Dose-Escalated Photon IMRT or Proton Beam Radiation Therapy Versus Standard-Dose Radiation Therapy and Temozolomide in Treating Patients With Newly Diagnosed Glioblastoma

Adult Glioblastoma Clinical Trial

Official title:

Randomized Phase II Trial of Hypofractionated Dose-Escalated Photon IMRT or Proton Beam Therapy Versus Conventional Photon Irradiation With Concomitant and Adjuvant Temozolomide in Patients With Newly Diagnosed Glioblastoma

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02179086
• Other study ID #: NRG-BN001
• Secondary ID: NCI-2014-01072NR
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: October 27, 2014
• Est. completion date: May 2026

Study information

• Verified date: January 2024
• Source: NRG Oncology
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This randomized phase II trial studies how well dose-escalated photon intensity-modulated radiation therapy (IMRT) or proton beam radiation therapy works compared with standard-dose radiation therapy when given with temozolomide in patients with newly diagnosed glioblastoma. Radiation therapy uses high-energy x-rays and other types of radiation to kill tumor cells and shrink tumors. Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Drugs, such as temozolomide, may make tumor cells more sensitive to radiation therapy. It is not yet known whether dose-escalated photon IMRT or proton beam radiation therapy is more effective than standard-dose radiation therapy with temozolomide in treating glioblastoma.

Description:

PRIMARY OBJECTIVES:

I. To determine if dose-escalated and -intensified photon IMRT or proton beam therapy (using a dose-per-fraction escalation with simultaneous integrated boost) with concomitant and adjuvant temozolomide improves overall survival, as compared to standard-dose photon irradiation with concomitant and adjuvant temozolomide.

SECONDARY OBJECTIVES:

I. To indirectly compare dose-escalated and -intensified photon IMRT to dose-escalated and -intensified proton beam therapy in terms of overall survival.

II. To indirectly compare and record toxicities of dose-escalated and -intensified photon IMRT versus dose-escalated and -intensified proton beam therapy and directly compare the toxicities of these approaches versus standard-dose photon irradiation on the backbone of concomitant and adjuvant temozolomide.

III. To determine if dose-escalated and -intensified photon IMRT or proton beam therapy (using a dose-per-fraction escalation with simultaneous integrated boost) with concomitant and adjuvant temozolomide improves perceived cognitive symptom severity, as compared to standard-dose photon irradiation with concomitant and adjuvant temozolomide.

IV. To determine if dose-escalated and -intensified photon IMRT or proton beam therapy (using a dose-per-fraction escalation with simultaneous integrated boost) with concomitant and adjuvant temozolomide improves neurocognitive function, as compared to standard-dose photon irradiation with concomitant and adjuvant temozolomide.

V. To indirectly determine if dose-escalated and -intensified proton beam therapy with concomitant and adjuvant temozolomide improves perceived cognitive symptom severity, as compared to dose-escalated and -intensified photon IMRT, and to directly compare symptom burden with these approaches versus standard-dose photon irradiation on the backbone of concomitant and adjuvant temozolomide.

VI. To indirectly determine if dose-escalated and -intensified proton beam therapy with concomitant and adjuvant temozolomide improves neurocognitive function, as compared to dose-escalated and -intensified photon IMRT, and to directly compare neurocognitive function with these approaches versus standard-dose photon irradiation on the backbone of concomitant and adjuvant temozolomide.

TERTIARY OBJECTIVES:

I. Tissue banking for future translational science projects that will be determined based on the state of the science at the time the primary endpoint is reported and will be submitted to National Cancer Institute (NCI) for review and approval.

II. To prospectively compare CD4 lymphopenia between dose-escalated and intensified proton beam therapy, dose-escalated and -intensified photon IMRT, and standard-dose photon irradiation and determine whether CD4 lymphopenia impacts overall survival.

III. To explore the most appropriate and clinically relevant technological parameters to ensure quality and effectiveness throughout radiation therapy processes, including imaging, simulation, patient immobilization, target and critical structure definition, treatment planning, image guidance and delivery.

• To establish feasibility and clinical relevancy of quality assurance guidelines.

• To evaluate efficacy of quality assurance tools.

