Concurrent Bevacizumab With or Without Radiation Therapy in Treating Patients With Recurrent Glioblastoma

Glioblastoma Clinical Trial

Official title:

Randomized Phase II Trial of Concurrent Bevacizumab and Re-irradiation Versus Bevacizumab Alone as Treatment for Recurrent Glioblastoma

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02671981
• Other study ID #: RTOG 1205
• Secondary ID: NCI-2012-01732RT
• Status: Active, not recruiting
• Phase: Phase 2
• First received: January 29, 2016
• Last updated: April 29, 2016
• Start date: December 2012

Study information

• Verified date: April 2016
• Source: Radiation Therapy Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

This randomized phase II trial studies how well bevacizumab with or without radiation therapy works in treating patients with glioblastoma that has returned after a period of improvement. Monoclonal antibodies, such as bevacizumab, may block tumor growth by targeting certain cells. 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. It is not yet known whether bevacizumab is more effective with or without radiation therapy in treating patients with recurrent glioblastoma.

Description:

PRIMARY OBJECTIVES:

I. To establish an improvement in overall survival in recurrent glioblastoma multiforme (GBM) patients receiving bevacizumab and re-irradiation compared with patients receiving bevacizumab alone.

SECONDARY OBJECTIVES:

I. To estimate and compare the rate of objective response in patients with measurable disease.

II. To estimate and compare the 6-month progression-free survival rate. III. To estimate and compare progression-free survival. IV. To estimate and compare the rate of treatment adverse events. V. To estimate and compare the rate of >= grade 3 acute or delayed central nervous system (CNS) toxicity.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive bevacizumab intravenously (IV) over 30-90 minutes every 2 weeks.

ARM II: Patients receive bevacizumab as in Arm I and undergo radiation therapy using intensity-modulated radiation therapy (IMRT), 3-dimensional conformal radiation therapy (3D-CRT), or proton beam radiation therapy (RT) 5 days a week for 2 weeks.

In both arms, courses with bevacizumab repeat every 2 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 2 months for 1 year, every 6 months for 1 year and then annually thereafter.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 182
• Est. primary completion date: July 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histopathologically proven diagnosis of glioblastoma or variants (gliosarcoma, giant cell glioblastoma etc); patients will be eligible if the original histology was lower-grade glioma and a subsequent diagnosis of glioblastoma or gliosarcoma is made

• Patients who did not have recent surgery for their glioblastoma must have shown unequivocal radiographic evidence for tumor progression by contrast-enhanced MRI scan (or CT scan for patients with non-compatible devices) within 21 days prior to registration; Note: patients who did have surgery with a post-operative contrast-enhanced scan falling outside the 5-week window prior to registration, per definition of recent surgery, must have a repeat magnetic resonance imaging (MRI) scan (or computed tomography [CT] scan for patients with non-compatible devices) within 21 days prior to registration

• Patients must have passed an interval of 6 months or greater between completion of prior radiotherapy and registration; if patients have not passed an interval of at least 6 months, they may still be eligible if they meet one or more of the following criteria:

• New areas of tumor outside the original radiotherapy fields as determined by the investigator, or

• Histologic confirmation of tumor through biopsy or resection, or

• Nuclear medicine imaging, magnetic resonance (MR) spectroscopy, or MR perfusion imaging consistent with true progressive disease, rather than radiation necrosis obtained within 28 days of registration AND an interval of at least 90 days between completion of radiotherapy and registration

• Patients unable to undergo MR imaging because of non-compatible devices can be enrolled provided CT scans are obtained and are of sufficient quality; patients without non-compatible devices may not use CT scans performed to meet this requirement

• Prior history of standard dose CNS radiation of 60 Gy in 30 fractions or 59.4 Gy in 1.8 Gy fractions, or equivalent or lower doses

• Patients who have received prior treatment with non-standard radiation therapy (RT) dose and fractionation, interstitial brachytherapy, stereotactic radiosurgery, etc. are eligible as long as the criterion is met or approved by a principal investigator

• Patients must have recovered from the toxic effects of prior therapy, and there must be a minimum time of 28 days prior to registration from the administration of any investigational agent or prior cytotoxic therapy with the following exceptions:

