Temozolomide and Radiation Therapy With or Without Bevacizumab in Treating Patients With Newly Diagnosed Glioblastoma

Glioblastoma Clinical Trial

Official title:

Phase III Double-blind Placebo-Controlled Trial of Conventional Concurrent Chemoradiation and Adjuvant Temozolomide Plus Bevacizumab Versus Conventional Concurrent Chemoradiation and Adjuvant Temozolomide in Patients With Newly Diagnosed Glioblastoma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00884741
• Other study ID #: NCI-2009-01670
• Secondary ID: NCI-2009-01670RT
• Status: Completed
• Phase: Phase 3
• Start date: April 15, 2009
• Est. completion date: March 17, 2013

Study information

• Verified date: July 2019
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This randomized phase III trial studies temozolomide (TMZ) and radiation therapy (RT) to compare how well they work with or without bevacizumab in treating patients with newly diagnosed glioblastoma or gliosarcoma. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high-energy x-rays to kill tumor cells. Monoclonal antibodies, such as bevacizumab, may find tumor cells and help kill them. It is not yet known whether temozolomide and radiation therapy are more effective when given together with or without bevacizumab in treating glioblastoma or gliosarcoma.

Description:

PRIMARY OBJECTIVES:

I. To determine whether the addition of bevacizumab to temozolomide and radiation improves efficacy as measured by progression-free and/or overall survival.

II. To assess the association between overall survival and K^trans change from T1 to T2. (ACRIN 6686) III. To assess the association between overall survival and spin echo cerebral blood volume (CBV) change from T1 to T2. (ACRIN 6686)

SECONDARY OBJECTIVES:

I. To determine whether the tumor molecular profile conferring a mesenchymal/angiogenic phenotype is associated with a selective increase in benefit, as measured by either overall survival or progression-free survival, from the addition of bevacizumab.

II. To compare and record the toxicities of the conventional and bevacizumab-containing regimens.

III. To assess the association between progression-free survival and K^trans change from T1 to T2. (ACRIN 6686) IV. To assess the association between progression-free survival and spin echo CBV change from T1 to T2. (ACRIN 6686) V. To assess the association between values of K^trans and spin echo CBV measured separately at T0 and at T1, and overall and progression-free survival. (ACRIN 6686) VI. To assess the association between overall survival and K^trans changes from T0 to T1 and from T2 to T3. (ACRIN 6686) VII. To assess the association between overall survival and spin echo CBV changes from T0 to T1 and from T2 to T3. (ACRIN 6686) VIII. To assess the association between overall survival and apparent diffusion coefficient (ADC) change from T0 to T1. (ACRIN 6686) IX. To assess the association between overall survival and ADC change from T1 to T2. (ACRIN 6686) X. To assess the association between progression-free survival and ADC change from T0 to T1. (ACRIN 6686) XI. To assess the association between progression-free survival and ADC change from T1 to T2. (ACRIN 6686) XII. To assess the association between T1 values of ADC and overall and progression-free survival. (ACRIN 6686) XIII. To assess the association between change in lesion size between T1 and T3, as measured by advanced magnetic resonance imaging (MRI), and overall and progression-free survival. (ACRIN 6686)

TERTIARY OBJECTIVES:

I. To determine the differential acute effects associated with the addition of bevacizumab to temozolomide and radiation, as compared to the conventional arm, on measures of neurocognitive function, health-related quality of life, and symptoms during radiation and across the longitudinal progression-free interval.

II. To determine the relationship of neurocognitive function, health-related quality of life, and symptoms, with progression-free and overall survival.

III. To determine the association between tumor molecular profile (i.e., mesenchymal/angiogenic phenotype and proneural phenotype) and neurocognitive function, health-related quality of life, and symptoms.

IV. To describe the association between health-related quality of life as measured by the European Organization for Research and Treatment Quality of Life Questionnaire-Core 30/Brain Cancer Module-20 (EORTC-QL30/BCM20) and mean symptom severity as measured by the M. D. Anderson Symptom Inventory Brain Tumor Module (MDASI-BT) in patients enrolled in this study.

V. To evaluate the relationship between self-reported neurocognitive function and objectively measured tests of neurocognitive function (NCF).

VI. To assess the association between measures of change in enhancing tumor size at week 22 and overall survival in participants with glioma receiving chemoradiotherapy with and without bevacizumab.

VII. To assess the association between measures of change in T2-based tumor size at week 22 and overall survival in participants with glioma receiving chemoradiotherapy with and without bevacizumab.

VIII. To assess the association between changes in ADC values and overall survival in participants with glioma receiving chemoradiotherapy with and without bevacizumab.

OUTLINE: Patients are randomized to 1 of 2 treatment arms (there are also two registration steps prior to randomization which are labeled as "arms" in ClinicalTrials.gov to facilitate entry of results into the website).

ARM I: Patients undergo intensity-modulated radiation therapy or 3-dimensional conformal radiation therapy 5 days a week for 6 weeks and receive temozolomide orally (PO) once daily (QD) for up to 7 weeks. Beginning 4 weeks after completion of chemotherapy and radiation therapy, patients receive temozolomide PO QD on days 1-5. Treatment with temozolomide repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Patients also receive placebo IV over 30-90 minutes once every 2 weeks beginning in week 4 of chemotherapy and radiation therapy and continuing until the completion of temozolomide.

ARM II: Patients undergo radiation therapy and receive temozolomide as in Arm I. Patients also receive bevacizumab IV over 30-90 minutes once every 2 weeks beginning in week 4 of chemoradiotherapy and continuing until the completion of adjuvant temozolomide.

After completion of study treatment, patients are followed up every 3 months for 1 year, every 4 months for 1 year, and then every 6 months thereafter.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 637
• Est. completion date: March 17, 2013
• Est. primary completion date: March 17, 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histologically proven diagnosis of glioblastoma or gliosarcoma (World Health Organization [WHO] grade IV) confirmed by central review prior to step 2 registration

• Tumor tissue that is determined by central pathology review prior to step 2 registration to be of sufficient size for analysis of O-6-methylguanine-DNA methyltransferase (MGMT) and determination of molecular profile

• Patients must have at least 1 block of tumor tissue; submission of 2 blocks is strongly encouraged to maximize the chances of eligibility; at least 1 cubic centimeter of tissue composed primarily of tumor must be present

• CUSA (Cavitron ultrasonic aspirator)-derived material is not allowed; fresh frozen tumor tissue acquisition is encouraged

• Diagnosis must be made by surgical excision, either partial or complete; stereotactic biopsy is not allowed because it will not provide sufficient tissue for MGMT analysis

• The tumor tissue should be sent as soon as possible to maximize the likelihood of eligibility; tumor tissue should be submitted by 4 weeks after the surgical procedure so that the study registration and treatment can commence by the mandatory 5 week post-surgery outer limit

• Sites must submit tissue fir central review in order to obtain the MGMT analysis; patients from sites not following protocol-specified process for obtaining MGMT results will be made ineligible

• The tumor must have a supratentorial component

• History/physical examination within 14 days prior to step 2 registration

• The patient must have recovered from the effects of surgery, postoperative infection, and other complications before step 2 registration

• A diagnostic contrast-enhanced MRI of the brain must be performed preoperatively and postoperatively prior to the initiation of radiotherapy; the postoperative scan must be performed within 28 days prior to step 1 registration

• An MRI or computed tomography (CT) scan (potentially in addition to the postoperative scan) must be obtained within 10 days prior to the start of radiation therapy and must not demonstrate significant postoperative hemorrhage defined as > 1 cm diameter of blood; if > 1 cm of acute blood is detected, the patient will be ineligible for this trial; the radiation planning MRI or CT scan may be used to determine presence of hemorrhage

• Patients unable to undergo MR imaging because of non-compatible devices can be enrolled, provided pre- and postoperative contrast-enhanced CT scans are obtained and are of sufficient quality; preoperative and postoperative scans must be the same type; such patients cannot be enrolled into the advanced imaging component

• Documentation of steroid doses within 14 days prior to step 2 registration

• Karnofsky performance status >= 70

• Absolute neutrophil count (ANC) >= 1,800 cells/mm^3

• Platelets >= 100,000 cells/mm^3

• Hemoglobin >= 10.0 g/dL (Note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 10.0 g/dl is acceptable)

• Blood urea nitrogen (BUN) =< 30 mg/dL within 14 days prior to step 2 registration

• Creatinine =< 1.7 mg/dl within 14 days prior to step 2 registration

• Urine protein screened by urine analysis for urine protein creatinine (UPC) ratio; for UPC ratio > 0.5, 24-hour urine protein should be obtained and the level should be < 1000 mg

• Bilirubin =< 2.0 mg/dl within 14 days prior to step 2 registration

• Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) =< 3 x normal range within 14 days prior to step 2 registration

• Systolic blood pressure =< 160 mg Hg or diastolic pressure =< 90 mm Hg within 14 days prior to step 2 registration

• Electrocardiogram without evidence of acute cardiac ischemia within 14 days prior to step 2 registration

• Prothrombin time/international normalized ratio (PT INR) < 1.4 for patients not on warfarin confirmed by testing within 14 days prior to step 2 registration

• Patients on full-dose anticoagulants (e.g., warfarin or low molecular weight [LMW] heparin) must meet both of the following criteria:

• No active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices)

