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

• Sponsor: Radiation Therapy Oncology Group (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT01730950
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 182
• Locations: 31
• Arms: 2
• Patients Per Site: 5.9

Study Details

Study Description

Brief Summary

This randomized phase II trial studies how well bevacizumab with or without radiation therapy works in treating patients with recurrent glioblastoma. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry cancer-killing substances to them. 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 know whether bevacizumab is more effective with or without radiation therapy in treating patients with recurrent glioblastoma

Condition or Disease	Intervention/Treatment	Phase
Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Recurrent Adult Brain Tumor	Biological: bevacizumab; Radiation: radiation therapy	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

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

SECONDARY OBJECTIVES:

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

2. 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.

In both arms, courses 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 182 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Randomized Phase II Trial of Concurrent Bevacizumab and Re-Irradiation Versus Bevacizumab Alone as Treatment for Recurrent Glioblastoma
• Actual Study Start Date: Dec 20, 2012
• Actual Primary Completion Date: Sep 3, 2018

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Bevacizumab Bevacizumab every 2 weeks	Biological: bevacizumab; Staring within 14 days of randomization, IV 10mg/kg every two weeks until disease progression.; Other Names: anti-VEGF humanized monoclonal antibody anti-VEGF monoclonal antibody Avastin rhuMAb VEGF
Experimental: Bevacizumab + RT Radiation therapy with bevacizumab every 2 weeks	Biological: bevacizumab; Staring within 14 days of randomization, IV 10mg/kg every two weeks until disease progression.; Other Names: anti-VEGF humanized monoclonal antibody anti-VEGF monoclonal antibody Avastin rhuMAb VEGF ; Radiation: radiation therapy; Starting with second dose of bevacizumab, 35 Gy in 10 fractions of 3.5 Gy each delivered on consecutive treatment days (typically 5 fractions per week).; Other Names: 3D conformal radiation therapy photon beam radiation therapy proton beam radiation therapy Intensity Modulated Radiation Therapy (IMRT) Image-Guided Radiation Treatment (IGRT) 3D-CRT

Outcome Measures

Primary Outcome Measures

1. Overall Survival [From randomization to last follow-up. Maximum follow-up at time of analysis was 52.8 months.]

   Survival time is defined as time from randomization to the date of death from any cause or last known follow-up (censored). Survival rates are estimated by the Kaplan-Meier method. The protocol specifies that the distributions of failure times will be compared between the arms, which is reported in the statistical analysis results. Eighteen-month rates are provided. Analysis was planned to occur when 135 deaths were reported.

Secondary Outcome Measures

1. Percentage of Participants With Complete or Partial Best Response [From randomization to last follow-up. Maximum follow-up at time of analysis was 52.8 months.]

   Best observed objective response determined by serial measures of the product of the two largest perpendicular cross-sectional diameters using MacDonald Criteria: Complete Response (CR): complete disappearance of measurable enhancing lesion sustained ≥ 4 weeks; and no new lesions; and no corticosteroids. Partial Response (PR): ≥ 50% decrease from baseline in sum of products of the measurable enhancing lesion sustained ≥ 4 weeks; and no new lesions; and stable/reduced corticosteroid dose. Progression (P): ≥ 25% increase in sum of products of enhancing lesions (patient has not had steroid dose decreased since the last evaluation period); or any new lesions. A concomitant decrease in steroid dose rules out progression designation during initial 12 weeks after radiotherapy. Stable Disease (SD): all of following: does not qualify for CR, PR, or P; receiving stable/decreasing doses of steroids. Estimated using an exact binomial distribution.

2. Percentage of Participants Progression-free at 6 Months [From randomization to six months]

   Best observed objective response determined by serial measures of the product of the two largest perpendicular cross-sectional diameters using MacDonald Criteria: Progression (P): ≥ 25% increase in sum of products of enhancing lesions (patient has not had steroid dose decreased since the last evaluation period); or any new lesions. A concomitant decrease in steroid dose rules out progression designation during initial 12 weeks after radiotherapy. Progression-free at 6 months means patient alive without progression at 6 months.

3. Progression-free Survival [From randomization to last follow-up. Maximum follow-up at time of analysis was 52.8 months.]

   Progression using using MacDonald Criteria is defined as ≥ 25% increase from baseline in sum of products of the two largest perpendicular cross-sectional diameters of enhancing lesions (patient has not had steroid dose decreased since the last evaluation period); or any new lesions. A concomitant decrease in steroid dose rules out progression designation during initial 12 weeks after radiotherapy. Progression-free survival time is defined as time from randomization to the date of first progression, death, or last known follow-up (censored). Progression-free survival rates are estimated using the Kaplan-Meier method. The protocol specifies that the distributions of failure times will be compared between the arms, which is reported in the statistical analysis results. Eighteen-month rates are provided. Analysis was planned to occur when 135 deaths were reported.

4. Percentage of Participants With Grade 3+ Central Nervous System (CNS) Toxicity Within 90 Days of Start of Radiation Therapy Reported as Possibly/Probably/Definitely Related to Protocol Treatment [From randomization to last follow-up. Maximum follow-up at time of analysis was 52.8 months.]

   Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE.

5. Number of Participants With Grade 3+ CNS Toxicity More Than 90 Days of Start of Radiation Therapy Reported as Possibly/Probably/Definitely Related to Protocol Treatment [From 91 days after the start of radiation therapy to end of follow-up. Maximum follow-up at the time of analysis is 58.2 months.]

   Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE. Estimated using an exact binomial distribution together with 95% confidence interval. The difference between the two groups will be tested using a chi square test.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 magnetic resonance imaging (MRI) scan (or computed tomography [CT] scan for patients with non-compatible devices) CT scan within 21 days prior to registration.

• Note: Patients who did have surgery with a post-operative contrast-enhance scan falling outside the 5 week window prior to registration, must have a repeat MRI scan (or CT scan for patients with non-compatible devices) within 21 days prior to registration.

• Patients also 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

• 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+ (patients discovered to have >= 2+ proteinuria on dipstick urinalysis at baseline 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; UPC ratio is calculated using one of the following formulas:

• [urine protein]/[urine creatinine]: if both protein and creatinine are reported in mg/dL

• [(urine protein) x 0.088]/[urine creatinine]: if urine creatinine is reported in mmol/L

• Patients must not be pregnant (positive pregnancy test) or breast feeding; pregnancy test must be done within 14 days prior to registration; effective contraception (men and women) must be used in patients of child-bearing potential while on trial and for 6 months after

• Patients on full-dose anticoagulants (e.g., warfarin or low molecular weigh [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 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; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic

• 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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294
2	Arizona Oncology Services Foundation	Phoenix	Arizona	United States	85013
3	Arizona Oncology-Deer Valley Center	Phoenix	Arizona	United States	85027
4	John Muir Medical Center	Walnut Creek	California	United States	94598
5	Yale University	New Haven	Connecticut	United States	06520-8032
6	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida	United States	33136
7	Queen's Medical Center	Honolulu	Hawaii	United States	96813
8	Radiation Oncology Associates PC	Fort Wayne	Indiana	United States	46804
9	IU Health Methodist Hospital	Indianapolis	Indiana	United States	46202
10	Memorial Hospital of South Bend	South Bend	Indiana	United States	46601
11	Norton Health Care Pavilion - Downtown	Louisville	Kentucky	United States	40202
12	Maine Medical Center- Scarborough Campus	Scarborough	Maine	United States	04074
13	Lowell General Hospital	Lowell	Massachusetts	United States	01854
14	University of Michigan University Hospital	Ann Arbor	Michigan	United States	48109
15	West Michigan Cancer Center	Kalamazoo	Michigan	United States	49007
16	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
17	Nebraska Methodist Hospital	Omaha	Nebraska	United States	68114
18	University of Rochester	Rochester	New York	United States	14642
19	Cone Health Cancer Center	Greensboro	North Carolina	United States	27403
20	Summa Akron City Hospital	Akron	Ohio	United States	44304
21	Summa Barberton Hospital	Barberton	Ohio	United States	44203
22	Lancaster General Hospital	Lancaster	Pennsylvania	United States	17604
23	Radiation Therapy Oncology Group	Philadelphia	Pennsylvania	United States	19103
24	Allegheny Cancer Center at Allegheny General Hospital	Pittsburgh	Pennsylvania	United States	15212
25	Medical University of South Carolina	Charleston	South Carolina	United States	29425
26	University of Texas Medical Branch	Galveston	Texas	United States	77555-0565
27	North Star Lodge Cancer Center at Yakima Valley Memorial Hospital	Yakima	Washington	United States	98902
28	Saint Vincent Hospital	Green Bay	Wisconsin	United States	54301
29	Saint Mary's Hospital	Green Bay	Wisconsin	United States	54303
30	Bay Area Medical Center	Marinette	Wisconsin	United States	54143
31	Door County Cancer Center	Sturgeon Bay	Wisconsin	United States	54235-1495

Sponsors and Collaborators

• Radiation Therapy Oncology Group
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Christina Tsien, Washington University School of Medicine
• Study Chair: Jeffrey Raizer, MD, Northwestern University
• Study Chair: Adam P. Dicker, MD, PhD, Jefferson Medical College of Thomas Jefferson University
• Study Chair: Martha M. Matuszak, PhD, University of Michigan

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 3, 2016
• Informed Consent Form - Oct 3, 2016

More Information

Publications

None provided.

• Responsible Party: Radiation Therapy Oncology Group
• ClinicalTrials.gov Identifier: NCT01730950
• Other Study ID Numbers: RTOG-1205; NCI-2012-01732; U10CA021661; NCT02671981
• First Posted: Nov 21, 2012
• Last Update Posted: Oct 23, 2020
• Last Verified: Sep 1, 2020

• Additional relevant MeSH terms: Glioblastoma; Gliosarcoma; Recurrence; Bevacizumab; Antineoplastic Agents, Immunological; Antibodies; Immunoglobulins; Antibodies, Monoclonal

Study Results

Participant Flow

Arm/Group Title	Bevacizumab	Bevacizumab + RT
Arm/Group Description	Bevacizumab (IV 10mg/kg) every 2 weeks until disease progression.	Radiation therapy (35Gy in 10 fractions of 3.5 Gy) with bevacizumab (IV 10mg/kg) every 2 weeks until disease progression.
Period Title: Overall Study
STARTED	90	92
Eligible Population	84	86
Adverse Event Population	76	83
Response Population	78	77
6-month Progression-free Analysis	79	81
Delayed Toxicity Population	0	83
COMPLETED	84	86
NOT COMPLETED	6	6

Baseline Characteristics

Arm/Group Title	Bevacizumab	Bevacizumab + RT	Total
Arm/Group Description	Bevacizumab (IV 10mg/kg) every 2 weeks until disease progression.	Radiation therapy (35Gy in 10 fractions of 3.5 Gy) with bevacizumab (IV 10mg/kg) every 2 weeks until disease progression.	Total of all reporting groups
Overall Participants	84	86	170
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	57	60	59
Sex: Female, Male (Count of Participants)
Female	38 45.2%	43 50%	81 47.6%
Male	46 54.8%	43 50%	89 52.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	8 9.5%	3 3.5%	11 6.5%
Not Hispanic or Latino	72 85.7%	81 94.2%	153 90%
Unknown or Not Reported	4 4.8%	2 2.3%	6 3.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	4 4.8%	0 0%	4 2.4%
Asian	6 7.1%	2 2.3%	8 4.7%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	3 3.6%	2 2.3%	5 2.9%
White	66 78.6%	75 87.2%	141 82.9%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	5 6%	7 8.1%	12 7.1%
Karnofsky Performance Status (Count of Participants)
60	3 3.6%	8 9.3%	11 6.5%
70-80	42 50%	41 47.7%	83 48.8%
90-100	39 46.4%	37 43%	76 44.7%
Neurologic Function (Count of Participants)
No symptoms	21 25%	24 27.9%	45 26.5%
Minor symptoms	40 47.6%	36 41.9%	76 44.7%
Moderate symptoms (fully active)	17 20.2%	15 17.4%	32 18.8%
Moderate symptoms (required assistance)	6 7.1%	9 10.5%	15 8.8%
Severe symptoms	0 0%	2 2.3%	2 1.2%
Surgery for Initial Brain Tumor (Count of Participants)
Biopsy only	8 9.5%	7 8.1%	15 8.8%
Subtotal resection	20 23.8%	25 29.1%	45 26.5%
Gross total resection	56 66.7%	52 60.5%	108 63.5%
Other	0 0%	2 2.3%	2 1.2%
Recent Resection (Count of Participants)
No / biopsy only	49 58.3%	57 66.3%	106 62.4%
Yes	35 41.7%	29 33.7%	64 37.6%
Histologic Tumor Type (Count of Participants)
Glioblastoma (WHO Grade IV)	79 94%	82 95.3%	161 94.7%
Gliosarcoma	2 2.4%	2 2.3%	4 2.4%
Other	3 3.6%	2 2.3%	5 2.9%

Outcome Measures

1. Primary Outcome

Title	Overall Survival
Description	Survival time is defined as time from randomization to the date of death from any cause or last known follow-up (censored). Survival rates are estimated by the Kaplan-Meier method. The protocol specifies that the distributions of failure times will be compared between the arms, which is reported in the statistical analysis results. Eighteen-month rates are provided. Analysis was planned to occur when 135 deaths were reported.
Time Frame	From randomization to last follow-up. Maximum follow-up at time of analysis was 52.8 months.

Outcome Measure Data

Analysis Population Description

Eligible participants

Arm/Group Title	Bevacizumab	Bevacizumab + RT
Arm/Group Description	Bevacizumab (IV 10mg/kg) every 2 weeks until disease progression.	Radiation therapy (35 Gy in 10 fractions of 3.5 Gy) with bevacizumab (IV 10mg/kg) every 2 weeks until disease progression.
Measure Participants	84	86
Number (95% Confidence Interval) [percentage of participants]	25.1 29.9%	21.6 25.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bevacizumab, Bevacizumab + RT
	Comments	Null hypothesis: median survival time for both arms is 9 months; alternative hypothesis: participants receiving radiation therapy plus bevacizumab will have an improvement in median survival time to 13 months. One hundred and sixty eligible participants provides 80% power to detect a 31% reduction in the hazard ratio to 0.69 at a one-sided significance level of 0.10. Analysis was planned to occur when 135 deaths were reported, expected to occur 16 to 21 months after trial closure.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.46
	Comments
	Method	Log Rank
	Comments	Two-side significance level = 0.05
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.98
	Confidence Interval	(2-Sided) 95%; 0.70 to 1.38
	Parameter Dispersion	Type: Value:
	Estimation Comments	Reference level = Bevacizumab

2. Secondary Outcome

Title	Percentage of Participants With Complete or Partial Best Response
Description	Best observed objective response determined by serial measures of the product of the two largest perpendicular cross-sectional diameters using MacDonald Criteria: Complete Response (CR): complete disappearance of measurable enhancing lesion sustained ≥ 4 weeks; and no new lesions; and no corticosteroids. Partial Response (PR): ≥ 50% decrease from baseline in sum of products of the measurable enhancing lesion sustained ≥ 4 weeks; and no new lesions; and stable/reduced corticosteroid dose. Progression (P): ≥ 25% increase in sum of products of enhancing lesions (patient has not had steroid dose decreased since the last evaluation period); or any new lesions. A concomitant decrease in steroid dose rules out progression designation during initial 12 weeks after radiotherapy. Stable Disease (SD): all of following: does not qualify for CR, PR, or P; receiving stable/decreasing doses of steroids. Estimated using an exact binomial distribution.
Time Frame	From randomization to last follow-up. Maximum follow-up at time of analysis was 52.8 months.

