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.

Study Overview

• Status: Completed
• Conditions: Recurrent Childhood Medulloblastoma
• Intervention / Treatment: Other: pharmacological study; Other: laboratory biomarker analysis; Drug: vismodegib

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: Interventional
• Enrollment (Actual): 34
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94115
      • UCSF-Mount Zion
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60614
      • Lurie Children's Hospital-Chicago
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh of UPMC
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • St. Jude Children's Research Hospital
    • Memphis, Tennessee, United States, 38105
      • Pediatric Brain Tumor Consortium
  • Texas
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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.

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean steady-state total (protein bound and non-protein bound) GDC-0449 plasma concentrations (Css)	95% confidence interval estimates for 2 doses compared.	21 days
Pharmacokinetics of GDC-0449, including the elimination rate constant and terminal half life	We will study two BSA defined strata.	Up to 3 months after completion of study treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tumor responses	Descriptive statistics will be provided describing tumor responses.	Up to 30 days after completion of study treatment
Progression-free survival	Kaplan-Meier estimates of the distribution of progression-free survival (PFS) will be constructed.	Up to 30 days after completion of study treatment

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)

Study record dates

Study Major Dates

• Study Start: January 1, 2009
• Primary Completion (Actual): September 1, 2013

Study Registration Dates

• First Submitted: January 13, 2009
• First Submitted That Met QC Criteria: January 13, 2009
• First Posted (Estimate): January 14, 2009

Study Record Updates

• Last Update Posted (Estimate): April 2, 2014
• Last Update Submitted That Met QC Criteria: April 1, 2014
• Last Verified: June 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Disease Attributes; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroectodermal Tumors, Primitive; Recurrence; Medulloblastoma
• Other Study ID Numbers: NCI-2009-01180 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); U01CA081457 (U.S. NIH Grant/Contract); CDR0000631677; PBTC-025 (Other Identifier: CTEP)