Malignant Gliomas, Recurrent High-Grade Gliomas
Conditions
Keywords
AVASTIN, Recurrence, Chemotherapy, Anti-Angiogenesis, Radiotherapy, Brain Tumor, Malignant Glioma
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.
Interventions
DRUGBevacizumab
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.
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Progression Free Survival at 6 Months. | 6 months | 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. |
| Number of Participants With Adverse Events | 5 years | Here is the number of participants with adverse events. For the detailed list of adverse events see the adverse event module. |
Countries
United States
Participant flow
Recruitment details
88 participants were accrued to this study.
Pre-assignment details
Minimum washout period of 2-4 weeks required after molecularly targeted or cytotoxic agents.
Participants by arm
| Arm | Count |
|---|---|
| Anaplastic Glioma (AG) Anaplastic astrocytoma Anaplastic oligodendroglioma Anaplastic mixed oligoastrocytoma Malignant astrocytoma (not otherwise specified) | 32 |
| Glioblastoma Multiforme (GBM) Glioblastoma multiforme Gliosarcoma | 56 |
| Total | 88 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 11 | 3 |
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Anaplastic Glioma (AG) | Glioblastoma Multiforme (GBM) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 6 Participants | 8 Participants |
| Age, Categorical Between 18 and 65 years | 30 Participants | 50 Participants | 80 Participants |
| Age, Continuous | 45 years STANDARD_DEVIATION 12 | 52.33 years STANDARD_DEVIATION 10.6 | 48.66 years STANDARD_DEVIATION 11.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 1 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 29 Participants | 55 Participants | 84 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 28 Participants | 55 Participants | 83 Participants |
| Region of Enrollment United States | 32 participants | 56 participants | 88 participants |
| Sex: Female, Male Female | 10 Participants | 26 Participants | 36 Participants |
| Sex: Female, Male Male | 22 Participants | 30 Participants | 52 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 32 / 32 | 51 / 56 |
| serious Total, serious adverse events | 11 / 32 | 24 / 56 |
Outcome results
Primary
Number of Participants With Adverse Events
Here is the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.
Time frame: 5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Anaplastic Glioma (AG) | Number of Participants With Adverse Events | 32 Participants |
| Glioblastoma Multiforme (GBM) | Number of Participants With Adverse Events | 51 Participants |
Primary
Percentage of Participants With Progression Free Survival at 6 Months.
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.
Time frame: 6 months
Population: at the time of data cutoff for this endpoint, 31 patients in the AG arm and 48 patients in the GBM arm were evaluable for PFS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Anaplastic Glioma (AG) | Percentage of Participants With Progression Free Survival at 6 Months. | 20.9 Percentage of participants |
| Glioblastoma Multiforme (GBM) | Percentage of Participants With Progression Free Survival at 6 Months. | 29 Percentage of participants |