Clinical trial NCT00017147: S0001 RT and Carmustine With or Without O6BG in Patients With New Glioblastoma Multiforme or Gliosarcoma
Official title: A Phase III Study of Radiation Therapy (RT) and O6-Benzylguanine (O6-BG) Plus BCNU Versus RT and BCNU Alone for Newly Diagnosed Glioblastoma Multiforme (GBM) and Gliosarcoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Malignant Neoplasms of Eye, Brain and Other Parts of Central Nervous System
Keywords: adult glioblastoma
adult giant cell glioblastoma
adult gliosarcoma
Lead sponsor: SWOG Cancer Research Network
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
First posted: 2003-01-27
Enrollment: 183
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. O6-benzylguanine may help carmustine kill more tumor cells by making tumor cells more sensitive to the drug. It is not yet known whether radiation therapy and carmustine are more effective with or without O6-benzylguanine.

PURPOSE: Randomized phase III trial to compare the effectiveness of radiation therapy plus carmustine with or without O6-benzylguanine in treating patients who have newly diagnosed glioblastoma multiforme or gliosarcoma.

Detailed description: OBJECTIVES:

* Compare the overall survival, failure-free survival, and progression-free survival of patients with newly diagnosed glioblastoma multiforme or gliosarcoma treated with radiotherapy and carmustine with or without O6-benzylguanine.
* Compare the frequency and severity of toxic effects of these regimens in these patients.
* Correlate the survival of these patients with the expression of O6-alkylguanine-DNA alkyltransferase.

OUTLINE: This is a randomized study. Patients are stratified according to age (under 50 vs 50 and over), prior surgery (biopsy only vs resection), and Zubrod performance status (0-1 vs 2). Patients are randomized to 1 of 2 treatment arms.

* Arm I: Patients undergo radiotherapy daily 5 days a week over 7 weeks for a total of 34 fractions. Patients also receive chemotherapy comprising O6-benzylguanine IV over 1 hour followed 6 hours later by carmustine IV over 1 hour on day 1 of radiotherapy. Chemotherapy repeats every 6 weeks for a maximum of 7 courses in the absence of disease progression or unacceptable toxicity.
* Arm II: Patients undergo radiotherapy as in arm I. Patients receive carmustine IV as in arm I.

Patients are followed at week 48, every 4 months for 1 year, and then every 6 months for 4 years.

PROJECTED ACCRUAL: A total of 375 patients will be accrued for this study within 5 years.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histologically confirmed glioblastoma multiforme or gliosarcoma

  * Biopsy or surgical resection within the past 28 days

    * MRI\* with gadolinium performed before registration
    * Patients who undergo a simple biopsy only require preoperative MRI\* with gadolinium
* No more than 2 noncontiguous tumor sites based on T2-weighted MRI (in 3 dimensions)\*
* No prior radiotherapy-delivered cephalad to the interspace between the seventh cervical and the first thoracic vertebral body NOTE: \*If an MRI is not medically feasible, patients may have a CT scan with contrast

PATIENT CHARACTERISTICS:

Age:

* 18 and over

Performance status:

* Zubrod 0-2

Life expectancy:

* Not specified

Hematopoietic:

* Absolute neutrophil count at least 3,000/mm\^3
* Platelet count at least 100,000/mm\^3
* Hemoglobin at least 8 g/dL

Hepatic:

* Bilirubin no greater than 2 times upper limit of normal (ULN)
* SGOT/SGPT no greater than 2 times ULN
* Alkaline phosphatase no greater than 2 times ULN
* PT/PTT no greater than 1.2 times ULN

Renal:

* Not specified

Cardiac:

* No severe cardiac disease, including any of the following:

  * Uncontrolled arrhythmias or conduction defects
  * Major problems with edema (e.g., residual swelling in the legs from deep vein thrombosis)
  * Recent coronary artery disease
  * Poorly controlled hypertension (i.e., diastolic blood pressure greater than 110 mm Hg and/or systolic blood pressure greater than 180 mm Hg)

Pulmonary:

* DLCO at least 70% of predicted
* No severe pulmonary disease

Other:

* HIV negative
* No severe Cushing's syndrome
* No known allergies to any of the study drugs
* No major psychiatric illness
* No poorly controlled diabetes complicated by steroid treatment
* No other medical illness that cannot be adequately controlled or that would preclude study participation
* No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, or adequately treated stage I or II cancer currently in complete remission
* Not pregnant or nursing
* Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

* Not specified

Chemotherapy:

* No prior chemotherapy
* No other concurrent antitumor chemotherapy

Endocrine therapy:

