Low-dose Intra-arterial Bevacizumab for Edema and Radiation Necrosis Therapeutic Intervention (LIBERTI)
Phase: PHASE2
Conditions: Radiation Necrosis
Sponsor: Norton Healthcare

Pl Name: 
Justin Fraser, MD 
Title of 
Low~dose lntra~arterial Bevacizumab for Edema and Radiation necrosis Therapeutic Intervention (LIBERTI) 
Study: 
Pl Signature: 
Date: 
6/21/2016 
1. Add~ 
e for Protocol Correspondence? 
0Yes 0 No 
If yes, indicate new address: 
Title change? 
0Yes 0 No 
If yes, indicate new title: 
3. 
Is this a one-time request for a deviation from the currently approved protocol or an exception to the 
currently approved enrollment criteria? 
0 
Yes 0 No 
4. Consent/Assent Form Change? 
0 Yes 0 No 
If yes, be sure changes are reflected in all your revised consent/assent documents and any applicable 
HIPAA documents. 
5. Select One: 
0This modification does not increase risk to study participants. 
0This modification may or will increase risk to study participants. 
6. 
Is this modification request due to an Unanticipated Problem or Adverse Event? 0 Yes 0 No 
7. 
In your professional opinion, does this modification involve information that might relate to a 
subject's willingness to continue to take part in the research? 
0 Yes 0 No 
If yes, state how the information will be communicated to subjects (i.e., re-consent, send 
letter, etc.): 
8. Changes Made To: (check all that apply and attach appropriate documents) 
Form A: General Information Sheet 
D Anticipated Project End Date 
D Estimated # of Subjects 
D Subject Population 
D Vulnerable Subject Population 
D Impaired Consent Capacity (Form D 
0Children age 17 or less (Form W) 
D Pregnant Women (Form U) 
D Prisoners (Form V) 
D Other vulnerable population 
D Funding/Support (some federal agencies 
have specific requirements - see 
guidance) 
Form B: Research Description & Appendices 
D Objectives 
D Inclusion/Exclusion Criteria 
D Subject Recruitment 
D Procedures/Materials 
D Research Procedures 
D Grant Application 
0 Sponsor Protocol; Investigator Brochure 
Forms C-F 
D Consent Form (Form C-Medical; Nonmedical) or 
combined Informed Consent/HIPAA Fann 
D Assent Fann (Form D-Medical; Nonmedical) 
D Waiver of Informed Consent (Form E) 
FS.0000 
D Study Personnel (SP List Template) 
D Medical Device (Farm P) 
D Waiver of Documentation of Informed Consent (Form 
E) 
D Study Drug (Form 0) 
Other - Describe: 
1 
Forms 1-K 
D HIPAA De-Identification Certification (Form I) 
D HIPAA Waiver of Authorization (Form K) 
University of Kentucky Institutional Review Board (IRB) 

F5.0000 
.· · ··. IVlocli6~$1tidn Requ~sffol'itl 
Pl Name: 
Justin Fraser, MD 
Title of 
Study: 
Low-dose Intra-arterial Bevacizumab for Edema and Radiation necrosis Therapeutic Intervention 
(LIBERTI) 
REQUIRED: For each proposed modification, describe the currently approved procedures, forms, etc. and then 
summarize the proposed change, addition, etc. Include a justification for the modification request. Add additional 
sheets if necessary. 
Example: 
Currently Approved: study staff as listed on attached SP List Template 
Proposed Revision: add Jane Doe, MD, as co-investigator, Dr. Doe has completed human subject protections training, 
Dr. Doe is a new faculty member who will be working with subjects on this protocol and she is authorized to obtain 
consent. 
1. Currently Approved: Protocol Version 2 
Protocol Version 3 (see highlightes for changes. Added specific outcome measures. 
Proposed Revision: 
2. 
Currently Approved: 
Proposed Revision: 
3. 
Currently Approved: 
Proposed Revision: 
4. 
Currently Approved: 
Proposed Revision: 
J:\Master Outreach Documents\Survival Handbook\F - IRB app!ications-Forms\Other Forms\50000-MODJFICATION_REQUEST_FORM.doc 4/1/16 
2 
University of Kentucky Institutional Review Board (!RB) 

Norton Healthcareillept of Neurosurgery 
LIBERTI 
Version3 
STUDY TITLE: Low-dose Intra-arterial Bevacizumab for Edema and Radiation necrosis 
Therapeutic Intervention (LIBERTI) 
Participating Centers: 
Norton Healthcare 
University of Kentucky Healthcare 
Sponsor/Principal Investigator:Shervin R. Dashti, MD, PhD 
4950 Norton Healthcare Blvd. #205 
Louisville, KY 40241 
Telephone: 502-394-6390 
Fax: 502-394-6388 
Shervin. dashti@nortonhealthcare.org 
Version 3 
Date: 20 June 2016 
CONFIDENTIAL STATEMENT 
This document contains confidential information, which should not be copied, referred to , 
released or published without written approval from Shervin Dashti, MD or Norton Heathcare. 
Investigators are cautioned that the information is this protocol might be subject to change and 
revision. Any conclusion regarding efficacy and safety must be considered provisional. 
I 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
SCHEMA 
Version3 
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 ofbevacizumab will be given intra-arterially after 
blood-brain-barrier disruption using 25% Mannitol at 4-12 ml/sec for 30 seconds. 
