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

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by Radiation Therapy Oncology Group
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Radiation Therapy Oncology Group
ClinicalTrials.gov Identifier:
NCT01730950
First received: November 15, 2012
Last updated: May 19, 2014
Last verified: May 2014
  Purpose

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 Intervention Phase
Adult Giant Cell Glioblastoma
Adult Glioblastoma
Adult Gliosarcoma
Recurrent Adult Brain Tumor
Biological: bevacizumab
Radiation: intensity-modulated radiation therapy
Radiation: 3-dimensional conformal radiation therapy
Radiation: proton beam radiation therapy
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by Radiation Therapy Oncology Group:

Primary Outcome Measures:
  • Overall survival [ Time Frame: From randomization to the date of death or the last follow-up. Analysis occurs after XX deaths have bee reported. ] [ Designated as safety issue: No ]
    Estimated using the Kaplan-Meier method (Kaplan 1958), and differences between treatment arms will be tested in the log-rank test (Mantel 1966).


Secondary Outcome Measures:
  • Objective response [ Time Frame: Analysis occurs at the same time as the primary outcome analysis. ] [ Designated as safety issue: No ]
    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.

  • 6-month Progression-free survival (PFS) rate [ Time Frame: Up to 6-months ] [ Designated as safety issue: No ]
    Estimated using an exact binomial distribution together with 95% confidence interval. The difference between the two groups will be teated using a chi square test.

  • PFS [ Time Frame: Analysis occurs at the same time as the primary outcome analysis. ] [ Designated as safety issue: Yes ]
    Progression-free survival rates will be estimated using the Kaplan-Meier method (Kaplan 1958), and differences between treatment arms will be tested in the log-rank test (Mantel 1966). Multivariate analyses with the Cox proportional hazard model (Cox 1972) for PFS will be performed with the stratification variables as fixed variables to assess the treatment effect adjusting patient-specific risk factors.

  • Grade 3+ acute or delayed CNS toxicity rate [ Time Frame: Analysis occurs at the same time as the primary outcome analysis. ] [ Designated as safety issue: Yes ]
    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.


Estimated Enrollment: 178
Study Start Date: December 2012
Estimated Primary Completion Date: July 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Arm I (bevacizumab)
Patients receive bevacizumab IV over 30-90 minutes every 2 weeks.
Biological: bevacizumab
Given IV
Other Names:
  • anti-VEGF humanized monoclonal antibody
  • anti-VEGF monoclonal antibody
  • Avastin
  • rhuMAb VEGF
Experimental: Arm II (bevacizumab, IMRT or 3D-CRT)
Patients receive bevacizumab as patients in arm I and undergo radiation therapy using IMRT, 3D-CRT, or proton beam RT 5 days a week for 2 weeks.
Biological: bevacizumab
Given IV
Other Names:
  • anti-VEGF humanized monoclonal antibody
  • anti-VEGF monoclonal antibody
  • Avastin
  • rhuMAb VEGF
Radiation: intensity-modulated radiation therapy
Undergo IMRT
Other Name: IMRT
Radiation: 3-dimensional conformal radiation therapy
Undergo 3D-CRT
Other Names:
  • 3D conformal radiation therapy
  • 3D-CRT
Radiation: proton beam radiation therapy
Undergo proton beam RT

Detailed Description:

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.

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

ARM II: Patients receive bevacizumab as patients 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 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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

    • 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 MRI scan (or CT scan for patients with non-compatible devices) must be performed within 30 days 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
  • 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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01730950

  Show 31 Study Locations
Sponsors and Collaborators
Radiation Therapy Oncology Group
Investigators
Principal Investigator: Christina Tsien University of Michigan
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
  More Information

No publications provided

Responsible Party: Radiation Therapy Oncology Group
ClinicalTrials.gov Identifier: NCT01730950     History of Changes
Other Study ID Numbers: RTOG-1205, NCI-2012-01732, U10CA021661
Study First Received: November 15, 2012
Last Updated: May 19, 2014
Health Authority: United States: Institutional Review Board

Additional relevant MeSH terms:
Brain Neoplasms
Glioblastoma
Gliosarcoma
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Neoplasms
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Antibodies
Antibodies, Monoclonal
Bevacizumab
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on July 23, 2014