* No concurrent hormonal therapy except postmenopausal estrogen replacement therapy
* Corticosteroids at stable or decreasing dose for tumor edema allowed

Radiotherapy:

* See Disease Characteristics
* No prior radiotherapy
* No other concurrent radiotherapy (including intensity-modulated radiotherapy) to the index lesion(s)

Surgery:

* See Disease Characteristics
* No concurrent antitumor surgery

Other:

* No other concurrent investigational drugs
* No other concurrent antineoplastic drugs or therapy

Primary outcomes:
measure: Survival
timeFrame: assessed every 6 weeks for 42 weeks, then every 4 months for one year, followed by every 6 months for years 2 through 5
Secondary outcomes:
measure: Progression-free survival
timeFrame: assessed every 6 weeks for 42 weeks, then every 4 months for one year, followed by every 6 months for years 2 through 5
measure: Time to treatment failure
timeFrame: assessed every 6 weeks for 42 weeks, then every 4 months for one year, followed by every 6 months for years 2 through 5
measure: Toxicity
timeFrame: assessed weekly for 42 weeks
Other outcomes:
Locations:
city: Anchorage
country: United States
facility: Alaska Regional Hospital Cancer Center
state: Alaska
city: Phoenix
country: United States
facility: Banner Good Samaritan Medical Center
state: Arizona
city: Phoenix
country: United States
facility: CCOP - Western Regional, Arizona
state: Arizona
city: Phoenix
country: United States
facility: St. Joseph's Hospital and Medical Center
state: Arizona
city: Phoenix
country: United States
facility: Banner Thunderbird Medical Center
state: Arizona
city: Fairfield
country: United States
facility: North Bay Cancer Center
state: California
city: Colorado Springs
country: United States
facility: Memorial Hospital Cancer Center
state: Colorado
city: Denver
country: United States
facility: St. Anthony Central Hospital
state: Colorado
city: Denver
country: United States
facility: University of Colorado Cancer Center at University of Colorado Health Sciences Center
state: Colorado
city: Greeley
country: United States
facility: North Colorado Medical Center
state: Colorado
city: Loveland
country: United States
facility: McKee Medical Center
state: Colorado
city: Westminster
country: United States
facility: St. Anthony North Hospital
state: Colorado
city: Wheat Ridge
country: United States
facility: Exempla Lutheran Medical Center
state: Colorado
city: Pensacola
country: United States
facility: West Florida Cancer Institute at West Florida Hospital - Pensacola
state: Florida
city: Atlanta
country: United States
facility: Piedmont Hospital
state: Georgia
city: Atlanta
country: United States
facility: CCOP - Atlanta Regional
state: Georgia
city: Atlanta
country: United States
facility: Northside Hospital Cancer Center
state: Georgia
city: Atlanta
country: United States
facility: Saint Joseph's Hospital of Atlanta
state: Georgia
city: Austell
country: United States
facility: WellStar Cobb Hospital
state: Georgia
city: Decatur
country: United States
facility: Charles B. Eberhart Cancer Center at DeKalb Medical Center
state: Georgia
city: Gainesville
country: United States
facility: Northeast Georgia Medical Center
state: Georgia
city: Lawrenceville
country: United States
facility: Gwinnett Medical Center
state: Georgia
city: Marietta
country: United States
facility: Kennestone Cancer Center at Wellstar Kennestone Hospital
state: Georgia
city: Riverdale
country: United States
facility: Southern Regional Medical Center
state: Georgia
city: Idaho Falls
country: United States
facility: Hematology Oncology Associates of Eastern Idaho
state: Idaho
city: Alton
country: United States
facility: Saint Anthony's Hospital at Saint Anthony's Health Center
state: Illinois
city: Chicago
country: United States
facility: University of Illinois at Chicago Cancer Center
state: Illinois
city: Chicago
country: United States
facility: Veterans Affairs Medical Center - Chicago Westside Hospital
state: Illinois
city: Decatur
country: United States
facility: Decatur Memorial Hospital Cancer Care Institute
state: Illinois
city: Mt. Vernon
country: United States
facility: Good Samaritan Regional Health Center
state: Illinois
city: Springfield
country: United States
facility: Regional Cancer Center at Memorial Medical Center
state: Illinois
city: Beech Grove
country: United States
facility: St. Francis Hospital and Health Centers
state: Indiana
city: Davenport
country: United States
facility: Genesis Regional Cancer Center at Genesis Medical Center
state: Iowa
city: Davenport
country: United States
facility: Genesis Medical Center - West Campus
state: Iowa
city: Chanute
country: United States
facility: Cancer Center of Kansas - Chanute
