Bevacizumab for Recurrent Malignant Glioma

Background

• In vivo experiments have documented the ability of anti-vascular endothelial growth factor (VEGF) antibodies like bevacizumab to inhibit tumor growth in various preclinical tumor models, including gliomas.
• Given the pronounced neovasculature associated with over-expression of VEGF in malignant gliomas, and abundant published data demonstrating the dependence of glioma growth on the maintenance and proliferation of this neovasculature, bevacizumab represents a potentially promising new therapeutic approach to these otherwise refractory tumors.

Objective

• To establish data regarding the anti-tumor activity of bevacizumab in patients with recurrent high-grade gliomas as determined by progression-free-survival.
• To obtain information regarding the safety of bevacizumab administered to patients with recurrent high-grade gliomas.

Eligibility

• Adult patients with histologically proven intracranial malignant glioma
• Patients must have evidence for tumor progression by magnetic resonance imaging (MRI) scan
• 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

Design

• Patients will be treated with bevacizumab by intravenous injection at a dose of 10mg/kg every two weeks on a 4-week cycle.
• Prior to the first dose of bevacizumab and at the completion of the first 4-weeks of treatment, patients will undergo a fludeoxyglucose 18F -positron emission tomography (FDG-PET) scan (in cycle one only and then as needed) and a MRI perfusion scan.
• Peripheral blood circulating endothelial progenitor cells will be collected at the time of each MRI-perfusion scan. Additionally, patients will undergo a MRI perfusion scan within 48-96 hours of their first dose of bevacizumab (in cycle one only).
• For patients who are clinically/neurologically stable and with stable or responding radiographic disease at the end of each treatment cycle, treatment will continue with bevacizumab every 2 weeks, repeating MRI-perfusion scans at the conclusion (e.g. prior to another administration of bevacizumab) of each 4 week cycle.

A total of 88 patients will be enrolled on this study.

• 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