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

NCT ID: NCT00822458

Last Updated: 2014-04-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 34 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-01-31

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.

Conditions

Recurrent Childhood Medulloblastoma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

vismodegib

Intervention Type: DRUG

Given orally

laboratory biomarker analysis

Intervention Type: OTHER

pharmacological study

Intervention Type: OTHER

Interventions

vismodegib

Given orally

Intervention Type: DRUG

laboratory biomarker analysis

Intervention Type: OTHER

pharmacological study

Intervention Type: OTHER

Other Intervention Names

Erivedge; GDC-0449; Hedgehog antagonist GDC-0449; pharmacological studies

Eligibility Criteria

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

• Minimum Eligible Age: 3 Years
• Maximum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Amar Gajjar

Role: PRINCIPAL_INVESTIGATOR

Pediatric Brain Tumor Consortium

Locations

UCSF-Mount Zion

San Francisco, California, United States

Children's National Medical Center

Washington D.C., District of Columbia, United States

Lurie Children's Hospital-Chicago

Chicago, Illinois, United States

Duke University Medical Center

Durham, North Carolina, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, United States

Pediatric Brain Tumor Consortium

Memphis, Tennessee, United States

St. Jude Children's Research Hospital

Memphis, Tennessee, United States

Texas Children's Hospital

Houston, Texas, United States

Countries

United States

Other Identifiers

NCI-2009-01180

Identifier Type: REGISTRY

Identifier Source: secondary_id

CDR0000631677

Identifier Type: -

Identifier Source: secondary_id

PBTC-025

Identifier Type: OTHER

Identifier Source: secondary_id

PBTC-025

Identifier Type: OTHER

Identifier Source: secondary_id

U01CA081457

Identifier Type: NIH

Identifier Source: secondary_id

View Link

NCI-2009-01180

Identifier Type: -

Identifier Source: org_study_id