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

• Sponsor: Norton Healthcare (Other)
• Overall Status: Completed
• CT.gov ID: NCT02819479
• Collaborator: University of Kentucky (Other)
• Enrollment: 10
• Locations: 2
• Arm: 1
• Actual Duration (Months): 30.4
• Patients Per Site: 5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Radiation Necrosis	Drug: 25% Mannitol; Drug: Low-dose Intra-arterial Bevacizumab	Phase 2

Detailed Description

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:

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%), and major adverse events (30%). Major adverse events included venous sinus thrombosis, pulmonary embolus, and aspiration pneumonia.

The investigators of the present study 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 needed 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 intra-arterial (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 believed that this approach would 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 INCREASES

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 10 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Low-dose Intra-arterial Bevacizumab for Edema and Radiation Necrosis Therapeutic Intervention (LIBERTI)
• Actual Study Start Date: Nov 23, 2016
• Actual Primary Completion Date: Jun 6, 2019
• Actual Study Completion Date: Jun 6, 2019

Arms and Interventions

Arm

Intervention/Treatment

Experimental: 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.

Drug: 25% Mannitol; Route of administration: In this study, the first step of the treatment will be performing osmotic blood-brain-barrier disruption with administration of intra-arterial 25% Mannitol into the appropriate cervical artery.; Drug: Low-dose Intra-arterial Bevacizumab; Route of administration: In this study, the second step of the treatment will be administering intra-arterial targeted bevacizumab into the appropriate cervical artery.; Other Names: Avastin

Outcome Measures

Primary Outcome Measures

1. Change in Radiation Necrosis and Cerebral Edema After a Single Treatment of Low Dose Intra-arterial Avastin (Bevacizumab) [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.

Secondary Outcome Measures

1. 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)]

   We will determine how severely headache affect the patient's life before and after treatment by performing the Migraine Disability Assessment (MIDAS) questionnaire. MIDAS TOTAL SCORE is the sum of Items 1 through 5. A Total Score of 0-5 signifies little or no disability, score of 6-10 signifies mild disability, score of 11-20 signifies moderate disability, and score of 21+ signifies severe disability. The theoretical maximum score would be 450.

2. 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)]

   We will determine how severely headache affect the patient's life before and after treatment by performing the Migraine Disability Assessment (MIDAS) questionnaire. MIDAS DAYS of HEADACHE is Item 6 of the questionnaire which sums total number of days the patient had headache symptoms over the past 3 months regardless of headache severity or resultant disability. Min score of 0 days is the best possible score. Max Score of 90 days is worse possible score, meaning the patient experienced headache pain every day over past 3 months.

3. 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)]

   We will determine how severely headache affect the patient's life before and after treatment by performing the Migraine Disability Assessment (MIDAS) questionnaire. MIDAS PAIN LEVEL is Item 7 which rates the 3-month average headache PAIN LEVEL on scale from 0 to 10 where 0 = no pain at all, and 10 = pain as bad as it can be.

4. 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)]

   Quantitative change in headache will be assessed by performing the Headache Impact Test (HIT-6), which is a fixed-length 6-item questionnaire. The score for this questionnaire can range from 36 to 78, with 36 indicating minimum headache impact and the max score of 78 indicating worst possible headache impact.

5. 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)]

   Quantitative change in functional status will be assessed by performing Karnofsky Performance Status Scale (KPS). The KPS score can range from 0 to 100 where 0 is dead and 100 is fully alive and normal with no complaints and no evidence of disease.

6. 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]

   To assess the utility of intra-arterial (IA) bevacizumab treatment in allowing decreased steroid usage, total cumulative days of steroid usage were compared between the 12 months PRIOR TO and the 12 months IMMEDIATELY FOLLOWING IA bevacizumab. Days of steroid usage were tabulated via medical history and chart review at the baseline visit for the 12 months prior to IA bevacizumab and post-treatment on days 0 and 1, week 6, and months 3, 6, 9 and 12 for the 12 month total after IA bevacizumab treatment. Excluding topical steroid preparations, all days of enteral or parenteral steroid intake of any dose were included in the cumulative summation.

7. Post-operative Neurocognitive Change After Intra-arterial Bevacizumab [Baseline (before bevacizumab), and 3 months and 12 months after single dose intra-arterial Avastin (bevacizumab)]

   In order to investigate post-operative changes in Neurocognitive performance after intra-arterial bevacizumab, patients who consented underwent formal neuropsychological battery testing. Sixteen subtests from the Neuropsychological Assessment Battery (Stern & White, PAR Inc.) were chosen for brevity, sensitivity, and due to the wide range of available normative data (ages 18-97). For each subtest, T-score = 50 is the normative mean with SD = 10. Thus T-scores of 40-60 are within one standard deviation of the mean and are considered generally normal. Scores increasingly below 40 indicate decreased neurocognitive performance compared to healthy demographically matched persons. Scores significantly above 60 indicate increase neurocognitive performance compared to healthy demographically matched persons.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 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.

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Kentucky Medical Center	Lexington	Kentucky	United States	40536
2	Norton Brownsboro Hospital	Louisville	Kentucky	United States	40242

Sponsors and Collaborators

• Norton Healthcare
• University of Kentucky

Investigators

• Principal Investigator: Shervin R Dashti, MD,PhD, Norton Healthcare
• Principal Investigator: Justin Fraser, MD, University of Kentucky

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 21, 2016
• Informed Consent Form - Jun 8, 2018

More Information

Publications

None provided.

• Responsible Party: Shervin Dashti, MD, Principal Investigator, Norton Healthcare
• ClinicalTrials.gov Identifier: NCT02819479
• Other Study ID Numbers: 14-N0229
• First Posted: Jun 30, 2016
• Last Update Posted: May 24, 2022
• Last Verified: May 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Shervin Dashti, MD, Principal Investigator, Norton Healthcare: Radiation necrosis; Radiation adverse event; Intra-arterial chemotherapy; Bevacizumab; Blood brain barrier disruption; Blood brain barrier breakdown; Arteriovenous malformation; Stereotactic radiosurgery
• Additional relevant MeSH terms: Necrosis; Bevacizumab; Mannitol

Study Results

Participant Flow

Recruitment Details	Adults recruited from outpatient medical clinics at 2 academic medical centers (5 subjects per center) between Nov 2016 and Jan 2018. Enrollment was closed once 10 adult subjects were enrolled.
Pre-assignment Detail	This was a single-arm study. There was no wash out or run-in period after enrollment. There was no assignment to groups.