• 14 days from administration of vincristine

• 42 days from administration of nitrosoureas

• 21 days from administration of procarbazine

• Patients having undergone recent resection of their glioblastoma (within 5 weeks prior to registration) must have recovered from the effects of surgery; for CNS related core or needle biopsies, a minimum of 7 days must have elapsed prior to registration

• Residual disease following resection of recurrent glioblastoma is not mandated for eligibility into the study; to best assess the extent of residual disease post-operatively, a post-operative or intra-operative MRI scan (or CT scan for patients with non-compatible devices) must be performed prior to registration and should be within 96 hours post surgery (although 24 hours would be optimum)

• History/physical examination, including neurologic examination, within 14 days prior to registration

• Karnofsky performance status >= 60 within 14 days prior to registration

• Complete blood count (CBC)/differential obtained within 14 days prior to registration, with adequate bone marrow function

• Absolute neutrophil count (ANC) >= 1,500 cells/mm^3

• Platelets >= 75,000 cells/mm^3

• Hemoglobin >= 9.0 g/dl (Note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 9.0 g/dl is acceptable)

• Total bilirubin =< 2.0 mg/dL

• Serum glutamic oxaloacetic transaminase (SGOT) or aspartate aminotransferase (AST) =< 2.5 times the upper limit of normal

• Serum creatinine =< 1.8 mg/dL

• Urine protein: creatinine (UPC) ratio < 1.0 within 14 days prior to registration OR urine dipstick for proteinuria =< 2 positive (+) (patients discovered to have > 2+ proteinuria on dipstick urinalysis at baseline must have a UPC ratio done that is < 1.0 to be eligible; if the UPC ratio is >= 1.0 then the patients should undergo a 24-hour urine collection and must demonstrate =< 1g of protein in 24 hours to be eligible)

• Note: UPC ratio of spot urine is an estimation of the 24-hour urine protein excretion; a UPC ratio of 1 is roughly equivalent to a 24-hour urine protein of 1 gm

• Patients must not be pregnant (positive pregnancy test) or breast feeding; pregnancy test must be done within 7 days prior to registration; effective contraception (men and women) must be used in patients of child-bearing potential while on study treatment and for 6 months after

• 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 international normalized ratio (INR) (usually between 2 and 3) on a stable dose of oral anticoagulant or on a stable dose of low molecular weight heparin, within 14 days prior to registration

• Patient must be able to provide study-specific informed consent prior to study entry

Exclusion Criteria:

• More than three relapses

• Infratentorial, or leptomeningeal evidence of recurrent disease

• Recurrent or persistent tumor greater than 6 cm in maximum diameter

• Prior therapy with an inhibitor of vascular endothelial growth factor (VEGF) or VEGF receptor (VEGFR) (including bevacizumab)

• Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 1 year (for example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible)

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

• Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months prior to registration

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

• History of stroke or transient ischemic attack within 6 months prior to registration

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

• 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 registration

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

• 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; the need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive; protocol specific requirements may also exclude immuno-compromised patients

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

• Prior allergic reaction to the study drug (bevacizumab)

• Prior history of hypertensive crisis or hypertensive encephalopathy

• History of a non-healing wound, ulcer, or bone fracture within 90 days (3 months) prior to registration

• Gastrointestinal bleeding or any other hemorrhage/bleeding event Common Terminology Criteria for adverse Events (CTCAE), v. 4 grade 3 or greater within 30 days prior to registration

• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to registration (with the exception of craniotomy)

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Brain Neoplasms
• Giant Cell Glioblastoma
• Glioblastoma
• Gliosarcoma
• Recurrent Brain Neoplasm

Intervention

Radiation:
• 3-Dimensional Conformal Radiation Therapy
Undergo 3D-CRT

Biological:
• Bevacizumab
Given IV

Radiation:
• Intensity-Modulated Radiation Therapy
Undergo IMRT
• Proton Beam Radiation Therapy
Undergo proton beam RT

