Low-dose Intra-arterial Bevacizumab for Edema and Radiation Necrosis Therapeutic Intervention (LIBERTI)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 10
- 试验地点
- 2
- 主要终点
- Change in Radiation Necrosis and Cerebral Edema After a Single Treatment of Low Dose Intra-arterial Avastin (Bevacizumab)
研究概览
简要总结
To assess the overall safety and efficacy of intra-arterial (IA) bevacizumab for the treatment of radiation necrosis. A single 2.5 mg/kg dose of bevacizumab will be given intra-arterially after osmotic blood-brain-barrier disruption.
详细描述
BACKGROUND Radiation Necrosis: Stereotactic radiosurgery has become integral in treatment of brain tumors and arteriovenous malformations (AVM). In up to 10% of cases, this can lead to radiation necrosis (RN) with significant surrounding vasogenic edema and mass effect. Medical treatment for RN includes steroids, vitamin E, pentoxiphylline, and hyperbaric oxygen. Up to 20% of cases however, are medically refractory and experience progressive neurological decline and disabling headaches.
Surgical resection and laser interstitial thermal therapy (LITT) are sometimes used for treatment of medically refractory radiation necrosis. These invasive options carry risks of serious complications such as infection, seizures, neurological deficits, and hemorrhage, and may have a failure rate as high as 39% in patients with radiation necrosis of the brain.
Bevacizumab: Bevacizumab (Avastin, Genentech BioOncology, South San Francisco, CA) is a recombinant humanized version of a murine anti-human vascular endothelial growth factor (VEGF) monoclonal antibody. Recently, bevacizumab was shown in a small randomized controlled trial (n=14) to be effective in treatment of refractory radiation necrosis after radiation therapy in brain tumors1. Patients received 7.5 mg/kg IV-Bevacizumab every 3 weeks for 4 cycles. All patients receiving Bevacizumab and none of the patients receiving placebo had significant clinical and radiographic improvement.
PRE-CLINICAL DATA Role of vascular endothelial growth factor (VEGF) in radiation necrosis VEGF has been implicated in the pathophysiology of radiation necrosis. Reactive astrocytes immediately surrounding the necrotic core in RN are strongly VEGF-positive by immunohistochemistry. It is postulated that radiation causes microvascular injury leading to hypoxia. Hypoxia-induced VEGF up-regulation then drives an increase in vascular permeability, leading to the extensive vasogenic edema seen in RN. Bevacizumab binds circulating VEGF receptors with high specificity, blocking the down-stream signaling cascade.
CLINICAL DATA:
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients must have radiation necrosis based on radiographic evidence defined as:
- •Increased T1 contrast enhancement in the radiated area with central hypointensity
- •Increased surrounding vasogenic edema on FLAIR MRI images
- •The underlying lesion prompting the radiation can include: Benign lesions such as AVM, Meningioma, schwannoma, trigeminal neuralgia: No biopsy is necessary
- •Radiation necrosis must be symptomatic, including either severe headache, seizures, or neurological deficits.
- •Radiation necrosis must be refractory to steroid treatment; defined as failing a 3-week steroid regiment or not tolerating steroids because of side effects. Beyond 3 weeks, the side effects of steroid therapy worsen rapidly. The patient may receive other therapies such as Vitamine E, Pentoxyfylline, and hyperbaric oxygen during the trial.
- •Other inclusion criteria include:
- •Age >18 years.
- •Ability to understand and the willingness to sign a written informed consent document.
- •Both men and women and members of all races and ethnic groups are eligible for this trial.
- •Karnofsky Performance Status > or = 70%.
- •Life expectancy of greater than 3 months.
- •Patients must have normal organ and marrow function as defined below:
- •leukocytes greater than equal to1,500/mcL platelets greater than equal to 85,000/mcL creatinine less than equal to 1.8 mg/dl
- •Birth Control: The effects of Bevacizumab on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Women of childbearing age will have a urine pregnancy test immediately before each IA Bevacizumab treatment.
排除标准
- •Patients may not be started on any other investigational agents during the course of this trial. They may however continue previous medical regiments aimed for treatment of radiation necrosis. These include steroids, vitamin E, pentoxiphylline, and hyperbaric oxygen. We feel that these treatments are generally ineffectual and would not confound the results.
