Low-dose Intra-arterial Bevacizumab for Edema and Radiation Necrosis Therapeutic Intervention (LIBERTI)
Low-dose Intra-arterial Bevacizumab for Edema and Radiation Necrosis Therapeutic Intervention (LIBERTI)
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.
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.

 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:

 Bevacizumab was originally developed and tested as an anti-angiogenic treatment for various
 solid tumors. More recently, IV-Bevacizumab was shown in a small, randomized controlled trial
 (n=14) to be very 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. This improvement was durable at 10 months
 in 8 of 11 patients (4 patients crossed over from the control group). There was however, a
 very high rate of adverse events (60%), major adverse events (30%. Major adverse events
 included venous sinus thrombosis, pulmonary embolus, and aspiration pneumonia.

 The investigators recently published a case series of two pediatric patients with highly
 symptomatic steroid refractory radiation necrosis in the brain after stereotactic
 radiosurgery for treatment of cerebral arteriovenous malformations3. Both patients were
 refractory to all accepted medical therapies. Both were steroid dependent for a prolonged
 period and severely cushingoid. Both had suffered a significant decline in quality of life
 with severe headache and need to withdraw from school. In both instances, the patients made a
 remarkable progressive clinical and radiographic improvement after receiving a single 2.5
 mg/kg dose of intra-arterial bevacizumab, which was durable one-year later. To increase
 bevacizumab penetration into the brain, the investigators used intra-arterial Mannitol to
 disrupt the blood-brain barrier immediately prior to targeted intra-arterial drug
 administration.

 RATIONALE:

 RATIONALE: CURRENT IV BEVACIZUMAB REGIMEN FOR RADIATION NECROSIS AND ITS ASSOCIATED
 MORBIDITY:

 Current IV-bevacizumab regimens use a dose of 7.5 mg/kg every 3 weeks for 4 cycles. There are
 significant known side effects of bevacizumab including gastrointestinal perforation, deep
 venous thrombosis, venous sinus thrombosis, pulmonary embolus, intracranial hemorrhage, wound
 dehiscence, and severe hypertension. These complications are common to the anti-angiogenic
 class of drugs and reflect systemic exposure to bevacizumab. In our initial clinical
 experience, the investigators utilized a combination of IA-route of delivery and BBB
 disruption to reduce bevacizumab dose while maintaining efficacy. This is supported by the
 durable clinical and radiographic response in our patients after a single 2.5 mg/kg dose of
 bevacizumab. The investigators believe that this approach will reduce the incidence of
 serious systemic toxicities compared to the IV-bevacizumab regimens (7.5-15 mg/kg every 2-3
 weeks for several weeks to months).

 There are multiple recent reports of patients with radiation necrosis who improved with
 IV-bevacizumab, only to relapse months later. In fact 3/11 patients in the randomized
 controlled trial discussed above required repeat treatment with IV-bevacizumab because of RN
 symptom progression1. In contrast, the two patients in our series who received IA-bevacizumab
 continue to show progressive clinical and radiographic improvement more than one year later.
 The investigators believe that the increased penetration of bevacizumab into the brain
 because of the intra-arterial administration after blood-brain barrier disruption results in
 binding of virtually all VEGF molecules. The fact that the results are durable and
 progressively improving suggests that massive blocking of VEGF activity could have stopped a
 positive feedback loop of inflammation. Therefore, IA-bevacizumab may result in more
 effective and durable control of radiation necrosis compared to traditional IV-bevacizumab
 treatment.

 RATIONALE: INTRA-ARTERIAL (IA) ROUTE OF BEVACIZUMAB ADMINISTRATION SIGNIFICANTLY INCREASE
 DRUG DELIVERY TO THE BRAIN:

 IA-therapy decreases volume dilution of the drug in the circulation and reduces first-pass
 degradation via proteolytic catabolism, resulting in higher drug delivery to target brain
 tissue. Super-selective IA-injection of 99mTc-HMPAO (Ceretec®) into human cerebral arteries
 achieves a concentration of radiotracer in brain tissue 50 times higher than with IV
 injection. In clinical studies of cerebral chemotherapy, the concentration delivered to the
 tumor by using intra-arterial injection versus intravenous administration of chemotherapeutic
 agents was five times higher with hydrosoluble drugs and up to 50 times higher with
 liposoluble drugs. The investigators will infuse bevacizumab in the artery that supplies the
 territory affected by RN, such as cervical internal carotid artery and/or cervical vertebral
 artery.

