Clinical trial NCT00271609: Bevacizumab for Recurrent Malignant Glioma
Official title: A Phase II Trial of Bevacizumab for Patients With Recurrent High-Grade Gliomas
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Recurrent High-Grade Gliomas
Malignant Gliomas
Keywords: AVASTIN
Recurrence
Chemotherapy
Anti-Angiogenesis
Radiotherapy
Brain Tumor
Malignant Glioma
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2006-01-02
Enrollment: 88
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed description: 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.

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

Primary outcomes:
measure: Percentage of Participants With Progression Free Survival at 6 Months.
timeFrame: 6 months
measure: Number of Participants With Adverse Events
timeFrame: 5 years
Secondary outcomes:
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Cancer Institute, National Institutes of Health
name: Teri Kreisl, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Barker D, Wright E, Nguyen K, Cannon L, Fain P, Goldgar D, Bishop DT, Carey J, Baty B, Kivlin J, et al. Gene for von Recklinghausen neurofibromatosis is in the pericentromeric region of chromosome 17. Science. 1987 May 29;236(4805):1100-2. doi: 10.1126/science.3107130.
citation: Bigner SH, Bjerkvig R, Laerum OD. DNA content and chromosomal composition of malignant human gliomas. Neurol Clin. 1985 Nov;3(4):769-84.
citation: Moss AR. Occupational exposure and brain tumors. J Toxicol Environ Health. 1985;16(5):703-11. doi: 10.1080/15287398509530780.
citation: Kreisl TN, Zhang W, Odia Y, Shih JH, Butman JA, Hammoud D, Iwamoto FM, Sul J, Fine HA. A phase II trial of single-agent bevacizumab in patients with recurrent anaplastic glioma. Neuro Oncol. 2011 Oct;13(10):1143-50. doi: 10.1093/neuonc/nor091. Epub 2011 Aug 24.
citation: Odia Y, Shih JH, Kreisl TN, Fine HA. Bevacizumab-related toxicities in the National Cancer Institute malignant glioma trial cohort. J Neurooncol. 2014 Nov;120(2):431-40. doi: 10.1007/s11060-014-1571-6. Epub 2014 Aug 7.