- •Malignant brain tumor
- •Concomitant use of anticoagulation agents including Coumadin, anticoagulation dose Lovenox or Arixtra. Aspirin is acceptable.
- •Active bleeding or pathological condition that carries high risk of bleeding.
- •Abdominal fistula, abscess, or gastrointestinal tract perforation 28 days of study entry.
- •Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
- •Any major surgery in the prior 4 weeks. Also any major surgery expected to be performed in the ensuing 4 weeks after treatment.
- •Pregnant women are excluded from this study because Bevacizumab is expected to disrupt angiogenesis during pregnancy with the potential for teratogenic or abortive effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with Bevacizumab, breastfeeding should be discontinued if the mother is treated with Bevacizumab.
- •HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with Bevacizumab.
研究组 & 干预措施
Low-dose Intra-arterial Bevacizumab
A single intra-arterial targeted dose of 2.5 mg/kg bevacizumab will be administered after osmotic blood-brain-barrier disruption with intra-arterial 25% mannitol at rate of 4-12 ml/sec for 30 seconds.
干预措施: 25% Mannitol (Drug)
Low-dose Intra-arterial Bevacizumab
A single intra-arterial targeted dose of 2.5 mg/kg bevacizumab will be administered after osmotic blood-brain-barrier disruption with intra-arterial 25% mannitol at rate of 4-12 ml/sec for 30 seconds.
干预措施: Low-dose Intra-arterial Bevacizumab (Drug)
结局指标
主要结局
Change in Radiation Necrosis and Cerebral Edema After a Single Treatment of Low Dose Intra-arterial Avastin (Bevacizumab)
时间窗: Baseline (before treatment), and 3 months and 12 months after single dose intra-arterial Avastin (bevacizumab)
Imaging response to therapy will be quantitatively assessed on MRI using volumetric analysis. Regions of T2 and FLAIR prolongation above contralateral white matter will be calculated and quantified in cubic centimeters. Region of interest (ROI) will be created using a semi-automated, thresholding and region-growing technique. Enhancement of the lesion will be calculated using similar volumetric ROI analysis with a contrast threshold of 40% above background and measured in cubic centimeters.
次要结局
- Change in Headache Associated Morbidity Measured With MIDAS TOTAL SCORE After a Single Treatment of Low Dose Intra-arterial Avastin (Bevacizumab) Will be Measured.(Baseline (before treatment), and 6 weeks, 3 months, 6 months, 9 months, and 12 months after single dose intra-arterial Avastin (bevacizumab))
- Change in Headache Associated Morbidity Measured With MIDAS DAYS of HEADACHE After a Single Treatment of Low Dose Intra-arterial Avastin (Bevacizumab) Will be Measured.(Baseline (before treatment), and 6 weeks, 3 months, 6 months, 9 months, and 12 months after single dose intra-arterial Avastin (bevacizumab))
- Change in Headache Associated Morbidity Measured With MIDAS PAIN LEVEL After a Single Treatment of Low Dose Intra-arterial Avastin (Bevacizumab) Will be Measured.(Baseline (before treatment), and 6 weeks, 3 months, 6 months, 9 months, and 12 months after single dose intra-arterial Avastin (bevacizumab))
- Change in Headache Measured With Headache Impact Test (HIT-6) After a Single Treatment of Low Dose Intra-arterial Avastin (Bevacizumab)(Baseline (before treatment), and 6 weeks, 3 months, 6 months, 9 months, and 12 months after single dose intra-arterial Avastin (bevacizumab))
- Change in Functional Status After a Single Treatment of Low Dose Intra-arterial Bevacizumab(Baseline (before treatment), Day 1, and at 3 months, and 12 months after single dose intra-arterial Avastin (bevacizumab))
- Change in Steroid Usage After a Single Treatment of Low Dose Intra-arterial Avastin (Bevacizumab)(12 months prior to single dose of IA bevacizumab; 12 months following single dose of IA bevacizumab)
- Post-operative Neurocognitive Change After Intra-arterial Bevacizumab(Baseline (before bevacizumab), and 3 months and 12 months after single dose intra-arterial Avastin (bevacizumab))
研究者
Shervin Dashti, MD
Principal Investigator
Norton Healthcare