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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00822458
First received: January 13, 2009
Last updated: April 1, 2014
Last verified: June 2013

January 13, 2009
April 1, 2014
January 2009
September 2013   (final data collection date for primary outcome measure)
  • Mean steady-state total (protein bound and non-protein bound) GDC-0449 plasma concentrations (Css) [ Time Frame: 21 days ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    We will study two BSA defined strata.
Selection of an appropriate phase II dose based on observed toxicity and pharmacokinetic parameters [ Designated as safety issue: Yes ]
Complete list of historical versions of study NCT00822458 on ClinicalTrials.gov Archive Site
  • Tumor responses [ Time Frame: Up to 30 days after completion of study treatment ] [ Designated as safety issue: No ]
    Descriptive statistics will be provided describing tumor responses.
  • Progression-free survival [ Time Frame: Up to 30 days after completion of study treatment ] [ Designated as safety issue: No ]
    Kaplan-Meier estimates of the distribution of progression-free survival (PFS) will be constructed.
  • Tumor response [ Designated as safety issue: No ]
  • Progression-free survival [ Designated as safety issue: No ]
Not Provided
Not Provided
 
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

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.

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.

Interventional
Phase 1
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Recurrent Childhood Medulloblastoma
  • Drug: vismodegib
    Given orally
    Other Names:
    • Erivedge
    • GDC-0449
    • Hedgehog antagonist GDC-0449
  • Other: laboratory biomarker analysis
  • Other: pharmacological study
    Other Name: pharmacological studies
Experimental: 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.

Interventions:
  • Drug: vismodegib
  • Other: laboratory biomarker analysis
  • Other: pharmacological study
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
34
Not Provided
September 2013   (final data collection date for primary outcome measure)

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
Both
3 Years to 21 Years
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00822458
NCI-2009-01180, NCI-2009-01180, CDR0000631677, PBTC-025, PBTC-025, U01CA081457
Not Provided
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Amar Gajjar Pediatric Brain Tumor Consortium
National Cancer Institute (NCI)
June 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP