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

Study Overview
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Brief Summary
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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

Detailed Description
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PRIMARY OBJECTIVES: I. 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: 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. 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.

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

Conditions
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Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma, Recurrent Adult Brain Tumor

Intervention / Treatment
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* Biological: bevacizumab
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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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 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 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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Bevacizumab<br>Bevacizumab every 2 weeks | Biological: bevacizumab<br>* Staring within 14 days of randomization, IV 10mg/kg every two weeks until disease progression.<br>* Other names: rhuMAb VEGF;|
| Experimental: Bevacizumab + RT<br>Radiation therapy with bevacizumab every 2 weeks | Biological: bevacizumab<br>* Staring within 14 days of randomization, IV 10mg/kg every two weeks until disease progression.<br>* Other names: rhuMAb VEGF;Radiation: radiation therapy<br>* 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).<br>* Other names: 3D-CRT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | 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. | From randomization to last follow-up. Maximum follow-up at time of analysis was 52.8 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Complete or Partial Best Response | 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. | From randomization to last follow-up. Maximum follow-up at time of analysis was 52.8 months. | 
| Percentage of Participants Progression-free at 6 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. | From randomization to six months | 
| Progression-free Survival | 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. | From randomization to last follow-up. Maximum follow-up at time of analysis was 52.8 months. | 
| 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 | 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. | From randomization to last follow-up. Maximum follow-up at time of analysis was 52.8 months. | 
| 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 | 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. | 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. |