state: Kansas
city: Dodge City
country: United States
facility: Cancer Center of Kansas - Dodge City
state: Kansas
city: El Dorado
country: United States
facility: Cancer Center of Kansas, P.A. - El Dorado
state: Kansas
city: Kansas City
country: United States
facility: Veterans Affairs Medical Center - Kansas City
state: Kansas
city: Kansas City
country: United States
facility: Kansas Masonic Cancer Research Institute at the University of Kansas Medical Center
state: Kansas
city: Kingman
country: United States
facility: Cancer Center of Kansas - Kingman
state: Kansas
city: Liberal
country: United States
facility: Southwest Medical Center
state: Kansas
city: Newton
country: United States
facility: Cancer Center of Kansas - Newton
state: Kansas
city: Parsons
country: United States
facility: Cancer Center of Kansas, P.A. - Parsons
state: Kansas
city: Pratt
country: United States
facility: Pratt Cancer Center of Kansas
state: Kansas
city: Salina
country: United States
facility: Cancer Center of Kansas - Salina
state: Kansas
city: Salina
country: United States
facility: Salina Regional Health Center
state: Kansas
city: Topeka
country: United States
facility: Stormont-Vail Cancer Center
state: Kansas
city: Topeka
country: United States
facility: St. Francis Comprehensive Cancer Center
state: Kansas
city: Wellington
country: United States
facility: Cancer Center of Kansas - Wellington
state: Kansas
city: Wichita
country: United States
facility: Associates in Womens Health
state: Kansas
city: Wichita
country: United States
facility: Cancer Center of Kansas, P.A.
state: Kansas
city: Wichita
country: United States
facility: Cancer Center of Kansas, P.A. - Wichita
state: Kansas
city: Wichita
country: United States
facility: CCOP - Wichita
state: Kansas
city: Wichita
country: United States
facility: Via Christi Cancer Center at Via Christi Regional Medical Center
state: Kansas
city: Wichita
country: United States
facility: Wesley Medical Center
state: Kansas
city: Winfield
country: United States
facility: Cancer Center of Kansas - Winfield
state: Kansas
city: Baton Rouge
country: United States
facility: Baton Rouge General Regional Cancer Center
state: Louisiana
city: Baton Rouge
country: United States
facility: Mary Bird Perkins Cancer Center - Baton Rouge
state: Louisiana
city: New Orleans
country: United States
facility: MBCCOP - LSU Health Sciences Center
state: Louisiana
city: New Orleans
country: United States
facility: Medical Center of Louisiana - New Orleans
state: Louisiana
city: Battle Creek
country: United States
facility: Battle Creek Health System Cancer Care Center
state: Michigan
city: Big Rapids
country: United States
facility: Mecosta County General Hospital
state: Michigan
city: Grand Rapids
country: United States
facility: CCOP - Grand Rapids
state: Michigan
city: Grand Rapids
country: United States
facility: Lacks Cancer Center at Saint Mary's Mercy Medical Center
state: Michigan
city: Grand Rapids
country: United States
facility: Spectrum Health Cancer Care - Butterworth Campus
state: Michigan
city: Grand Rapids
country: United States
facility: Metropolitan Hospital
state: Michigan
city: Holland
country: United States
facility: Holland Community Hospital
state: Michigan
city: Muskegon
country: United States
facility: Hackley Hospital
state: Michigan
city: Petoskey
country: United States
facility: Northern Michigan Hospital
state: Michigan
city: Royal Oak
country: United States
facility: William Beaumont Hospital - Royal Oak Campus
state: Michigan
city: Traverse City
country: United States
facility: Munson Medical Center
state: Michigan
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Cape Girardeau
country: United States
facility: St. Francis Medical Center
state: Missouri
city: Gape Girardeau
country: United States
facility: Southeast Missouri Regional Cancer Center at Southeast Missouri Hospital
state: Missouri
city: Joplin
country: United States
facility: Freeman Cancer Institute at Freeman Health System
state: Missouri
city: Kansas City
country: United States
facility: CCOP - Kansas City
state: Missouri
city: Springfield
country: United States
facility: St. John's Regional Health Center
state: Missouri
city: Springfield
country: United States
facility: Hulston Cancer Center at Cox Medical Center South
state: Missouri
city: St. Louis
country: United States
facility: CCOP - St. Louis-Cape Girardeau
state: Missouri
city: St. Louis
country: United States
facility: David C. Pratt Cancer Center at St. John's Mercy
state: Missouri
city: Billings
country: United States
facility: CCOP - Montana Cancer Consortium
state: Montana
city: Billings
country: United States
facility: Deaconess Billings Clinic - Downtown
