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.

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.

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