 RATIONALE: BLOOD-BRAIN-BARRIER BREAKDOWN PRIOR TO INTRA-ARTERIAL THERAPY FURTHER ENHANCES
 DRUG DELIVERY TO THE BRAIN:

 The blood-brain-barrier is a selective permeability barrier that block entry of many drugs
 into the brain. Bevacizumab is a monoclonal antibody with a high molecular weight (149 kDa).
 There is convincing evidence in the literature that the concentration in the brain of high
 molecular weight molecules can be significantly increased after osmotic BBB disruption.
 Several tumor clinical trials have shown that localization of monoclonal antibodies to the
 brain is poor without BBB disruption (0.0006%-0.0043% of the injected dose/g of tumor). There
 is also evidence of a 20-fold increase in permeability to immunoreactive IgM Mab with BBB
 disruption in rats. The investigators believe that using blood-brain-barrier disruption
 significantly increases delivery of Bevacizumab to the affected brain. The investigators will
 use the protocol described by Neuwelt and colleagues, using infusion of 25% Mannitol over 30
 seconds. This protocol has been shown to temporarily disrupt the blood brain barrier, peaking
 at 15 minutes and dissipating in 4 hours. IA-chemotherapy following BBBD has been shown to be
 feasible and safe across multiple centers with low incidence of complications27. The efficacy
 and safety profile was reproducible across multiple centers. In fact, safety of this protocol
 has been established in more than 6000 patients treated worldwide with BBBD for
 intra-arterial chemotherapy infusion. The main possible complication is seizure, which occurs
 in <6% of cases. It is important to note that these seizures generally occurred in patients
 with widespread malignant pathology such as Glioblastoma and CNS lymphoma who were treated
 with very toxic chemotherapy agents immediately after BBBD. Recent refinements to the osmotic
 BBBD protocol have incorporated the use of general anesthesia, as well as prophylaxis with an
 anti-epileptic agent and Valium to reduce seizure threshold and the chance of seizures.

 SAFETY OF CEREBRAL INTRA-ARTERIAL BEVACIZUMAB TREATMENT:

 Safety of IA-Bevacizumab treatment after hyperosmotic BBBD was recently established in a
 series of malignant glioma patients. This was done through super-selective injection of
 intracranial tumor arterial pedicles for purpose of anti-tumor effects. Dose-escalation was
 performed from 2 mg/kg to 15 mg/kg without reaching maximal tolerated dose. There was a
 significant decrease in the contrast enhancing and FLAIR signal characteristics of the tumor
 and surrounding brain at one month after treatment. Overall toxicity for this cohort was
 comparable to previous reports for IV Bevacizumab therapy. Specifically, hyperosmotic
 BBB-breakdown followed by IA-Bevacizumab administration did not cause any direct
 neurotoxicity; there were no cases of intracranial hemorrhage. Multiple other reports of BBBD
 followed by intra-arterial bevacizumab treatment for other pathologies such as vestibular
 schwannoma, ependymoma, and malignant brainstem glioma have also demonstrated good safety
 profile with no obvious neurotoxicity.

 TREATMENT PLAN:

 VASCULAR ACCESS, CEREBRAL ANGIOGRAM, AND OSMOTIC BLOOD-BRAIN-BARRIER DISRUPTION:

 The investigators will use the protocol described by Neuwelt and colleagues, using infusion
 of 25% Mannitol over 30 seconds. The safety of this protocol has been established in more
 than 6000 patients treated worldwide with BBBD for intra-arterial chemotherapy infusion.

 The patients are to be premedicated with 6 mg Dexamethasone and 1000 mg Keppra. General
 endotracheal anesthesia will be induced. The femoral artery will be accessed using the
 Seldinger technique. A 5-French diagnostic catheter will be used to catheterize the cervical
 internal carotid artery ipsilateral to the area of radiation necrosis. Baseline internal
 carotid angiogram will be performed.

 The anesthesiologist will be instructed to maintain SBP >120 or at pre-operative baseline,
 whichever value is higher. This is important for efficient bulk flow of drug through the
 blood brain barrier opening. The catheter is positioned at C1-2 level in the cervical
 internal carotid artery and C6-7 for a vertebral artery infusion. Optimal rate of Mannitol
 infusion will be determined by performing injection of contrast at 4 ml/sec for 3 seconds
 into vessel. If there is no reflux of contrast into the external carotid artery, the
 injection rate injection will be increased by 2 ml/sec to maximum of 12 ml/sec. The lowest
 rate at which there is reflux into the external carotid artery will be chosen (the rate to
 just exceed cerebral blood flow.

 Next, 5 mg IV Valium and 0.2 mg IV Atropine are to be administered. Warm (37 degrees Co) 25%
 Mannitol is filtered through a 5-micron filter, and then infused into the ipsilateral
 cervical carotid artery at the rate determined above for a total of 30 seconds.

 INTRA-ARTERIAL BEVACIZUMAB ADMINISTRATION:

 Test injection of contrast will be done in the artery. If there is any evidence of
 catheter-induced vasospasm, the catheter may be withdrawn more proximally within the artery.
 Repeat test injection of contrast will be done to document resolution of vasospasm. Within 5
 minutes of Mannitol infusion, 2.5 mg/kg bevacizumab in a volume of 100 ml will be
 administered into the artery over 10 minutes. Repeat angiogram will be performed to document
 BBBD, as well as to rule out thromboembolic phenomenon.
Inclusion Criteria:

 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 severe headache, seizures, and
 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 >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.

 Exclusion Criteria:

 -  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.