state: Montana
city: Billings
country: United States
facility: Hematology-Oncology Centers of the Northern Rockies - Billings
state: Montana
city: Billings
country: United States
facility: Northern Rockies Radiation Oncology Center
state: Montana
city: Billings
country: United States
facility: St. Vincent Healthcare
state: Montana
city: Billings
country: United States
facility: Deaconess Billings Clinic Cancer Center
state: Montana
city: Bozeman
country: United States
facility: Bozeman Deaconess Hospital
state: Montana
city: Bozeman
country: United States
facility: Internal Medicine Associates of Bozeman
state: Montana
city: Butte
country: United States
facility: St. James Community Hospital
state: Montana
city: Great Falls
country: United States
facility: Great Falls Clinic
state: Montana
city: Great Falls
country: United States
facility: Sletten Regional Cancer Institute
state: Montana
city: Helena
country: United States
facility: St. Peter's Hospital
state: Montana
city: Kalispell
country: United States
facility: Glacier Oncology, PLLC
state: Montana
city: Kalispell
country: United States
facility: Kalispell Medical Oncology
state: Montana
city: Miles City
country: United States
facility: Eastern Montana Cancer Center
state: Montana
city: Missoula
country: United States
facility: Community Medical Center
state: Montana
city: Missoula
country: United States
facility: Montana Cancer Center at St. Patrick Hospital and Health Sciences Center
state: Montana
city: Missoula
country: United States
facility: Montana Cancer Specialists at Montana Cancer Center
state: Montana
city: Kearney
country: United States
facility: Good Samaritan Health Systems
state: Nebraska
city: Rochester
country: United States
facility: James P. Wilmot Cancer Center at University of Rochester Medical Center
state: New York
city: Charlotte
country: United States
facility: Presbyterian Cancer Center at Presbyterian Hospital
state: North Carolina
city: Goldsboro
country: United States
facility: Wayne Memorial Hospital, Incorporated
state: North Carolina
city: Chillicothe
country: United States
facility: Adena Regional Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Taussig Cancer Center
state: Ohio
city: Columbus
country: United States
facility: Riverside Methodist Hospital Cancer Care
state: Ohio
city: Columbus
country: United States
facility: CCOP - Columbus
state: Ohio
city: Columbus
country: United States
facility: Grant Riverside Cancer Services
state: Ohio
city: Columbus
country: United States
facility: Mount Carmel West Hospital
state: Ohio
city: Columbus
country: United States
facility: Doctors Hospital at Ohio Health
state: Ohio
city: Dayton
country: United States
facility: Grandview Hospital
state: Ohio
city: Dayton
country: United States
facility: Good Samaritan Hospital
state: Ohio
city: Dayton
country: United States
facility: David L. Rike Cancer Center at Miami Valley Hospital
state: Ohio
city: Dayton
country: United States
facility: Samaritan North Cancer Care Center
state: Ohio
city: Dayton
country: United States
facility: Veterans Affairs Medical Center - Dayton
state: Ohio
city: Dayton
country: United States
facility: CCOP - Dayton
state: Ohio
city: Delaware
country: United States
facility: Grady Memorial Hospital
state: Ohio
city: Independence
country: United States
facility: Community Oncology Group - Independence
state: Ohio
city: Kettering
country: United States
facility: Charles F. Kettering Memorial Hospital
state: Ohio
city: Lancaster
country: United States
facility: Fairfield Medical Center
state: Ohio
city: Marietta
country: United States
facility: Strecker Cancer Center at Marietta Memorial Hospital
state: Ohio
city: Middletown
country: United States
facility: Middletown Regional Hospital
state: Ohio
city: Newark
country: United States
facility: Licking Memorial Cancer Care Program at Licking Memorial Hospital
state: Ohio
city: Springfield
country: United States
facility: Mercy Medical Center Oncology Unit
state: Ohio
city: Springfield
country: United States
facility: Community Hospital of Springfield and Clark County
state: Ohio
city: Troy
country: United States
facility: UVMC Cancer Care Center at Upper Valley Medical Center
state: Ohio
city: Westerville
country: United States
facility: Mount Carmel Cancer Services at Mount Carmel St. Ann's Hospital
state: Ohio
city: Wooster
country: United States
facility: Cleveland Clinic - Wooster
state: Ohio
city: Xenia
country: United States
facility: Ruth G. McMillan Cancer Center at Greene Memorial Hospital
state: Ohio
city: Zanesville
country: United States
facility: Genesis - Good Samaritan Hospital
state: Ohio
city: Glesham
country: United States