Outcome Measure Data

Analysis Population Description

Eligible participants with response evaluations

Arm/Group Title	Bevacizumab	Bevacizumab + RT
Arm/Group Description	Bevacizumab (IV 10mg/kg) every 2 weeks until disease progression.	Radiation therapy (35 Gy in 10 fractions of 3.5 Gy) with bevacizumab (IV 10mg/kg) every 2 weeks until disease progression.
Measure Participants	78	77
Number (95% Confidence Interval) [percentage of participants]	20.5 24.4%	29.9 34.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bevacizumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.18
	Comments
	Method	Chi-squared
	Comments	Two-sided significance level = 0.05

3. Secondary Outcome

Title	Percentage of Participants Progression-free at 6 Months
Description	Best observed objective response determined by serial measures of the product of the two largest perpendicular cross-sectional diameters using MacDonald Criteria: Progression (P): ≥ 25% increase in sum of products of enhancing lesions (patient has not had steroid dose decreased since the last evaluation period); or any new lesions. A concomitant decrease in steroid dose rules out progression designation during initial 12 weeks after radiotherapy. Progression-free at 6 months means patient alive without progression at 6 months.
Time Frame	From randomization to six months

Outcome Measure Data

Analysis Population Description

Eligible participants with data at six months

Arm/Group Title	Bevacizumab	Bevacizumab + RT
Arm/Group Description	Bevacizumab (IV 10mg/kg) every 2 weeks until disease progression.	Radiation therapy (35 Gy in 10 fractions of 3.5 Gy) with bevacizumab (IV 10mg/kg) every 2 weeks until disease progression.
Measure Participants	79	81
Number (95% Confidence Interval) [percentage of participants]	29.1 34.6%	54.3 63.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bevacizumab, Bevacizumab + RT
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	Chi-squared
	Comments	Two-sided significance level = 0.05

4. Secondary Outcome

Title	Progression-free Survival
Description	Progression using using MacDonald Criteria is defined as ≥ 25% increase from baseline in sum of products of the two largest perpendicular cross-sectional diameters of enhancing lesions (patient has not had steroid dose decreased since the last evaluation period); or any new lesions. A concomitant decrease in steroid dose rules out progression designation during initial 12 weeks after radiotherapy. Progression-free survival time is defined as time from randomization to the date of first progression, death, or last known follow-up (censored). Progression-free survival rates are estimated using the Kaplan-Meier method. The protocol specifies that the distributions of failure times will be compared between the arms, which is reported in the statistical analysis results. Eighteen-month rates are provided. Analysis was planned to occur when 135 deaths were reported.
Time Frame	From randomization to last follow-up. Maximum follow-up at time of analysis was 52.8 months.

Outcome Measure Data

Analysis Population Description

Eligible participants

Arm/Group Title	Bevacizumab	Bevacizumab + RT
Arm/Group Description	Bevacizumab (IV 10mg/kg) every 2 weeks until disease progression.	Radiation therapy (35 Gy in 10 fractions of 3.5 Gy) with bevacizumab (IV 10mg/kg) every 2 weeks until disease progression.
Measure Participants	84	86
Number (95% Confidence Interval) [percentage of participants]	8.9 10.6%	7.9 9.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bevacizumab, Bevacizumab + RT
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.05
	Comments
	Method	Log Rank
	Comments	Two-sided significance level = 0.05
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.73
	Confidence Interval	(2-Sided) 95%; 0.53 to 1.00
	Parameter Dispersion	Type: Value:
	Estimation Comments	Reference level = Bevacizumab

5. Secondary Outcome

Title	Percentage of Participants With Grade 3+ Central Nervous System (CNS) Toxicity Within 90 Days of Start of Radiation Therapy Reported as Possibly/Probably/Definitely Related to Protocol Treatment
Description	Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE.
Time Frame	From randomization to last follow-up. Maximum follow-up at time of analysis was 52.8 months.

Outcome Measure Data

Analysis Population Description

Eligible participants on the radiation therapy arm who started radiation therapy

Arm/Group Title	Bevacizumab + RT
Arm/Group Description	Radiation therapy (35 Gy in 10 fractions of 3.5 Gy) with bevacizumab (IV 10mg/kg) every 2 weeks until disease progression.
Measure Participants	83
Number (95% Confidence Interval) [percentage of participants]	4.8 5.7%

6. Secondary Outcome

Title	Number of Participants With Grade 3+ CNS Toxicity More Than 90 Days of Start of Radiation Therapy Reported as Possibly/Probably/Definitely Related to Protocol Treatment
Description	Adverse events were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to AE. Estimated using an exact binomial distribution together with 95% confidence interval. The difference between the two groups will be tested using a chi square test.
Time Frame	From 91 days after the start of radiation therapy to end of follow-up. Maximum follow-up at the time of analysis is 58.2 months.