• In-range INR (between 2 and 3) on a stable dose of oral anticoagulant or on a stable dose of LMW heparin

• Patient must provide study specific informed consent prior to study entry

• Women of childbearing potential and male participants must practice adequate contraception

• For females of child-bearing potential, negative serum pregnancy test within 14 days prior to step 2 registration

Exclusion Criteria:

• Prior invasive malignancy (except for non-melanomatous skin cancer) unless disease free for >= 3 years; (for example, carcinoma in situ of the breast, oral cavity, and cervix are all permissible)

• Recurrent or multifocal malignant gliomas

• Metastases detected below the tentorium or beyond the cranial vault

• Prior chemotherapy or radiosensitizers for cancers of the head and neck region; note that prior chemotherapy for a different cancer is allowable, except prior temozolomide or bevacizumab; prior use of Gliadel wafers or any other intratumoral or intracavitary treatment are not permitted

• Prior radiotherapy to the head or neck (except for T1 glottic cancer), resulting in overlap of radiation fields

• Severe, active co-morbidity, defined as follows:

• Unstable angina and/or congestive heart failure within the last 6 months

• Transmural myocardial infarction within the last 6 months

• Evidence of recent myocardial infarction or ischemia by the findings of S-T elevations of >= 2 mm using the analysis of an electrocardiogram (EKG) performed within 14 days of step 2 registration

• New York Heart Association grade II or greater congestive heart failure requiring hospitalization within 12 months prior to step 2 registration

• History of stroke, cerebral vascular accident (CVA) or transient ischemic attack within 6 months

• Serious and inadequately controlled cardiac arrhythmia

• Significant vascular disease (e.g., aortic aneurysm, history of aortic dissection) or clinically significant peripheral vascular disease

• Evidence of bleeding diathesis or coagulopathy

• Serious or non-healing wound, ulcer, or bone fracture or history of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to step 2 registration, with the exception of the craniotomy for tumor resection

• Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration

• Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of step 2 registration

• Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; note, however, that laboratory tests for liver function and coagulation parameters are not required for entry into this protocol

• Acquired immune deficiency syndrome (AIDS) based upon current Center for Disease Control (CDC) definition; note, however, that HIV testing is not required for entry into this protocol; the need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive

• Active connective tissue disorders, such as lupus or scleroderma, that in the opinion of the treating physician may put the patient at high risk for radiation toxicity

• Any other major medical illnesses or psychiatric impairments that in the investigator's opinion will prevent administration or completion of protocol therapy

• Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception

• Pregnant or lactating women

• Patients treated on any other therapeutic clinical protocols within 30 days prior to study entry or during participation in the study

• For American College of Radiology Imaging Network (ACRIN) 6686 Advanced Imaging:

inability to undergo MRI (e.g., due to safety reasons, such as presence of a pacemaker)

Related Conditions & MeSH terms

• Glioblastoma
• Gliosarcoma
• Supratentorial Glioblastoma

Intervention

Radiation:
• 3-Dimensional Conformal Radiation Therapy
Undergo 3-dimentional conformal radiation therapy

Biological:
• Bevacizumab
Given IV

Radiation:
• Intensity-Modulated Radiation Therapy
Undergo intensity-modulated radiation therapy

Other:
• Laboratory Biomarker Analysis
Correlative studies
• Placebo
Given IV
• Quality-of-Life Assessment
Ancillary studies

