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

Phase 1

Completed

Conditions: Adult Gliosarcoma
Adult Giant Cell Glioblastoma
Adult Glioblastoma

Interventions: Radiation: 3-Dimensional Conformal Radiation Therapy
Procedure: Cognitive Assessment
Other: Laboratory Biomarker Analysis
Drug: Temozolomide
Drug: Vorinostat

Registration Number: NCT00731731

Lead Sponsor: 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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 125

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 & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (radiation therapy, vorinostat, temozolomide)	3-Dimensional Conformal Radiation Therapy	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.
Treatment (radiation therapy, vorinostat, temozolomide)	Cognitive Assessment	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.
Treatment (radiation therapy, vorinostat, temozolomide)	Laboratory Biomarker Analysis	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.
Treatment (radiation therapy, vorinostat, temozolomide)	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.
Treatment (radiation therapy, vorinostat, temozolomide)	Vorinostat	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.

Primary Outcome Measures

Name	Time	Method
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)	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
Overall Survival at 15 Months (Phase II)	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

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

Trial Locations

Locations (110): Cancer Center of Kansas-Independence
🇺🇸
Independence, Kansas, United States
Munson Medical Center
🇺🇸
Traverse City, Michigan, United States
Garneau, Stewart C MD (UIA Investigator)
🇺🇸
Moline, Illinois, United States
Emory University Hospital/Winship Cancer Institute
🇺🇸
Atlanta, Georgia, United States
Straub Clinic and Hospital
🇺🇸
Honolulu, Hawaii, United States
Castle Medical Center
🇺🇸
Kailua, Hawaii, United States
Mayo Clinic in Florida
🇺🇸
Jacksonville, Florida, United States
Sharis, Christine M MD (UIA Investigator)
🇺🇸
Moline, Illinois, United States
Stoffel, Thomas J MD (UIA Investigator)
🇺🇸
Moline, Illinois, United States
Queen's Cancer Center - Pearlridge
🇺🇸
'Aiea, Hawaii, United States
Iowa-Wide Oncology Research Coalition NCORP
🇺🇸
Des Moines, Iowa, United States
McFarland Clinic PC - Ames
🇺🇸
Ames, Iowa, United States
Mercy Cancer Center-West Lakes
🇺🇸
Clive, Iowa, United States
Mercy Medical Center-West Lakes
🇺🇸
West Des Moines, Iowa, United States
Porubcin, Michael MD (UIA Investigator)
🇺🇸
Moline, Illinois, United States
Medical Oncology and Hematology Associates-Laurel
🇺🇸
Des Moines, Iowa, United States
Ascension Via Christi Hospitals Wichita
🇺🇸
Wichita, Kansas, United States
Cancer Center of Kansas - Chanute
🇺🇸
Chanute, Kansas, United States
Medical Oncology and Hematology Associates-Des Moines
🇺🇸
Des Moines, Iowa, United States
Cancer Center of Kansas - El Dorado
🇺🇸
El Dorado, Kansas, United States
Mercy Medical Center - Des Moines
🇺🇸
Des Moines, Iowa, United States
Constantinou, Costas L MD (UIA Investigator)
🇺🇸
Bettendorf, Iowa, United States
Cancer Center of Kansas-Kingman
🇺🇸
Kingman, Kansas, United States
Regions Hospital
🇺🇸
Saint Paul, Minnesota, United States
Johns Hopkins University/Sidney Kimmel Cancer Center
🇺🇸
Baltimore, Maryland, United States
Rush University Medical Center
🇺🇸
Chicago, Illinois, United States
Presence Resurrection Medical Center
🇺🇸
Chicago, Illinois, United States
Massachusetts General Hospital Cancer Center
🇺🇸
Boston, Massachusetts, United States
Dana-Farber Cancer Institute
🇺🇸
Boston, Massachusetts, United States
Cleveland Clinic Foundation
🇺🇸
Cleveland, Ohio, United States
Mayo Clinic in Arizona
🇺🇸
Scottsdale, Arizona, United States
AdventHealth Orlando
🇺🇸
Orlando, Florida, United States
University of Hawaii Cancer Center
🇺🇸
Honolulu, Hawaii, United States
Pali Momi Medical Center
🇺🇸
'Aiea, Hawaii, United States
Hawaii Cancer Care Inc - Waterfront Plaza
🇺🇸
Honolulu, Hawaii, United States
Queen's Cancer Center - Kuakini
🇺🇸
Honolulu, Hawaii, United States
Kuakini Medical Center
🇺🇸
Honolulu, Hawaii, United States
The Cancer Center of Hawaii-Liliha
🇺🇸
Honolulu, Hawaii, United States
Iowa Methodist Medical Center
🇺🇸
Des Moines, Iowa, United States
Siouxland Regional Cancer Center
🇺🇸
Sioux City, Iowa, United States
Iowa Lutheran Hospital
🇺🇸
Des Moines, Iowa, United States
Lawrence Memorial Hospital
🇺🇸
Lawrence, Kansas, United States
Cancer Center of Kansas - Wellington
🇺🇸
Wellington, Kansas, United States
Cancer Center of Kansas-Liberal
🇺🇸
Liberal, Kansas, United States
Cancer Center of Kansas - Pratt
🇺🇸
Pratt, Kansas, United States
Cancer Center of Kansas - Newton
