Bevacizumab With or Without Radiation Therapy in Treating Patients With Recurrent Glioblastoma
Condition: Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Recurrent Adult Brain Tumor
MeSH terms: Glioblastoma; Gliosarcoma; Recurrence
Intervention: bevacizumab; radiation therapy
Intervention description: Staring within 14 days of randomization, IV 10mg/kg every two weeks until disease progression.; 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).
Intervention MeSH terms: Bevacizumab; Antineoplastic Agents, Immunological; Antibodies; Immunoglobulins; Antibodies, Monoclonal
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 182.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

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
    

Eligibility 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.

             * 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)