Outcome Measure Data

Analysis Population Description

Eligible participants on the radiation therapy arm who started radiation therapy and were alive at least 91 days from the start of radiation therapy

Arm/Group Title	Bevacizumab + RT
Arm/Group Description	Radiation therapy (35 Gy in 10 fractions of 3.5 Gy) with bevacizumab (IV 10mg/kg) every 2 weeks until disease progression.
Measure Participants	83
Count of Participants [Participants]	0 0%

Adverse Events

Time Frame	Adverse events were to be reported every 2 months for first year, every 6 months for second year, then annually until study completion. Maximum follow-up at time of analysis was 52.8 months.
Arm/Group Title	Bevacizumab		Bevacizumab + RT
Arm/Group Description	Bevacizumab (IV 10mg/kg) every 2 weeks until disease progression.		Radiation therapy (35Gy in 10 fractions of 3.5 Gy) with bevacizumab (IV 10mg/kg) every 2 weeks until disease progression.
All Cause Mortality
	Bevacizumab		Bevacizumab + RT
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/76 (5.3%)		8/83 (9.6%)
Serious Adverse Events
	Bevacizumab		Bevacizumab + RT
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	27/76 (35.5%)		29/83 (34.9%)
Blood and lymphatic system disorders
Anemia	1/76 (1.3%)		0/83 (0%)
Blood and lymphatic system disorders - Other	1/76 (1.3%)		0/83 (0%)
Thrombotic thrombocytopenic purpura	1/76 (1.3%)		0/83 (0%)
Cardiac disorders
Sinus bradycardia	1/76 (1.3%)		0/83 (0%)
Eye disorders
Blurred vision	1/76 (1.3%)		0/83 (0%)
Gastrointestinal disorders
Colonic obstruction	0/76 (0%)		1/83 (1.2%)
Colonic perforation	0/76 (0%)		1/83 (1.2%)
Nausea	1/76 (1.3%)		1/83 (1.2%)
Upper gastrointestinal hemorrhage	0/76 (0%)		1/83 (1.2%)
Vomiting	1/76 (1.3%)		0/83 (0%)
General disorders
Death NOS	1/76 (1.3%)		2/83 (2.4%)
Edema limbs	1/76 (1.3%)		0/83 (0%)
Fatigue	1/76 (1.3%)		1/83 (1.2%)
General disorders and administration site conditions - Other	0/76 (0%)		1/83 (1.2%)
Neck edema	1/76 (1.3%)		0/83 (0%)
Non-cardiac chest pain	1/76 (1.3%)		0/83 (0%)
Pain	1/76 (1.3%)		1/83 (1.2%)
Sudden death NOS	0/76 (0%)		1/83 (1.2%)
Hepatobiliary disorders
Cholecystitis	0/76 (0%)		1/83 (1.2%)
Infections and infestations
Infections and infestations - Other	1/76 (1.3%)		0/83 (0%)
Lung infection	2/76 (2.6%)		2/83 (2.4%)
Sepsis	1/76 (1.3%)		2/83 (2.4%)
Urinary tract infection	1/76 (1.3%)		1/83 (1.2%)
Wound infection	2/76 (2.6%)		1/83 (1.2%)
Injury, poisoning and procedural complications
Fall	0/76 (0%)		2/83 (2.4%)
Wound dehiscence	1/76 (1.3%)		0/83 (0%)
Investigations
Investigations - Other	1/76 (1.3%)		0/83 (0%)
Metabolism and nutrition disorders
Alkalosis	1/76 (1.3%)		0/83 (0%)
Dehydration	1/76 (1.3%)		1/83 (1.2%)
Hypokalemia	1/76 (1.3%)		1/83 (1.2%)