Locations

Country	Name	City	State
Canada	Allan Blair Cancer Centre	Regina	Saskatchewan
Israel	Tel Aviv Sourasky Medical Center	Tel Aviv
United States	Akron General Medical Center	Akron	Ohio
United States	Summa Akron City Hospital/Cooper Cancer Center	Akron	Ohio
United States	Saint Joseph Mercy Hospital	Ann Arbor	Michigan
United States	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan
United States	Anne Arundel Medical Center	Annapolis	Maryland
United States	Emory University Hospital Midtown	Atlanta	Georgia
United States	Emory University/Winship Cancer Institute	Atlanta	Georgia
United States	Northside Hospital	Atlanta	Georgia
United States	Piedmont Hospital	Atlanta	Georgia
United States	Sutter Cancer Centers Radiation Oncology Services-Auburn	Auburn	California
United States	University Medical Center Brackenridge	Austin	Texas
United States	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland
United States	Summa Barberton Hospital	Barberton	Ohio
United States	Southside Hospital	Bay Shore	New York
United States	UPMC-Heritage Valley Health System Beaver	Beaver	Pennsylvania
United States	Upper Chesapeake Medical Center	Bel Air	Maryland
United States	Sanford Clinic North-Bemidgi	Bemidji	Minnesota
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	Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital Cancer Center	Boston	Massachusetts
United States	Tufts Medical Center	Boston	Massachusetts
United States	Rocky Mountain Cancer Centers-Boulder	Boulder	Colorado
United States	Saint Vincent's Medical Center	Bridgeport	Connecticut
United States	Montefiore Medical Center - Moses Campus	Bronx	New York
United States	Providence Saint Joseph Medical Center/Disney Family Cancer Center	Burbank	California
United States	Lahey Hospital and Medical Center	Burlington	Massachusetts
United States	University of Vermont Medical Center	Burlington	Vermont
United States	Sutter Cancer Centers Radiation Oncology Services-Cameron Park	Cameron Park	California
United States	Cape Radiation Oncology	Cape Girardeau	Missouri
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Carolinas Medical Center/Levine Cancer Institute	Charlotte	North Carolina
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 Illinois	Chicago	Illinois
United States	Clackamas Radiation Oncology Center	Clackamas	Oregon
United States	Case Western Reserve University	Cleveland	Ohio
United States	Memorial Hospital Colorado Springs	Colorado Springs	Colorado
United States	Penrose-Saint Francis Healthcare	Colorado Springs	Colorado
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	Riverside Methodist Hospital	Columbus	Ohio
United States	Northside Hospital-Forsyth	Cumming	Georgia
United States	Geisinger Medical Center	Danville	Pennsylvania
United States	University of Miami Sylvester Comprehensive Cancer Center at Deerfield Beach	Deerfield Beach	Florida
United States	Saint John Hospital and Medical Center	Detroit	Michigan
United States	Epic Care-Dublin	Dublin	California
United States	Inova Fairfax Hospital	Falls Church	Virginia
United States	Roger Maris Cancer Center	Fargo	North Dakota
United States	Poudre Valley Hospital	Fort Collins	Colorado
United States	Parkview Hospital Randallia	Fort Wayne	Indiana
United States	Radiation Oncology Associates PC	Fort Wayne	Indiana
United States	Fresno Cancer Center	Fresno	California
United States	University of Texas Medical Branch	Galveston	Texas
United States	Gaston Memorial Hospital	Gastonia	North Carolina
United States	Saint Mary's Hospital	Green Bay	Wisconsin
United States	Saint Vincent Hospital	Green Bay	Wisconsin
United States	Cone Health Cancer Center	Greensboro	North Carolina
United States	UPMC Cancer Centers - Arnold Palmer Pavilion	Greensburg	Pennsylvania
United States	Greenville Health System Cancer Institute-Eastside	Greenville	South Carolina
United States	Greenville Health System Cancer Institute-Faris	Greenville	South Carolina
United States	Gibbs Cancer Center-Pelham	Greer	South Carolina
United States	Greenville Health System Cancer Institute-Greer	Greer	South Carolina
United States	Comprehensive Cancer Centers of Nevada - Henderson	Henderson	Nevada
United States	Penn State Milton S Hershey Medical Center	Hershey	Pennsylvania
United States	Queen's Medical Center	Honolulu	Hawaii
United States	IU Health Methodist Hospital	Indianapolis	Indiana
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Baptist Cancer Institute	Jacksonville	Florida
United States	Joliet Oncology-Hematology Associates Limited	Joliet	Illinois
United States	West Michigan Cancer Center	Kalamazoo	Michigan
United States	Kansas City Cancer Center - South	Kansas City	Missouri
United States	Kansas City Cancer Centers - North	Kansas City	Missouri
United States	Research Medical Center	Kansas City	Missouri
United States	Saint Luke's Hospital of Kansas City	Kansas City	Missouri
United States	University of Kansas Cancer Center	Kansas City	Kansas
United States	Northwest Cancer Clinic	Kennewick	Washington
United States	Tri-Cities Cancer Center	Kennewick	Washington
United States	Kettering Medical Center	Kettering	Ohio
United States	Tennessee Cancer Specialists-Dowell Springs	Knoxville	Tennessee
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	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada
United States	Comprehensive Cancer Centers of Nevada - Central Valley	Las Vegas	Nevada
United States	Comprehensive Cancer Centers of Nevada - Northwest	Las Vegas	Nevada
United States	Comprehensive Cancer Centers of Nevada-Summerlin	Las Vegas	Nevada
United States	UTMB Cancer Center at Victory Lakes	League City	Texas
United States	Kansas City Cancer Center-Lee's Summit	Lee's Summit	Missouri
United States	Baptist Health Lexington	Lexington	Kentucky
United States	University of Kentucky/Markey Cancer Center	Lexington	Kentucky
United States	Saint Mary Mercy Hospital	Livonia	Michigan
United States	Longmont United Hospital	Longmont	Colorado
