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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Recurrent Childhood Medulloblastoma

Intervention / Treatment
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* Drug: vismodegib
* Other: laboratory biomarker analysis
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>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. | Drug: vismodegib<br>* Given orally<br>* Other names: Hedgehog antagonist GDC-0449;Other: laboratory biomarker analysis<br> <br> Other: pharmacological study<br> <br> * Other names: pharmacological studies;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean steady-state total (protein bound and non-protein bound) GDC-0449 plasma concentrations (Css) | 95% confidence interval estimates for 2 doses compared. | 21 days | 
| Pharmacokinetics of GDC-0449, including the elimination rate constant and terminal half life | We will study two BSA defined strata. | Up to 3 months after completion of study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor responses | Descriptive statistics will be provided describing tumor responses. | 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. | Up to 30 days after completion of study treatment |