IV. To explore the most appropriate and clinically relevant advanced and standard MRI imaging parameters.

• To evaluate the feasibility of differentiating pseudo-progression and true progression in a multi institutional setting using MR diffusion and perfusion imaging.

• To evaluate for early, imaging biomarkers of response and overall survival.

OUTLINE: Patients are assigned to 1 of 2 groups depending on enrolling institution. Within each group, patients will be randomized 1:2 in favor of the experimental arms.

GROUP I (PHOTON IMRT CENTERS): Patients are randomized to 1 of 2 treatment arms.

ARM A1: Patients undergo standard-dose photon irradiation using 3-dimensional conformal radiation therapy (3D-CRT) or IMRT once daily (QD), 5 days a week for 23 fractions plus a boost of 7 additional fractions.

ARM B: Patients undergo dose-escalated and -intensified photon IMRT QD, 5 days a week for a total of 30 fractions.

GROUP II (PROTON CENTERS): Patients are randomized to 1 of 2 treatment arms.

ARM A2: Patients undergo standard-dose photon irradiation using 3D-CRT or IMRT as in Arm A1.

ARM C: Patients undergo dose-escalated and -intensified proton beam radiation therapy QD, 5 days a week for a total of 30 fractions.

In all treatment arms, patients receive temozolomide orally (PO) QD on days 1-49 of radiation therapy. Beginning 4 weeks later, patients receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.

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.

Other known NCT identifiers

• NCT02163135

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 624
• Est. completion date: May 2026
• Est. primary completion date: May 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• PRIOR TO STEP 1 REGISTRATION

• A diagnostic contrast-enhanced magnetic resonance imaging (MRI) (no other scan type allowed) of the brain must be performed postoperatively within 72 hours of resection; the enhancing tumor must have a maximal diameter of 5 cm; the tumor diameter will be the greatest diameter as measured on the contrast-enhanced postoperative MRI and will include residual disease and/or the postoperative surgical cavity as appropriate; for cases where residual disease or postoperative surgical cavity is NOT identifiable (e.g., polar glioblastomas [GBMs] where a polar lobectomy is performed), the patient will be excluded from the trial

• The GBM tumor must be located in the supratentorial compartment only (any component involving the brain stem or cerebellum is not allowed)

• Patients must provide study-specific informed consent prior to step 1 registration

• PRIOR TO STEP 2 REGISTRATION

• Histologically proven diagnosis of glioblastoma (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 quantity for analysis of O(6)-methylguanine-DNA-methyltransferase (MGMT) status

• 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

• Diagnosis must be made by surgical excision, either partial or complete; stereotactic biopsy or cavitron ultrasonic suction aspirator (CUSA) technique are not allowed

• History/physical examination within 28 days prior to step 2 registration

• The patient must have recovered from effects of surgery, postoperative infection, and other complications within 28 days prior to step 2 registration

• Documentation of steroid doses within 28 days prior to step 2 registration

• Karnofsky performance status >= 70 within 28 days prior to step 2 registration

• Age >= 18

• 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)

• Bilirubin =< 1.5 upper limit of normal (ULN)

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN

• Negative serum pregnancy test obtained for females of child-bearing potential within 28 days prior to step 2 registration

Exclusion Criteria:

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

• Recurrent or multifocal malignant gliomas

• Any site of distant disease (for example, drop metastases from the GBM tumor site)

• Prior chemotherapy or radiosensitizers for cancers of the head and neck region; note that prior chemotherapy for a different cancer is allowable (except temozolomide)

• 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 at step 2 registration

• Transmural myocardial infarction within the last 6 months prior to step 2 registration

• 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 28 days prior to step 2 registration

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

• Serious and inadequately controlled arrhythmia at step 2 registration

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

• Acute bacterial or fungal infection requiring intravenous antibiotics at the time of step 2 registration

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

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

• Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; note, however, that human immunodeficiency virus (HIV) testing is not required for entry into this protocol

• Any other severe immunocompromised condition

• 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

• End-stage renal disease (ie, on dialysis or dialysis has been recommended)

• Any other major medical illnesses or psychiatric treatments 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

• Patents treated on any other therapeutic clinical protocols within 30 days prior to step 2 registration

• Inability to undergo MRI (e.g., due to safety reasons, such as presence of a pacemaker, or severe claustrophobia)

• Postoperative tumor plus surgical bed size exceeds 5 cm in maximum diameter.

Related Conditions & MeSH terms

• Adult Giant Cell Glioblastoma
• Adult Glioblastoma
• Adult Gliosarcoma
• Glioblastoma
• Gliosarcoma

Intervention

Radiation:
• 3-dimensional conformal radiation therapy
Undergo standard-dose 3D-CRT
• intensity-modulated radiation therapy
Undergo standard-dose IMRT
• photon beam radiation therapy
Undergo dose-escalated and -intensified photon IMRT
• intensity-modulated radiation therapy
Undergo dose-escalated and -intensified photon IMRT
• proton beam radiation therapy
Undergo dose-escalated and -intensified proton beam radiation therapy

Drug:
• temozolomide
Given PO

Other:
• laboratory biomarker analysis
Correlative studies

Locations

Country	Name	City	State
Canada	CHUM - Centre Hospitalier de l'Universite de Montreal	Montreal	Quebec
Canada	CHUM - Hopital Notre-Dame	Montreal	Quebec
Canada	McGill University Department of Oncology	Montreal	Quebec
Canada	The Research Institute of the McGill University Health Centre (MUHC)	Montreal	Quebec
Canada	Ottawa Hospital and Cancer Center-General Campus	Ottawa	Ontario
Canada	CHU de Quebec-L'Hotel-Dieu de Quebec (HDQ)	Quebec City	Quebec
Canada	Saskatoon Cancer Centre	Saskatoon	Saskatchewan
Canada	BCCA-Vancouver Island Cancer Centre	Victoria	British Columbia
Canada	Windsor Regional Cancer Centre	Windsor	Ontario
United States	Cleveland Clinic Akron General	Akron	Ohio
United States	Saint Joseph Mercy Hospital	Ann Arbor	Michigan
United States	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan
United States	Langlade Hospital and Cancer Center	Antigo	Wisconsin
United States	Mission Hospital	Asheville	North Carolina
United States	Emory Proton Therapy Center	Atlanta	Georgia
United States	Emory University Hospital Midtown	Atlanta	Georgia
United States	Emory University Hospital/Winship Cancer Institute	Atlanta	Georgia
United States	Sutter Cancer Centers Radiation Oncology Services-Auburn	Auburn	California
United States	Austin Cancer Centers-Central Austin	Austin	Texas
United States	Austin Cancer Centers-North	Austin	Texas
United States	Dell Seton Medical Center at The University of Texas	Austin	Texas
United States	Texas Oncology - Central Austin Cancer Center	Austin	Texas
United States	Texas Oncology - South Austin Cancer Center	Austin	Texas
United States	Texas Oncology-Austin Midtown	Austin	Texas
United States	AIS Cancer Center at San Joaquin Community Hospital	Bakersfield	California
United States	Maryland Proton Treatment Center	Baltimore	Maryland
United States	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland
United States	Memorial Sloan Kettering Basking Ridge	Basking Ridge	New Jersey
United States	McLaren Cancer Institute-Bay City	Bay City	Michigan
United States	UHHS-Chagrin Highlands Medical Center	Beachwood	Ohio
United States	UM Upper Chesapeake Medical Center	Bel Air	Maryland
United States	Sanford Joe Lueken Cancer Center	Bemidji	Minnesota
United States	Alta Bates Summit Medical Center-Herrick Campus	Berkeley	California
United States	Central Vermont Medical Center/National Life Cancer Treatment	Berlin	Vermont
United States	Saint Luke's University Hospital-Bethlehem Campus	Bethlehem	Pennsylvania
United States	Billings Clinic Cancer Center	Billings	Montana
United States	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama
United States	Sanford Bismarck Medical Center	Bismarck	North Dakota
United States	Boca Raton Regional Hospital	Boca Raton	Florida
United States	Prisma Health Cancer Institute - Spartanburg	Boiling Springs	South Carolina
United States	Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho
United States	Boston Medical Center	Boston	Massachusetts
United States	Massachusetts General Hospital Cancer Center	Boston	Massachusetts
United States	Tufts Medical Center	Boston	Massachusetts
United States	Montefiore Medical Center - Moses Campus	Bronx	New York
United States	New York-Presbyterian/Brooklyn Methodist Hospital	Brooklyn	New York
United States	University of Vermont Medical Center	Burlington	Vermont
United States	Sutter Cancer Centers Radiation Oncology Services-Cameron Park	Cameron Park	California
United States	Eden Hospital Medical Center	Castro Valley	California
United States	Mercy Hospital	Cedar Rapids	Iowa
United States	Geauga Hospital	Chardon	Ohio
United States	Medical University of South Carolina	Charleston	South Carolina
United States	John H Stroger Jr Hospital of Cook County	Chicago	Illinois
United States	Northwestern University	Chicago	Illinois
United States	Rush University Medical Center	Chicago	Illinois
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	University of Cincinnati Cancer Center-UC Medical 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	UCHealth Memorial Hospital Central	Colorado Springs	Colorado
United States	Central Maryland Radiation Oncology in Howard County	Columbia	Maryland
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	Riverside Methodist Hospital	Columbus	Ohio
United States	Memorial Sloan Kettering Commack	Commack	New York
United States	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas
United States	Mass General/North Shore Cancer Center	Danvers	Massachusetts
United States	Beaumont Hospital - Dearborn	Dearborn	Michigan
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	Northwestern Medicine Cancer Center Kishwaukee	DeKalb	Illinois
United States	Texas Oncology - Denison Cancer Center	Denison	Texas
United States	Iowa Methodist Medical Center	Des Moines	Iowa
United States	Henry Ford Hospital	Detroit	Michigan
United States	Saint Luke's Hospital of Duluth	Duluth	Minnesota
United States	Northeast Radiation Oncology Center	Dunmore	Pennsylvania
United States	Mercy Cancer Center-Elyria	Elyria	Ohio
United States	Ephrata Cancer Center	Ephrata	Pennsylvania
United States	Willamette Valley Cancer Center	Eugene	Oregon
United States	Sanford Roger Maris Cancer Center	Fargo	North Dakota
United States	McLaren Cancer Institute-Flint	Flint	Michigan
United States	Texas Oncology-Flower Mound	Flower Mound	Texas
United States	Poudre Valley Hospital	Fort Collins	Colorado
United States	Parkview Hospital Randallia	Fort Wayne	Indiana
United States	Parkview Regional Medical Center	Fort Wayne	Indiana
United States	Radiation Oncology Associates PC	Fort Wayne	Indiana
United States	Texas Oncology - Fort Worth Cancer Center	Fort Worth	Texas
United States	Fresno Cancer Center	Fresno	California
United States	University of Florida Health Science Center - Gainesville	Gainesville	Florida
United States	University of Texas Medical Branch	Galveston	Texas
United States	Northwestern Medicine Cancer Center Delnor	Geneva	Illinois
United States	Adams Cancer Center	Gettysburg	Pennsylvania
United States	UM Baltimore Washington Medical Center/Tate Cancer Center	Glen Burnie	Maryland
United States	Spectrum Health at Butterworth Campus	Grand Rapids	Michigan
United States	Trinity Health Grand Rapids Hospital	Grand Rapids	Michigan
United States	Marin General Hospital	Greenbrae	California
United States	Prisma Health Cancer Institute - Eastside	Greenville	South Carolina
United States	Prisma Health Cancer Institute - Faris	Greenville	South Carolina
United States	Self Regional Healthcare	Greenwood	South Carolina
United States	Prisma Health Cancer Institute - Greer	Greer	South Carolina
United States	Legacy Mount Hood Medical Center	Gresham	Oregon
United States	UPMC Pinnacle Cancer Center/Community Osteopathic Campus	Harrisburg	Pennsylvania
United States	Memorial Sloan Kettering Westchester	Harrison	New York
United States	Hartford Hospital	Hartford	Connecticut
United States	M D Anderson Cancer Center	Houston	Texas
United States	Memorial Hermann Memorial City Medical Center	Houston	Texas
United States	Cleveland Clinic Cancer Center Independence	Independence	Ohio
United States	Community Cancer Center East	Indianapolis	Indiana
United States	Community Cancer Center North	Indianapolis	Indiana
United States	Community Cancer Center South	Indianapolis	Indiana
United States	IU Health Methodist Hospital	Indianapolis	Indiana
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Baptist MD Anderson Cancer Center	Jacksonville	Florida
United States	Baptist Medical Center South	Jacksonville	Florida
United States	University of Florida Health Science Center - Jacksonville	Jacksonville	Florida
United States	West Michigan Cancer Center	Kalamazoo	Michigan
United States	North Kansas City Hospital	Kansas City	Missouri
United States	University of Kansas Cancer Center	Kansas City	Kansas
United States	University of Kansas Cancer Center - North	Kansas City	Missouri
United States	Tennessee Cancer Specialists-Dowell Springs	Knoxville	Tennessee
United States	Gundersen Lutheran Medical Center	La Crosse	Wisconsin
United States	Northwell Health/Center for Advanced Medicine	Lake Success	New York
United States	McLaren Cancer Institute-Lapeer Region	Lapeer	Michigan
United States	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada
United States	UTMB Cancer Center at Victory Lakes	League City	Texas
United States	Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center	Lebanon	New Hampshire
United States	Sechler Family Cancer Center	Lebanon	Pennsylvania
United States	University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	Trinity Health Saint Mary Mercy Livonia Hospital	Livonia	Michigan
United States	Logan Regional Hospital	Logan	Utah
United States	Loma Linda University Medical Center	Loma Linda	California
United States	Cedars Sinai Medical Center	Los Angeles	California
United States	Los Angeles General Medical Center	Los Angeles	California
United States	USC / Norris Comprehensive Cancer Center	Los Angeles	California
United States	Norton Hospital Pavilion and Medical Campus	Louisville	Kentucky
United States	Lowell General Hospital	Lowell	Massachusetts
United States	Covenant Medical Center-Lakeside	Lubbock	Texas
United States	University of Wisconsin Carbone Cancer Center	Madison	Wisconsin
United States	Fremont - Rideout Cancer Center	Marysville	California
United States	Hillcrest Hospital Cancer Center	Mayfield Heights	Ohio
United States	Froedtert Menomonee Falls Hospital	Menomonee Falls	Wisconsin
United States	UH Seidman Cancer Center at Lake Health Mentor Campus	Mentor	Ohio
United States	Miami Cancer Institute	Miami	Florida
United States	UH Seidman Cancer Center at Southwest General Hospital	Middleburg Heights	Ohio
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Memorial Medical Center	Modesto	California
United States	McLaren Cancer Institute-Macomb	Mount Clemens	Michigan
United States	McLaren Cancer Institute-Central Michigan	Mount Pleasant	Michigan
United States	IU Health Ball Memorial Hospital	Muncie	Indiana
United States	Intermountain Medical Center	Murray	Utah
United States	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey
United States	Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital	New Brunswick	New Jersey
United States	UC Comprehensive Cancer Center at Silver Cross	New Lenox	Illinois
United States	Ochsner Medical Center Jefferson	New Orleans	Louisiana
United States	Laura and Isaac Perlmutter Cancer Center at NYU Langone	New York	New York
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center	New York	New York
United States	Kaiser Permanente Oakland-Broadway	Oakland	California
United States	McKay-Dee Hospital Center	Ogden	Utah
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Saint Joseph Hospital - Orange	Orange	California
United States	UC Irvine Health/Chao Family Comprehensive Cancer Center	Orange	California
United States	University of Kansas Cancer Center-Overland Park	Overland Park	Kansas
United States	McLaren Cancer Institute-Owosso	Owosso	Michigan
United States	Palo Alto Medical Foundation Health Care	Palo Alto	California
United States	Advocate Lutheran General Hospital	Park Ridge	Illinois
United States	University Hospitals Parma Medical Center	Parma	Ohio
United States	Capital Health Medical Center-Hopewell	Pennington	New Jersey
United States	OSF Saint Francis Medical Center	Peoria	Illinois
United States	McLaren Cancer Institute-Northern Michigan	Petoskey	Michigan
United States	Jefferson Torresdale Hospital	Philadelphia	Pennsylvania
United States	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania
United States	University of Pennsylvania/Abramson Cancer Center	Philadelphia	Pennsylvania
United States	Mayo Clinic Hospital in Arizona	Phoenix	Arizona
United States	Saint Joseph's Hospital and Medical Center	Phoenix	Arizona
United States	Pomona Valley Hospital Medical Center	Pomona	California