United States	Saint John Medical Center	Longview	Washington
United States	Kaiser Permanente Los Angeles Medical Center	Los Angeles	California
United States	Norton Hospital Pavilion and Medical Campus	Louisville	Kentucky
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	Bay Area Medical Center	Marinette	Wisconsin
United States	Blount Memorial Hospital	Maryville	Tennessee
United States	UPMC Cancer Center at UPMC McKeesport	McKeesport	Pennsylvania
United States	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida
United States	University of South Alabama Mitchell Cancer Institute	Mobile	Alabama
United States	Memorial Medical Center	Modesto	California
United States	UPMC-Coraopolis/Heritage Valley Radiation Oncology	Moon Township	Pennsylvania
United States	Fox Chase Cancer Center at Virtua Memorial Hospital of Burlington County	Mount Holly	New Jersey
United States	Skagit Valley Hospital Regional Cancer Care Center	Mount Vernon	Washington
United States	D N Greenwald Center	Mukwonago	Wisconsin
United States	Edward Hospital/Cancer Center	Naperville	Illinois
United States	The Hospital of Central Connecticut	New Britain	Connecticut
United States	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey
United States	UMDNJ - Robert Wood Johnson University Hospital	New Brunswick	New Jersey
United States	North Shore-LIJ Health System/Center for Advanced Medicine	New Hyde Park	New York
United States	UC Comprehensive Cancer Center at Silver Cross	New Lennox	Illinois
United States	Saint Luke's Roosevelt Hospital Center - Saint Luke's Division	New York	New York
United States	UMDNJ - New Jersey Medical School	Newark	New Jersey
United States	Kaiser Permanente Oakland-Broadway	Oakland	California
United States	Oconomowoc Memorial Hospital-ProHealth Care Inc	Oconomowoc	Wisconsin
United States	Integris Southwest Medical Center	Oklahoma City	Oklahoma
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Nebraska Methodist Hospital	Omaha	Nebraska
United States	Kansas City Cancer Centers-Southwest	Overland Park	Kansas
United States	Parker Adventist Hospital	Parker	Colorado
United States	Aria Health-Torresdale Campus	Philadelphia	Pennsylvania
United States	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania
United States	University of Pennsylvania/Abramson Cancer Center	Philadelphia	Pennsylvania
United States	Arizona Oncology-Deer Valley Center	Phoenix	Arizona
United States	Saint Joseph's Hospital and Medical Center	Phoenix	Arizona
United States	Allegheny General Hospital	Pittsburgh	Pennsylvania
United States	UPMC-Passavant Hospital	Pittsburgh	Pennsylvania
United States	UPMC-Saint Clair Hospital Cancer Center	Pittsburgh	Pennsylvania
United States	UPMC-Saint Margaret	Pittsburgh	Pennsylvania
United States	UPMC-Shadyside Hospital	Pittsburgh	Pennsylvania
United States	Edward Hospital/Cancer Center?Plainfield	Plainfield	Illinois
United States	Saint Joseph Mercy Oakland	Pontiac	Michigan
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	Geisinger Medical Oncology-Pottsville	Pottsville	Pennsylvania
United States	Kaiser Permanente-Rancho Cordova Cancer Center	Rancho Cordova	California
United States	Rapid City Regional Hospital	Rapid City	South Dakota
United States	Saint Mary's Regional Medical Center	Reno	Nevada
United States	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia
United States	University of Rochester	Rochester	New York
United States	Rohnert Park Cancer Center	Rohnert Park	California
United States	Phelps County Regional Medical Center	Rolla	Missouri
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	South Sacramento Cancer Center	Sacramento	California
United States	Sutter General Hospital	Sacramento	California
United States	Barnes-Jewish West County Hospital	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Kaiser Permanente Medical Center - Santa Clara	Santa Clara	California
United States	Maine Medical Center- Scarborough Campus	Scarborough	Maine
United States	Arizona Oncology Services Foundation	Scottsdale	Arizona
United States	University of Washington Medical Center	Seattle	Washington
United States	Virginia Mason CCOP	Seattle	Washington
United States	Virginia Mason Medical Center	Seattle	Washington
United States	Greenville Health System Cancer Institute-Seneca	Seneca	South Carolina
United States	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota
United States	Memorial Hospital of South Bend	South Bend	Indiana
United States	Kaiser Permanente Cancer Treatment Center	South San Francisco	California
United States	Greenville Health System Cancer Institute-Spartanburg	Spartanburg	South Carolina
United States	Spartanburg Medical Center	Spartanburg	South Carolina
United States	Baystate Medical Center	Springfield	Massachusetts
United States	Mercy Hospital Springfield	Springfield	Missouri
United States	Door County Cancer Center	Sturgeon Bay	Wisconsin
United States	William Beaumont Hospital - Troy	Troy	Michigan
United States	The University of Arizona Medical Center-University Campus	Tucson	Arizona
United States	Sutter Cancer Centers Radiation Oncology Services-Vacaville	Vacaville	California
United States	PeaceHealth Southwest Medical Center	Vancouver	Washington
United States	Virtua West Jersey Hospital Voorhees	Voorhees	New Jersey
United States	John Muir Medical Center-Walnut Creek	Walnut Creek	California
United States	Saint John Macomb-Oakland Hospital	Warren	Michigan
United States	Cadence Cancer Center in Warrenville	Warrenville	Illinois
United States	Waukesha Memorial Hospital	Waukesha	Wisconsin
United States	Reading Hospital	West Reading	Pennsylvania
United States	SCL Health Lutheran Medical Center	Wheat Ridge	Colorado
United States	Geisinger Wyoming Valley/Henry Cancer Center	Wilkes-Barre	Pennsylvania
United States	Novant Health Forsyth Medical Center	Winston-Salem	North Carolina
United States	North Star Lodge Cancer Center at Yakima Valley Memorial Hospital	Yakima	Washington