Drug:
• Temozolomide
Given orally

Locations

Country	Name	City	State
Canada	CHUM - Hopital Notre-Dame	Montreal	Quebec
Canada	McGill University Department of Oncology	Montreal	Quebec
Canada	Allan Blair Cancer Centre	Regina	Saskatchewan
Canada	Doctor H. Bliss Murphy Cancer Centre	St. John's	Newfoundland and Labrador
Canada	Health Sciences North	Sudbury	Ontario
Israel	Tel Aviv Sourasky Medical Center	Tel Aviv
United States	Abington Memorial Hospital	Abington	Pennsylvania
United States	Akron General Medical Center	Akron	Ohio
United States	Summa Akron City Hospital/Cooper Cancer Center	Akron	Ohio
United States	New York Oncology Hematology PC - Albany	Albany	New York
United States	Lovelace Medical Center-Downtown	Albuquerque	New Mexico
United States	New Mexico Oncology Hematology Consultants	Albuquerque	New Mexico
United States	University of New Mexico Cancer Center	Albuquerque	New Mexico
United States	Inova Alexandria Hospital	Alexandria	Virginia
United States	Lehigh Valley Hospital-Cedar Crest	Allentown	Pennsylvania
United States	McFarland Clinic PC-William R Bliss Cancer Center	Ames	Iowa
United States	Providence Alaska Medical Center	Anchorage	Alaska
United States	Saint Joseph Mercy Hospital	Ann Arbor	Michigan
United States	Anne Arundel Medical Center	Annapolis	Maryland
United States	Langlade Hospital and Cancer Center	Antigo	Wisconsin
United States	Radiology Associates of Appleton/ThedaCare Regional Medical Center	Appleton	Wisconsin
United States	Texas Oncology-Arlington South	Arlington	Texas
United States	Northwest Community Hospital	Arlington Heights	Illinois
United States	Mission Hospital-Memorial Campus	Asheville	North Carolina
United States	Emory University Hospital/Winship Cancer Institute	Atlanta	Georgia
United States	Piedmont Hospital	Atlanta	Georgia
United States	Sutter Cancer Centers Radiation Oncology Services-Auburn	Auburn	California
United States	Rocky Mountain Cancer Centers-Aurora	Aurora	Colorado
United States	Saint Agnes Hospital	Baltimore	Maryland
United States	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland
United States	Summa Barberton Hospital	Barberton	Ohio
United States	Mary Bird Perkins Cancer Center	Baton Rouge	Louisiana
United States	UHHS-Chagrin Highlands Medical Center	Beachwood	Ohio
United States	UPMC-Heritage Valley Health System Beaver	Beaver	Pennsylvania
United States	Texas Oncology Bedford	Bedford	Texas
United States	PeaceHealth Saint Joseph Medical Center	Bellingham	Washington
United States	Sanford Clinic North-Bemidgi	Bemidji	Minnesota
United States	Alta Bates Summit Medical Center-Herrick Campus	Berkeley	California
United States	Saint Luke's University Hospital-Bethlehem Campus	Bethlehem	Pennsylvania
United States	Billings Clinic Cancer Center	Billings	Montana
United States	IU Health Bloomington	Bloomington	Indiana
United States	Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho
United States	Massachusetts General Hospital Cancer Center	Boston	Massachusetts
United States	Boulder Community Hospital	Boulder	Colorado
United States	Harrison Medical Center	Bremerton	Washington
United States	Saint Vincent's Medical Center	Bridgeport	Connecticut
United States	Montefiore Medical Center - Moses Campus	Bronx	New York
United States	Maimonides Medical Center	Brooklyn	New York
United States	Saint Joseph Regional Cancer Center	Bryan	Texas
United States	Bryn Mawr Hospital	Bryn Mawr	Pennsylvania
United States	University of Vermont Medical Center	Burlington	Vermont
United States	Fairview Ridges Hospital	Burnsville	Minnesota
United States	Sutter Cancer Centers Radiation Oncology Services-Cameron Park	Cameron Park	California
United States	Sands Cancer Center	Canandaigua	New York
United States	Aultman Health Foundation	Canton	Ohio
United States	Mercy Medical Center	Canton	Ohio
United States	Cape Radiation Oncology	Cape Girardeau	Missouri
United States	Mercy San Juan Medical Center	Carmichael	California
United States	Physicians' Clinic of Iowa PC	Cedar Rapids	Iowa
United States	Carolinas Medical Center/Levine Cancer Institute	Charlotte	North Carolina
United States	Novant Health Presbyterian Medical Center	Charlotte	North Carolina
United States	Erlanger Medical Center	Chattanooga	Tennessee
United States	John H Stroger Jr Hospital of Cook County	Chicago	Illinois
United States	Northwestern University	Chicago	Illinois
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	University of Cincinnati/Barrett Cancer Center	Cincinnati	Ohio
United States	Case Western Reserve University	Cleveland	Ohio
United States	Cleveland Clinic Cancer Center/Fairview Hospital	Cleveland	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	MetroHealth Medical Center	Cleveland	Ohio
United States	Penrose-Saint Francis Healthcare	Colorado Springs	Colorado
United States	Grant Medical Center	Columbus	Ohio
United States	John B Amos Cancer Center	Columbus	Georgia
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	Riverside Methodist Hospital	Columbus	Ohio
United States	The Mark H Zangmeister Center	Columbus	Ohio
United States	Concord Hospital	Concord	New Hampshire
United States	John Muir Medical Center-Concord Campus	Concord	California
United States	Mercy Hospital	Coon Rapids	Minnesota
United States	Siteman Cancer Center at West County Hospital	Creve Coeur	Missouri
United States	Texas Oncology Methodist Charlton Cancer Center	Dallas	Texas
United States	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas
United States	Geisinger Medical Center	Danville	Pennsylvania