INTRA-ARTERIAL DOSING SCHEMA 
Dose NUMBER 
Agent 
Dose#!: Day 0 
2.5 mg/kg X 1 dose 
2 

Norton Healthcareillept of Neurosurgery 
LIBERTI 
Version 3 
INVESTIGATOR'S STATEMENT AND SIGNATURE 
I have read and understand this protocol, attachments, and (name of study drug). I agree to 
conduct the study as outlined in the protocol and to comply with all the terms and conditions set 
out therein. I confirm that I will conduct the study in accordance with ICH GCP guidelines and 
the ethical principles of the Helsinki Declaration. 
Sponsor/Principal Investigator: 
Signature: _____________ _ 
Date: --------
Printed Name: ------------------
3 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
Version3 
CONTACT DETAILS OF KEY PERSONNEL 
Role 
Name 
Contact Information 
4950 Norton Healthcare Blvd. #205 
Sponsor/Principal 
Shervin R. Dashti, MD, 
Louisville, KY 40241 
Telephone: 502-394-6390 
Investigator 
PhD 
Fax: 502-394-6388 
Shervin. dashtiifllnortonhealthcare. or<' 
UK Medical Center 
Department of Neurosurgery 
Principal Investigator 
Justin Fraser, MD 
Medical Science Building Room MS 108A 
Lexington, KY 40536-0298 
Telephone: (859) 323-0616 
Jfr 235fn'lukv. edu 
UK Center for Clinical and Translational 
Science 
800 Rose Street, Pavilion H, Room C300 
Sponsor'Project Manager 
Elodie Elayi 
Lexington KY, 40536 
Telephone: (859) 323-7939 
Fax: (859) 257-9560 
Elodie. elayJ@ukv.edu 
Bluegrass Research Consultants, Inc. 
8020 Sea Hero Run 
Sponsor Study Monitor 
Karen Bowen, RN 
Versailles, KY 40383 
Phone: (859)396-4655 
FAX: 
(859)873-9963 
Bowen 7 Jifllwindstream. net 
4950 Norton Healthcare Blvd. #205 
Shervin R. Dashti, MD, 
Louisville, KY 40241 
SAE Reporting 
PhD 
Telephone: 502-394-6390 
Fax: 502-394-6388 
Shervin. dashtifn'lnortonhealthcare. ON! 
4 

Norton HealthcareIDept of Neurosurgery 
LIBERTI 
Version 3 
Page 
1.0 
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 
7 
1.1 
Radiation Necrosis 
1.2 
Bevacizumab 
1.3 
Preclinical Data 
1.4 
Clinical Data 
Case Study 1 
. . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
8 
Case Study 2 
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 
1.5 
Clinical Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 
11 
1.6 
Rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 
12 
1. 7 
Safety of cerebral intra-arterial bevacizumab treatment . . . . . . . . . . . . . . . . . . . 
13 
2.0 
OBJECTIVES 
2.1 
Primary Objective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 
13 
2.2 
Secondary Objective(s) ...... ... ............ ..................................... 
14 
2.3 
Tertiary Objective(s) ...... ..................... ............ ...................... 
14 
3.0 
STUDY DESIGN ......... ......... ............ ......... ... ... ......... ... ... ...... ....... 
14 
4.0 
PATIENT SELECTION 
4.1 
Inclusion Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 
4.2 
Exclusion Criteria .. . ... .. . ... .. . .. . .. . . .. ... ... . . . . . . . . . . .. . .. . . . . . . . . . . . . . . . ... . . . 15 
5.0 
REGISTRATION . . . . .. ... . . . . . . .. . ... . . . . . . ... ... . . . .. . . . . . .. . . . . .. ... .. . . .. . . . .. . . . . ..... 15 
5 .1 
General Guidelines 
5 .2 
Registration Process 
6.0 
TREATMENT PLAN ..................................................................... 16 
6.1 
Vascular Access, Cerebral Angiogram, and Osmotic Blood Brain Barrier Disruption 
6.2 
Intra-Arterial Bevacizumab Administration 
6.3 
Post-Operative Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 
6.4 
General Concomitant Medications and Supportive Care Guidelines 
6.5 
Duration of Therapy 
6.6 
Duration of Follow Up 
6.7 
Definition of Dose-Limiting Toxicity 
6.8 
Criteria for Removal from Study 
7.0 
DOSE MODIFICATIONS ................................................................ 17 
8.0 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
8.1 
Adverse Events and Potential Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 
8.2 
Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 
8.2.1 
Adverse Events ............................................................. 21 
8.2.2 Significance of an Adverse Event 
8.2.3 
Serious Adverse Events 
8.2.4 Expectedness 
8.2.5 Attribution 
8.3 
Reporting Procedures for All Adverse Events ................................... 22 
8.4 
Serious Adverse Events Reporting Procedure 
8.5 
Data Safety and Toxicity Committee 
9.0 
PHARMACEUTICALINFORMATION .. ; ........................................... 23 
5 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
Version3 
10.0 
CORRELATIVE I SPECIAL STUDIES ...... ... . .. . .. . . .. .. .. .... . .. . . . . .. .. .. .. .. . 24 
1 0 .1 
Imaging Correlate 
10.2 
Neurocognitive correlate 
10.3 
Headache Correlate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . 25 
11.0 
STUDY PARAMETERS AND CALENDAR . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 
12.0 
MEASUREMENT OF EFEECT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 
12.1 
Decrease in Cerebral Edema 
13.0 
12.2 
Definitions 
12.3 
Duration of Response 
STATISTICAL CONSIDERATIONS 
13 .1 
Study design/Endpoints 
13.2 
Sample Size/Accrual Rate 
13.3 
Stratification Factors 
13 .4 
J\J!alysis of seconc!ary Endpoints 
13.5 
Q]Jtcm:tieMeasur~ 
28 
14.0 
REFERENCES ......................................................................... 