Arm/Group Title	Low-dose Intra-arterial Bevacizumab
Arm/Group Description	A single intra-arterial 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. 25% Mannitol: Route of administration: In this study, the first step of the treatment will be performing osmotic blood-brain-barrier disruption with administration of intra-arterial 25% Mannitol into the appropriate cervical artery. Low-dose Intra-arterial Bevacizumab: Route of administration: In this study, the second step of the treatment will be administering intra-arterial bevacizumab into the appropriate cervical artery.
Period Title: Overall Study
STARTED	10
COMPLETED	8
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Low-dose Intra-arterial Avastin (Bevacizumab)
Arm/Group Description	A single intra-arterial 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. 25% Mannitol: Route of administration: In this study, the first step of the treatment will be performing osmotic blood-brain-barrier disruption with administration of intra-arterial 25% Mannitol into the appropriate cervical artery. Low-dose Intra-arterial Bevacizumab: Route of administration: In this study, the second step of the treatment will be administering intra-arterial bevacizumab into the appropriate cervical artery.
Overall Participants	10
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	35.1 (14.8)
Sex: Female, Male (Count of Participants)
Female	8 80%
Male	2 20%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 10%
Not Hispanic or Latino	9 90%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 10%
White	9 90%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	10 100%
MRI of Brain: volume of radiation necrosis (cubic centimeters, or cm^3) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cubic centimeters, or cm^3]	14.5 (12.1)
MRI of Brain: volume of edema (cubic centimeters, or cm^3) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cubic centimeters, or cm^3]	86.8 (95.9)
Headache severity via Migraine Disability Assessment (MIDAS) TOTAL SCORE (units on a scale from 0 to 450) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale from 0 to 450]	81.7 (110.1)
DAYS of Headache via Migraine Disability Assessment (MIDAS) (Days of headache over past 3 months) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Days of headache over past 3 months]	33.3 (29.8)
Headache PAIN LEVEL via Migraine Disability Assessment (MIDAS) (units on a scale from 0 to 10) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale from 0 to 10]	6.9 (2.2)
Headache severity via Headache Impact Test (HIT-6) (units on a scale from 36 - 78) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale from 36 - 78]	62.4 (7.5)
Cumulative Days of Steroid use during 12 months Pre-Bevacizumab (Days) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [Days]	52.5
Karnofsky Performance Status Scale (% on Karnofsky scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [% on Karnofsky scale]	79.0 (9.9)
Digits Forward via Neuropsychological Assessment Battery (T score with Mean=50, SD=10) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [T score with Mean=50, SD=10]	41.1 (11.8)
Digits Backward via Neuropsychological Assessment Battery (T score with Mean=50, SD=10) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [T score with Mean=50, SD=10]	44.9 (8.3)
Numbers and Letters Speed via Neuropsychological Assessment Battery (T score with Mean=50, SD=10) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [T score with Mean=50, SD=10]	38.2 (10.7)
Numbers and Letters Errors via Neuropsychological Assessment Battery (T score with Mean=50, SD=10) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [T score with Mean=50, SD=10]	44.6 (3.8)
Numbers and Letters Efficiency via Neuropsychological Assessment Battery (T score with Mean=50, SD=10) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [T score with Mean=50, SD=10]	41.0 (14.6)
Naming via Neuropsychological Assessment Battery (T score with Mean=50, SD=10) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [T score with Mean=50, SD=10]	47.6 (3.4)
List Learning List Immediate Recall via Neuropsychological Assessment Battery (T score with Mean=50, SD=10) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [T score with Mean=50, SD=10]	44.6 (2.4)
List Learning List Long Delayed Recall via Neuropsychological Assessment Battery (T score with Mean=50, SD=10) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [T score with Mean=50, SD=10]	44.6 (3.5)
Shape Learning Immediate Recognition via Neuropsychological Assessment Battery (T score with Mean=50, SD=10) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [T score with Mean=50, SD=10]	42.9 (3.0)
Shape Learning Delayed Recognition via Neuropsychological Assessment Battery (T score with Mean=50, SD=10) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [T score with Mean=50, SD=10]	41.3 (3.6)
Story Learning Phrase Unit Immediate Recall via Neuropsychological Assessment Battery (T score with Mean=50, SD=10) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [T score with Mean=50, SD=10]	43.2 (2.9)
Story Learning Phrase Unit Delayed Recall via Neuropsychological Assessment Battery (T score with Mean=50, SD=10) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [T score with Mean=50, SD=10]	43.7 (2.3)
Design Construction via Neuropsychological Assessment Battery (T score with Mean=50, SD=10) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [T score with Mean=50, SD=10]	41.4 (3.5)
Mazes via Neuropsychological Assessment Battery (T score with Mean=50, SD=10) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [T score with Mean=50, SD=10]	39.8 (2.9)
Categories via Neuropsychological Assessment Battery (T score with Mean=50, SD=10) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [T score with Mean=50, SD=10]	41.8 (2.2)
Word Generation via Neuropsychological Assessment Battery (T score with Mean=50, SD=10) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [T score with Mean=50, SD=10]	45.0 (3.7)
Full Scale Intelligence Quotient (FSIQ) via Wechsler Test of Adult Reading (units on a scale from 28 to 210) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale from 28 to 210]	95.8 (4.1)

Outcome Measures

1. Primary Outcome

Title	Change in Radiation Necrosis and Cerebral Edema After a Single Treatment of Low Dose Intra-arterial Avastin (Bevacizumab)
Description	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.
Time Frame	Baseline (before treatment), and 3 months and 12 months after single dose intra-arterial Avastin (bevacizumab)

Outcome Measure Data

Analysis Population Description

10 adult subjects presented with medically refractory radiation necrosis of the brain and disabling headache. All were treated with steroids prior to study enrollment.