Hyponatremia	1/76 (1.3%)		1/83 (1.2%)
Metabolism and nutrition disorders - Other	1/76 (1.3%)		0/83 (0%)
Musculoskeletal and connective tissue disorders
Back pain	2/76 (2.6%)		1/83 (1.2%)
Generalized muscle weakness	1/76 (1.3%)		3/83 (3.6%)
Muscle weakness left-sided	1/76 (1.3%)		1/83 (1.2%)
Muscle weakness lower limb	0/76 (0%)		1/83 (1.2%)
Muscle weakness right-sided	0/76 (0%)		1/83 (1.2%)
Musculoskeletal deformity	0/76 (0%)		1/83 (1.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other	1/76 (1.3%)		1/83 (1.2%)
Nervous system disorders
Cerebrospinal fluid leakage	0/76 (0%)		1/83 (1.2%)
Cognitive disturbance	1/76 (1.3%)		1/83 (1.2%)
Encephalopathy	3/76 (3.9%)		2/83 (2.4%)
Headache	1/76 (1.3%)		0/83 (0%)
Intracranial hemorrhage	1/76 (1.3%)		1/83 (1.2%)
Seizure	5/76 (6.6%)		7/83 (8.4%)
Stroke	1/76 (1.3%)		0/83 (0%)
Syncope	0/76 (0%)		2/83 (2.4%)
Tremor	1/76 (1.3%)		0/83 (0%)
Psychiatric disorders
Confusion	1/76 (1.3%)		1/83 (1.2%)
Renal and urinary disorders
Proteinuria	1/76 (1.3%)		2/83 (2.4%)
Respiratory, thoracic and mediastinal disorders
Aspiration	0/76 (0%)		2/83 (2.4%)
Dyspnea	1/76 (1.3%)		0/83 (0%)
Skin and subcutaneous tissue disorders
Alopecia	1/76 (1.3%)		0/83 (0%)
Vascular disorders
Hematoma	2/76 (2.6%)		1/83 (1.2%)
Hypertension	1/76 (1.3%)		0/83 (0%)
Hypotension	1/76 (1.3%)		0/83 (0%)
Thromboembolic event	2/76 (2.6%)		0/83 (0%)
Vasculitis	1/76 (1.3%)		0/83 (0%)
Other (Not Including Serious) Adverse Events
	Bevacizumab		Bevacizumab + RT
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	70/76 (92.1%)		73/83 (88%)
Blood and lymphatic system disorders
Anemia	12/76 (15.8%)		10/83 (12%)
Blood and lymphatic system disorders - Other	7/76 (9.2%)		1/83 (1.2%)
Eye disorders
Blurred vision	9/76 (11.8%)		10/83 (12%)
Eye disorders - Other	5/76 (6.6%)		7/83 (8.4%)
Gastrointestinal disorders
Abdominal pain	5/76 (6.6%)		3/83 (3.6%)
Constipation	12/76 (15.8%)		8/83 (9.6%)
Diarrhea	10/76 (13.2%)		12/83 (14.5%)
Dyspepsia	5/76 (6.6%)		4/83 (4.8%)
Nausea	20/76 (26.3%)		14/83 (16.9%)
Vomiting	7/76 (9.2%)		7/83 (8.4%)
General disorders
Edema limbs	15/76 (19.7%)		9/83 (10.8%)
Fatigue	34/76 (44.7%)		47/83 (56.6%)
Gait disturbance	14/76 (18.4%)		16/83 (19.3%)
General disorders and administration site conditions - Other	6/76 (7.9%)		2/83 (2.4%)
Pain	10/76 (13.2%)		12/83 (14.5%)
Infections and infestations
Infections and infestations - Other	4/76 (5.3%)		5/83 (6%)
Urinary tract infection	6/76 (7.9%)		8/83 (9.6%)
Injury, poisoning and procedural complications
Bruising	5/76 (6.6%)		4/83 (4.8%)
Fall	8/76 (10.5%)		6/83 (7.2%)
Investigations
Alanine aminotransferase increased	7/76 (9.2%)		11/83 (13.3%)
Aspartate aminotransferase increased	4/76 (5.3%)		6/83 (7.2%)
Lymphocyte count decreased	11/76 (14.5%)		7/83 (8.4%)
