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

Recurrent Childhood Medulloblastoma Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00822458
• Other study ID #: NCI-2009-01180
• Secondary ID: NCI-2009-01180CD
• Status: Completed
• Phase: Phase 1
• First received: January 13, 2009
• Last updated: April 1, 2014
• Start date: January 2009

Study information

• Verified date: June 2013
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 34
• Est. primary completion date: September 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 3 Years to 21 Years

Eligibility

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 Design

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Medulloblastoma
• Recurrent Childhood Medulloblastoma

Intervention

Drug:
• vismodegib
Given orally

Other:
• laboratory biomarker analysis

• pharmacological study

Locations

Country	Name	City	State
United States	Lurie Children's Hospital-Chicago	Chicago	Illinois
United States	Duke University Medical Center	Durham	North Carolina
United States	Texas Children's Hospital	Houston	Texas
United States	Pediatric Brain Tumor Consortium	Memphis	Tennessee
United States	St. Jude Children's Research Hospital	Memphis	Tennessee
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	UCSF-Mount Zion	San Francisco	California
United States	Children's National Medical Center	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Primary	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	No
Secondary	Tumor responses	Descriptive statistics will be provided describing tumor responses.	Up to 30 days after completion of study treatment	No
Secondary	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	No