30 
6 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
1. BACKGROUND 
Version 3 
1.1. Radiation Necrosis: Stereotactic radiosurgery has become integral in treatment of brain 
tumors and arteriovenous malformations (A VM). 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. 
1.2. 
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, bevacizurnab was shown in a 
small randomized controlled trial (n=l4) 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. 
1.3. Preclinical 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 immunohistochemistry2. 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. 
1.4. 
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=l4) 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. 
We 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 oflife 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, we used intra-arterial Mannitol to 
disrupt the blood-brain barrier immediately prior to targeted intra-arterial drug 
administration. 
7 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
Version3 
Case 1: A 12-year-old right handed female presented with severe headaches. MRI of 
the brain showed a 3 .2 cm left posterior frontal arteriovenous malformation (Spetzler-
Martin Grade III) with mild surrounding vasogenic edema. There were no signs of 
hemorrhage. She was initially treated with a 2-week course of steroids with significant 
improvement in headaches along with decreased edema on MRI. After considering 
treatment options including observation, endovascular embolization and/or surgical 
resection, the patient and her family chose stereotactic radiosurgery. She underwent SRS 
with a dose of 21 Gy prescribed to the A VM with a volume of 9 .9 cm3• 
Eight months later, the patient presented with severe headaches and focal seizures 
affecting the right arm and leg. MRI of the brain at this time demonstrated increasing 
T2 FLAIR signal as well as new Gadolinium signal on the Tl sequences. She was treated 
with anti-epileptics for her seizures and oral steroids for presumed radiation necrosis. 
Her seizure episodes resolved, but her severe headache persisted. She was initially 
started on 24 mg per day of dexamethasone tapering over 3 weeks. Because of worsening 
headache and progressively worsening right hemiparesis, repeated attempts to reduce 
dexamethasone dose below 6 mg daily proved unsuccessful over the ensuing 9 months. 
Courses of pentoxiphylline, vitamin E, and hyperbaric oxygen were all administered per 
study protocols without success4•5. Despite these interventions, she declined to 4/5 
strength in the proximal right upper and lower extremities and 0/5 strength in her right 
hand and foot. She experienced a 60-pound weight gain with severe cushingoid features. 
She complained of constant severe (10 on the 10-point scale) headache. She also 
experienced severe emotional !ability, causing her to withdraw from school. 
Given the progressive neurological decline and the lack of alternative therapies, the 
option of IV-bevacizumab treatment was initially explored. However, this proved to be 
not available for our pediatric patient population. Hence, the option of low dose intra-
arterial (IA) bevacizumab treatment was considered. Our rational for this approach was 
to use a smaller dose ofbevacizumab in a more directed fashion (IA-administration after 
BBB disruption), in order to maintain efficacy while reducing systemic toxicity6. 
The 
off-label uses of the medication, as well as the risks, including intracranial hemorrhage, 
were reviewed in detail. An informed written consent was signed by the parents, and 
assent was provided by the patient. We performed intra-arterial infusion of 2.5 mg/kg 
bevacizumab after hyperosmotic blood-brain-barrier breakdown. There were no acute 
complications from the procedure. 
Within 12 hours of IA-bevacizumab administration, the patient experienced complete 
resolution (0 on the 10-point scale) of her previously intractable headaches. She also felt 
subjectively stronger on her right side. She was started on a long steroid taper under 
supervision of the Endocrine Service. Two months later, MRI of the brain revealed an 
82% decrease in FLAIR signal and a 6% decrease in contrast enhancement (Figures IA 
and lB, middle panel). There was an associated markedly reduced mass effect. MRI of 
the brain at 5 months revealed 78% decreased FLAIR signal and 22% decreased contrast 
enhancement (Figures 1). MRI of the brain 5 months and 11 months later showed 
relative stability of the radiographic improvement, despite active weaning of steroids. · 
At 18 months clinical follow-up, the patient had made a progressive and prominent 
improvement in her proximal right arm and leg strength. She was able to walk long 
distances with the help of an electronic drop-foot unit. She has continued to lose weight 
(50 pounds so far). She experiences occasional moderate (5-6 on a 10-point scale) 
headaches that would last several hours, but not the constant very severe headaches 
she was experiencing before treatment. Her emotional !ability resolved and she was able 
8 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
to go back to school. 
Figure 1: 
before treatment 
3 months after 
treatment 
5 months after 
treatment 
11 months after 
treatment 
Version 3 
9 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
Version 3 
Case 2: An 11-year-old right-handed female presented with right hemiparesis, 
headache, nausea and vomiting. CT of the head revealed intraparenchymal and 
intraventricular hemorrhage and hydrocephalus. She required temporary external 
ventricular drainage. MRI imaging demonstrated a Spetzler-Martin Grade II A VM of 
the corpus callosum. She underwent embolization with only partial obliteration of the 
A VM 2 months later. She then underwent stereotactic radiosurgery to the residual 
A VM nidus with a dose of l 8Gy prescribed to the A VM with a volume of 4.3 cm3• 
She developed moderate headache within the first month after treatment, which 
responded to a 2-week course of steroids. Six-months after stereotactic radiosurgery, 
the patient developed mild to moderate headaches, which initially responded to 
ibuprofen. MRI showed evidence of mild vasogenic edema surrounding the AVM site. 
