Bevacizumab for Recurrent Malignant Glioma
Condition: Recurrent High-Grade Gliomas; Malignant Gliomas
MeSH terms: Glioma; Recurrence
Intervention: Bevacizumab
Intervention description: 10 mg/kg intravenously over 90 minutes every 2 weeks on a 28 day cycle. First dose is given over 90 minutes and subsequent doses are given over 30 minutes.
Intervention MeSH terms: Bevacizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 88.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: AVASTIN; Recurrence; Chemotherapy; Anti-Angiogenesis; Radiotherapy; Brain Tumor; Malignant Glioma

Summary:

      Background:

      Bevacizumab is a genetically engineered antibody that blocks the growth of new blood vessels
      in tumors. Inhibiting the formation of these blood vessels may slow or stop disease
      progression by diminishing the supply of life-sustaining nutrients and oxygen the blood
      delivers to the tumor.

      Bevacizumab is approved for treating colorectal cancer and has shown activity against brain
      tumor cells in laboratory and animal tests.

      Objectives:

      To examine the safety and side effects of bevacizumab in patients with recurrent brain
      tumors.

      To determine the anti-tumor activity of bevacizumab in patients with recurrent brain tumors.

      Eligibility:

      Patients 18 years of age and older with a brain tumor that continues to grow after receiving
      standard treatments.

      Design:

      Patients complete the following procedures during the study:

        -  Infusions of bevacizumab through a vein once every 2 weeks in 4-week treatment cycles.

        -  Positron emission tomography (PET) scan before the first dose of bevacizumab, at the end
           of the first treatment cycle, and as needed after that.

        -  Magnetic resonance imaging (MRI) scan before the first dose of bevacizumab, within 48-96
           hours after the first dose of bevacizumab in the first treatment cycle, and then every 4
           weeks. One tube of blood for research is collected at the time of each MRI scan to look
           at specific cells.

        -  Physical and neurological examinations every 2 weeks for the first treatment cycle and
           then every 4 weeks.

        -  Quality-of-life questionnaires every 4 weeks.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

          -  Patients with histologically proven intracranial malignant glioma will be eligible for
             this protocol.

          -  Malignant glioma include glioblastoma multiforme (GBM),

          -  gliosarcoma,

          -  anaplastic astrocytoma (AA),

          -  anaplastic oligodendroglioma (AO),

          -  anaplastic mixed oligoastrocytoma (AMO),

          -  or malignant astrocytoma NOS (not otherwise specified).

          -  Patients must have evidence for tumor progression by magnetic resonance imaging (MRI)
             or computed tomography (CT) scan.

          -  This scan should be performed within 14 days prior to registration and on a fixed dose
             of steroids for at least 5 days.

          -  If the steroid dose is increased between the date of imaging and registration a new
             baseline MR/CT is required.

          -  The same type of scan, i.e., MRI or CT must be used throughout the period of protocol
             treatment for tumor measurement.

          -  Patients having undergone recent resection of recurrent or progressive tumor will be
             eligible as long as all of the following conditions apply:

          -  They have recovered from the effects of surgery.

          -  Residual disease following resection of recurrent tumor is not mandated for
             eligibility into the study.

          -  To best assess the extent of residual disease post-operatively, a CT/ MRI should be
             done:

          -  no later than 96 hours in the immediate post-operative period or

          -  at least 4 weeks post-operatively, and

          -  within 14 days of registration, and

          -  on a steroid dosage that has been stable for at least 5 days.

          -  If the 96 hour scan is more than 21 days before registration, the scan needs to be
             repeated.

          -  If the steroid dose is increased between the date of imaging and registration, a new
             baseline MRI/CT is required on a stable steroid dosage for at least 5 days.

          -  Patients must have progressed after radiation therapy and must have an interval of
             greater than or equal to 4 weeks from the completion of radiation therapy to study
             entry.

          -  All patients must sign an informed consent indicating that they are aware of the
             investigational nature of this study.

          -  Patients must be greater than or equal to 18 years old,

          -  and with a life expectancy greater than 8 weeks.

          -  Patients must have a Karnofsky performance status of greater than or equal to 60.

