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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00731731
Recruitment Status : Active, not recruiting
First Posted : August 11, 2008
Results First Posted : May 13, 2015
Last Update Posted : December 23, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This phase I/II trial studies 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. 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.

Condition or disease Intervention/treatment Phase
Adult Giant Cell Glioblastoma Adult Glioblastoma Adult Gliosarcoma Radiation: 3-Dimensional Conformal Radiation Therapy Procedure: Cognitive Assessment Other: Laboratory Biomarker Analysis Drug: Temozolomide Drug: Vorinostat Phase 1 Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of vorinostat in patients with newly diagnosed glioblastoma multiforme (GBM) and gliosarcomas, who are also receiving concomitant radiation therapy (RT) and temozolomide (TMZ). (Phase I) II. To define the safety of vorinostat with RT and TMZ in this population. (Phase II) III. To determine the efficacy of vorinostat in combination with RT and TMZ followed by vorinostat in combination with TMZ in patients with newly-diagnosed GBM and gliosarcomas as measured by overall survival at 15 months (OS15). (Phase II)

SECONDARY OBJECTIVES:

I. To determine progression-free survival in newly diagnosed GBM and gliosarcoma patients treated with the study regimen. (Phase II) II. To further evaluate the safety profile of vorinostat in combination with RT and TMZ in this patient population. (Phase II) III. Determine the neurocognitive effects in patients treated on this protocol and correlate these results with outcome endpoints. (Phase II)

TERTIARY OBJECTIVES:

I. To explore the extent to which the tumor's molecular characteristics and expression profile correlate with outcome.

II. Evaluate potential mechanisms of therapy resistance in tumor samples obtained at the time of tumor progression.

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

Patients undergo radiotherapy and receive vorinostat orally (PO) once daily (QD) on days 1-5, 8-12, 15-19, 22-26, 29-33, and 36-40. Patients also receive temozolomide PO QD on days 1-42. Beginning 4-6 weeks later, patients receive vorinostat PO QD on days 1-7 and 15-21 and temozolomide PO QD 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.

After completion of study treatment, patients are followed up every 2 months for 1 year, every 3 months for 1 year and then every 6 months for 3 years.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 125 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II Study of Vorinostat (Suberoylanilide Hydroxamic Acid [SAHA]), Temozolomide, and Radiation Therapy in Patients With Newly Diagnosed Glioblastoma
Actual Study Start Date : July 10, 2009
Actual Primary Completion Date : February 2, 2014


Arm Intervention/treatment
Experimental: Treatment (radiation therapy, vorinostat, temozolomide)
Patients undergo radiotherapy and receive vorinostat PO QD on days 1-5, 8-12, 15-19, 22-26, 29-33, and 36-40. Patients also receive temozolomide PO QD on days 1-42. Beginning 4-6 weeks later, patients receive vorinostat PO QD on days 1-7 and 15-21 and temozolomide PO QD 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.
Radiation: 3-Dimensional Conformal Radiation Therapy
Undergo radiotherapy
Other Names:
  • 3-dimensional radiation therapy
  • 3D CONFORMAL RADIATION THERAPY
  • 3D CRT
  • 3D-CRT
  • Conformal Therapy
  • Radiation Conformal Therapy
  • Radiation, 3D Conformal

Procedure: Cognitive Assessment
Ancillary studies

Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Temozolomide
Given PO
Other Names:
  • CCRG-81045
  • Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-
  • M & B 39831
  • M and B 39831
  • Methazolastone
  • RP-46161
  • SCH 52365
  • Temcad
  • Temodal
  • Temodar
  • Temomedac
  • TMZ

Drug: Vorinostat
Given PO
Other Names:
  • L-001079038
  • MSK-390
  • SAHA
  • Suberanilohydroxamic Acid
  • Suberoylanilide Hydroxamic Acid
  • Zolinza




Primary Outcome Measures :
  1. Maximum Tolerated Dose of Vorinostat, Defined as the Dose at Which Fewer Than One-third of Patients Experience DLTs, Graded According to NCI CTCAE (Common Toxicity Criteria for Adverse Effects) Version 3.0 (Phase I) [ Time Frame: 10 weeks ]

    The Maximum Tolerated Dose (MTD) will be based on the assessment of Dose Limiting Toxicity (DLT) during the first 10 weeks of treatment only, and will be defined as the dose at which fewer than one-third of patients experience a DLT to vorinostat. The MTD is the dose level at which 0/3 or 1/6 patients experience DLT with the next higher dose having at least 2/3 or 2/6 patients encountering DLT.

    >

    >

    DLT will be defined as any of the following events occurring during treatment with vorinostat and temozolomide and attributable to one or both study drugs:

    • Grade 3 or 4 thrombocytopenia, grade 4 anemia or grade 4 neutropenia lasting > 7 days
    • Any non-hematologic grade 3 or greater adverse event, excluding alopecia and venous thromboembolism
    • Grade 4 radiation-induced skin changes
    • Failure to recover from toxicities to be eligible for re-treatment with vorinostat and temozolomide ≤ 14 days of the last dose of the two drugs

  2. Overall Survival at 15 Months (Phase II) [ Time Frame: Time from study registration to the date of death from any cause, assessed up to 5 years ]
    The primary endpoint will be survival status at 15 months (OS15). In addition, survival will be estimated using a Kaplan-Meier curve. For this analysis, patients who are still alive at the time of analysis have survival time censored at the last contact date.


Secondary Outcome Measures :
  1. Incidence of Adverse Events, Based on CTC (Common Toxicity Criteria) Severity Grade [ Time Frame: Up to 5 years ]
    Safety variables will be summarized by descriptive statistics. Adverse Events (AEs) that occur will be reported for each phase and dose level and described in terms of incidence and severity. Parameters will be described based on the CTC severity grading. Distribution by CTC severity grade and clinical relevance will be given.

  2. Time to Tumor Progression (Phase II) [ Time Frame: Up to 5 years ]
    Progression free survival time will be defined from date of registration to date of progression or death.

  3. Incidence of Adverse Events, as Per NCI CTCAE Version 3.0 (Phase II) [ Time Frame: Up to 5 years ]
    The maximum grade for each type of treatment-related adverse event will be recorded for each patient, and frequency tables for each arm will be reviewed to determine patterns. In addition, we will review all adverse event data that is graded as 3, 4, or 5 and classified as either "unrelated" or "unlikely to be related" to study treatment in the event of an actual relationship developing.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • PRE-REGISTRATION:
  • Central pathology review submission; this review is mandatory prior to registration to confirm eligibility; it should be initiated as soon after surgery as possible
  • Treatment should begin >= 2 weeks and =< 5 weeks following surgery
  • REGISTRATION:
  • Histologically confirmed glioblastoma multiforme as determined by pre-registration central pathology review; Note: gliosarcomas and other grade 4 astrocytoma variants (e.g., giant cell) are eligible
  • Measurable or evaluable disease by gadolinium magnetic resonance imaging (MRI) or contrast computed tomography (CT) scan; Note: patients who have had a gross total resection (GTR) are eligible on the basis of evaluable disease

    • Must begin partial brain radiotherapy on the same day that vorinostat and temozolomide begin
  • Karnofsky performance status of >= 60
  • Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2
  • Absolute neutrophil count (ANC) >= 1,500/mm^3
  • Platelet count >= 100,000/mm^3
  • White blood cell (WBC) >= 3,000/mm^3
  • Hemoglobin >= 10.0 g/dL; Note: this level may be reached by transfusion
  • Total bilirubin =< 2.0 x institutional upper limit of normal (ULN)
  • Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 2.0 x ULN
  • Creatinine =< 1.5 mg/dL
  • Life expectancy >= 12 weeks
  • Negative serum pregnancy test done =< 7 days prior to registration, for women of childbearing potential only
  • For Phase I established MTD and Phase II patients only: Willing and able to complete neurocognitive testing
  • Ability to provide informed written consent
  • Willing to return to Alliance or Adult Brain Tumor Consortium (ABTC) enrolling institution for follow-up
  • Phase I established MTD patients and Phase II patients: Willing to provide mandatory tissue samples (slides or blocks) for research purposes
  • Willing to forego other cytotoxic and non-cytotoxic drug therapy against the tumor while being treated with vorinostat and temozolomide

Exclusion Criteria:

  • Any of the following:

    • Pregnant women
    • Nursing women
    • Men or women of childbearing potential who are unwilling to employ adequate contraception throughout the duration of the study and for 12 weeks after treatment has ended
  • Prior cytotoxic drug therapy, non-cytotoxic drug therapy, or experimental drug therapy for brain tumors
  • Prior cranial RT
  • Prior Gliadel wafers
  • Known hypersensitivity to any of the components of vorinostat or other agents used in study
  • Valproic acid, another histone deacetylase inhibitor, =< 2 weeks prior to registration and during treatment
  • Other active malignancy =< 3 years prior to registration; Exception: non-melanotic 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
  • Uncontrolled infection
  • Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive and currently receiving antiretroviral therapy; Note: patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial
  • Co-morbid systemic illness or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with proper assessment of safety and adverse events of the prescribed regimens
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements
  • History of myocardial infarction or unstable angina =< 6 months prior to registration or congestive heart failure (CHF) requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
  • New York Heart Association (NYHA) >= Class II Congestive Heart Failure
  • Inability to take oral medications
  • Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm
  • Congenital long QT syndrome
  • Prolonged corrected (QTc) interval (> 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00731731


Locations
Hide Hide 110 study locations
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United States, Arizona
Mayo Clinic in Arizona
Scottsdale, Arizona, United States, 85259
United States, California
UCSF Medical Center-Parnassus
San Francisco, California, United States, 94143
United States, Florida
Mayo Clinic in Florida
Jacksonville, Florida, United States, 32224-9980
AdventHealth Orlando
Orlando, Florida, United States, 32803
United States, Georgia
Emory University Hospital/Winship Cancer Institute
Atlanta, Georgia, United States, 30322
United States, Hawaii
Hawaii Oncology Inc-Pali Momi
'Aiea, Hawaii, United States, 96701
Pali Momi Medical Center
'Aiea, Hawaii, United States, 96701
Hawaii Cancer Care Inc-POB II
Honolulu, Hawaii, United States, 96813
Queen's Medical Center
Honolulu, Hawaii, United States, 96813
Straub Clinic and Hospital
Honolulu, Hawaii, United States, 96813
University of Hawaii Cancer Center
Honolulu, Hawaii, United States, 96813
Hawaii Oncology Inc-Kuakini
Honolulu, Hawaii, United States, 96817
Kuakini Medical Center
Honolulu, Hawaii, United States, 96817
The Cancer Center of Hawaii-Liliha
Honolulu, Hawaii, United States, 96817
Kapiolani Medical Center for Women and Children
Honolulu, Hawaii, United States, 96826
Castle Medical Center
Kailua, Hawaii, United States, 96734
Wilcox Memorial Hospital and Kauai Medical Clinic
Lihue, Hawaii, United States, 96766
United States, Illinois
Rush University Medical Center
Chicago, Illinois, United States, 60612
Presence Resurrection Medical Center
Chicago, Illinois, United States, 60631
Garneau, Stewart C MD (UIA Investigator)
Moline, Illinois, United States, 61265
Porubcin, Michael MD (UIA Investigator)
Moline, Illinois, United States, 61265
Sharis, Christine M MD (UIA Investigator)
Moline, Illinois, United States, 61265
Spector, David MD (UIA Investigator)
Moline, Illinois, United States, 61265
Stoffel, Thomas J MD (UIA Investigator)
Moline, Illinois, United States, 61265
Trinity Medical Center
Moline, Illinois, United States, 61265
United States, Iowa
McFarland Clinic PC - Ames
Ames, Iowa, United States, 50010
Constantinou, Costas L MD (UIA Investigator)
Bettendorf, Iowa, United States, 52722
Medical Oncology and Hematology Associates-West Des Moines
Clive, Iowa, United States, 50325
Mercy Cancer Center-West Lakes
Clive, Iowa, United States, 50325
Iowa Methodist Medical Center
Des Moines, Iowa, United States, 50309
Iowa-Wide Oncology Research Coalition NCORP
Des Moines, Iowa, United States, 50309
Medical Oncology and Hematology Associates-Des Moines
Des Moines, Iowa, United States, 50309
Medical Oncology and Hematology Associates-Laurel
Des Moines, Iowa, United States, 50314
Mercy Medical Center - Des Moines
Des Moines, Iowa, United States, 50314
Iowa Lutheran Hospital
Des Moines, Iowa, United States, 50316
Siouxland Regional Cancer Center
Sioux City, Iowa, United States, 51101
Methodist West Hospital
West Des Moines, Iowa, United States, 50266-7700
Mercy Medical Center-West Lakes
West Des Moines, Iowa, United States, 50266
United States, Kansas
Cancer Center of Kansas - Chanute
Chanute, Kansas, United States, 66720
Cancer Center of Kansas - Dodge City
Dodge City, Kansas, United States, 67801
Cancer Center of Kansas - El Dorado
El Dorado, Kansas, United States, 67042
Cancer Center of Kansas - Fort Scott
Fort Scott, Kansas, United States, 66701
Cancer Center of Kansas-Independence
Independence, Kansas, United States, 67301
Cancer Center of Kansas-Kingman
Kingman, Kansas, United States, 67068
Lawrence Memorial Hospital
Lawrence, Kansas, United States, 66044
Cancer Center of Kansas-Liberal
Liberal, Kansas, United States, 67905
Cancer Center of Kansas - Newton
Newton, Kansas, United States, 67114
Cancer Center of Kansas - Parsons
Parsons, Kansas, United States, 67357
Cancer Center of Kansas - Pratt
Pratt, Kansas, United States, 67124
Cancer Center of Kansas - Salina
Salina, Kansas, United States, 67401
Cancer Center of Kansas - Wellington
Wellington, Kansas, United States, 67152
Associates In Womens Health
Wichita, Kansas, United States, 67208
Cancer Center of Kansas-Wichita Medical Arts Tower
Wichita, Kansas, United States, 67208
Ascension Via Christi Hospitals Wichita
Wichita, Kansas, United States, 67214
Cancer Center of Kansas - Wichita
Wichita, Kansas, United States, 67214
Wichita NCI Community Oncology Research Program
Wichita, Kansas, United States, 67214
Cancer Center of Kansas - Winfield
Winfield, Kansas, United States, 67156
United States, Maryland
Johns Hopkins University/Sidney Kimmel Cancer Center
Baltimore, Maryland, United States, 21287
Cancer Trials Support Unit
Rockville, Maryland, United States, 20850-2062
United States, Massachusetts
Massachusetts General Hospital Cancer Center
Boston, Massachusetts, United States, 02114
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02215
United States, Michigan
Henry Ford Hospital
Detroit, Michigan, United States, 48202
Cancer Research Consortium of West Michigan NCORP
Grand Rapids, Michigan, United States, 49503
Mercy Health Saint Mary's
Grand Rapids, Michigan, United States, 49503
Spectrum Health at Butterworth Campus
Grand Rapids, Michigan, United States, 49503
Munson Medical Center
Traverse City, Michigan, United States, 49684
United States, Minnesota
Sanford Joe Lueken Cancer Center
Bemidji, Minnesota, United States, 56601
Fairview Ridges Hospital
Burnsville, Minnesota, United States, 55337
Mercy Hospital
Coon Rapids, Minnesota, United States, 55433
Essentia Health Cancer Center
Duluth, Minnesota, United States, 55805
Fairview-Southdale Hospital
Edina, Minnesota, United States, 55435
Unity Hospital
Fridley, Minnesota, United States, 55432
Hutchinson Area Health Care
Hutchinson, Minnesota, United States, 55350
Minnesota Oncology Hematology PA-Maplewood
Maplewood, Minnesota, United States, 55109
Saint John's Hospital - Healtheast
Maplewood, Minnesota, United States, 55109
Abbott-Northwestern Hospital
Minneapolis, Minnesota, United States, 55407
Hennepin County Medical Center
Minneapolis, Minnesota, United States, 55415
North Memorial Medical Health Center
Robbinsdale, Minnesota, United States, 55422
Mayo Clinic
Rochester, Minnesota, United States, 55905
Coborn Cancer Center at Saint Cloud Hospital
Saint Cloud, Minnesota, United States, 56303
Metro Minnesota Community Oncology Research Consortium
Saint Louis Park, Minnesota, United States, 55416
Park Nicollet Clinic - Saint Louis Park
Saint Louis Park, Minnesota, United States, 55416
Regions Hospital
Saint Paul, Minnesota, United States, 55101
United Hospital
Saint Paul, Minnesota, United States, 55102
Saint Francis Regional Medical Center
Shakopee, Minnesota, United States, 55379
Lakeview Hospital
Stillwater, Minnesota, United States, 55082
Ridgeview Medical Center
Waconia, Minnesota, United States, 55387
Rice Memorial Hospital
Willmar, Minnesota, United States, 56201
Minnesota Oncology Hematology PA-Woodbury
Woodbury, Minnesota, United States, 55125
United States, Montana
Billings Clinic Cancer Center
Billings, Montana, United States, 59101
Montana Cancer Consortium NCORP
Billings, Montana, United States, 59102
United States, Nebraska
Nebraska Cancer Research Center
Lincoln, Nebraska, United States, 68510
Missouri Valley Cancer Consortium
Omaha, Nebraska, United States, 68106
Alegent Health Immanuel Medical Center
Omaha, Nebraska, United States, 68122
Alegent Health Bergan Mercy Medical Center
Omaha, Nebraska, United States, 68124
Alegent Health Lakeside Hospital
Omaha, Nebraska, United States, 68130
United States, North Carolina
Wake Forest University Health Sciences
Winston-Salem, North Carolina, United States, 27157
United States, North Dakota
Sanford Broadway Medical Center
Fargo, North Dakota, United States, 58122
Sanford Clinic North-Fargo
Fargo, North Dakota, United States, 58122
United States, Ohio
Cleveland Clinic Foundation
Cleveland, Ohio, United States, 44195
United States, Pennsylvania
University of Pennsylvania/Abramson Cancer Center
Philadelphia, Pennsylvania, United States, 19104
University of Pittsburgh Cancer Institute (UPCI)
Pittsburgh, Pennsylvania, United States, 15232
Geisinger Wyoming Valley/Henry Cancer Center
Wilkes-Barre, Pennsylvania, United States, 18711
United States, South Dakota
Rapid City Regional Hospital
Rapid City, South Dakota, United States, 57701
Sanford USD Medical Center - Sioux Falls
Sioux Falls, South Dakota, United States, 57117-5134
United States, Virginia
University of Virginia Cancer Center
Charlottesville, Virginia, United States, 22908
United States, Wisconsin
Green Bay Oncology at Saint Vincent Hospital
Green Bay, Wisconsin, United States, 54301-3526
Saint Vincent Hospital Cancer Center Green Bay
Green Bay, Wisconsin, United States, 54301
Green Bay Oncology Limited at Saint Mary's Hospital
Green Bay, Wisconsin, United States, 54303
Saint Vincent Hospital Cancer Center at Saint Mary's
Green Bay, Wisconsin, United States, 54303
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Evanthia Galanis Alliance for Clinical Trials in Oncology

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00731731    
Other Study ID Numbers: NCI-2009-00672
NCI-2009-00672 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
N0874
ABTC 0902
CDR0000609743
N0874 ( Other Identifier: Alliance for Clinical Trials in Oncology )
N0874 ( Other Identifier: CTEP )
U10CA180821 ( U.S. NIH Grant/Contract )
U10CA025224 ( U.S. NIH Grant/Contract )
First Posted: August 11, 2008    Key Record Dates
Results First Posted: May 13, 2015
Last Update Posted: December 23, 2019
Last Verified: November 2019
Additional relevant MeSH terms:
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Glioblastoma
Gliosarcoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Temozolomide
Vorinostat
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Histone Deacetylase Inhibitors
Enzyme Inhibitors