Eight months after radiosurgery, she then developed intractable headaches that were 
associated with nausea and vomiting. Repeat MRI demonstrated worsening cerebral 
edema with new contrast enhancement consistent with radiation necrosis in the left 
frontal lobe. There were no associated motor or sensory symptoms. A 21-day steroid 
course starting with 24 mg per day ofDexamethasone was initiated. This steroid taper 
could not however, be weaned below 8 mg ofDexamethasone daily over the ensuing 
3 months secondary to recurrent severe headache, nausea and vomiting. Courses of 
pentoxiphylline and vitamin E were tried without success. Over time, she developed 
significant steroid related symptoms. The patient also required a hospitalization for 
fluid overload. In less than 3 months, the patient gained over 30 pounds and had a BMI 
of25.5. As a result of her symptoms she too had to withdraw from school. 
Based on the initial experience with Case #1, we discussed the option of intra-arterial 
bevacizumab treatment. The off-label uses of the medication as well as the risks 
including intracranial hemorrhage were reviewed in detail. An informed written 
consent was signed by the parents, and the patient provided assent. 
The patient underwent intra-arterial infusion of 2.5 mg/kg bevacizumab into the left 
internal carotid artery after hyperosmotic blood-brain-barrier breakdown. There were 
no complications. 
Immediately after IA-bevacizumab administration, the patient experienced complete 
resolution of her intractable headache and she was successfully weaned off steroids 
within 4 weeks. MRI of the brain 3 months later revealed 74% decrease in FLAIR 
signal volume and a 33.6% decrease in contrast enhancement (Figure 2). MRI of the 
brain 10 months later showed even further decrease in cerebral edema, which was in 
fact completely resolved. At 16 months clinical follow-up, the patient was headaches 
free and was back in school. She lost 30 pounds and was back at her baseline weight. 
10 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
Figure 2: 
before 
treatment 
3months 
after 
treatment 
10 months 
after 
treatment 
1.5. 
Clinical Pharmacokinetics: 
Version3 
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. VEGF is a tyrosine kinase that plays an important 
role in angiogenesis and modulation of vascular permeability. VEGF-A binds with high 
11 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
Version 3 
specificity to VEGF-receptor-1 (VEGFR-1) and VEGF-receptor-2 (VEGFR-2) on 
vascular endothelial cells. These modulate down-stream signaling pathways affecting 
various cellular processes. VEGF has recently been implicated in the pathophysiology 
of radiation necrosis. Reactive astrocytes immediately surrounding the necrotic core in 
RN are strongly VEGF-positive by immunohistochemistry2. 
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. The elimination half-life 
ofbevacizumab is 19 days7• 
1.6. 
Rationale: 
Current IV bevacizumab regimen for RN and its associated morbidity 
Current IV-bevacizumab regimens use a dose of7.5 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, pulmon!l!"Y. embolus, 
intracranial hemorrhage, wound dehiscence, and severe hypertension 8•14• 
These 
complications are common to the anti-angiogenic class of drugs and reflect systemic 
exposure to bevacizumab. In our initial clinical experience, we 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 ofbevacizumab. We 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-bevacizurnab 
because of RN symptom progression'. 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. We believe that the increased penetration of 
bevacizurnab 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. 
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 15, 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 16• 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. We will infuse bevacizumab in the artery that 
supplies the territory affected by RN, such as cervical internal carotid artery and/or 
12 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
cervical vertebral artery. 
Version 3 
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 17,18 19. Several tumor clinical trials have shown that 
localization of monoclonal antibodies to the brain is ;oor without BBB disruption 
(0.0006%-0.0043% of the injected dose/g of tumor) 20-2 24 21,25. There is also evidence 
of a 20-fold increase in permeability to immunoreactive IgM Mab with BBB disruption 
in rats24. We believe that using blood-brain-barrier disruption significantly increases 
delivery of Bevacizumab to the affected brain. We will use the protocol described by 
Neuwelt and colleagues, using infusion of 25% Mannitol over 30 seconds26• 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 infusion27,28• 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. 
1. 7 Safety of cerebral intra-arterial bevacizumab treatment 
Safety of IA-Bevacizumab treatment after hyperosmotic BBBD was recently 
established in a series of malignant glioma patients29• 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, 
ependym?ma, and 1,llalignant bra~n~tem glioma have also demonstrated good safety 
profile with no obv10us neurotox1c1ty30-3 . 
2. OBJECTIVES 
2.1. Primary Objective: To assess the efficacy of intra-aiterial (IA) bevacizumab for the 
treatment of radiation necrosis. 
13 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
2.2. 
Secondary Objective: 
Version 3 
• 
To assess the degree of clinical and radiographic response to a single treatment 
• 
To assess the durability ofresponse to a single treatment 
• 
To assess time to steroid independence 
• 
To assess neurocognitive improvement 
2.3. Tertiary Objective: Cost analysis of a single treatment oflow dose intrarterial 
bevacizumab as compared to conventional intravenous bevaizumab use for radiation 
necrosis (7.5 mg/kg IV-Bevacizumab every 3 weeks for 4 cycles) 
3. STUDY DESIGN: Single Arm Phase II clinical trial 
4. PATIENT SELECTION 
4.1. Inclusion Criteria 
Patients must have radiation necrosis based on radiographic evidence defined as: 
• Increased Tl 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 
A VM, Meningioma, schwanuoma, 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 :'.':1,500/mcL 
platelets 
:'.':85,000/mcL 
creatinine 
;<S; 1. 8 mg/ di 
• 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. 
14 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
4.2. Exclusion Criteria 
Version 3 
• 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 :o:;2s 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. 
5. REGISTRATION 
5.1. General Guidelines: Eligible patients will be entered into the study at the participating 
site by the Study Coordinator at that site. Patients must emoll in the study within 4 weeks 
following registration. Patients should begin protocol treatment within 4 weeks of 
emollment. Issues that would cause treatment delays should be discussed with the 
Principal Investigator. 
