Vorinostat, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme

Condition(s) targeted: Brain and Central Nervous System Tumors

Intervention: temozolomide (Drug); vorinostat (Drug); adjuvant therapy (Procedure); radiation therapy (Procedure)

Phase: Phase 1/Phase 2

Status: Not yet recruiting

Sponsored by: North Central Cancer Treatment Group

Official(s) and/or principal investigator(s):
Evanthia Galanis, MD, Study Chair, Affiliation: Mayo Clinic
Patrick Y. Wen, MD, Study Chair, Affiliation: Dana-Farber Cancer Institute

RATIONALE: Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving vorinostat together with temozolomide and radiation therapy may kill more tumor cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of vorinostat when given together with temozolomide and radiation therapy and to see how well they work in treating patients with newly diagnosed glioblastoma multiforme.

Official title: Phase I/II Study of Vorinostat (Suberoylanilide Hydroxamic Acid [SAHA]), Temozolomide, and Radiation Therapy in Patients With Newly Diagnosed Glioblastoma

Study design: Treatment

Primary outcome:

Maximum tolerated dose of vorinostat (Phase I)

Overall survival (Phase II)

Secondary outcome:

Toxicity (Phase I)

Time to tumor progression (Phase II)

Safety (Phase II)

Correlation of tumor molecular characteristics and expression profile with response, survival, and safety

Detailed description: OBJECTIVES:

Primary

- To determine the maximum tolerated dose of vorinostat when administered with

temozolomide and radiotherapy in patients with newly diagnosed glioblastoma multiforme. (Phase I)

- To determine the efficacy of this regimen, in terms of overall survival, in these

patients. (Phase II)

Secondary

- To determine the toxicity of this regimen in these patients. (Phase I)

- To determine progression-free survival of patients treated with this regimen. (Phase

II)

- To further evaluate the safety profile of this regimen in these patients. (Phase II)

Tertiary

- To correlate tumor molecular characteristics and expression profile with outcome.

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.

After completion of study treatment, patients are followed every 3 months for 2 years and then every 6 months for 13 years.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

DISEASE CHARACTERISTICS:

- 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

PATIENT CHARACTERISTICS:

- Karnofsky performance status 60-100%

- 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)

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- 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

- 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

- No concurrent treatment for another malignancy other than hormonal therapy

Clinical trial summary from the National Cancer Institute's PDQ® database

Starting date: September 2008
Last updated: October 22, 2008