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

Phase 2
18 Years
Open (Enrolling)
Recurrent High-Grade Gliomas, Malignant Gliomas

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Trial Information

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


- 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.


- 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.


- Adult patients with histologically proven intracranial malignant glioma

- Patients must have evidence for tumor progression by magnetic resonance imaging (MRI)

- 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


- 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

- 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

- 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

- 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


- 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

- 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

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Percentage of Participants With Progression Free Survival at 6 Months.

Outcome Description:

Percentage of participants surviving without progression of disease after six months of study entry. Progression is defined as a 25% increase in lesions, clear worsening of any evaluable disease, or appearance of any new lesion/site (e.g. by computed tomography, magnetic resonance imaging), or failure to return for evaluation due to death or deteriorating condition.

Outcome Time Frame:

6 months

Safety Issue:


Principal Investigator

Teri Kreisl, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute, National Institutes of Health


United States: Federal Government

Study ID:




Start Date:

December 2005

Completion Date:

May 2014

Related Keywords:

  • Recurrent High-Grade Gliomas
  • Malignant Gliomas
  • Recurrence
  • Chemotherapy
  • Anti-Angiogenesis
  • Radiotherapy
  • Brain Tumor
  • Malignant Glioma
  • Glioma



National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda, Maryland  20892