          -  Patients must have recovered from the toxic effects of prior therapy:

          -  2 weeks from any investigational agent,

          -  4 weeks from prior cytotoxic therapy,

          -  two weeks from vincristine,

          -  6 weeks from nitrosoureas,

          -  3 weeks from procarbazine administration,

          -  and 1 week for non-cytotoxic agents, e.g., interferon,

          -  tamoxifen,

          -  thalidomide,

          -  cis-retinoic acid, etc. (radiosensitizer does not count).

          -  Any questions related to the definition of non-cytotoxic agents should be directed to
             the Study Chair.

          -  Patients must have adequate bone marrow function (white blood count (WBC) -greater
             than or equal to 3,000/microliters,

          -  absolute neutrophil count (ANC) greater than or equal to 1,500/mm^3,

          -  platelet count of greater than or equal to 100,000/mm^3,

          -  and hemoglobin greater than or equal to 10 gm/dl),

          -  adequate liver function (serum glutamic oxaloacetic transaminase (SGOT) and -bilirubin
             less than 2 times upper limit of normal (ULN)),

          -  and adequate renal function (creatinine less than 1.5 mg/dL and/or creatinine
             -clearance greater than or equal to 60 cc/min) before starting therapy.

          -  These tests must be performed within 14 days prior to registration. -Eligibility level
             for hemoglobin may be reached by transfusion.

          -  Patients must not have any significant medical illnesses that in the investigator's
             opinion cannot be adequately controlled with appropriate therapy or would compromise
             the patients' ability to tolerate this therapy

          -  This study was designed to include women and minorities, but was not designed to
             measure differences of intervention effects.

          -  Males and females will be recruited with no preference to gender.

          -  No exclusion to this study will be based on race.

          -  Minorities will actively be recruited to participate.

          -  Urine protein should be screened by dipstick or urine analysis for Urine Protein
             Creatinine (UPC) ratio.

          -  For proteinuria greater than or equal to 1+ or urine protein:

          -  creatinine UPC ratio greater than 1.0,

          -  24-hour urine protein should be obtained and the level should be less than 1000 mg for
             patient enrollment.

          -  Patients must practice adequate contraception

        EXCLUSION CRITERIA:

          -  Patients who, in the view of the treating physician,

          -  have significant active cardiac,

          -  hepatic,

          -  renal,

          -  or psychiatric diseases are ineligible.

          -  No concurrent use of other standard chemotherapeutics or investigative agents.

          -  Patients known to have a malignancy that has required treatment in the last 12 months
             and/or is expected to require treatment in the next 12 months (except non-melanoma
             skin cancer or carcinoma in-situ in the cervix).

          -  Patients who have an active infection.

          -  Pregnant (positive pregnancy test) or nursing women.

          -  Both fertile men and women must agree to use adequate contraceptive measures during
             study therapy and for at least 6 months after the completion of bevacizumab therapy.

          -  Patients who have any disease that will obscure toxicity.

          -  Patients with evidence of acute intracranial/intratumoral hemorrhage on pre-study CT
             scan.

          -  Concurrent anti-coagulation or anti-platelet medication (including aspirin,
             -non-steroidal anti-inflammatories,

          -  cyclooxygenase 2 (COX-2) inhibitors).

          -  Serious or non-healing wound,

          -  ulcer

          -  or bone fracture

          -  History of abdominal fistula,

          -  gastrointestinal perforation

          -  or intra-abdominal abscess within 28 days

          -  Invasive procedures defined as follows:

          -  Major surgical procedure,

          -  open biopsy

          -  or significant traumatic injury within 28 days prior to Day 1 therapy

          -  Anticipation of need for major surgical procedures during the course of the study

          -  Core biopsy within 7 days prior to day 1 (D1) therapy

          -  Patients with clinically significant cardiovascular disease

          -  History of cerebrovascular accident (CVA) within 6 months

          -  Uncontrolled hypertension (greater than 150/100 mmHg)

          -  Myocardial infarction or unstable angina within 6 months

          -  New York Heart Association grade II or greater congestive heart failure

          -  Serious cardiac arrhythmia requiring medication

          -  Unstable angina pectoris

          -  Clinically significant peripheral vascular disease

          -  Evidence of bleeding diathesis or coagulopathy

          -  Prothrombin time (PT) international normalized ratio (INR) greater than 1.5

          -  Patients with known hypersensitivity of Chinese hamster ovary cell products or other
             recombinant human antibodies