United States	Beaumont Hospital-Dearborn	Dearborn	Michigan
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	Dekalb Medical Center	Decatur	Georgia
United States	Texas Oncology-Denton South	Denton	Texas
United States	Porter Adventist Hospital	Denver	Colorado
United States	Iowa Methodist Medical Center	Des Moines	Iowa
United States	Mercy Medical Center - Des Moines	Des Moines	Iowa
United States	Saint John Hospital and Medical Center	Detroit	Michigan
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	Saint Luke's Hospital of Duluth	Duluth	Minnesota
United States	Northeast Radiation Oncology Center	Dunmore	Pennsylvania
United States	Pocono Medical Center	East Stroudsburg	Pennsylvania
United States	Marshfield Clinic Cancer Center at Sacred Heart	Eau Claire	Wisconsin
United States	Sacred Heart Hospital	Eau Claire	Wisconsin
United States	Swedish Medical Center	Englewood	Colorado
United States	The Regional Cancer Center	Erie	Pennsylvania
United States	Willamette Valley Cancer Center	Eugene	Oregon
United States	Saint Anne's Hospital	Fall River	Massachusetts
United States	Sanford Broadway Medical Center	Fargo	North Dakota
United States	Genesys Regional Medical Center-West Flint Campus	Flint	Michigan
United States	Poudre Valley Hospital	Fort Collins	Colorado
United States	Broward Health Medical Center	Fort Lauderdale	Florida
United States	Parkview Hospital Randallia	Fort Wayne	Indiana
United States	Radiation Oncology Associates PC	Fort Wayne	Indiana
United States	The Klabzuba Cancer Center	Fort Worth	Texas
United States	California Cancer Center - North Fresno	Fresno	California
United States	Cancer Care Associates of Fresno Medical Group Inc	Fresno	California
United States	Saint Jude Medical Center	Fullerton	California
United States	Fox Chase Cancer Center Buckingham	Furlong	Pennsylvania
United States	Northeast Georgia Medical Center-Gainesville	Gainesville	Georgia
United States	University of Texas Medical Branch	Galveston	Texas
United States	Adams Cancer Center	Gettysburg	Pennsylvania
United States	Bellin Memorial Hospital	Green Bay	Wisconsin
United States	Saint Vincent Hospital Cancer Center at Saint Mary's	Green Bay	Wisconsin
United States	Saint Vincent Hospital Cancer Center Green Bay	Green Bay	Wisconsin
United States	UPMC Cancer Centers - Arnold Palmer Pavilion	Greensburg	Pennsylvania
United States	Cherry Tree Cancer Center	Hanover	Pennsylvania
United States	Hartford Hospital	Hartford	Connecticut
United States	Ingalls Memorial Hospital	Harvey	Illinois
United States	Margaret R Pardee Memorial Hospital	Hendersonville	North Carolina
United States	Penn State Milton S Hershey Medical Center	Hershey	Pennsylvania
United States	Memorial Regional Hospital/Joe DiMaggio Children's Hospital	Hollywood	Florida
United States	University of Hawaii Cancer Center	Honolulu	Hawaii
United States	M D Anderson Cancer Center	Houston	Texas
United States	Cape Cod Hospital	Hyannis	Massachusetts
United States	Community Cancer Center East	Indianapolis	Indiana
United States	Community Cancer Center North	Indianapolis	Indiana
United States	IU Health Central Indiana Cancer Centers-East	Indianapolis	Indiana
United States	IU Health Methodist Hospital	Indianapolis	Indiana
United States	Saint Vincent Hospital and Health Care Center	Indianapolis	Indiana
United States	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa
United States	Jackson-Madison County General Hospital	Jackson	Tennessee
United States	Baptist MD Anderson Cancer Center	Jacksonville	Florida
United States	Baptist Medical Center South	Jacksonville	Florida
United States	Integrated Community Oncology Network-Southside Cancer Center	Jacksonville	Florida
United States	Mayo Clinic in Florida	Jacksonville	Florida
United States	Integrated Community Oncology Network-Florida Cancer Center Beaches	Jacksonville Beach	Florida
United States	UW Cancer Center Johnson Creek	Johnson Creek	Wisconsin
United States	UPMC-Johnstown/John P. Murtha Regional Cancer Center	Johnstown	Pennsylvania
United States	West Michigan Cancer Center	Kalamazoo	Michigan
United States	The University of Kansas Cancer Center-North	Kansas City	Missouri
United States	The University of Kansas Cancer Center-South	Kansas City	Missouri
United States	Truman Medical Center	Kansas City	Missouri
United States	University of Kansas Cancer Center	Kansas City	Kansas
United States	CHI Health Good Samaritan	Kearney	Nebraska
United States	Armstrong Center for Medicine and Health	Kittanning	Pennsylvania
United States	Thompson Cancer Survival Center	Knoxville	Tennessee
United States	Gundersen Lutheran Medical Center	La Crosse	Wisconsin
United States	UC San Diego Moores Cancer Center	La Jolla	California
United States	Lancaster General Hospital	Lancaster	Pennsylvania
United States	Sparrow Hospital	Lansing	Michigan
United States	Nevada Cancer Research Foundation CCOP	Las Vegas	Nevada
United States	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire
United States	Central Maine Medical Center	Lewiston	Maine
United States	Saint Elizabeth Regional Medical Center	Lincoln	Nebraska
United States	Rocky Mountain Cancer Centers-Littleton	Littleton	Colorado
United States	Saint Barnabas Medical Center	Livingston	New Jersey
United States	Monmouth Medical Center	Long Branch	New Jersey
United States	Texas Oncology-Longview Cancer Center	Longview	Texas
United States	USC / Norris Comprehensive Cancer Center	Los Angeles	California
United States	The James Graham Brown Cancer Center at University of Louisville	Louisville	Kentucky
