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

• ClinicalTrials.gov Identifier: NCT00822458
• Recruitment Status: Completed
• First Posted: January 14, 2009
• Last Update Posted: April 2, 2014
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Recurrent Childhood Medulloblastoma	Drug: vismodegib; Other: laboratory biomarker analysis; Other: pharmacological study	Phase 1

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 34 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I Pharmacokinetic and Safety Study in Children With Recurrent or Refractory Medulloblastoma to Identify a Pharmacokinetic Based Dose for GDC-0449
• Study Start Date: January 2009
• Actual Primary Completion Date: September 2013

Arms and Interventions

Arm

Intervention/treatment

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.

Drug: vismodegib; Given orally; Other Names: Erivedge; GDC-0449; Hedgehog antagonist GDC-0449; Other: laboratory biomarker analysis; Other: pharmacological study; Other Name: pharmacological studies

Outcome Measures

Primary Outcome Measures :

1. 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.
2. 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.

Secondary Outcome Measures :

1. Tumor responses [ Time Frame: Up to 30 days after completion of study treatment ]
   Descriptive statistics will be provided describing tumor responses.
2. 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.

Eligibility Criteria

• Ages Eligible for Study: 3 Years to 21 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, California

UCSF-Mount Zion

San Francisco, California, United States, 94115

United States, District of Columbia

Children's National Medical Center

Washington, District of Columbia, United States, 20010

United States, Illinois

Lurie Children's Hospital-Chicago

Chicago, Illinois, United States, 60614

United States, North Carolina

Duke University Medical Center

Durham, North Carolina, United States, 27710

United States, Pennsylvania

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States, 19104

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, United States, 15224

United States, Tennessee

Pediatric Brain Tumor Consortium

Memphis, Tennessee, United States, 38105

St. Jude Children's Research Hospital

Memphis, Tennessee, United States, 38105

United States, Texas

Texas Children's Hospital

Houston, Texas, United States, 77030

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Amar Gajjar; Pediatric Brain Tumor Consortium

More Information

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00822458
• Other Study ID Numbers: 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 )
• First Posted: January 14, 2009
• Last Update Posted: April 2, 2014
• Last Verified: June 2013

Additional relevant MeSH terms:

Medulloblastoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors, Primitive; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue