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

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

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.

Study Overview

• Status: Completed
• Conditions: Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Drug: Temozolomide; Drug: Vorinostat; Procedure: Cognitive Assessment; Radiation: 3-Dimensional Conformal Radiation Therapy

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.

• Study Type: Interventional
• Enrollment (Actual): 125
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / 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.

Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Temozolomide; Given PO; Other Names: Temodar; SCH 52365; Temodal; Temcad; Methazolastone; RP-46161; Temomedac; TMZ; 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; Drug: Vorinostat; Given PO; Other Names: SAHA; Suberoylanilide Hydroxamic Acid; MSK-390; Zolinza; L-001079038; Suberanilohydroxamic Acid; Procedure: Cognitive Assessment; Ancillary studies; 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; 3D Conformal; Radiation, 3D Conformal

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	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	10 weeks
Overall Survival at 15 Months (Phase II)	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.	Time from study registration to the date of death from any cause, assessed up to 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Adverse Events, Based on CTC (Common Toxicity Criteria) Severity Grade	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.	Up to 5 years
Time to Tumor Progression (Phase II)	Progression free survival time will be defined from date of registration to date of progression or death.	Up to 5 years
Incidence of Adverse Events, as Per NCI CTCAE Version 3.0 (Phase II)	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.	Up to 5 years

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)

Publications and helpful links

General Publications

• Cerhan JH, Anderson SK, Butts AM, Porter AB, Jaeckle K, Galanis E, Brown PD. Examiner accuracy in cognitive testing in multisite brain-tumor clinical trials: an analysis from the Alliance for Clinical Trials in Oncology. Neurooncol Pract. 2019 Jul;6(4):283-288. doi: 10.1093/nop/npy048. Epub 2018 Nov 24.

Study record dates

Study Major Dates

• Study Start (ACTUAL): July 10, 2009
• Primary Completion (ACTUAL): February 2, 2014
• Study Completion (ACTUAL): November 1, 2019

Study Registration Dates

• First Submitted: August 8, 2008
• First Submitted That Met QC Criteria: August 8, 2008
• First Posted (ESTIMATE): August 11, 2008

Study Record Updates

• Last Update Posted (ACTUAL): August 4, 2022
• Last Update Submitted That Met QC Criteria: August 3, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Gliosarcoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Histone Deacetylase Inhibitors; Temozolomide; Vorinostat
• Other Study ID Numbers: NCI-2009-00672 (REGISTRY: CTRP (Clinical Trial Reporting Program)); U10CA180821 (U.S. NIH Grant/Contract); U10CA025224 (U.S. NIH Grant/Contract); N0874 (OTHER: CTEP); ABTC 0902; CDR0000609743