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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

Phase 1
3 Years
21 Years
Open (Enrolling)
Recurrent Childhood Medulloblastoma

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Trial Information

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


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


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.

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

- 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

- 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

- 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

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Mean steady-state total (protein bound and non-protein bound) GDC-0449 plasma concentrations (Css)

Outcome Description:

95% confidence interval estimates for 2 doses compared.

Outcome Time Frame:

21 days

Safety Issue:


Principal Investigator

Amar Gajjar

Investigator Role:

Principal Investigator

Investigator Affiliation:

Pediatric Brain Tumor Consortium


United States: Food and Drug Administration

Study ID:




Start Date:

January 2009

Completion Date:

Related Keywords:

  • Recurrent Childhood Medulloblastoma
  • Medulloblastoma



Duke University Medical Center Durham, North Carolina  27710
Pediatric Brain Tumor Consortium Memphis, Tennessee  38105