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GDC-0449 in Treating Young Patients With Medulloblastoma That is Recurrent or Did Not Respond to Previous Treatment

A Phase I Pharmacokinetic and Safety Study in Children With Recurrent or Refractory Medulloblastoma to Identify a Pharmacokinetic Based Dose for GDC-0449

Status
Completed
Phases
Phase 1
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT00822458
Enrollment
34
Registered
2009-01-14
Start date
2009-01-31
Completion date
Unknown
Last updated
2014-04-02

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Recurrent Childhood Medulloblastoma

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.

Interventions

DRUGvismodegib

Given orally

OTHERlaboratory biomarker analysis
OTHERpharmacological study

Sponsors

National Cancer Institute (NCI)
Lead SponsorNIH

Study design

Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE

Eligibility

Sex/Gender
ALL
Age
3 Years to 21 Years
Healthy volunteers
No

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: * ≤ 0.8 mg/dL (for patients ≤ 5 years of age) * ≤ 1.0 mg/dL (for patients 6 to 10 years of age) * ≤ 1.2 mg/dL (for patients 11 to 15 years of age) * ≤ 1.5 mg/dL (for patients \> 15 years of age) * Total bilirubin ≤ 1.5 times upper limit of normal (ULN) for age * ALT/AST ≤ 2.5 times ULN for age * Serum albumin ≥ 2.5 g/dL * Not pregnant or nursing * Negative pregnancy test * Fertile female patients must use 2 effective methods of contraception during and for 12 months following study treatment * Fertile male patients must use effective barrier contraception during and for 12 months following study treatment * Body surface area \> 0.67 m\^2 and ≤ 2.5 m\^2 * Able to swallow capsules * No malabsorption syndrome or other condition that would interfere with enteral absorption * No history of congestive heart failure * No history of ventricular arrhythmia requiring medication * No uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, or hypokalemia, defined as less than the lower limit of normal despite adequate electrolyte supplementation * No clinically important history of liver disease, including viral hepatitis or cirrhosis * No concurrent clinically significant unrelated systemic illness (e.g., serious infection) or significant cardiac, pulmonary, hepatic, or other organ dysfunction that would compromise the patient's ability to tolerate study treatment or would likely interfere with study procedures or results * NOTE: \* In the absence of bone marrow involvement * Recovered from prior treatment-related toxicity * At least 3 months since prior craniospinal radiotherapy (at doses ≥ 23 Gy) * At least 8 weeks since prior local radiotherapy to primary tumor * At least 2 weeks since prior focal radiotherapy to symptomatic metastatic sites * More than 4 weeks since prior myelosuppressive chemotherapy or immunotherapy (6 weeks for nitrosoureas) * More than 1 week since prior colony-stimulating factors (e.g., filgrastim \[G-CSF\], sargramostim \[GM-CSF\], or erythropoietin) * No other concurrent anticancer or investigational drug therapy * Concurrent dexamethasone allowed provided dosage is stable or decreasing for ≥ 1 week prior to study entry

Design outcomes

Primary

MeasureTime frameDescription
Mean steady-state total (protein bound and non-protein bound) GDC-0449 plasma concentrations (Css)21 days95% confidence interval estimates for 2 doses compared.
Pharmacokinetics of GDC-0449, including the elimination rate constant and terminal half lifeUp to 3 months after completion of study treatmentWe will study two BSA defined strata.

Secondary

MeasureTime frameDescription
Tumor responsesUp to 30 days after completion of study treatmentDescriptive statistics will be provided describing tumor responses.
Progression-free survivalUp to 30 days after completion of study treatmentKaplan-Meier estimates of the distribution of progression-free survival (PFS) will be constructed.

Countries

United States

Outcome results

None listed

Source: ClinicalTrials.gov · Data processed: Feb 4, 2026