This randomized phase II trial is studying how well GDC-0449 works in treating patients with recurrent glioblastoma multiforme that can be removed by surgery. GDC-0449 may be effective in treating patients with glioblastoma multiforme.
PRIMARY OBJECTIVES: I. 6-month progression-free survival (PFS-6) measured from start of treatment following surgery. SECONDARY OBJECTIVES: I. Toxicity. (Clinical) II. Overall survival. (Clinical) III. Tumor response. Partial Response (PR) + Complete Response (CR): MacDonald criteria). (Clinical) Correlative Studies * Determination of in vivo drug effect in recurrent Glioblastoma Multiform (GBM). (Correlative studies) * Determination of in vitro drug effect on CD133+ glioma-derived neurospheres. (Correlative studies) * Determination of Sonic Hedgehog pathway activation in primary vs. recurrent GBM. (Correlative studies) TERTIARY OBJECTIVES: I. Correlate clinical outcome (6 mo PFS) with biologic correlates (1-3) above. OUTLINE: This is a multicenter study. Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive oral Hedgehog antagonist GDC-0449 once daily for 7 days before surgery. Arm II: Patients do not receive treatment before surgery. Beginning within 28 days after surgical resection, all patients receive oral Hedgehog antagonist GDC-0449 once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Fresh and paraffin-embedded tissue samples are collected for correlative laboratory studies. After completion of study treatment, patients are followed up every 2 months.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
44
Given orally
undergo surgery
correlative studies
University of California at Los Angeles
Los Angeles, California, United States
University of California San Francisco
San Francisco, California, United States
Emory University/Winship Cancer Institute
Atlanta, Georgia, United States
6 Months Progression-free Survival (PFS)
Estimated using Kaplan Meier curves. six months calculated from date of treatment onset post-operatively. MRI scan at 6 months must be free of progression Progressive disease Progressive neurological abnormalities not explained by other causes or greater than 25% increase in size of tumor or if new lesion.
Time frame: 6 months
Overall Survival Time
The overall failure rate will be estimated along with 95% confidence intervals. A median time of survival will be estimated using standard methods.. Start date based on onset of treatment.
Time frame: 3 years
Best Tumor Response Assessed by the Modified Macdonald Radiographic Response Criteria
The Macdonald criteria, roughly similarly to other systems, divides response into 4 types of response based on imaging (MRI) and clinical features 1: complete response; 2: partial response; 3:stable disease; 4:progression Complete response imaging features: disappearance of all enhancing disease (measurable and non-measurable) sustained for at least 4 weeks; no new lesions clinical features; no corticosteroids; clinically stable or improved Partial response imaging features: 50% or more decrease of all measurable enhancing lesions sustained for at least 4 weeks: no new lesions clinical features: stable or reduced corticosteroids; clinically stable or improved Stable disease imaging features: does not qualify for complete response, partial response or progression clinical features: clinically stable Progression imaging features: 25% of more increase in enhancing lesions; any new lesions clinical features: clinical deterioration
Time frame: evaluated every 8 weeks - 1 year
Toxicity Incidence Grade 3 or 4 According to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0
NCI CTCAE grade 3 or 4 possible, probable or definitely related events Grade 3 - severe Grade 4 - life threatening
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correlative studies
Dana-Farber Cancer Institute
Boston, Massachusetts, United States
Henry Ford Hospital
Detroit, Michigan, United States
Wake Forest University Health Sciences
Winston-Salem, North Carolina, United States
University Hospitals Case Medical Center
Cleveland, Ohio, United States
Cleveland Clinic Foundation
Cleveland, Ohio, United States
University of Pennsylvania/Abramson Cancer Center
Philadelphia, Pennsylvania, United States
Time frame: 30 days from last dose of drug treatment - 1.5 years
Incidence of CD133+ Neurospheres by Arm
number of tumor-derived CD133 neurospheres undergoing proliferation and self-renewal
Time frame: 12 hours post-vismodegib administration
Changes in Sonic Hedgehog Pathway Activation
determined by Reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC) (Gli-1, Gli-2, PATCH (PTCH-1b)
Time frame: Pre-tumor resection and post tumor resection (12 hours)
Determine Drug Effect (Pharmacokinetics) in Plasma for Arm 1
samples collected pre tumor resection (day of surgery) and post-tumor resection (day of surgery
Time frame: Day of surgery