch
Bethesda, Maryland, United States
Memorial Sloan-Kettering Cancer Center
New York, New York, United States
Duke University Medical Center
Durham, North Carolina, United States
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States
Children's Hospital of Pittsburgh of UPMC
Pittsburgh, Pennsylvania, United States
...and 2 more locations