Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Objectives

Primary

1. To determine the maximum-tolerated dose of vorinostat when administered with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma multiforme. (Phase I)
2. To determine the efficacy of this regimen, in terms of overall survival, in these patients. (Phase II)

Secondary

1. To determine the toxicity of this regimen in these patients. (Phase I)
2. To determine progression-free survival of patients treated with this regimen. (Phase II)
3. To further evaluate the safety profile of this regimen in these patients. (Phase II)
4. To determine the neurocognitive effects in these patients and correlate the results with outcome endpoints. (Phase II)

Tertiary

1. To correlate tumor molecular characteristics and expression profile with outcome. (exploratory)
2. To evaluate potential mechanisms of therapy resistance in tumor samples obtained at the time of tumor progression. (exploratory)

Entry 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

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 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
• No concurrent treatment for another malignancy other than hormonal therapy

Patient Characteristics:

• Karnofsky performance status (PS) 60-100% OR ECOG PS 0-2
• Life expectancy ≥ 12 weeks
• ANC ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• WBC ≥ 3,000/mm³
• 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)

Expected Enrollment

Outcomes

Maximum-tolerated dose of vorinostat (Phase I)
Overall survival (Phase II)

Toxicity (Phase I)
Time to tumor progression (Phase II)
Safety (Phase II)

Outline

This is a multicenter, phase I, dose-escalation study of vorinostat followed by a phase II study.

Patients undergo 3D-conformal or intensity-modulated radiotherapy daily, 5 days a week, for 6 weeks. Patients receive oral vorinostat once daily on days 1-5, 8-12, 15-19, 22-26, 29-33, and 36-40 and 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 up every 3 months for 2 years and then every 6 months for 1 year.

Trial Contact Information

Trial Lead Organizations

North Central Cancer Treatment Group

Evanthia Galanis, MD, Protocol chair		Ph: 507-284-3559

Adult Brain Tumor Consortium

Patrick Wen, MD, Protocol chair		Ph: 617-632-2166; 866-790-4500 Email: pwen@partners.org

