Phase II Study of Vorinostat (SAHA) in Combination With Bortezomib (PS-341) in Patients With Recurrent Glioblastoma Multiforme
Overview
- Phase
- Phase 2
- Intervention
- vorinostat
- Conditions
- Adult Giant Cell Glioblastoma
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 44
- Locations
- 213
- Primary Endpoint
- Progression-free Survival at 6 Months
- Status
- Completed
- Last Updated
- 11 years ago
Overview
Brief Summary
This phase II trial is studying how well giving vorinostat together with bortezomib works in treating patients with progressive, recurrent glioblastoma multiforme. Vorinostat and bortezomib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving vorinostat together with bortezomib may kill more tumor cells.
Detailed Description
PRIMARY OBJECTIVES: I. To determine the clinical efficacy of vorinostat (SAHA) and bortezomib, in terms of progression-free survival (PFS) at 6 months, in patients with progressive, recurrent glioblastoma multiforme. SECONDARY OBJECTIVES: I. To determine the clinical efficacy of this regimen, in terms of overall survival, PFS at 12 months, time to progression, and objective response rate, in these patients. II. To identify molecular predictors of response in baseline tumor specimens from these patients. III. To determine molecular changes in response to this regimen in tumor specimens from patients undergoing surgery. OUTLINE: This is a multicenter study. Patients are stratified according to planned surgery (no \[stratum 1\] vs yes \[stratum 2\]). STRATUM 1 (NOT UNDERGOING SURGERY): Patients receive oral vorinostat (SAHA) once daily on days 1-14 and bortezomib intravenously (IV) on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. STRATUM 2 (UNDERGOING SURGERY): Patients receive oral SAHA once daily for 2 days prior to surgery and then on the day of surgery. Patients also receive bortezomib IV on the day of surgery. After receiving the 3rd dose of SAHA, patients undergo surgery to remove the tumor. Beginning at least 7 days after surgery, patients receive SAHA and bortezomib as in stratum 1. Tumor tissue samples are collected at baseline and during surgery (stratum 2) for correlative laboratory studies. Tissue samples are analyzed for baseline total and phosphorylated AKT and p27\^KIp1 expression by IHC. Tissue samples from patients in stratum 2 are also analyzed for histone acetylation status; markers of proteasome inhibition; total and phosphorylated Bax expression by IHC; and gene expression profiles. After completion of study therapy, patients are followed every 3 months for 2 years and then every 6 months thereafter.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Histologically confirmed glioblastoma multiforme
- •Gliosarcoma or other grade 4 astrocytoma variant (e.g., giant cell glioblastoma) allowed
- •Recurrent disease
- •Must have evidence of tumor progression by MRI or CT scan after radiotherapy or after the most recent antitumor therapy
- •Bidimensionally measurable or evaluable disease by MRI or CT scan
- •Patients receiving corticosteroids must be on a fixed dose for at least 1 week prior to baseline scan
- •ECOG performance status 0-2
- •WBC ≥ 3,000/mm³
- •ANC ≥ 1,500/mm³
- •Platelet count ≥ 100,000/mm³
Exclusion Criteria
- Not provided
Arms & Interventions
Stratum 1 (not undergoing surgery)
Patients receive oral vorinostat (SAHA) once daily on days 1-14 and bortezomib IV on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: vorinostat
Stratum 1 (not undergoing surgery)
Patients receive oral vorinostat (SAHA) once daily on days 1-14 and bortezomib IV on days 1, 4, 8, and 11. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Intervention: bortezomib
Stratum 2 (undergoing surgery)
Patients receive oral SAHA once daily for 2 days prior to surgery and then on the day of surgery. Patients also receive bortezomib IV on the day of surgery. After receiving the 3rd dose of SAHA, patients undergo surgery to remove the tumor. Beginning at least 7 days after surgery, patients receive SAHA and bortezomib as in stratum 1.
Intervention: vorinostat
Stratum 2 (undergoing surgery)
Patients receive oral SAHA once daily for 2 days prior to surgery and then on the day of surgery. Patients also receive bortezomib IV on the day of surgery. After receiving the 3rd dose of SAHA, patients undergo surgery to remove the tumor. Beginning at least 7 days after surgery, patients receive SAHA and bortezomib as in stratum 1.
Intervention: therapeutic conventional surgery
Stratum 2 (undergoing surgery)
Patients receive oral SAHA once daily for 2 days prior to surgery and then on the day of surgery. Patients also receive bortezomib IV on the day of surgery. After receiving the 3rd dose of SAHA, patients undergo surgery to remove the tumor. Beginning at least 7 days after surgery, patients receive SAHA and bortezomib as in stratum 1.
Intervention: bortezomib
Outcomes
Primary Outcomes
Progression-free Survival at 6 Months
Time Frame: At 6 months
Estimated using the Binomial point estimator (number of successes divided by the total number of evaluable patients). A patient is classified as a success if alive and progression-free at 6 months. For patients with bidimensionally measurable disease (measurable disease), progression is defined as \> 25% increase in product of perpendicular diameters of contrast enhancement or mass or appearance of new lesions. For patients without bidimensionally measurable disease (evaluable disease), progression is defined as unequivocal increase in size of contrast enhancement or increase in mass effect as agreed upon independently by primary physician and quality control physicians or appearance of new lesions.
Secondary Outcomes
- Overall Survival(From study registration to date of death due to any cause or last follow-up (up to 5 years))
- Time to Progression(From study registration to date of progression (up to 5 years))
- Proportion of Confirmed Tumor Response Defined as an Objective Status of Confirmed Response (CR), Partial Response (PR), or Regression (REGR) on Two Consecutive Evaluations(Assessed up to 5 years)