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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00641706
First received: March 21, 2008
Last updated: September 11, 2013
Last verified: September 2013
  Purpose

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


Condition Intervention Phase
Adult Giant Cell Glioblastoma
Adult Glioblastoma
Adult Gliosarcoma
Recurrent Adult Brain Tumor
Drug: vorinostat
Procedure: surgery
Drug: bortezomib
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase II Study of Vorinostat (SAHA) in Combination With Bortezomib (PS-341) in Patients With Recurrent Glioblastoma Multiforme

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Progression-free Survival at 6 Months [ Time Frame: At 6 months ] [ Designated as safety issue: No ]
    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 Outcome Measures:
  • Overall Survival [ Time Frame: From study registration to date of death due to any cause or last follow-up (up to 5 years) ] [ Designated as safety issue: No ]
    Estimated using Kaplan-Meier survival curve.

  • Time to Progression [ Time Frame: From study registration to date of progression (up to 5 years) ] [ Designated as safety issue: No ]
    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.

  • Proportion of Confirmed Tumor Response Defined as an Objective Status of Confirmed Response (CR), Partial Response (PR), or Regression (REGR) on Two Consecutive Evaluations [ Time Frame: Assessed up to 5 years ] [ Designated as safety issue: No ]

    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.



Enrollment: 45
Study Start Date: July 2008
Primary Completion Date: July 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm A (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.
Drug: vorinostat
Given orally
Other Names:
  • L-001079038
  • SAHA
  • suberoylanilide hydroxamic acid
  • Zolinza
Drug: bortezomib
Given IV
Other Names:
  • LDP 341
  • MLN341
  • VELCADE
Experimental: Arm B (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 Arm A.
Drug: vorinostat
Given orally
Other Names:
  • L-001079038
  • SAHA
  • suberoylanilide hydroxamic acid
  • Zolinza
Procedure: surgery
Patient undergoes therapeutic conventional surgery
Drug: bortezomib
Given IV
Other Names:
  • LDP 341
  • MLN341
  • VELCADE

Detailed Description:

Primary Outcome Measure:

  • Progression-free Survival at 6 Months

Secondary Outcome Measures:

  • Overall Survival
  • Time to Progression
  • Proportion of Confirmed Tumor Response Defined as an Objective Status of Confirmed Response (CR), Partial Response (PR), or Regression (REGR) on Two Consecutive Evaluations

Outline: This is a multicenter study. Patients are stratified according to planned surgery (no [stratum 1] vs yes [stratum 2]).

Arm A (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.

Arm B (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 Arm A.

Tumor tissue samples are collected at baseline and during surgery (Arm B) for correlative laboratory studies. Tissue samples are analyzed for baseline total and phosphorylated Protein Kinase B (AKT) and p27^Kip1 expression by immuno-histochemistry (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 until 5 years from registration.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically confirmed glioblastoma multiforme by central path review.
  • Evidence of tumor progression by MRI or CT scan following radiation therapy (RT) or following the most recent anti-tumor therapy.
  • Bidimensionally measurable or evaluable disease by MRI or CT scan.
  • ≥8 weeks since the completion of RT prior to registration.
  • ≥18 years of age.
  • Fixed (or no) dose of corticosteroids ≥1 week prior to baseline scan.
  • The following laboratory values obtained ≤14 days prior to registration:

    • white blood cell count (WBC) ≥3000/mm3
    • absolute neutrophil count (ANC) ≥1500/mm3
    • platelet count (PLT) ≥100,000/mm3
    • Hemoglobin (Hgb) ≥9 g/dL
    • Total bilirubin≤1.5 x upper normal limit (UNL)
    • serum glutamate oxaloacetate transaminase (SGOT) (aspartate aminotransferase (AST)) ≤3 x UNL
    • Creatinine ≤ UNL
  • Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, 1, or 2.
  • Willingness to discontinue taking during this study any of the following Category I medications that are generally accepted to have a risk of causing Torsades de Pointes:

    • 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
  • Willingness to provide mandatory correlative laboratory tissue samples.
  • Arm A (Patients NOT undergoing surgery): ≤1 chemotherapy regimen for progressive/recurrent disease. Arm B (Patients undergoing surgery at time of recurrence): Any number of chemotherapy regimens for progressive/recurrent disease. NOTE: Adjuvant chemotherapy for all groups is allowed and does not count toward the number of regimens for progressive/recurrent disease.
  • Negative pregnancy test done ≤7 days prior to registration, for women of childbearing potential only.
  • Willingness to return to a North Central Cancer Treatment Group institution for follow-up.

Exclusion Criteria:

  • Any of the following:

    • ≤6 weeks since last day of nitrosourea-based chemotherapy and/or
    • ≤4 weeks since last day of other chemotherapy prior to registration
    • ≤2 weeks since last day of small molecule cell cycle inhibitors prior to registration
    • ≤4 weeks since last day of Avastin®prior to registration
  • ≤6 weeks since prior stereotactic radiosurgery or interstitial brachytherapy prior to registration. EXCEPTION: Separate lesion on MRI which is not part of the previous treatment field.
  • Any of the following:

    • Pregnant women
    • Nursing women
    • Men or women of childbearing potential who are unwilling to employ adequate contraception during the study and for 6 months following the last dose of vorinostat
  • Known hypersensitivity to any of the components of vorinostat or bortezomib.
  • History of myocardial infarction or unstable angina ≤6 months prior to registration or congestive heart failure (CHF) requiring use of ongoing maintenance therapy, or history of life-threatening ventricular arrhythmias.
  • Uncontrolled intercurrent illness that would limit compliance with study requirements.
  • Other active malignancy ≤3 years prior to registration. EXCEPTIONS: Nonmelanotic skin cancer or carcinoma-in-situ of the cervix. NOTE: If there is a history of prior malignancy, they must not be receiving other specific treatment (other than hormonal therapy) for their cancer.
  • Co-morbid systemic illnesses or other severe concurrent disease which would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and adverse events.
  • Immunocompromised patients. NOTE: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial.
  • Use of valproic acid, another histone deacetylase inhibitor, for ≤7 days prior to registration.
  • Receiving enzyme-inducing antiepileptic drugs (EIACs) or any other potent cytochrome P450 3A4 (CYP3A4) inducer such as rifampin or St. John's wort.
  • ≥grade 2 peripheral neuropathy due to any cause or ≥grade 1 peripheral neuropathy with pain.
  • Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm.
  • Prior treatment with vorinostat or bortezomib.
  • Inability to take oral medications.
  • Congenital long QT syndrome.
  • Prolonged corrected QT interval (QTc) (>450 msec).
  • Any of the following Category I drugs that are generally accepted to have a risk of causing Torsades de Pointes ≤7 days prior to registration

    • 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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00641706

  Show 215 Study Locations
Sponsors and Collaborators
Investigators
Principal Investigator: Evanthia Galanis North Central Cancer Treatment Group
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00641706     History of Changes
Other Study ID Numbers: NCI-2009-00668, CDR0000590113, U10CA025224, N0779
Study First Received: March 21, 2008
Results First Received: March 6, 2013
Last Updated: September 11, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Brain Neoplasms
Glioblastoma
Gliosarcoma
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Neoplasms
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Vorinostat
Bortezomib
Histone Deacetylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Protease Inhibitors

ClinicalTrials.gov processed this record on April 17, 2014