Arm/Group Title	Low-dose Intra-arterial Avastin (Bevacizumab)
Arm/Group Description	A single intra-arterial 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. 25% Mannitol: Route of administration: In this study, the first step of the treatment will be performing osmotic blood-brain-barrier disruption with administration of intra-arterial 25% Mannitol into the appropriate cervical artery. Low-dose Intra-arterial bevacizumab: Route of administration: In this study, the second step of the treatment will be administering intra-arterial bevacizumab into the appropriate cervical artery.
Measure Participants	10
Vol EDEMA at Baseline	86.8 (95.9)
Vol EDEMA at 3 months	38.6 (37.5)
Vol EDEMA at 12 months	32.6 (33.7)
Vol Radiation Necrosis at Baseline	14.5 (12.1)
Vol Radiation Necrosis at 3 months	6.6 (7.5)
Vol Radiation Necrosis at 12 months	3.2 (3.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Low-dose Intra-arterial Avastin (Bevacizumab)
	Comments	CHANGE IN VOLUME OF RADIATION NECROSIS: To explore durability of radiographic responses, we invoked a linear mixed model in which we addressed heterogeneity of time points by fitting the most appropriate model among compound symmetry, Huyhn-Felt structure, and an unstructured covariance matrix (multivariate analysis of variance).
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.012
	Comments	The threshold for statistical significance was p < 0.05.
	Method	Mixed Models Analysis
	Comments	F(1,14) = 8.29
Method of Estimation	Estimation Parameter	eta^2
	Estimated Value	0.37
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Low-dose Intra-arterial Avastin (Bevacizumab)
	Comments	CHANGE IN VOLUME OF CEREBRAL EDEMA: To explore durability of radiographic responses, we invoked a linear mixed model in which we addressed heterogeneity of time points by fitting the most appropriate model among compound symmetry, Huyhn-Felt structure, and an unstructured covariance matrix (multivariate analysis of variance).
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.09
	Comments	The threshold for statistical significance was p < 0.05.
	Method	Mixed Models Analysis
	Comments	F(1,14) = 3.29
Method of Estimation	Estimation Parameter	eta^2
	Estimated Value	0.19
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change in Headache Associated Morbidity Measured With MIDAS TOTAL SCORE After a Single Treatment of Low Dose Intra-arterial Avastin (Bevacizumab) Will be Measured.
Description	We will determine how severely headache affect the patient's life before and after treatment by performing the Migraine Disability Assessment (MIDAS) questionnaire. MIDAS TOTAL SCORE is the sum of Items 1 through 5. A Total Score of 0-5 signifies little or no disability, score of 6-10 signifies mild disability, score of 11-20 signifies moderate disability, and score of 21+ signifies severe disability. The theoretical maximum score would be 450.
Time Frame	Baseline (before treatment), and 6 weeks, 3 months, 6 months, 9 months, and 12 months after single dose intra-arterial Avastin (bevacizumab)

Outcome Measure Data

Analysis Population Description

10 adult subjects presented with medically refractory radiation necrosis of the brain and disabling headache.

Arm/Group Title	Low-dose Intra-arterial Avastin (Bevacizumab)
Arm/Group Description	A single intra-arterial 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. 25% Mannitol: Route of administration: In this study, the first step of the treatment will be performing osmotic blood-brain-barrier disruption with administration of intra-arterial 25% Mannitol into the appropriate cervical artery. Low-dose Intra-arterial bevacizumab: Route of administration: In this study, the second step of the treatment will be administering intra-arterial bevacizumab into the appropriate cervical artery.
Measure Participants	10
MIDAS TOTAL at Baseline	81.7 (110.1)
MIDAS TOTAL at 6 weeks	49.7 (66.6)
MIDAS TOTAL at 3 months	22.1 (30.3)
MIDAS TOTAL at 6 months	28.3 (46.2)
MIDAS TOTAL at 9 months	24.4 (33.7)
MIDAS TOTAL at 12 months	15.6 (26.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Low-dose Intra-arterial Avastin (Bevacizumab)
	Comments	To explore durability of clinical response, Migraine Disability Assessment (MIDAS) TOTAL SCORES were analyzed using a linear mixed model in which we addressed heterogeneity of time points by fitting the most appropriate model among compound symmetry, Huyhn Felt structure, and an unstructured covariance matrix (multivariate analysis of variance)
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments	The threshold for statistical significance was p < 0.05.
	Method	Mixed Models Analysis
	Comments	F(5,34) = 2.74
Method of Estimation	Estimation Parameter	eta^2
	Estimated Value	0.29
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	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.
Description	We will determine how severely headache affect the patient's life before and after treatment by performing the Migraine Disability Assessment (MIDAS) questionnaire. MIDAS DAYS of HEADACHE is Item 6 of the questionnaire which sums total number of days the patient had headache symptoms over the past 3 months regardless of headache severity or resultant disability. Min score of 0 days is the best possible score. Max Score of 90 days is worse possible score, meaning the patient experienced headache pain every day over past 3 months.
Time Frame	Baseline (before treatment), and 6 weeks, 3 months, 6 months, 9 months, and 12 months after single dose intra-arterial Avastin (bevacizumab)

Outcome Measure Data

Analysis Population Description

10 adult subjects presented with medically refractory radiation necrosis of the brain and disabling headache.