facility: Legacy Mount Hood Medical Center
state: Oregon
city: Milwaukie
country: United States
facility: Providence Milwaukie Hospital
state: Oregon
city: Portland
country: United States
facility: Legacy Good Samaritan Hospital & Medical Center Comprehensive Cancer Center
state: Oregon
city: Portland
country: United States
facility: Providence Cancer Center at Providence Portland Medical Center
state: Oregon
city: Portland
country: United States
facility: CCOP - Columbia River Oncology Program
state: Oregon
city: Portland
country: United States
facility: Providence St. Vincent Medical Center
state: Oregon
city: Portland
country: United States
facility: Institute of Oncology at Vilnius University
state: Oregon
city: Salem
country: United States
facility: Salem Hospital Regional Cancer Center
state: Oregon
city: Tualatin
country: United States
facility: Legacy Meridian Park Hospital
state: Oregon
city: Kingsport
country: United States
facility: Christine LaGuardia Phillips Cancer Center at Wellmont Holston Valley Medical Center
state: Tennessee
city: Fort Sam Houston
country: United States
facility: Brooke Army Medical Center
state: Texas
city: Lackland AFB
country: United States
facility: Wilford Hall Medical Center
state: Texas
city: Temple
country: United States
facility: CCOP - Scott and White Hospital
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute at University of Utah
state: Utah
city: Danville
country: United States
facility: Danville Regional Medical Center
state: Virginia
city: Bellingham
country: United States
facility: St. Joseph Hospital Community Cancer Center
state: Washington
city: Bremerton
country: United States
facility: Olympic Hematology and Oncology
state: Washington
city: Federal Way
country: United States
facility: St. Francis Hospital
state: Washington
city: Mt. Vernon
country: United States
facility: Skagit Valley Hospital Cancer Care Center
state: Washington
city: Olympia
country: United States
facility: Capital Medical Center
state: Washington
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: Seattle
country: United States
facility: Group Health Central Hospital
state: Washington
city: Seattle
country: United States
facility: Harborview Medical Center
state: Washington
city: Seattle
country: United States
facility: Swedish Cancer Institute at Swedish Medical Center - First Hill Campus
state: Washington
city: Seattle
country: United States
facility: University Cancer Center at University of Washington Medical Center
state: Washington
city: Sedro-Wooley
country: United States
facility: North Puget Oncology at United General Hospital
state: Washington
city: Spokane
country: United States
facility: Cancer Care Northwest - Spokane South
state: Washington
city: Tacoma
country: United States
facility: Allenmore Hospital
state: Washington
city: Tacoma
country: United States
facility: CCOP - Northwest
state: Washington
city: Tacoma
country: United States
facility: St. Clare Hospital
state: Washington
city: Vancouver
country: United States
facility: Southwest Washington Medical Center Cancer Center
state: Washington
city: Wenatchee
country: United States
facility: Central Washington Hospital
state: Washington
city: Wenatchee
country: United States
facility: Wenatchee Valley Clinic
state: Washington
city: Sheridan
country: United States
facility: Welch Cancer Center
state: Wyoming
Study officials:
affiliation: University of Utah
name: Deborah T. Blumenthal, MD
role: STUDY_CHAIR
affiliation: University of Washington
name: Alexander M. Spence, MD
role: STUDY_CHAIR
affiliation: Celilo Cancer Center at Mid-Columbia Medical Center
name: Keith J. Stelzer, MD, PhD
role: STUDY_CHAIR
References:
citation: Blumenthal DT, Wade M, Rankin CJ, et al.: MGMT methylation in newly-diagnosed glioblastoma multiforme (GBM): from the S0001 phase III study of radiation therapy (RT) and O6-benzylguanine, (O6BG) plus BCNU versus RT and BCNU alone for newly diagnosed GBM. [Abstract] J Clin Oncol 24 (Suppl 18): A-1512, 2006.
citation: Quezado M, Ronchetti R, Rapkiewicz A, Santi M, Blumenthal DT, Rushing EJ. Chromogenic in situ hybridization accurately identifies EGFR amplification in small cell glioblastoma multiforme, a common subtype of primary GBM. Clin Neuropathol. 2005 Jul-Aug;24(4):163-9.
citation: Blumenthal DT, Rankin C, Stelzer KJ, Spence AM, Sloan AE, Moore DF Jr, Padula GD, Schulman SB, Wade ML, Rushing EJ. A Phase III study of radiation therapy (RT) and O(6)-benzylguanine + BCNU versus RT and BCNU alone and methylation status in newly diagnosed glioblastoma and gliosarcoma: Southwest Oncology Group (SWOG) study S0001. Int J Clin Oncol. 2015 Aug;20(4):650-8. doi: 10.1007/s10147-014-0769-0. Epub 2014 Nov 19.