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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00822458
Recruitment Status : Completed
First Posted : January 14, 2009
Last Update Posted : April 2, 2014
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE January 13, 2009
First Posted Date  ICMJE January 14, 2009
Last Update Posted Date April 2, 2014
Study Start Date  ICMJE January 2009
Actual Primary Completion Date September 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 3, 2013)
  • Mean steady-state total (protein bound and non-protein bound) GDC-0449 plasma concentrations (Css) [ Time Frame: 21 days ]
    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 ]
    We will study two BSA defined strata.
Original Primary Outcome Measures  ICMJE
 (submitted: January 13, 2009)
Selection of an appropriate phase II dose based on observed toxicity and pharmacokinetic parameters
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 3, 2013)
  • Tumor responses [ Time Frame: Up to 30 days after completion of study treatment ]
    Descriptive statistics will be provided describing tumor responses.
  • Progression-free survival [ Time Frame: Up to 30 days after completion of study treatment ]
    Kaplan-Meier estimates of the distribution of progression-free survival (PFS) will be constructed.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 13, 2009)
  • Tumor response
  • Progression-free survival
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE GDC-0449 in Treating Young Patients With Medulloblastoma That is Recurrent or Did Not Respond to Previous Treatment
Official Title  ICMJE A Phase I Pharmacokinetic and Safety Study in Children With Recurrent or Refractory Medulloblastoma to Identify a Pharmacokinetic Based Dose for GDC-0449
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Recurrent Childhood Medulloblastoma
Intervention  ICMJE
  • Drug: vismodegib
    Given orally
    Other Names:
    • Erivedge
    • GDC-0449
    • Hedgehog antagonist GDC-0449
  • Other: laboratory biomarker analysis
  • Other: pharmacological study
    Other Name: pharmacological studies
Study Arms  ICMJE 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
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 1, 2014)
34
Original Estimated Enrollment  ICMJE
 (submitted: January 13, 2009)
18
Study Completion Date  ICMJE Not Provided
Actual Primary Completion Date September 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 3 Years to 21 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00822458
Other Study ID Numbers  ICMJE NCI-2009-01180
NCI-2009-01180 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
CDR0000631677
PBTC-025 ( Other Identifier: Pediatric Brain Tumor Consortium )
PBTC-025 ( Other Identifier: CTEP )
U01CA081457 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Amar Gajjar Pediatric Brain Tumor Consortium
PRS Account National Cancer Institute (NCI)
Verification Date June 2013

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