Arm/Group Title	Low-dose Intra-arterial Avastin (Bevacizumab)
Arm/Group Description	A single intra-arterial 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. 25% Mannitol: Route of administration: In this study, the first step of the treatment will be performing osmotic blood-brain-barrier disruption with administration of intra-arterial 25% Mannitol into the appropriate cervical artery. Low-dose Intra-arterial bevacizumab: Route of administration: In this study, the second step of the treatment will be administering intra-arterial bevacizumab into the appropriate cervical artery.
Measure Participants	10
MIDAS DAYS of HEADACHE at Baseline	33.3 (29.8)
MIDAS DAYS of HEADACHE at 6 weeks	25.8 (35.0)
MIDAS DAYS of HEADACHE at 3 months	9.0 (9.3)
MIDAS DAYS of HEADACHE at 6 months	14.6 (14.1)
MIDAS DAYS of HEADACHE at 9 months	12.4 (17.6)
MIDAS DAYS of HEADACHE at 12 months	11.5 (17.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Low-dose Intra-arterial Avastin (Bevacizumab)
	Comments	To explore durability of clinical response, Migraine Disability Assessment (MIDAS) DAYS OF HEADACHE were analyzed using a linear mixed model in which we addressed heterogeneity of time points by fitting the most appropriate model among compound symmetry, Huyhn Felt structure, and an unstructured covariance matrix (multivariate analysis of variance).
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.019
	Comments	The threshold for statistical significance was p < 0.05.
	Method	Mixed Models Analysis
	Comments	F(5,34) = 3.17
Method of Estimation	Estimation Parameter	eta^2
	Estimated Value	0.37
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change in Headache Associated Morbidity Measured With MIDAS PAIN LEVEL After a Single Treatment of Low Dose Intra-arterial Avastin (Bevacizumab) Will be Measured.
Description	We will determine how severely headache affect the patient's life before and after treatment by performing the Migraine Disability Assessment (MIDAS) questionnaire. MIDAS PAIN LEVEL is Item 7 which rates the 3-month average headache PAIN LEVEL on scale from 0 to 10 where 0 = no pain at all, and 10 = pain as bad as it can be.
Time Frame	Baseline (before treatment), and 6 weeks, 3 months, 6 months, 9 months, and 12 months after single dose intra-arterial Avastin (bevacizumab)

Outcome Measure Data

Analysis Population Description

10 adult subjects presented with medically refractory radiation necrosis of the brain and disabling headache.

Arm/Group Title	Low-dose Intra-arterial Avastin (Bevacizumab)
Arm/Group Description	A single intra-arterial 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. 25% Mannitol: Route of administration: In this study, the first step of the treatment will be performing osmotic blood-brain-barrier disruption with administration of intra-arterial 25% Mannitol into the appropriate cervical artery. Low-dose Intra-arterial bevacizumab: Route of administration: In this study, the second step of the treatment will be administering intra-arterial bevacizumab into the appropriate cervical artery.
Measure Participants	10
MIDAS PAIN LEVEL at Baseline	6.9 (2.2)
MIDAS PAIN LEVEL at 6 weeks	6.4 (1.8)
MIDAS PAIN LEVEL at 3 months	4.7 (2.9)
MIDAS PAIN LEVEL at 6 months	5.0 (2.9)
MIDAS PAIN LEVEL at 9 months	4.8 (3.0)
MIDAS PAIN LEVEL at 12 months	4.8 (3.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Low-dose Intra-arterial Avastin (Bevacizumab)
	Comments	To explore durability of clinical response, Migraine Disability Assessment (MIDAS) MIDAS PAIN LEVEL data were analyzed using a linear mixed model in which we addressed heterogeneity of time points by fitting the most appropriate model among compound symmetry, Huyhn Felt structure, and an unstructured covariance matrix (multivariate analysis of variance).
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0006
	Comments	The threshold for statistical significance was p < 0.05.
	Method	Mixed Models Analysis
	Comments	F(5,35) = 3.96
Method of Estimation	Estimation Parameter	eta^2
	Estimated Value	0.3
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Change in Headache Measured With Headache Impact Test (HIT-6) After a Single Treatment of Low Dose Intra-arterial Avastin (Bevacizumab)
Description	Quantitative change in headache will be assessed by performing the Headache Impact Test (HIT-6), which is a fixed-length 6-item questionnaire. The score for this questionnaire can range from 36 to 78, with 36 indicating minimum headache impact and the max score of 78 indicating worst possible headache impact.
Time Frame	Baseline (before treatment), and 6 weeks, 3 months, 6 months, 9 months, and 12 months after single dose intra-arterial Avastin (bevacizumab)

Outcome Measure Data

Analysis Population Description

10 adult subjects presented with medically refractory radiation necrosis of the brain and disabling headache. All 10 received single treatment of low dose intra-arterial bevacizumab.

Arm/Group Title	Low-dose Intra-arterial Avastin (Bevacizumab)
Arm/Group Description	A single intra-arterial 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. 25% Mannitol: Route of administration: In this study, the first step of the treatment will be performing osmotic blood-brain-barrier disruption with administration of intra-arterial 25% Mannitol into the appropriate cervical artery. Low-dose Intra-arterial bevacizumab: Route of administration: In this study, the second step of the treatment will be administering intra-arterial bevacizumab into the appropriate cervical artery.
Measure Participants	10
Headache Impact Test-6, Baseline	62.4 (7.5)
Headache Impact Test-6, 6 Weeks	54.5 (11.4)
Headache Impact Test-6, 3 months	52.3 (13.0)
Headache Impact Test-6, 6 months	53.3 (13.6)
Headache Impact Test-6, 9 months	53.2 (15.4)
Headache Impact Test-6, 12 months	52.1 (14.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Low-dose Intra-arterial Avastin (Bevacizumab)
	Comments	To explore durability of clinical response, Headache Impact Test (HIT-6™) scores were analyzed using a linear mixed model in which we addressed heterogeneity of time points by fitting the most appropriate model among compound symmetry, Huyhn-Felt structure, and an unstructured covariance matrix (multivariate analysis of variance).
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments	The threshold for statistical significance was p < 0.05.
	Method	Mixed Models Analysis
	Comments	F(5, 35) = 2.98
Method of Estimation	Estimation Parameter	eta^2
	Estimated Value	0.30
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Change in Functional Status After a Single Treatment of Low Dose Intra-arterial Bevacizumab
Description	Quantitative change in functional status will be assessed by performing Karnofsky Performance Status Scale (KPS). The KPS score can range from 0 to 100 where 0 is dead and 100 is fully alive and normal with no complaints and no evidence of disease.
Time Frame	Baseline (before treatment), Day 1, and at 3 months, and 12 months after single dose intra-arterial Avastin (bevacizumab)

Outcome Measure Data

Analysis Population Description

10 adult subjects presented with medically refractory radiation necrosis of the brain and disabling headache. All were treated with steroids prior to study enrollment.

