Phase II Study of BKM120 for Subjects With Recurrent Glioblastoma
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase II Study of BKM 120 for Patients With Recurrent Glioblastoma and Activated PI3K Pathway|
- Cohort I: To evaluate PI3K pathway modulation of BKM120 in tumor tissue. [ Time Frame: 1 year ] [ Designated as safety issue: No ]PI3-Kinase pathway modulation will be measured using immunohistochemistry analyses of unstained tumor tissue to identify PI3-Kinase mutations including PIK3CA mutations, PTEN mutations, and PTEN deletion by immunohistochemistry. Expression of pAKT will also be analyzed using immunohistochemistry.
- Cohort II: To investigate the treatment efficacy of BKM120 in participants with recurrent GBM as measured by 6-month progression-free survival [ Time Frame: 1 year ] [ Designated as safety issue: No ]Treatment efficacy will be based upon 6-month progression-free survival status. Progressive disease is defined using RANO (Response Assessment in Neuro-Oncology criteria.
- Cohort I: To evaluate BKM120 concentration in tumor tissue, plasma, and cerebrospinal fluid. [ Time Frame: 1 year ] [ Designated as safety issue: No ]Blood will be collected over various time points prior to surgery to determine individual pharmacokinetics. During surgery, tumor tissue, plasma, and cerebrospinal fluid will be collected simultaneously. Tumor and plasma concentrations of the drug will be measured by liquid chromatography with tandem mass spectrometry to derive a tumor/plasma ratio. Descriptive statistics (mean, SD, CV% or median (range)) will be performed on all plasma concentration-time data and derived PK parameters.
- Cohort I: To evaluate effects of BKM120 on tumor cell proliferation and tumor cell death [ Time Frame: 1 year ] [ Designated as safety issue: No ]Modulation in pAKT scoring as measured by reduction of staining intensity of one degree or more will be reported as consistent with a positive response to drug. In addition, participants will be independently scored as a positive response if a reduction in the percentage of pAKT positive cells within a tumor is greater than 50%, and therefore less likely due to normal geographic variation in positivity patterns. All pathway modulation scores will be correlated with effects on tumor growth by measuring Ki-67 (proliferation) and cleaved caspase 3 (CC3) (apoptosis/cell death).
- Cohort I: To investigate the safety profile of BKM120 in participants with recurrent GBM [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]To assess the probability of toxicity associated with the treatment, the proportion of subjects with different grades of toxicities will be analyzed in order to further expand the safety profile for BKM120.
- Cohort I: To investigate pharmacokinetics of BKM120 in this population [ Time Frame: 1 year ] [ Designated as safety issue: No ]Pharmacokinetic parameters of BKM120 will be determined, either using a two-stage compartmental analysis or using a non-linear mixed-effect approach. Pharmacokinetic parameters that will be derived include, but are not limited to oral drug clearance (CL/F), central and peripheral volume of distribution (V1 and V2) and absorption rate constant (Ka). Descriptive statistics (mean, SD, CV% or median (range)) will be performed on all plasma concentration-time data and derived PK parameters.
- Cohort II: To investigate the radiographic response to BKM120 [ Time Frame: 1 year ] [ Designated as safety issue: No ]Participants will be evaluated for radiographic response. Response rate will be the proportion of participants with measurable disease who experience complete or partial radiographic response determined by the RANO Criteria
- Cohort II: To investigate median progression free survival and overall survival of participants with recurrent GBM receiving treatment with BKM120 [ Time Frame: 1 year ] [ Designated as safety issue: No ]Median time to progression (defined using RANO criteria) and duration of survival will be measured in months for all enrolled cohort II participants.
|Study Start Date:||May 2011|
|Estimated Study Completion Date:||March 2016|
|Estimated Primary Completion Date:||November 2015 (Final data collection date for primary outcome measure)|
Experimental: Cohort I: Surgical subjects
Subjects scheduled for surgery
100 mg once daily, orally, for 28 daysProcedure: Surgery
Experimental: Cohort II: Non-surgical subjects
Subjects not candidates for surgery
100 mg once daily, orally, for 28 days
For patients who will be having surgery, BKM will be taken orally for 8-12 days prior to surgery. Prior to surgery they will have a FDG-PET scan and during surgery a sample of tumor will be taken for research. Patients will resume oral BKM120 between 14 and 35 days after surgery.
For patients who are not having surgery and post-surgery patients, BKM120 will be taken orally for 28 days (1 cycle). Patients will continue on BKM120 as long as their brain tumor does not get worse and they do not have severe or intolerable side effects.
While on study, patients will have routine blood tests, a physical examination, and questionnaires to assess mood (each cycle), as well as an assessment of tumor by MRI or CT (~ every 8 weeks), and research blood samples at various timepoints for genetic studies and other tests that will measure any additional effect of the study drug and disease status. Participants may also be required to undergo a electrocardiogram and/or MUGA scan to monitor heart function during the study.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01339052
|United States, California|
|University of California, Los Angeles|
|Los Angeles, California, United States, 90095|
|University of California, San Francisco|
|San Francisco, California, United States, 94143|
|United States, Massachusetts|
|Massachusetts General Hospital|
|Boston, Massachusetts, United States, 02114|
|Dana-Farber Cancer Institute|
|Boston, Massachusetts, United States, 02215|
|United States, New York|
|Memorial Sloan-Kettering Cancer Center|
|New York, New York, United States, 10065|
|United States, Texas|
|UT, MD Anderson Cancer Center|
|Houston, Texas, United States, 77030|
|United States, Utah|
|Huntsman Cancer Institute, University of Utah|
|Salt Lake City, Utah, United States, 84112|
|Principal Investigator:||Patrick Y Wen, MD||Dana-Farber Cancer Institute|