A Phase II Trial of Bevacizumab for Patients With Recurrent High-Grade Gliomas

Inclusion 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