🇺🇸
Newton, Kansas, United States
Cancer Center of Kansas - Salina
🇺🇸
Salina, Kansas, United States
Cancer Center of Kansas - Parsons
🇺🇸
Parsons, Kansas, United States
Associates In Womens Health
🇺🇸
Wichita, Kansas, United States
Cancer Center of Kansas-Wichita Medical Arts Tower
🇺🇸
Wichita, Kansas, United States
Wichita NCI Community Oncology Research Program
🇺🇸
Wichita, Kansas, United States
Cancer Center of Kansas - Wichita
🇺🇸
Wichita, Kansas, United States
Cancer Center of Kansas - Winfield
🇺🇸
Winfield, Kansas, United States
Cancer Trials Support Unit
🇺🇸
Rockville, Maryland, United States
Spectrum Health at Butterworth Campus
🇺🇸
Grand Rapids, Michigan, United States
Cancer Research Consortium of West Michigan NCORP
🇺🇸
Grand Rapids, Michigan, United States
Mercy Health Saint Mary's
🇺🇸
Grand Rapids, Michigan, United States
Sanford Joe Lueken Cancer Center
🇺🇸
Bemidji, Minnesota, United States
Fairview Ridges Hospital
🇺🇸
Burnsville, Minnesota, United States
Hutchinson Area Health Care
🇺🇸
Hutchinson, Minnesota, United States
Mercy Hospital
🇺🇸
Coon Rapids, Minnesota, United States
Unity Hospital
🇺🇸
Fridley, Minnesota, United States
Essentia Health Cancer Center
🇺🇸
Duluth, Minnesota, United States
Fairview Southdale Hospital
🇺🇸
Edina, Minnesota, United States
Minnesota Oncology Hematology PA-Maplewood
🇺🇸
Maplewood, Minnesota, United States
Saint John's Hospital - Healtheast
🇺🇸
Maplewood, Minnesota, United States
North Memorial Medical Health Center
🇺🇸
Robbinsdale, Minnesota, United States
Coborn Cancer Center at Saint Cloud Hospital
🇺🇸
Saint Cloud, Minnesota, United States
Metro Minnesota Community Oncology Research Consortium
🇺🇸
Saint Louis Park, Minnesota, United States
Park Nicollet Clinic - Saint Louis Park
🇺🇸
Saint Louis Park, Minnesota, United States
United Hospital
🇺🇸
Saint Paul, Minnesota, United States
Ridgeview Medical Center
🇺🇸
Waconia, Minnesota, United States
Rice Memorial Hospital
🇺🇸
Willmar, Minnesota, United States
Minnesota Oncology Hematology PA-Woodbury
🇺🇸
Woodbury, Minnesota, United States
Billings Clinic Cancer Center
🇺🇸
Billings, Montana, United States
Montana Cancer Consortium NCORP
🇺🇸
Billings, Montana, United States
Nebraska Cancer Research Center
🇺🇸
Lincoln, Nebraska, United States
Sanford Broadway Medical Center
🇺🇸
Fargo, North Dakota, United States
Sanford Clinic North-Fargo
🇺🇸
Fargo, North Dakota, United States
University of Pennsylvania/Abramson Cancer Center
🇺🇸
Philadelphia, Pennsylvania, United States
Rapid City Regional Hospital
🇺🇸
Rapid City, South Dakota, United States
Geisinger Wyoming Valley/Henry Cancer Center
🇺🇸
Wilkes-Barre, Pennsylvania, United States
University of Virginia Cancer Center
🇺🇸
Charlottesville, Virginia, United States
Saint Vincent Hospital Cancer Center at Saint Mary's
🇺🇸
Green Bay, Wisconsin, United States
Green Bay Oncology at Saint Vincent Hospital
🇺🇸
Green Bay, Wisconsin, United States
Saint Vincent Hospital Cancer Center Green Bay
🇺🇸
Green Bay, Wisconsin, United States
Wilcox Memorial Hospital and Kauai Medical Clinic
🇺🇸
Lihue, Hawaii, United States
Kapiolani Medical Center for Women and Children
🇺🇸
Honolulu, Hawaii, United States
Green Bay Oncology Limited at Saint Mary's Hospital
🇺🇸
Green Bay, Wisconsin, United States
Saint Francis Regional Medical Center
🇺🇸
Shakopee, Minnesota, United States
Lakeview Hospital
🇺🇸
Stillwater, Minnesota, United States
Sanford USD Medical Center - Sioux Falls
🇺🇸
Sioux Falls, South Dakota, United States
University of Pittsburgh Cancer Institute (UPCI)
🇺🇸
Pittsburgh, Pennsylvania, United States
UCSF Medical Center-Parnassus
🇺🇸
San Francisco, California, United States
Henry Ford Hospital
🇺🇸
Detroit, Michigan, United States
Hennepin County Medical Center
🇺🇸
Minneapolis, Minnesota, United States
Abbott-Northwestern Hospital
🇺🇸
Minneapolis, Minnesota, United States
Mayo Clinic in Rochester
🇺🇸
Rochester, Minnesota, United States
Missouri Valley Cancer Consortium
🇺🇸
Omaha, Nebraska, United States
Alegent Health Immanuel Medical Center
🇺🇸
Omaha, Nebraska, United States
Alegent Health Bergan Mercy Medical Center
🇺🇸
Omaha, Nebraska, United States
Alegent Health Lakeside Hospital
🇺🇸
Omaha, Nebraska, United States
Wake Forest University Health Sciences
🇺🇸
Winston-Salem, North Carolina, United States
Queen's Medical Center
🇺🇸
Honolulu, Hawaii, United States
Spector, David MD (UIA Investigator)
🇺🇸
Moline, Illinois, United States
Trinity Medical Center
🇺🇸
Moline, Illinois, United States
Medical Oncology and Hematology Associates-West Des Moines
🇺🇸
Clive, Iowa, United States
Methodist West Hospital
🇺🇸
West Des Moines, Iowa, United States
Cancer Center of Kansas - Dodge City
🇺🇸
Dodge City, Kansas, United States
Cancer Center of Kansas - Fort Scott
🇺🇸
Fort Scott, Kansas, United States