If a patient does not receive protocol therapy following 
registration, the patient's registration on the study may be canceled. 
The Study 
Coordinators should be notified of cancellations as soon as possible. 
5.2. Registration Process: To register a patient, the following documents should be 
completed by the research nurse or data manager: 
• 
Copy of required laboratory tests 
• 
Signed patient consent form 
• 
HIP AA authorization form 
• 
Other appropriate forms (e.g., Eligibility Screening Worksheet, Registration Form). 
• 
Assign a patient study number 
• 
Register the patient in the study 
15 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
6. TREATMENT PLAN 
Version3 
Treatment will be administered on an outpatient basis. Reported adverse events and potential 
risks are described in Section 7. 
6.1. Vascular Access, Cerebral Angiogram, and Osmotic Blood-Brain-Barrier 
Disruption: 
We will use the protocol described by Neuwelt and colleagues, using infusion of 25% 
Manoitol over 30 seconds26. The safety of this protocol has been established in more than 
6000 patients treated worldwide with BBBD for intra-arterial chemotherapy infusion27•28. 
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 Cl-2 level in the cervical 
internal carotid artery and C6-7 for a vertebral artery infusion. Optimal rate of Manoitol 
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 
C0) 25% Manoitol 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. 
*It is important to warm the 25% Mannitol for adequate amouot of time to prevent 
crystallization. Filtering with 5-micron filter is important because of the propensity of 
Manoitol to crystalize at such high concentrations. 
**Dexamethasone is given for its anti-inflammatory effect 
* * *Keppra and Valium are given to increase seizure threshold because a small risk of 
seizure has been observed with osmotic BBBD. This was in the setting of IA-delivery of 
highly toxic chemotherapy agents in patient with malignant brain tumors such as CNS 
lymphoma. 
****Atropine is given because of very small potential risk ofbradycardia associated with 
stimulating the carotid bulb during injection of Manoi to I. 
6.2. 
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 ofManoitol 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. 
16 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
Version 3 
Angiogram of the femoral artery will then be performed. The femoral sheath will be 
removed and hemostasis will be achieved using a closure device and/or digital pressure 
for 20 minutes according to the surgeon's preference. 
6.3. 
Post-Operative Care: The patient is then monitored in the recovery unit with Q 15 min 
neurological exam and continuous heart rate and pulse-oximetric measurement for 2-4 
hours. The patient will then be observed overnight in TCU. The patient will be discharged 
home the following morning if clinically stable. 
6.4. General Concomitant Medication and Supportive Care Guidelines: Because there is 
a potential for interaction of Bevacizumab with other concomitantly administered drugs, 
the case report form must capture the concurrent use of all other drugs, over-the-counter 
medications, or alternative therapies. 
6.5. Duration of Therapy: One treatment drug dose only 
6.6. Duration of Follow-Up: Patients will be followed for 1 year. Patients with adverse 
events will be followed until resolution or stabilization of the adverse event. 
6.7. Definition of Dose-Limiting Toxicity: Development of Grade 3 or 4 major adverse event 
as described in section 8.2. 
*Management and dose modifications associated with the above adverse events are 
outlined in Section 7. 
6.8. Criteria for Removal from the Study: Patients will be removed from study upon request 
from the patient. The reason for study removal and the date the patient was removed must 
be documented in the Case Report Form. 
7. 
DOSE MODIFICATION: None 
8. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
8.1 
Adverse Events and Potential Risks List 
17 

Norton Healthcareillept of Neurosurgery 
LIBERTI 
Bevacizun1ab. 
-:category 
><Boot 
- system) 
_ A<f_vers\rEvents Wit.Ii l'Ossibfe 
__ Re1a_t1oosi111ltoaevac1zumab 
•-_ (CTCAE v3:ir1:erm) 
Version3 
\,le_r_!lion 1.2 Jun_e 19 _2_0071 
.'AO<>ntspecifioA!l}'eraeEv~ntlisl'-•·-··--
- -
-
'CA5AEl:)--C-
---
AU~rg'i9 reacikHl<'hyp~rs~nsHivity (induding drug f-ev:er) 
Cardiac is-ohemia!lnfaroti-on-
Cardiac tro onin I (Cini) 
Hyp-erte-nsion 
H otens!on 
Fatigue (asthenia, 1-:!thatgy, malaise) 
Fever (ln the- absence--ru n-WtroPenia. '.\'here 
ne-utrope-nla is ~ft~-~-~s_f~.9: -::~ __ .9_ x iOslL} 
Diarrhea 
Fistula GI ~ Se-lect 
-_Heartbum.1dy.sp€"p~ii!_ ____ _ 
lieus (funcUonJ:I cbsltuction of bv~~l l.~ .• 
neurooonst aft.on 
Leak (in-duding 3naston10Uo}, GI: large bow_e-l 
18 
H 
i?ttt?nsion 
-Fevei{iilfhe absence of neVtrop&nia, wht?te 
____ _ fJ_~RII_o enia i.s defint!cl~_§_~l~~ <1.0 x 101/t _ 
Urticaria hlv-e.s. wefts. WIJ~als 
_Anorexia 
Consti ation 
Heartburn_l!!r_~ef!PSia 
Mucc.sJtfr;!~tomaUli$ (fun.<::tio11all$yn1ptomailc) ~ 
Se]ect 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
-
-
._-
--
-
-- --
-
-
-
--
- -
-
----
:clitegoiY .. 