United States	Saint Joseph Mercy Oakland	Pontiac	Michigan
United States	Legacy Good Samaritan Hospital and Medical Center	Portland	Oregon
United States	Utah Valley Regional Medical Center	Provo	Utah
United States	Kaiser Permanente-Rancho Cordova Cancer Center	Rancho Cordova	California
United States	Renown Regional Medical Center	Reno	Nevada
United States	Saint Mary's Regional Medical Center	Reno	Nevada
United States	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia
United States	Mayo Clinic in Rochester	Rochester	Minnesota
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	Texas Oncology - Round Rock Cancer Center	Round Rock	Texas
United States	Texas Oncology-Seton Williamson	Round Rock	Texas
United States	William Beaumont Hospital-Royal Oak	Royal Oak	Michigan
United States	South Sacramento Cancer Center	Sacramento	California
United States	Sutter Medical Center Sacramento	Sacramento	California
United States	University of California Davis Comprehensive Cancer Center	Sacramento	California
United States	Coborn Cancer Center at Saint Cloud Hospital	Saint Cloud	Minnesota
United States	Saint George Regional Medical Center	Saint George	Utah
United States	Norris Cotton Cancer Center-North	Saint Johnsbury	Vermont
United States	Lakeland Medical Center Saint Joseph	Saint Joseph	Michigan
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Regions Hospital	Saint Paul	Minnesota
United States	Huntsman Cancer Institute/University of Utah	Salt Lake City	Utah
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	California Pacific Medical Center-Pacific Campus	San Francisco	California
United States	North Coast Cancer Care	Sandusky	Ohio
United States	UH Seidman Cancer Center at Firelands Regional Medical Center	Sandusky	Ohio
United States	Palo Alto Medical Foundation-Santa Cruz	Santa Cruz	California
United States	Lewis Cancer and Research Pavilion at Saint Joseph's/Candler	Savannah	Georgia
United States	Mayo Clinic in Arizona	Scottsdale	Arizona
United States	FHCC at Northwest Hospital	Seattle	Washington
United States	SCCA Proton Therapy Center	Seattle	Washington
United States	University of Washington Medical Center - Montlake	Seattle	Washington
United States	Prisma Health Cancer Institute - Seneca	Seneca	South Carolina
United States	Willis-Knighton Medical and Cancer Center	Shreveport	Louisiana
United States	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota
United States	ProCure Proton Therapy Center-Somerset	Somerset	New Jersey
United States	Kaiser Permanente Cancer Treatment Center	South San Francisco	California
United States	Memorial Medical Center	Springfield	Illinois
United States	Cleveland Clinic Cancer Center Strongsville	Strongsville	Ohio
United States	Texas Oncology Cancer Center Sugar Land	Sugar Land	Texas
United States	Palo Alto Medical Foundation-Sunnyvale	Sunnyvale	California
United States	Moffitt Cancer Center	Tampa	Florida
United States	University of Toledo	Toledo	Ohio
United States	William Beaumont Hospital - Troy	Troy	Michigan
United States	Arizona Oncology Associates-West Orange Grove	Tucson	Arizona
United States	Banner University Medical Center - Tucson	Tucson	Arizona
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	Legacy Salmon Creek Hospital	Vancouver	Washington
United States	Virtua Voorhees	Voorhees	New Jersey
United States	John Muir Medical Center-Walnut Creek	Walnut Creek	California
United States	Northwestern Medicine Cancer Center Warrenville	Warrenville	Illinois
United States	UW Cancer Center at ProHealth Care	Waukesha	Wisconsin
United States	Aspirus Regional Cancer Center	Wausau	Wisconsin
United States	University of Cincinnati Cancer Center-West Chester	West Chester	Ohio
United States	Reading Hospital	West Reading	Pennsylvania
United States	UHHS-Westlake Medical Center	Westlake	Ohio
United States	Wheeling Hospital/Schiffler Cancer Center	Wheeling	West Virginia
United States	Novant Health Forsyth Medical Center	Winston-Salem	North Carolina
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina
United States	Cleveland Clinic Wooster Family Health and Surgery Center	Wooster	Ohio
United States	WellSpan Health-York Cancer Center	York	Pennsylvania