U.S.A.
Arizona
	Scottsdale
	Mayo Clinic Scottsdale
		Clinical Trials Office - All Mayo Clinic Locations	Ph:  507-538-7623
California
	San Francisco
	UCSF Helen Diller Family Comprehensive Cancer Center
		Clinical Trials Office - UCSF Helen Diller Family Comprehensive Cancer Center	Ph:  877-827-3222
Florida
	Jacksonville
	Mayo Clinic - Jacksonville
		Clinical Trials Office - All Mayo Clinic Locations	Ph:  507-538-7623
Illinois
	Moline
	Trinity Cancer Center at Trinity Medical Center - 7th Street Campus
		Costas Constantinou, MD	Ph:  563-359-9876
Iowa
	Ames
	McFarland Clinic, PC
		Clinical Trials Office - McFarland Clinic, PC	Ph:  515-239-2621
	Clive
	Medical Oncology and Hematology Associates - West Des Moines
		Robert Behrens	Ph:  515-875-9713
	Mercy Cancer Center - West Lakes
		Robert Behrens	Ph:  515-643-8206 888-221-4849
	Des Moines
	CCOP - Iowa Oncology Research Association
		Robert Behrens	Ph:  515-244-7586 888-244-6061
	John Stoddard Cancer Center at Iowa Lutheran Hospital
		Clinical Trials Office - John Stoddard Cancer Center at Iowa Lutheran Hospital	Ph:  515-241-8704
	John Stoddard Cancer Center at Iowa Methodist Medical Center
		Clinical Trials Office - John Stoddard Cancer Center at Iowa Methodist Medical Center	Ph:  515-241-6727
	Medical Oncology and Hematology Associates at John Stoddard Cancer Center
		Robert Behrens	Ph:  515-282-2921
	Medical Oncology and Hematology Associates at Mercy Cancer Center
		Robert Behrens	Ph:  515-643-8740
	Mercy Cancer Center at Mercy Medical Center - Des Moines
		Robert Behrens	Ph:  515-643-8206 888-221-4849
	Sioux City
	Siouxland Hematology-Oncology Associates, LLP
		Donald Wender, MD, PhD	Ph:  712-252-0088
	West Des Moines
	Mercy Cancer Center at Mercy Medical Center - Des Moines
		Robert Behrens	Ph:  515-643-8206 888-221-4849
	Methodist West Hospital
		Robert Behrens	Ph:  515-343-1000
Massachusetts
	Boston
	Dana-Farber/Harvard Cancer Center at Dana-Farber Cancer Institute
		Eudocia Lee	Ph:  617-632-3474 866-790-4500
Minnesota
	Burnsville
	Fairview Ridges Hospital
		Daniel Anderson	Ph:  952-892-2000
	Coon Rapids
	Mercy and Unity Cancer Center at Mercy Hospital
		Daniel Anderson	Ph:  763-236-6000
	Edina
	Fairview Southdale Hospital
		Clinical Trials Office - Fairview Southdale Hospital	Ph:  612-625-3650
	Fridley
	Mercy and Unity Cancer Center at Unity Hospital
		Daniel Anderson	Ph:  763-236-5000
	Hutchinson
	Hutchinson Area Health Care
		Daniel Anderson	Ph:  320-234-5000 800-454-3903
	Maplewood
	HealthEast Cancer Care at St. John's Hospital
		Daniel Anderson	Ph:  651-232-7970
	Minnesota Oncology Hematology, PA - Maplewood
		Daniel Anderson	Ph:  612-779-7978
	Minneapolis
	Virginia Piper Cancer Institute at Abbott - Northwestern Hospital
		Clinical Trials Office - Virginia Piper Cancer Institute	Ph:  612-863-5654
	Robbinsdale
	Humphrey Cancer Center at North Memorial Outpatient Center
		Clinical Trials Office - Humphrey Cancer Center at North Memorial Outpatient Center	Ph:  763-520-1893
	Rochester
	Mayo Clinic Cancer Center
		Clinical Trials Office - All Mayo Clinic Locations	Ph:  507-538-7623
	Saint Cloud
	CentraCare Clinic - River Campus
		Donald Jurgens	Ph:  320-252-5131
	Saint Louis Park
	CCOP - Metro-Minnesota
		Daniel Anderson	Ph:  952-993-1517
	Park Nicollet Cancer Center
		Daniel Anderson	Ph:  952-993-3248
	Saint Paul
	United Hospital
		Daniel Anderson	Ph:  651-241-8000
	Shakopee
	St. Francis Cancer Center at St. Francis Medical Center
		Daniel Anderson	Ph:  952-403-2031
	St. Paul
	Regions Hospital Cancer Care Center
		Clinical Trials Office - Regions Hospital Cancer Care Center	Ph:  651-254-1517
	Waconia
	Ridgeview Medical Center
		Daniel Anderson	Ph:  952-442-2191 800-967-4620
	Woodbury
	Minnesota Oncology Hematology, PA - Woodbury
		Daniel Anderson	Ph:  651-735-7414
Nebraska
	Lincoln
	Cancer Resource Center - Lincoln
		Gamini Soori, MD, FACP, FRCP, MBA	Ph:  402-393-3110
	Omaha
	CCOP - Missouri Valley Cancer Consortium
		Gamini Soori, MD, FACP, FRCP, MBA	Ph:  402-393-3110
North Carolina
	Winston-Salem
	Wake Forest University Comprehensive Cancer Center
		Clinical Trials Office - Wake Forest University Comprehensive Cancer Center	Ph:  336-713-6771
Ohio
	Cleveland
	Cleveland Clinic Taussig Cancer Center
		Clinical Trials Office - Cleveland Clinic Taussig Cancer Center	Ph:  866-223-8100
South Dakota
	Rapid City
	Rapid City Regional Hospital
		Richard Tenglin	Ph:  605-719-2360
Virginia
	Charlottesville
	University of Virginia Cancer Center
		David Schiff, MD	Ph:  434-982-4415

Registry Information
Official Title		Phase I/II Study of Vorinostat (Suberoylanilide Hydroxamic Acid [SAHA]), Temozolomide, and Radiation Therapy in Patients with Newly Diagnosed Glioblastoma
Trial Start Date		2009-07-10
Trial Completion Date		2009-10-01 (estimated)
Registered in ClinicalTrials.gov		NCT00731731
Date Submitted to PDQ		2008-07-28
Information Last Verified		2012-02-11
NCI Grant/Contract Number		CA25224

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