United States	Lowell General Hospital	Lowell	Massachusetts
United States	Covenant Medical Center-Lakeside	Lubbock	Texas
United States	Dean Hematology and Oncology Clinic	Madison	Wisconsin
United States	University of Wisconsin Hospital and Clinics	Madison	Wisconsin
United States	Elliot Hospital	Manchester	New Hampshire
United States	Minnesota Oncology Hematology PA-Maplewood	Maplewood	Minnesota
United States	Bay Area Medical Center	Marinette	Wisconsin
United States	Marshfield Clinic	Marshfield	Wisconsin
United States	Marshfield Medical Center	Marshfield	Wisconsin
United States	Mercy Medical Center - North Iowa	Mason City	Iowa
United States	Toledo Clinic Cancer Centers-Maumee	Maumee	Ohio
United States	Hillcrest Hospital Cancer Center	Mayfield Heights	Ohio
United States	Loyola University Medical Center	Maywood	Illinois
United States	UPMC Cancer Center at UPMC McKeesport	McKeesport	Pennsylvania
United States	Lake University Ireland Cancer Center	Mentor	Ohio
United States	Baptist Hospital of Miami	Miami	Florida
United States	Mount Sinai Medical Center	Miami Beach	Florida
United States	Southwest General Health Center Ireland Cancer Center	Middleburg Heights	Ohio
United States	Froedtert and the Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Abbott-Northwestern Hospital	Minneapolis	Minnesota
United States	Marshfield Clinic-Minocqua Center	Minocqua	Wisconsin
United States	Providence Hospital	Mobile	Alabama
United States	Memorial Medical Center	Modesto	California
United States	Trinity Medical Center	Moline	Illinois
United States	Intercommunity Cancer Center	Monroeville	Pennsylvania
United States	IU Health Ball Memorial Hospital	Muncie	Indiana
United States	Intermountain Medical Center	Murray	Utah
United States	Edward Hospital/Cancer Center	Naperville	Illinois
United States	Allegheny Valley Hospital	Natrona Heights	Pennsylvania
United States	The Hospital of Central Connecticut	New Britain	Connecticut
United States	Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital	New Brunswick	New Jersey
United States	UPMC Jameson	New Castle	Pennsylvania
United States	Yale University	New Haven	Connecticut
United States	Ochsner Medical Center Jefferson	New Orleans	Louisiana
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	Sentara Norfolk General Hospital	Norfolk	Virginia
United States	William Backus Hospital	Norwich	Connecticut
United States	Bay Area Tumor Institute	Oakland	California
United States	Kaiser Permanente Oakland-Broadway	Oakland	California
United States	South Nassau Communities	Oceanside	New York
United States	West Texas Cancer Center	Odessa	Texas
United States	McKay-Dee Hospital Center	Ogden	Utah
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Alegent Health Bergan Mercy Medical Center	Omaha	Nebraska
United States	Alegent Health Immanuel Medical Center	Omaha	Nebraska
United States	Nebraska Methodist Hospital	Omaha	Nebraska
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Saint Joseph Hospital - Orange	Orange	California
United States	21st Century Oncology-Orange Park	Orange Park	Florida
United States	Saint Charles Hospital	Oregon	Ohio
United States	Florida Hospital Orlando	Orlando	Florida
United States	UF Cancer Center at Orlando Health	Orlando	Florida
United States	University of Kansas Cancer Center-Overland Park	Overland Park	Kansas
United States	21st Century Oncology-Palatka	Palatka	Florida
United States	Paoli Memorial Hospital	Paoli	Pennsylvania
United States	Advocate Lutheran General Hospital	Park Ridge	Illinois
United States	Singing River Hospital	Pascagoula	Mississippi
United States	Sacred Heart Hospital	Pensacola	Florida
United States	Methodist Medical Center of Illinois	Peoria	Illinois
United States	Aria Health-Torresdale Campus	Philadelphia	Pennsylvania
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania
United States	FirstHealth of the Carolinas-Moore Regional Hosiptal	Pinehurst	North Carolina
United States	Allegheny General Hospital	Pittsburgh	Pennsylvania
United States	UPMC Jefferson Regional Radiation Oncology	Pittsburgh	Pennsylvania
United States	UPMC-Passavant Hospital	Pittsburgh	Pennsylvania
United States	UPMC-Shadyside Hospital	Pittsburgh	Pennsylvania
United States	Pomona Valley Hospital Medical Center	Pomona	California
United States	Legacy Good Samaritan Hospital and Medical Center	Portland	Oregon
United States	Providence Portland Medical Center	Portland	Oregon
United States	Providence Saint Vincent Medical Center	Portland	Oregon
United States	Naval Medical Center - Portsmouth	Portsmouth	Virginia
United States	Hudson Valley Oncology Associates	Poughkeepsie	New York
United States	Kansas City NCI Community Oncology Research Program	Prairie Village	Kansas
United States	Rhode Island Hospital	Providence	Rhode Island
United States	Utah Valley Regional Medical Center	Provo	Utah
United States	Duke Women's Cancer Care Raleigh	Raleigh	North Carolina
United States	Kaiser Permanente-Rancho Cordova Cancer Center	Rancho Cordova	California
United States	Rapid City Regional Hospital	Rapid City	South Dakota
United States	Riverview Medical Center/Booker Cancer Center	Red Bank	New Jersey
United States	Renown Regional Medical Center	Reno	Nevada
United States	Southern Regional Medical Center	Riverdale	Georgia
United States	North Memorial Medical Health Center	Robbinsdale	Minnesota
United States	Highland Hospital	Rochester	New York
United States	Mayo Clinic	Rochester	Minnesota
United States	University of Rochester	Rochester	New York
United States	University Radiation Oncology	Rochester	New York