Sponsors (3)

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

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall survival (OS) compared between dose-escalated and -intensified photon IMRT or proton beam therapy with concomitant and adjuvant temozolomide and the standard-dose photon irradiation with concomitant and adjuvant temozolomide	OS rate will be estimated using the Kaplan-Meier method, and differences between treatment arms will be tested in a stratified log-rank test, consistent with the stratified randomization. The OS rates by MGMT, recursive partitioning analysis (RPA) class and other prognostic factors will be estimated by Kaplan-Meier methods and compared using the log-rank test. Multivariate analyses with the Cox proportional hazard model for OS will be performed to assess the treatment effect adjusting for patient-specific risk factors.	Date of randomization to the date of death due to any cause, assessed up to 5 years
Secondary	OS when compared between dose-escalated and -intensified photon IMRT to dose-escalated and -intensified proton beam therapy	If the instrumental variable assumptions hold, OS rate will be estimated using the Kaplan-Meier method, and differences between treatment arms will be tested in the log-rank test.	Date of randomization to the date of death, assessed up to 5 years
Secondary	Progression-free survival (PFS)	PFS rates will be estimated using the Kaplan-Meier method and comparisons between treatment arms will be made in the same manner as for OS.	Date of randomization to the date of progression or death, assessed up to 5 years
Secondary	Incidence of treatment-related toxicity, as measured by the Common Terminology Criteria for Adverse Events version 4	Differences in observed severities of toxicities (grade 3+) between groups will be estimated using an exact binomial distribution together with 95% confidence interval. The difference between the 2 groups will be tested using a chi square test. If the instrumental variable assumptions hold the experimental arms will also be compared.	Up to 5 years
Secondary	Change in perceived cognitive function, as measured by M.D. Anderson Symptom Inventory Brain Tumor	The change from baseline to each follow-up time point for the perceived cognitive symptom severity score will each be compared using a t-test with alpha=0.05, or Wilcoxon test if the data is not normally distributed, between treatment arms within each group. If the instrumental variable assumptions hold and the perceived cognitive function is significantly different within both groups, a test will be performed to compare between the 2 experimental arms.	Baseline to up to 60 weeks
Secondary	Change in neurocognitive function, as measured by Hopkins' Verbal Learning Test-Revised, Trail Making Test Parts A and B, and Controlled Oral Word Association Test	The change from baseline to each follow-up time point for the perceived Clinical Trial Battery (CTB) composite score will each be compared using a t-test with alpha=0.05, or Wilcoxon test if the data is not normally distributed, between treatment arms within each group. If the instrumental variable assumptions hold and the CTB composite score is significantly different within both groups, a test will be performed to compare between the 2 experimental arms.	Baseline to up to 60 weeks
Secondary	Change in CD4 lymphopenia count	The change from baseline to the completion of radiation will be compared between the control and experimental arms in each group using a t-test. If the instrumental variable assumptions hold, then it will be compared between the experimental arms. A repeated measures analysis, using a mixed effects model, will be used to assess the change of CD4 lymphopenia across time. CD4 count at 2 months after beginning therapy (dichotomized at 200) was shown to be prognostic of OS. This will be assessed here based on the CD4 count at the completion of chemoradiation which matches best to 2-months.	Baseline to up to 5 years
Secondary	Use of magnetic resonance diffusion and perfusion imaging to differentiate between tumor progression and pseudo-progression	Retrospective analysis will be performed to evaluate and refine the method and the threshold cut-off point determined from our previous single institute data set to determine progression using the first one-third of the patient data collected in this trial. If the initial analysis supports our preliminary results with sufficient high sensitivity and specificity, e.g., 80% specificity and 90% sensitivity or higher, results will be validated using the remaining two-thirds of the imaging data.	Up to 5 years