. · .. (Bj)(ly .. 
Adver~.: i:venfs Wlth Possible.· 
.~el~tlQnalJi1fto eevaolzumiil>' 
.. (CTCAE v!l.O Term! . 
svlitemJ 
Perlorntion, Gt· Select 
Hemonha. e-. GI - s~ree-t 
Henlorth-11 &, CNS 
H-en1orrhl.lge, GU; v:igfna 
___________ H~@9trha ~. pulmot1"" iu 
_r tf!S if-ate 
llJfl 
H-en1oahag~. puln1on.<1.ryiupp~r 
nose-
lnfeoOon \\'ith norntal ;\..NC or Grade 1 or 2 neu!rophils 
-Se.le.ct 
lnfeotio-n with nc.rm,sl ANC or-Gride-1 or 2 n~u~rophilr. 
- Sele.ct {pa!vis. pe.:it:cn~al t:.al.'ity, rae:tum. !>C!otum, 
skin. \VOUnd\ 
-ASi, SGOT (5~WITI glut1mlc oxafo3i~UC. 
tt~ns.amiffil5-e 
Brrlrubln (hyperbiti:rtJb\nemla} 
Pain - musel:G 
Pain_-NR§_ 
Bronchos asm, wheezin 
Cough 
Voiee .:hang--~dysarthria ('l.g .. hoatM-fle:S!;, ios~ or 
3\mratiOn in voice, lat r. ltts,} 
Pulffi9naryNpper Resi;-itafOt)'- Oth~t tnasaf-septitl 
Erloraooni 
Version3 
•• •. '.Ajje11t Speci~l~:~fji!•~Yetlt tlal' 
---- -
Von1itin 
Hen1orrha e- Gf ~ Sele.;t 
Hen1orrha 
CllS 
Hernorrha 
H~n1orrha e 
Hen1orrha 
Alkaline h-0$ hatase 
Al T SGPT f.serun1 alutan1ic • ruvio tran$atnlnas~ 
AST,-SGOf(~~runi gluliunic ox~lt>~C@t.ir;: 
tr11n.s_<!_minas-e 
Bilin1bin (h 
erbifirublnenri~ 
t1asat cavff ti aranasal sinus r~ac.llons 
Voi~ changes!dy.sarthri;i {~.Y~, hoar.seness, loss or 
alteration In voice la n itis) 
'This tobie will be updated as the toxicity profile of the agent rs revised. Up<!ates will be distributed to a!f Prlnclpal 
lnves!igaiors at the time of revl.sion. The eurrent version can be obtained by conlaoting Afl...EEJ}SMQ@teeh· 
res.OOffL Your name-, the nn1ne of th.e Investigator, the protocol and the_ agent shoutd be inciuded in th-e e~n1ail 
19 

Norton Healthcareillept of Neurosurgery 
LIBERTI 
8.2 Adverse Event Definitions: 
Version3 
CTCAE term (AE description) and grade: The descriptions and grading Events 
(CTCAE) version 4.0 will be utilized for AE reporting. All appropriate treatment areas 
should have access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 
4.0 can be downloaded from the CTEP web site (http://ctep.cancer.gov). 
Significance of an Adverse Event 
Grades 1 are mild adverse events. (e.g., minor event requiring no specific medical 
intervention; asymptomatic laboratory findings only; marginal clinical relevance) 
Grades 2 are moderate adverse events (e.g., minimal intervention; local intervention; 
non-invasive intervention; transfusion; 
elective interventional radiological 
procedure; therapeutic endoscopy or operation). 
Grades 3 are severe and undesirable adverse events (e.g., significant symptoms 
requiring hospitalization or invasive intervention; transfusion; elective interventional 
radiological procedure; therapeutic endoscopy or operation). 
Grades 4 are life threatening or disabling adverse events (e.g., complicated by acute, 
life-threatening metabolic or cardiovascular complications such as circulatory 
failure, hemorrhage, sepsis; life-threatening physiologic consequences; need for 
intensive care or emergent invasive procedure; emergent interventional radiological 
procedure, therapeutic endoscopy or operation) . 
Grades 5 are ata a verse event resultm,,. m eat 
f: 
1 d 
. d 
h 
Grades 
Grade 1 
Grade 2 
Grade2 
Grade3 
Grade3 
4&52 
Unexpected 
Expected 
Unexpected 
Unexpected 
Un ex-
with 
: without 
with 
' 
without 
Expected 
and 
and Expected 
pected 
Hospitali- r Hospitali-
Hospitali- ! Hospitali-
Expected 
zation 
zation 
zation 
zation 
10 
: 
10 
: 
24-Hour; 
Unrelated 
Not 
Not 
Not 
Calendar 
Not 
Calendar 
Not 
5 Calendar 
Unlikely 
Required 
Required Required 
Days 
Required 
Days 
Required 
Days 
Possible 
Not 
10 
Not 
24-Hour; i 24-Hour; 
10 
' 
Not 
24-Hour; 
Probable 
Required 
Calendar Required 5 Calendar: 5 Calendar Calendar : Required 
5 Calendar 
Definite 
Days 
Days 
' 
Days 
Days 
' 
Days 
' 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the last 
dose of treatment with an agent under a CTEP IND require reporting as follows: 
AdEERS 24-hour notification followed by complete report within 5 calendar days for: 
• Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
• Grade 4 unexpected events 
• Grade 5 expected events and unexpected events 
2 Although an AdEERS 24-hour notification is not required for death clearly related to progressive disease, a full report 
is required as outlined in the table. 
