Vorinostat and Bortezomib in Treating Patients With Progressive, Recurrent Glioblastoma Multiforme

Study Overview
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Brief Summary
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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
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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.

Official Title
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Phase II Study of Vorinostat (SAHA) in Combination With Bortezomib (PS-341) in Patients With Recurrent Glioblastoma Multiforme

Conditions
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Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma, Recurrent Adult Brain Tumor

Intervention / Treatment
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* Drug: vorinostat
* Procedure: therapeutic conventional surgery
* Drug: bortezomib


Participation Criteria
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Eligibility Criteria
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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 Hemoglobin ≥ 9 g/dL Total bilirubin ≤ 1.5 times upper limit of normal (ULN) AST ≤ 3 times ULN Creatinine normal Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 6 months after the last dose of vorinostat Willing to provide mandatory correlative laboratory tissue samples Able to take oral medications No uncontrolled infection No known hypersensitivity to any of the components of vorinostat or bortezomib No myocardial infarction or unstable angina within the past 6 months No congestive heart failure requiring use of ongoing maintenance therapy or history of life-threatening ventricular arrhythmias No concurrent uncontrolled illness including, but not limited to, any of the following: Ongoing or active infection Psychiatric illness or social situation that would limit compliance with study requirements No other active malignancy within the past 3 years except nonmelanoma skin cancer or carcinoma in situ of the cervix No comorbid systemic illness or other severe concurrent disease that, in the judgment of the investigator, would preclude study entry or significantly interfere with proper assessment of safety and toxicity of the prescribed study regimens Not immunocompromised Patients known to be HIV positive are eligible provided there is no clinical evidence of an immunocompromised state No peripheral neuropathy ≥ grade 2 No peripheral neuropathy with pain ≥ grade 1 No congenital long QT syndrome No prolonged OTC interval (> 450 msec) No other concurrent anticancer therapy (other than hormonal therapy) At least 8 weeks since prior radiotherapy More than 6 weeks since prior stereotactic radiosurgery or interstitial brachytherapy, unless there is a separate lesion on MRI that is not part of the prior treatment field More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas) No more than 1 prior chemotherapy regimen* for progressive/recurrent disease (stratum 1) Patients in stratum 2 may have received any number of prior chemotherapy regimens* for progressive/recurrent disease More than 2 weeks since prior small molecule cell cycle inhibitors More than 7 days since prior valproic acid More than 7 days since prior category I drugs that are generally accepted to have a risk of causing Torsades de Pointes including: Quinidine, procainamide, disopyramide Amiodarone, sotalol, ibutilide, dofetilide Erythromycin, clarithromycin Chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide Cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin,lidoflazine More than 4 weeks since prior bevacizumab No prior treatment with vorinostat or bortezomib No concurrent enzyme-inducing antiepileptic drugs (e.g., phenytoin,fosphenytoin, carbamazepine, phenobarbital, or primidone) No other concurrent potent CYP3A4 inducer (e.g., rifampin or St. John's wort) No other concurrent investigational therapy for the primary neoplasm

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stratum 1 (not undergoing surgery)<br>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. | Drug: vorinostat<br>* Given orally<br>* Other names: Zolinza;Drug: bortezomib<br>* Given IV<br>* Other names: VELCADE;|
| Experimental: Stratum 2 (undergoing surgery)<br>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. | Drug: vorinostat<br>* Given orally<br>* Other names: Zolinza;Procedure: therapeutic conventional surgery<br>* Patient undergoes surgery<br>Drug: bortezomib<br>* Given IV<br>* Other names: VELCADE;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival 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. | At 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Estimated using Kaplan-Meier survival curve. | From study registration to date of death due to any cause or last follow-up (up to 5 years) | 
| Time to Progression | Estimated using Kaplan-Meier survival curve. Patients who died were considered to have disease progression at the time of death unless there was documented evidence that no progression occurred before death. 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. | 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 | Confidence intervals for the true proportion will be calculated using the exact binomial method. Measurable patients must achieve at least a 50% reduction in the product of perpendicular diameters of contrast enhancement or mass with no new lesions with the patient being on stable or decreased steroid dose. Evaluable patients must achieve unequivocal reduction in size of contrast-enhancement or decrease in mass effect as agreed upon independently by primary physician and quality control physicians; no new lesions. Patient should be on stable or decreased steroid dose. | Assessed up to 5 years |