United States	Rohnert Park Cancer Center	Rohnert Park	California
United States	Sutter Cancer Centers Radiation Oncology Services-Roseville	Roseville	California
United States	The Permanente Medical Group-Roseville Radiation Oncology	Roseville	California
United States	William Beaumont Hospital-Royal Oak	Royal Oak	Michigan
United States	Mercy General Hospital Radiation Oncology Center	Sacramento	California
United States	South Sacramento Cancer Center	Sacramento	California
United States	Sutter Medical Center Sacramento	Sacramento	California
United States	Saint Mary's of Michigan	Saginaw	Michigan
United States	Integrated Community Oncology Network-Flager Cancer Center	Saint Augustine	Florida
United States	Coborn Cancer Center at Saint Cloud Hospital	Saint Cloud	Minnesota
United States	Dixie Medical Center Regional Cancer Center	Saint George	Utah
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Park Nicollet Clinic - Saint Louis Park	Saint Louis Park	Minnesota
United States	Regions Hospital	Saint Paul	Minnesota
United States	United Hospital	Saint Paul	Minnesota
United States	Siteman Cancer Center at Saint Peters Hospital	Saint Peters	Missouri
United States	Cancer Care Center, Incorporated	Salem	Ohio
United States	Salem Hospital	Salem	Oregon
United States	Huntsman Cancer Institute/University of Utah	Salt Lake City	Utah
United States	LDS Hospital	Salt Lake City	Utah
United States	Utah Cancer Specialists-Salt Lake City	Salt Lake City	Utah
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	University of California San Diego	San Diego	California
United States	California Pacific Medical Center-Pacific Campus	San Francisco	California
United States	North Coast Cancer Care	Sandusky	Ohio
United States	Kaiser Permanente Medical Center - Santa Clara	Santa Clara	California
United States	Memorial University Medical Center	Savannah	Georgia
United States	Maine Medical Center- Scarborough Campus	Scarborough	Maine
United States	Arizona Oncology Services Foundation	Scottsdale	Arizona
United States	Mayo Clinic in Arizona	Scottsdale	Arizona
United States	Swedish Medical Center-First Hill	Seattle	Washington
United States	Virginia Mason Medical Center	Seattle	Washington
United States	UPMC Cancer Center at UPMC Northwest	Seneca	Pennsylvania
United States	Texas Cancer Center-Sherman	Sherman	Texas
United States	Louisiana State University Health Sciences Center Shreveport	Shreveport	Louisiana
United States	Sanford Cancer Center-Oncology Clinic	Sioux Falls	South Dakota
United States	Northern Indiana Cancer Research Consortium	South Bend	Indiana
United States	Kaiser Permanente Cancer Treatment Center	South San Francisco	California
United States	Sparta Cancer Treatment Center	Sparta	New Jersey
United States	Spartanburg Medical Center	Spartanburg	South Carolina
United States	Cancer Care Northwest - Spokane South	Spokane	Washington
United States	D'Amour Center for Cancer Care	Springfield	Massachusetts
United States	Memorial Medical Center	Springfield	Illinois
United States	Trinity's Tony Teramana Cancer Center	Steubenville	Ohio
United States	Saint Michael's Hospital	Stevens Point	Wisconsin
United States	Stony Brook University Medical Center	Stony Brook	New York
United States	Robert and Carol Weissman Cancer Center at Martin Health	Stuart	Florida
United States	Texas Oncology Cancer Center Sugar Land	Sugar Land	Texas
United States	Flower Hospital	Sylvania	Ohio
United States	State University of New York Upstate Medical University	Syracuse	New York
United States	North Suburban Medical Center	Thornton	Colorado
United States	Mercy Saint Anne Hospital	Toledo	Ohio
United States	Arizona Oncology Associates-West Orange Grove	Tucson	Arizona
United States	Natalie Warren Bryant Cancer Center at Saint Francis	Tulsa	Oklahoma
United States	Tyler Cancer Center	Tyler	Texas
United States	Sutter Cancer Centers Radiation Oncology Services-Vacaville	Vacaville	California
United States	Compass Oncology Vancouver	Vancouver	Washington
United States	PeaceHealth Southwest Medical Center	Vancouver	Washington
United States	Ridgeview Medical Center	Waconia	Minnesota
United States	John Muir Medical Center-Walnut Creek	Walnut Creek	California
United States	Saint John Macomb-Oakland Hospital	Warren	Michigan
United States	UPMC Washington Hospital Radiation Oncology	Washington	Pennsylvania
United States	ProHealth Waukesha Memorial Hospital	Waukesha	Wisconsin
United States	Aspirus Regional Cancer Center	Wausau	Wisconsin
United States	University Pointe	West Chester	Ohio
United States	Reading Hospital	West Reading	Pennsylvania
United States	UHHS-Westlake Medical Center	Westlake	Ohio
United States	Diagnostic and Treatment Center	Weston	Wisconsin
United States	Marshfield Clinic - Weston Center	Weston	Wisconsin
United States	SCL Health Lutheran Medical Center	Wheat Ridge	Colorado
United States	Wheeling Hospital/Schiffler Cancer Center	Wheeling	West Virginia
United States	Via Christi Regional Medical Center	Wichita	Kansas
United States	Wesley Medical Center	Wichita	Kansas
United States	Novant Health Forsyth Medical Center	Winston-Salem	North Carolina
United States	Southeast Clinical Oncology Research (SCOR) Consortium NCORP	Winston-Salem	North Carolina
United States	Aspirus UW Cancer Center	Wisconsin Rapids	Wisconsin
United States	Lankenau Medical Center	Wynnewood	Pennsylvania
United States	North Star Lodge Cancer Center at Yakima Valley Memorial Hospital	Yakima	Washington
United States	WellSpan Health-York Hospital	York	Pennsylvania