December 15, 2004 
Note: All deaths on study require both routine and expedited reporting 
regardless of causality. Attribution to treatment or other cause must be 
provided. 
20 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
8.2.1 
Serious Adverse Events: 
• 
Results in death. 
Version 3 
• 
Is a life-threatening adverse experience. The term life threatening in 
the definition of serious refers to an adverse event in which the subject was at 
risk of death at the time of the event. It does not refer to an adverse event 
which hypothetically might have caused death if it were more severe. 
• 
Requires inpatient hospitalization or prolongation of existing 
hospitalization. Any adverse event leading to hospitalization or prolongation 
of hospitalization will be considered as Serious, UNLESS at least one of the 
following expectations is met: 
o The admission results in a hospital stay of less than 12 hours OR 
o The admission is pre-planned (i.e., elective or scheduled surgery 
arranged prior to the start of the study) OR 
o The admission is not associated with an adverse event (e.g., social 
hospitalization for purposes of respite care. 
However it should be noted that invasive treatment during any 
hospitalization may fulfill the criteria of "medically important" and as 
such may be reportable as a serious adverse event dependant on clinical 
judgment. In addition where local regulatory authorities specifically 
require a more stringent definition, the local regulation takes precedent. 
• 
Results in persistent or significant disability /incapacity. 
The 
definition of disability is a substantial disruption of a person's ability to 
conduct normal life's functions. 
• 
Is a congenital anomaly /birth defect. 
• 
Is an important medical event. Important medical events that may not 
result death, be life-threatening, or require hospitalization may be considered 
a serious adverse experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical 
or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood disease 
or disorders, or convulsions that do not result in inpatient hospitalization, or 
the development of drug dependency or drug abuse. 
8.2.2 
Expectedness: Adverse Events can be Expected or Unexpected. 
• 
An expected adverse event is an event previously known or anticipated to 
result from participation in the research study or any underlying disease, 
disorder, or condition of the subject. The event will be listed in the consent 
form and research protocol. 
• 
An unexpected adverse event is an adverse event not previously known or 
anticipated to result from the research study or any underlying disease, 
disorder, or condition of the subject. 
8.2.3 Attribution 
Definite - The AE is clearly related to the study treatment. 
Probable - The AE is likely related to the study treatment. 
Possible - The AE may be related to the study treatment. 
Unlikely - The AE is doubtfully related to the study treatment. 
Unrelated - The AE is clearly NOT related to the study treatment. 
21 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
8.3 
Reporting Procedures for all Adverse Events 
Version3 
All participating investigators will assess the occurrence of AEs throughout the subject's 
participation in the study. Subjects will be followed for toxicity for 30 days after treatment 
has been discontinued or until death, whichever occurs first. The clinical course of each 
event will be followed until resolution, stabilization, or until it has been determined that 
the study treatment or participation is not the cause. 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject which occur after the subject has signed the 
informed consent are fully recorded in the subject's case report form, subject's medical 
records, and/or any other institutional requirement. Source documentation must be 
available to support all adverse events. 
A laboratory test abnormality considered clinically relevant (e.g., causing the ·subject to 
withdraw from the study), requiring treatment or causing apparent clinical manifestations, 
or judged relevant by the investigator, should be reported as an adverse event. 
The investigator will provide the following for all adverse events: 
• 
Description of the event 
• 
Date of onset and resolution 
• 
Grade of toxicity 
• 
Attribution of relatedness to the investigational agent 
• 
Action taken as a result of the event 
• 
Outcome of event 
In this study, descriptions and grading scales found in the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 available at http://ctep.cancer.gov will 
be utilized for AE reporting. 
Investigative sites will report adverse events to their respective IRB according to the local 
IRB 's policies and procedures in reporting adverse events. 
8.4 
Serious Adverse Event Reporting Procedures 
Serious adverse events that occur beginning with the signing of the informed consent form, 
during treatment, or within 30 days of the last dose of treatment must be reported to the 
Norton Healthcare Principal Investigator. Investigative sites will report serious adverse 
events to their respective IRB according to the local IRB' s policies and procedures in 
reporting serious adverse events. 
8.5 
Data Safety Toxicity Committee 
It is the Norton Healthcare's Principal Investigator's responsibility to ensure that ALL 
serious adverse events are reported to the Norton Healthcare's Data Safety Toxicity 
Committee. This submission is simultaneous with submission to the Sponsor or other 
Regulatory body. 
22 

Norton Healthcareillept of Neurosurgery 
LIBERTI 
9. PHARMACEEUTICAL INFORMATION 
Version 3 
A list of the adverse events and potential risks associated with bevacizumab administered in this 
study can be found in Section 8.0 
Name of Agent 
Chemical Name: 
Other Names: 
Classification: 
bevacizumab 
Avastin 
anti-angiogenic 
Molecular Formula: Avastin (bevacizumab) is a recombinant humanized monoclonal IgG 1 
antibody that binds to and inhibits the biologic activity of human vascular endothelial growth 
factor (VEGF) in in vitro and in vivo assay systems. Bevacizumab contains human framework 
regions and the complementarity-determining regions of a murine antibody that binds to VEGF. 
Avastin has an approximate molecular weight of 149 k:D. Bevacizumab is produced in a 
mammalian cell (Chinese Hamster Ovary) expression system in a nutrient medium containing the 
antibiotic gentamicin. Gentamicin is not detectable in the final product. 
Mode of Action: Bevacizumab binds VEGF and prevents the interaction ofVEGF to its receptors 
(Flt-1 and KDR) on the surface of endothelial cells. The interaction of VEGF with its receptors 
leads to endothelial cell proliferation and new blood vessel formation in in vitro models of 
angiogenesis. Administration of bevacizumab to xenotransplant models of colon cancer in nude 
( athymic) mice caused reduction of microvascular growth and inhibition of metastatic disease 
progression. 
