PRIMARY OBJECTIVES:
I. To determine the maximum tolerated dose of vorinostat when administered with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma multiforme. (Phase I) II. To determine the efficacy of this regimen, in terms of overall survival, in these patients. (Phase II)
SECONDARY OBJECTIVES:
I. To determine the toxicity of this regimen in these patients. (Phase I) II. To determine progression-free survival of patients treated with this regimen. (Phase II) III. To further evaluate the safety profile of this regimen in these patients. (Phase II) IV. To determine the neurocognitive effects in these patients and correlate the results with outcome endpoints. (Phase II)
TERTIARY OBJECTIVES:
I. To correlate tumor molecular characteristics and expression profile with outcome.
II. To evaluate potential mechanisms of therapy resistance in tumor samples obtained at the time of tumor progression.
OUTLINE: This is a multicenter, phase I, dose-escalation study of vorinostat followed by a phase II study.
Patients undergo radiotherapy and receive oral vorinostat once daily on days 1-5, 8-12, 15-19, 22-26, 29-33, and 36-40. Patients also receive oral temozolomide once daily on days 1-42. Beginning 4-6 weeks later, patients receive oral vorinostat once daily on days 1-7 and 15-21 and oral temozolomide once daily on days 1-5. Treatment with vorinostat and temozolomide repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Patients enrolled in phase II and those who are treated at the maximum tolerated dose in phase I submit tumor tissue samples for correlative laboratory studies. Studies include assessment of histone acetylation status by immunohistochemistry; gene expression profiling; and assessment of MGMT methylation status by polymerase chain reaction. Patients enrolled in phase II and those who are treated at the maximum tolerated dose in phase I complete a neurocognitive assessment prior to, during, and after completion of study therapy. The assessment includes the Hopkins Verbal Learning Test (HVLT-R) (Revised), the Controlled Oral Word Association test from the Multilingual Aphasia Examination (COWA), the Trail Making Test A: Visual scanning speed, and the Trail Making Test B: Divided attention.
After completion of study treatment, patients are followed every 3 months for 2 years and then every 6 months for 1 year.
Inclusion Criteria:
- Histologically confirmed glioblastoma multiforme, including gliosarcoma or other grade 4 astrocytoma variant (e.g., giant cell glioblastoma)
- Bidimensionally measurable or evaluable disease by gadolinium MRI or contrast-enhanced CT scan
- Has undergone surgery for the brain tumor within the past 2-5 weeks
- Karnofsky performance status (PS) 60-100% or ECOG PS 0-2
- Life expectancy ≥ 12 weeks
- ANC ≥ 1,500/mm^3
- Platelet count ≥ 100,000/mm^3
- WBC ≥ 3,000/mm^3
- Hemoglobin ≥ 10.0 g/dL (transfusion allowed)
- Total bilirubin ≤ 2.0 times upper normal limit (ULN)
- AST ≤ 2.0 times ULN
- Creatinine ≤ 1.5 mg/dL
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception during and for 12 weeks after completion of study treatment
- No known hypersensitivity to any of the components of vorinostat or other drugs used in the study
- No other active malignancy within the past 3 years, except nonmelanotic skin cancer or carcinoma in situ of the cervix
- No uncontrolled infection
- Known HIV positivity allowed provided there is no clinical evidence of an immunocompromised state
- No co-morbid systemic illness or other concurrent severe illness that, in the opinion of the investigator, would preclude study participation
- No concurrent uncontrolled illness (e.g., ongoing or active infection or psychiatric illness/social situation) that would preclude study compliance
- No myocardial infarction or unstable angina within the past 6 months
- No congestive heart failure requiring ongoing maintenance therapy
- No life-threatening ventricular arrhythmias
- No congenital long QT syndrome
- No prolonged QTc interval (i.e., QTc > 450 msec)
- Able to take oral medications
- Willing to provide mandatory tissue samples for research studies (for patients treated at the maximum tolerated dose)
- Willing and able to complete neurocognitive assessments (patients enrolled in phase II and those who are treated at the maximum tolerated dose in phase I)
- No concurrent treatment for another malignancy other than hormonal therapy
- No prior cytotoxic, non-cytotoxic, or experimental drug therapy for the brain tumor
- No prior cranial radiotherapy
- No prior Gliadel wafers
- More than 7 days since prior and no concurrent Category I drugs that have a risk of causing torsades de pointes (e.g., 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, or lidoflazine)
- More than 2 weeks since prior and no concurrent valproic acid or other histone deacetylase inhibitors
- Concurrent corticosteroids allowed provided patient is on a fixed or decreasing dose for ≥ 5 days prior to study enrollment
- No other concurrent investigational agents for the brain tumor
- No other concurrent cytotoxic or non-cytotoxic drug therapy for the brain tumor
- No concurrent stereotactic radiosurgery or brachytherapy
- No concurrent antiretroviral therapy for HIV-positive patients
Last updated: 01/14/2013
NCT ID: NCT00731731
IRB Number:08-005172
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