Neutrophil count decreased	8/76 (10.5%)		4/83 (4.8%)
Platelet count decreased	21/76 (27.6%)		12/83 (14.5%)
Weight loss	4/76 (5.3%)		8/83 (9.6%)
White blood cell decreased	9/76 (11.8%)		7/83 (8.4%)
Metabolism and nutrition disorders
Anorexia	8/76 (10.5%)		10/83 (12%)
Hyperglycemia	14/76 (18.4%)		12/83 (14.5%)
Hypoalbuminemia	7/76 (9.2%)		2/83 (2.4%)
Hypocalcemia	6/76 (7.9%)		3/83 (3.6%)
Hypokalemia	7/76 (9.2%)		3/83 (3.6%)
Hyponatremia	5/76 (6.6%)		6/83 (7.2%)
Musculoskeletal and connective tissue disorders
Arthralgia	4/76 (5.3%)		8/83 (9.6%)
Back pain	5/76 (6.6%)		8/83 (9.6%)
Generalized muscle weakness	9/76 (11.8%)		5/83 (6%)
Muscle weakness left-sided	8/76 (10.5%)		5/83 (6%)
Muscle weakness lower limb	6/76 (7.9%)		5/83 (6%)
Muscle weakness right-sided	4/76 (5.3%)		5/83 (6%)
Muscle weakness upper limb	4/76 (5.3%)		3/83 (3.6%)
Musculoskeletal and connective tissue disorder - Other	6/76 (7.9%)		3/83 (3.6%)
Myalgia	4/76 (5.3%)		4/83 (4.8%)
Pain in extremity	6/76 (7.9%)		3/83 (3.6%)
Nervous system disorders
Ataxia	4/76 (5.3%)		2/83 (2.4%)
Cognitive disturbance	8/76 (10.5%)		4/83 (4.8%)
Dizziness	12/76 (15.8%)		13/83 (15.7%)
Dysarthria	5/76 (6.6%)		4/83 (4.8%)
Dysphasia	18/76 (23.7%)		11/83 (13.3%)
Headache	37/76 (48.7%)		31/83 (37.3%)
Lethargy	4/76 (5.3%)		1/83 (1.2%)
Memory impairment	12/76 (15.8%)		17/83 (20.5%)
Nervous system disorders - Other	10/76 (13.2%)		8/83 (9.6%)
Paresthesia	4/76 (5.3%)		5/83 (6%)
Peripheral sensory neuropathy	8/76 (10.5%)		3/83 (3.6%)
Seizure	11/76 (14.5%)		14/83 (16.9%)
Psychiatric disorders
Anxiety	13/76 (17.1%)		8/83 (9.6%)
Confusion	11/76 (14.5%)		12/83 (14.5%)
Depression	8/76 (10.5%)		9/83 (10.8%)
Insomnia	9/76 (11.8%)		12/83 (14.5%)
Renal and urinary disorders
Hematuria	3/76 (3.9%)		7/83 (8.4%)
Proteinuria	16/76 (21.1%)		20/83 (24.1%)
Renal and urinary disorders - Other	4/76 (5.3%)		3/83 (3.6%)
Urinary incontinence	7/76 (9.2%)		4/83 (4.8%)
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	5/76 (6.6%)		3/83 (3.6%)
Cough	8/76 (10.5%)		15/83 (18.1%)
Dyspnea	7/76 (9.2%)		9/83 (10.8%)
Epistaxis	1/76 (1.3%)		8/83 (9.6%)
Hoarseness	6/76 (7.9%)		6/83 (7.2%)
Skin and subcutaneous tissue disorders
Alopecia	4/76 (5.3%)		11/83 (13.3%)
Dry skin	4/76 (5.3%)		5/83 (6%)
Pruritus	5/76 (6.6%)		2/83 (2.4%)
Rash acneiform	4/76 (5.3%)		2/83 (2.4%)
Rash maculo-papular	3/76 (3.9%)		5/83 (6%)
Skin and subcutaneous tissue disorders - Other	4/76 (5.3%)		7/83 (8.4%)
Vascular disorders
Hypertension	33/76 (43.4%)		29/83 (34.9%)
Thromboembolic event	6/76 (7.9%)		4/83 (4.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

PI's are required to abide by the sponsor's publication guidelines which require review by coauthors and subsequent review and approval by the sponsor.