Arm/Group Title	Low-dose Intra-arterial Bevacizumab
Arm/Group Description	A single intra-arterial 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. 25% Mannitol: Route of administration: In this study, the first step of the treatment will be performing osmotic blood-brain-barrier disruption with administration of intra-arterial 25% Mannitol into the appropriate cervical artery. Low-dose Intra-arterial Bevacizumab: Route of administration: In this study, the second step of the treatment will be administering intra-arterial bevacizumab into the appropriate cervical artery.
Measure Participants	10
Karnofsky at Baseline	79.0 (9.9)
Karnofsky at Day 1	81.0 (7.4)
Karnofsky at Month 3	83.0 (11.6)
Karnofsky at Month 12	86.3 (7.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Low-dose Intra-arterial Avastin (Bevacizumab)
	Comments	To explore durability of clinical response, Karnofsky Performance Status Scale (KPS) data were analyzed using a linear mixed model in which we addressed heterogeneity of time points by fitting the most appropriate model among compound symmetry, Huyhn-Felt structure, and an unstructured covariance matrix (multivariate analysis of variance).
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.23
	Comments	The threshold for statistical significance was p < 0.05.
	Method	Mixed Models Analysis
	Comments	F(2,14) = 1.62
Method of Estimation	Estimation Parameter	eta^2
	Estimated Value	0.19
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Change in Steroid Usage After a Single Treatment of Low Dose Intra-arterial Avastin (Bevacizumab)
Description	To assess the utility of intra-arterial (IA) bevacizumab treatment in allowing decreased steroid usage, total cumulative days of steroid usage were compared between the 12 months PRIOR TO and the 12 months IMMEDIATELY FOLLOWING IA bevacizumab. Days of steroid usage were tabulated via medical history and chart review at the baseline visit for the 12 months prior to IA bevacizumab and post-treatment on days 0 and 1, week 6, and months 3, 6, 9 and 12 for the 12 month total after IA bevacizumab treatment. Excluding topical steroid preparations, all days of enteral or parenteral steroid intake of any dose were included in the cumulative summation.
Time Frame	12 months prior to single dose of IA bevacizumab; 12 months following single dose of IA bevacizumab

Outcome Measure Data

Analysis Population Description

10 adult patients age 31.0 (IQR 24.3, 42.8) years, including 8 (80%) women, 2 (20%) men, 9 (90%) white, 1 (10%) black, 9 (90%) Non-Hispanic, and 1 (10%) Hispanic

Arm/Group Title	Low-dose Intra-arterial Avastin (Bevacizumab)
Arm/Group Description	A single intra-arterial 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. 25% Mannitol: Route of administration: In this study, the first step of the treatment will be performing osmotic blood-brain-barrier disruption with administration of intra-arterial 25% Mannitol into the appropriate cervical artery. Low-dose Intra-arterial bevacizumab: Route of administration: In this study, the second step of the treatment will be administering intra-arterial bevacizumab into the appropriate cervical artery.
Measure Participants	10
12 months PRIOR to IA bevacizumab	61.5
12 months AFTER IA bevacizumab	13.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Low-dose Intra-arterial Avastin (Bevacizumab)
	Comments	Wilcoxon signed rank test (2-sided) was used to compare the total number of days on steroids in the 12 months prior versus the 12 months immediately following single dose IA Avastin (bevacizumab).
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.374
	Comments	The threshold for statistical significance was p < 0.05.
	Method	Wilcoxon (Mann-Whitney)
	Comments	Z = -0.889
Method of Estimation	Estimation Parameter	Pearson's r
	Estimated Value	-0.199
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Post-operative Neurocognitive Change After Intra-arterial Bevacizumab
Description	In order to investigate post-operative changes in Neurocognitive performance after intra-arterial bevacizumab, patients who consented underwent formal neuropsychological battery testing. Sixteen subtests from the Neuropsychological Assessment Battery (Stern & White, PAR Inc.) were chosen for brevity, sensitivity, and due to the wide range of available normative data (ages 18-97). For each subtest, T-score = 50 is the normative mean with SD = 10. Thus T-scores of 40-60 are within one standard deviation of the mean and are considered generally normal. Scores increasingly below 40 indicate decreased neurocognitive performance compared to healthy demographically matched persons. Scores significantly above 60 indicate increase neurocognitive performance compared to healthy demographically matched persons.
Time Frame	Baseline (before bevacizumab), and 3 months and 12 months after single dose intra-arterial Avastin (bevacizumab)

Outcome Measure Data

Analysis Population Description

10 adult subjects, 2 male and 8 female, 1 black and 9 white, 1 Hispanic and 9 non-Hispanic, recruited from outpatient medical clinics at 2 academic medical centers (5 subjects per center) between Nov 2016 and Jan 2018. 2 subjects experienced progression of radiation necrosis requiring intervention at approx. month 11. Their 12-month data are not included in the Neurocognitive reporting.