Sponsors (3)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)	NRG Oncology, Radiation Therapy Oncology Group

Countries where clinical trial is conducted

United States,  Canada,  Israel, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Quality of Life Measured by the M.D. Anderson Symptom Inventory Brain Tumor Module (MDASI-BT Tool) and EORTC Quality of Life Questionnaire-Core/Brain Cancer Module( QLQ-C30/BCM20)		Analysis can occur at or after time of primary outcome measure analysis.
Other	Neurocognitive Function Measured by the Hopkins Verbal Learning Test-Revised(HVLT-R), Trail Making Test Part A, Trail Making Test Part B, Controlled Oral Word Association Test (COWAT)		Analysis can occur at or after time of primary outcome measure analysis.
Primary	Overall Survival (OS)	Survival time was defined as time from randomization to date of death from any cause and was estimated by the Kaplan-Meier method. Patients last known to be alive were censored at the date of last contact. This analysis was planned to occur when 390 deaths had been reported.	From randomization to date of death or last follow-up. Analysis occurs after all 390 deaths have been reported.
Primary	Progression-free Survival (PFS)	Progression-free survival was defined as time from randomization to date of progression, death, or last follow-up, and was estimated by the Kaplan-Meier method. Patients last known to be alive were censored at the date of last contact. This analysis was planned to occur when 390 deaths had been reported.	From randomization to date of progression, death, or last follow-up for progression-free survival. Analysis occurs after all 390 deaths have been reported.
Secondary	Incidence of Grade 3 and Higher Treatment-related Toxicity as Assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (AEs) Version 3.0	AEs are graded by using CTCAE 3.0. The difference between the two randomized arms in the percentage of patients with grade 3 or higher toxicities reported as possibly/probably/definitely related to protocol treatment will be tested using a chi square test.	Up to 30 days