Sponsors (3)

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

Countries where clinical trial is conducted

United States,  Canada,  Israel, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall survival	Estimated using the Kaplan-Meier method and differences between treatment arms will be tested in the log-rank test.	From the date of randomization to the date of death or, otherwise, the last follow-up date on which the patient was reported alive, assessed up to 4 years	No
Secondary	PFS	Progression-free survival rates will be estimated using the Kaplan-Meier method, and differences between treatment arms will be tested in the log-rank test. Multivariate analyses with the Cox proportional hazard model for PFS will be performed with the stratification variables as fixed variables to assess the treatment effect adjusting patient-specific risk factors.	From randomization to progression or death, whichever occurs first, assessed up to 4 years	No
Secondary	Progression-free survival (PFS)	Progression-free survival rates will be estimated using the Kaplan-Meier method, and differences between treatment arms will be tested in the log-rank test. Multivariate analyses with the Cox proportional hazard model for PFS will be performed with the stratification variables as fixed variables to assess the treatment effect adjusting patient-specific risk factors.	At 6 months	No
Secondary	Rate of grade 3+ acute or delayed CNS toxicity	Estimated using an exact binomial distribution together with 95% confidence interval.	Up to 6 months	Yes
Secondary	Rate of objective response	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.	Up to 4 years	No
Secondary	Rate of treatment adverse events, graded according to National Cancer Institute CTCAE v. 4.0		Up to 4 years	Yes