Arm/Group Title	Low-dose Intra-arterial Bevacizumab
Arm/Group Description	A single intra-arterial 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. 25% Mannitol: Route of administration: In this study, the first step of the treatment will be performing osmotic blood-brain-barrier disruption with administration of intra-arterial 25% Mannitol into the appropriate cervical artery. Low-dose Intra-arterial Bevacizumab: Route of administration: In this study, the second step of the treatment will be administering intra-arterial bevacizumab into the appropriate cervical artery.
Measure Participants	10
Digits Forward at Baseline	41.1 (11.8)
Digits Forward at 3 months	44.1 (12.2)
Digits Forward at 12 months	42.3 (11.7)
Digits Backward at Baseline	44.9 (8.3)
Digits Backward at 3 months	44.9 (11.9)
Digits Backward at 12 months	40.3 (13.1)
Numbers & Letters SPEED at Baseline	38.2 (10.7)
Numbers & Letters SPEED at 3 months	36.7 (10.8)
Numbers & Letters SPEED at 12 months	36.8 (10.7)
Numbers & Letters Errors at BASELINE	44.6 (12.0)
Numbers & Letters Errors at 3 months	47.4 (12.6)
Numbers & Letters Errors at 12 months	52.9 (10.1)
Numbers & Letters EFFICIENCY at Baseline	41.0 (14.6)
Numbers & Letters EFFICIENCY at 3 Months	36.6 (11.8)
Numbers & Letters EFFICIENCY at 12 months	36.6 (11.1)
Naming at BASELINE	47.6 (10.6)
Naming at 3 months	49.9 (7.3)
Naming at 12 months	49.1 (10.9)
List Learning List Immediate Recall at BASELINE	44.6 (7.7)
List Learning List Immediate Recall at 3 months	44.2 (13.1)
List Learning List Immediate Recall at 12 months	46.4 (7.8)
List Learning List Long Delayed Recall at BASELINE	44.6 (11.1)
List Learning List Long Delayed Recall at 3 months	42.6 (11.0)
List Learning List Long Delayed Recall at 12 months	51.3 (12.1)
Shape Learning Immediate Recognition at BASELINE	42.9 (9.5)
Shape Learning Immediate Recognition at 3 months	48.6 (10.7)
Shape Learning Immediate Recognition at 12 months	50.0 (11.3)
Shape Learning Delayed Recognition at BASELINE	41.3 (11.3)
Shape Learning Delayed Recognition at 3 months	46.0 (12.2)
Shape Learning Delayed Recognition at 12 months	47.3 (9.1)
Story Learning Phrase Unit Immediate Recall at BASELINE	43.2 (9.2)
Story Learning Phrase Unit Immediate Recall at 3 months	47.1 (12.7)
Story Learning Phrase Unit Immediate Recall at 12 months	49.6 (12.8)
Story Learning Phrase Unit Delayed Recall at BASELINE	43.7 (7.3)
Story Learning Phrase Unit Delayed Recall at 3 months	48.5 (9.2)
Story Learning Phrase Unit Delayed Recall at 12 months	47.1 (8.0)
Design Construction at BASELINE	41.4 (11.1)
Design Construction at 3 months	41.6 (14.3)
Design Construction at 12 months	45.8 (9.6)
Mazes at BASELINE	39.8 (9.2)
Mazes at 3 months	43.3 (12.3)
Mazes at 12 months	43.0 (11.7)
Categories at BASELINE	41.8 (6.8)
Categories at 3 months	44.5 (10.4)
Categories at 12 months	39.9 (8.2)
Word Generation at BASELINE	45.0 (11.8)
Word Generation at 3 months	45.6 (9.8)
Word Generation at 12 months	49.0 (11.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Low-dose Intra-arterial Avastin (Bevacizumab)
	Comments	DIGITS FORWARD: To explore post-operative change in Neurocognitive performance after intra-arterial bevacizumab, repeated measures ANOVA was performed for the DIGITS FORWARD variable across 3 time points (BL, 3 months, 12 months) where IQ was placed in the model as covariate.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.660
	Comments	The threshold for statistical significance was p < 0.05.
	Method	One way Repeat Meas ANOVA
	Comments	F(2,5) = 0.451
Method of Estimation	Estimation Parameter	partial eta^2
	Estimated Value	0.153
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Low-dose Intra-arterial Avastin (Bevacizumab)
	Comments	DIGITS BACKWARD: To explore post-operative change in Neurocognitive performance after intra-arterial bevacizumab, repeated measures ANOVA was performed for the DIGITS BACKWARD variable across 3 time points (BL, 3 months, 12 months) where IQ was placed in the model as covariate.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.100
	Comments	The threshold for statistical significance was p < 0.05.
	Method	One way Repeat Meas ANOVA
	Comments	F(2,5) = 3.78
Method of Estimation	Estimation Parameter	partial eta^2
	Estimated Value	0.602
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Low-dose Intra-arterial Avastin (Bevacizumab)
	Comments	NUMBERS & LETTERS SPEED: To explore post-operative change in Neurocognitive performance after intra-arterial bevacizumab, repeated measures ANOVA was performed for the NUMBERS & LETTERS SPEED variable across 3 time points (BL, 3 months, 12 months) where IQ was placed in the model as covariate.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.149
	Comments	The threshold for statistical significance was p < 0.05.
	Method	One way Repeat Meas ANOVA
	Comments	F(2,5) = 2.847
Method of Estimation	Estimation Parameter	partial eta^2
	Estimated Value	0.532
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Low-dose Intra-arterial Avastin (Bevacizumab)
	Comments	NUMBERS & LETTERS ERRORS: To explore post-operative change in Neurocognitive performance after intra-arterial bevacizumab, repeated measures ANOVA was performed for the NUMBERS & LETTERS ERRORS variable across 3 time points (BL, 3 months, 12 months) where IQ was placed in the model as covariate.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.041
	Comments	The threshold for statistical significance was p < 0.05.
	Method	One way Repeat Meas ANOVA
	Comments	F(2,5) = 6.470
Method of Estimation	Estimation Parameter	partial eta^2
	Estimated Value	0.721
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Low-dose Intra-arterial Avastin (Bevacizumab)
	Comments	NUMBERS & LETTERS EFFICIENCY: To explore post-operative change in Neurocognitive performance after intra-arterial bevacizumab, repeated measures ANOVA was performed for the NUMBERS & LETTERS EFFICIENCY variable across 3 time points (BL, 3 months, 12 months) where IQ was placed in the model as covariate.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.124
	Comments
	Method	One way Repeat Meas ANOVA
	Comments	F (2,5) = 3.256
Method of Estimation	Estimation Parameter	partial eta^2
	Estimated Value	0.566
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Low-dose Intra-arterial Avastin (Bevacizumab)
	Comments	NAMING: To explore post-operative change in Neurocognitive performance after intra-arterial bevacizumab, repeated measures ANOVA was performed for the NAMING variable across 3 time points (BL, 3 months, 12 months) where IQ was placed in the model as covariate.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.898
	Comments	The threshold for statistical significance was p < 0.05.
	Method	One way Repeat Meas ANOVA
	Comments	F(2,5) = 0.110
Method of Estimation	Estimation Parameter	partial eta^2
	Estimated Value	0.042
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Low-dose Intra-arterial Avastin (Bevacizumab)
	Comments	LIST LEARNING LIST IMMEDIATE RECALL: To explore post-operative change in Neurocognitive performance after intra-arterial bevacizumab, repeated measures ANOVA was performed for the LIST LEARNING LIST IMMEDIATE RECALL variable across 3 time points (BL, 3 months, 12 months) where IQ was placed in the model as covariate.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.754
	Comments	The threshold for statistical significance was p < 0.05.
	Method	One way Repeat Meas ANOVA
	Comments	F(2,5) = 0.299
Method of Estimation	Estimation Parameter	partial eta^2
	Estimated Value	0.107
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Low-dose Intra-arterial Avastin (Bevacizumab)
	Comments	LIST LEARNING LIST LONG DELAYED RECALL: To explore post-operative change in Neurocognitive performance after intra-arterial bevacizumab, repeated measures ANOVA was performed for the LIST LEARNING LIST LONG DELAYED RECALL variable across 3 time points (BL, 3 months, 12 months) where IQ was placed in the model as covariate.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.031
	Comments	The threshold for statistical significance was p < 0.05.
	Method	One way Repeat Meas ANOVA
	Comments	F(2,5) = 7.556
Method of Estimation	Estimation Parameter	partial eta^2
	Estimated Value	0.751
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Low-dose Intra-arterial Avastin (Bevacizumab)
	Comments	SHAPE LEARNING IMMEDIATE RECOGNITION: To explore post-operative change in Neurocognitive performance after intra-arterial bevacizumab, repeated measures ANOVA was performed for the SHAPE LEARNING IMMEDIATE RECOGNITION variable across 3 time points (BL, 3 months, 12 months) where IQ was placed in the model as covariate.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.426
	Comments	The threshold for statistical significance was p < 0.05.
	Method	One way Repeat Meas ANOVA
	Comments	F(2,5) = 1.018
Method of Estimation	Estimation Parameter	partial eta^2
	Estimated Value	0.289
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Low-dose Intra-arterial Avastin (Bevacizumab)
	Comments	SHAPE LEARNING DELAYED RECOGNITION: To explore post-operative change in Neurocognitive performance after intra-arterial bevacizumab, repeated measures ANOVA was performed for the SHAPE LEARNING DELAYED RECOGNITION variable across 3 time points (BL, 3 months, 12 months) where IQ was placed in the model as covariate.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.326
	Comments	The threshold for statistical significance was p < 0.05.
	Method	One way Repeat Meas ANOVA
	Comments	F(2,5) = 1.412
Method of Estimation	Estimation Parameter	partial eta^2
	Estimated Value	0.361
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Low-dose Intra-arterial Avastin (Bevacizumab)
	Comments	STORY LEARNING PHRASE UNIT IMMEDIATE RECALL: To explore post-operative change in Neurocognitive performance after intra-arterial bevacizumab, repeated measures ANOVA was performed for the STORY LEARNING PHRASE UNIT IMMEDIATE RECALL variable across 3 time points (BL, 3 months, 12 months) where IQ was placed in the model as covariate.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.790
	Comments	The threshold for statistical significance was p < 0.05.
	Method	One way Repeat Meas ANOVA
	Comments	F(2,5) = 0.247
Method of Estimation	Estimation Parameter	partial eta^2
	Estimated Value	0.090
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Low-dose Intra-arterial Avastin (Bevacizumab)
	Comments	STORY LEARNING PHRASE UNIT DELAYED RECALL: To explore post-operative change in Neurocognitive performance after intra-arterial bevacizumab, repeated measures ANOVA was performed for the STORY LEARNING PHRASE UNIT DELAYED RECALL variable across 3 time points (BL, 3 months, 12 months) where IQ was placed in the model as covariate.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.505
	Comments	The threshold for statistical significance was p < 0.05.
	Method	One way Repeat Meas ANOVA
	Comments	F(2,5) = 0.786
Method of Estimation	Estimation Parameter	partial eta^2
	Estimated Value	0.239
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Low-dose Intra-arterial Avastin (Bevacizumab)
	Comments	DESIGN CONSTRUCTION: To explore post-operative change in Neurocognitive performance after intra-arterial bevacizumab, repeated measures ANOVA was performed for the DESIGN CONSTRUCTION variable across 3 time points (BL, 3 months, 12 months) where IQ was placed in the model as covariate.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.080
	Comments	The threshold for statistical significance was p < 0.05.
	Method	One way Repeat Meas ANOVA
	Comments	F(2,5) = 4.362
Method of Estimation	Estimation Parameter	partial eta^2
	Estimated Value	0.636
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Low-dose Intra-arterial Avastin (Bevacizumab)
	Comments	MAZES: To explore post-operative change in Neurocognitive performance after intra-arterial bevacizumab, repeated measures ANOVA was performed for the MAZES variable across 3 time points (BL, 3 months, 12 months) where IQ was placed in the model as covariate.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.052
	Comments	The threshold for statistical significance was p < 0.05.
	Method	One way Repeat Meas ANOVA
	Comments	F(2,5) = 5.654
Method of Estimation	Estimation Parameter	partial eta^2
	Estimated Value	0.693
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Low-dose Intra-arterial Avastin (Bevacizumab)
	Comments	CATEGORIES: To explore post-operative change in Neurocognitive performance after intra-arterial bevacizumab, repeated measures ANOVA was performed for the CATEGORIES variable across 3 time points (BL, 3 months, 12 months) where IQ was placed in the model as covariate.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.968
	Comments	The threshold for statistical significance was p < 0.05.
	Method	One way Repeat Meas ANOVA
	Comments	F(2,5) = 0.033
Method of Estimation	Estimation Parameter	partial eta^2
	Estimated Value	0.013
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Low-dose Intra-arterial Avastin (Bevacizumab)
	Comments	WORD GENERATION: To explore post-operative change in Neurocognitive performance after intra-arterial bevacizumab, repeated measures ANOVA was performed for the WORD GENERATION variable across 3 time points (BL, 3 months, 12 months) where IQ was placed in the model as covariate.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.469
	Comments	The threshold for statistical significance was p < 0.05.
	Method	One way Repeat Meas ANOVA
	Comments	F(2,5) = 0.884
Method of Estimation	Estimation Parameter	partial eta^2
	Estimated Value	0.261
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	1 year
Adverse Event Reporting Description	Adverse Event Monitoring performed on Day 0, Day 1, Week 6, Month 3, and Month 12
Arm/Group Title	Low-dose Intra-arterial Bevacizumab
Arm/Group Description	A single intra-arterial 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. 25% Mannitol: Route of administration: In this study, the first step of the treatment will be performing osmotic blood-brain-barrier disruption with administration of intra-arterial 25% Mannitol into the appropriate cervical artery. Low-dose Intra-arterial Bevacizumab: Route of administration: In this study, the second step of the treatment will be administering intra-arterial bevacizumab into the appropriate cervical artery.
All Cause Mortality
	Low-dose Intra-arterial Bevacizumab
	Affected / at Risk (%)	# Events
Total	0/10 (0%)
Serious Adverse Events
	Low-dose Intra-arterial Bevacizumab
	Affected / at Risk (%)	# Events
Total	6/10 (60%)
Cardiac disorders
Chest Pain	1/10 (10%)	1
Nervous system disorders
Seizure	2/10 (20%)	2
Acute encephalopathy	1/10 (10%)	1
Double Vision	1/10 (10%)	1
Headache	1/10 (10%)	1
Dizziness	1/10 (10%)	1
Dysarthria	1/10 (10%)	1
Left Lower Extremity Hemiparesis	1/10 (10%)	1
Left Upper Extremity Hemiparesis	1/10 (10%)	1
Cerebral Edema	1/10 (10%)	1
Other (Not Including Serious) Adverse Events
	Low-dose Intra-arterial Bevacizumab
	Affected / at Risk (%)	# Events
Total	9/10 (90%)
Blood and lymphatic system disorders
Thrombocytopenia	1/10 (10%)	1
Cardiac disorders
1st degree AV block	1/10 (10%)	1
Hypertension	1/10 (10%)	1
Worsening chest pain	1/10 (10%)	1
Ear and labyrinth disorders
Inner Ear pain	1/10 (10%)	1
Endocrine disorders
Steroid Induced Hyperglycemia	1/10 (10%)	1
Eye disorders
Blurred vision	4/10 (40%)	6
Diplopia	1/10 (10%)	1
Inability to focus	1/10 (10%)	1
Eye twitches	1/10 (10%)	1
Homonymous Hemianopia	1/10 (10%)	1
Loss of vision	1/10 (10%)	1
Vision loss in left eye	1/10 (10%)	1
Gastrointestinal disorders
Decreased appetite	1/10 (10%)	1
Loss of appetite	1/10 (10%)	1
Abdominal Pain	1/10 (10%)	1
Nausea	1/10 (10%)	1
Vomiting	2/10 (20%)	2
General disorders
Dehydration	1/10 (10%)	1
Fall	2/10 (20%)	2
Generalized Malaise	1/10 (10%)	1
Hypercholesterolemia	1/10 (10%)	1
Hypertriglyceridemia	1/10 (10%)	1
Nosebleeds	1/10 (10%)	1
Injury, poisoning and procedural complications
Fracture Left Hand	1/10 (10%)	1
Head Trauma	1/10 (10%)	1
Leg traumatic injury	1/10 (10%)	1
Ankle sprain due to fall	1/10 (10%)	2
Traumatic Fall	2/10 (20%)	2
Metabolism and nutrition disorders
Weight Loss	1/10 (10%)	1
Musculoskeletal and connective tissue disorders
Cervical strain	1/10 (10%)	1
Lower Back pain	1/10 (10%)	1
Neck pain	2/10 (20%)	2
Neck stiffness	1/10 (10%)	1
Hip Pain	1/10 (10%)	1
Knee pain	1/10 (10%)	1
Leg cramps	2/10 (20%)	3
Leg Muscle aches	1/10 (10%)	1
Partial toenail ingrown	1/10 (10%)	1
Nervous system disorders
Altered Mental Status	1/10 (10%)	1
Amnesia	1/10 (10%)	1
Anxiety	1/10 (10%)	1
Confusion	1/10 (10%)	2
Expressive aphasia	1/10 (10%)	1
Headache	5/10 (50%)	7
Hypersomnia	1/10 (10%)	1
Inability to focus attention	1/10 (10%)	1
Dizziness	1/10 (10%)	1
Numbness	2/10 (20%)	2
Cold sensation leg	1/10 (10%)	1
Calf muscle loss of tone	1/10 (10%)	1
Seizures	2/10 (20%)	2
Generalized Seizures	1/10 (10%)	1
Tonic/clonic Seizures	1/10 (10%)	2
Shot term memory problems	1/10 (10%)	1
Trouble performing simple tasks	1/10 (10%)	1
Unsteadiness	1/10 (10%)	1
Visual seizure	1/10 (10%)	1
Whole body shaking associated with seizures	1/10 (10%)	1
Worsening of left sided weakness	1/10 (10%)	1
Pregnancy, puerperium and perinatal conditions
Incomplete Spontaneous Abortion	1/10 (10%)	1
Pregnancy	1/10 (10%)	1
Psychiatric disorders
Generalized Anxiety	1/10 (10%)	1
Hallucinations	1/10 (10%)	1
Major Depressive Disorder	1/10 (10%)	1
Panic attacks	1/10 (10%)	1
Personality Changes	1/10 (10%)	1
Renal and urinary disorders
Urinary incontinence	1/10 (10%)	1
Respiratory, thoracic and mediastinal disorders
Asthma episode	1/10 (10%)	1
Upper Respiratory Infection	1/10 (10%)	1
Skin and subcutaneous tissue disorders
Acne	1/10 (10%)	1
hair loss	1/10 (10%)	1
Leg skin tear non-healing wound	1/10 (10%)	1
Scalp Pain	1/10 (10%)	1
Worsening Acne on extremities	1/10 (10%)	1
Worsening of striae bilateral arms	1/10 (10%)	1
Vascular disorders
Bilateral lower leg edema	1/10 (10%)	1

Limitations/Caveats

Pilot Phase 2 Single Arm Clinical Trial with small number of patients. Not powered sufficiently to provide definitive proof for change in current standard of care of medically refractory radiation necrosis of the brain.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.