Metabolism: The pharmacokinetic profile of bevacizumab was assessed using an assay that 
measures total serum bevacizumab concentrations (i.e., the assay did not distinguish between free 
bevacizumab and bevacizumab bound to VEGF ligand). Based on a population pharmacokinetic 
analysis of 491 patients who received 1 to 20 mg/kg of Avastin weekly, every 2 weeks, or every 3 
weeks, the estimated half-life ofbevacizumab was approximately 20 days (range 11-50 days). The 
predicted time to reach steady state was 100 days. The accumulation ratio following a dose of 10 
mg/kg ofbevacizumab every 2 weeks was 2.8. 
The clearance ofbevacizumab varied by body weight, gender, and tumor burden. After correcting 
for body weight, males had a higher bevacizumab clearance (0.262 L/day vs. 0.207 L/day) and a 
larger Ve (3.25 L vs. 2.66 L) than females. Patients with higher tumor burden (at or above median 
value of tumor surface area) had a higher bevacizumab clearance (0.249 L/day vs. 0.199 L/day) 
than patients with tumor burdens below the median. In Study 1, there was no evidence of lesser 
efficacy (hazard ratio for overall survival) in males or patients with higher tumor burden treated 
with Avastin as compared to females and patients with low tumor burden. The relationship between 
bevacizumab exposure and clinical outcomes has not been explored. 
Product description: 
-100 mg per 4 mL single-use vial 
-400 mg per 16 mL single-use vial 
23 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
Version3 
Solution preparation: Use appropriate aseptic technique. Parenteral drug products should be 
inspected visually for particulate matter and discoloration prior to administration, whenever 
solution and container permit. Withdraw necessary amount of Avastin and dilute in a total volume 
of 100 mL of0.9% Sodium Chloride Injection, USP. Discard any unused portion left in a vial, as 
the product contains no preservatives. 
. 
DO NOT ADMINISTER OR MIX WITH DEXTROSE SOLUTION. 
Storage requirements: Avastin vials [100 mg (NDC 50242-060-01) and 400 mg (NDC 50242-
061-01 )] are stable at 2-8°C (36-46°F). Avastin vials should be protected from light. Do not freeze 
or shake. 
Stability: Diluted Avastin solutions may be stored at 2-8°C (36-46°F) for up to 8 hours. Store in 
the original carton until time of use. No incompatibilities between Avastin and polyvinylchloride 
or polyolefin bags have been observed. 
Route of administration: 
In this study we will be performing intra-arterial infusion over a 14-minute period. 
Drug Procurement: Bevacizumab must be obtained from commercial sources. 
Drug Accountability: The investigator or designated study personnel are responsible for 
maintaining accurate dispensing records of the study drug. All study drugs must be accounted for, 
including study drug accidentally or deliberately destroyed. Under no circumstances will the 
investigator allow the investigational drug to be used other than as directed by the protocol. If 
appropriate, drug storage, drug dispensing, and drug accountability may be delegated to the 
pharmacy section of the investigative site. 
10. CORRELATIVE I SPECIAL STUDIES 
10.1 Imaging correlate 
Previous studies have shown that the use of bevacizumab alters the ability of gadolinium to 
produce enhancement in RN. Bevacizumab also decreases T2 FLAIR signal. In this Pilot 
Study, precontrast axial and sagittal Tl with the axial with fat-sat, T2, FLAIR, DWI/ ADC, 
susceptibility, post-contrast 3-plane FS Tl images, as well as brain perfusion will be used to 
evaluate for radiation necrosis and cerebral edema. All scans will be done on a 1.5-Tesla or 
higher MR. The scans will be performed before the 1st treatment, at 3 months, and 12 months, 
or as indicated for new clinical symptoms. All MRI's will be sent on CD to Core Lab at 
Norton Healthcare run by Dr. Kadner (board-certified neuro-radiologist). 
If a patient cannot have an MRI for medical reasons, then CT head with and without contrast 
will be used instead. 
10.2 Neuro-cognitive correlate 
In order to investigate the immediate and post-operative neurocognitive sequelae of 
bevacizumab, patients who consent to a formal neuropsychological battery will be tested at 
baseline (prior to IA bevacizumab administration), 3 and 12 months postoperative follow-up. 
The test battery was selected by a board certified neuropsychologist in order to thoroughly 
assess multiple cognitive domains and to be brief enough for patients to complete within one 
hour at each testing session. The neuropsychologist will conduct appropriate training sessions 
24 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
Version 3 
with an identified research assistant or nurse at each study site nntil inter-rater reliability is 
established (total ICC>.85) to assure both standardized administration and reduction of 
method error. Subtests from the NAB (Neuropsychological Assessment Battery, Stern & 
White, PAR Inc.) have been chosen for brevity, sensitivity, and due to the wide range of 
available normative data (ages 18-97). Subtests of the NAB can be administered alone or as 
part of the entire battery without loss of appropriate normative data, as each test across forms 
was administered to the same individuals in the standardization sample. Administration of 
the entire battery can take up to 4 hours, thus a subset of requisite performance measures was 
selected for inclusion in this study. In addition, the Wechsler Test of Adult Reading (WTAR, 
Pearson Inc.) will be administered to provide an estimate ofpremorbid cognitive functioning. 
Subtests chosen from the NAB include: Digits Forwards (DF); Digits Backwards (DB); Letter 
and Numbers (L&N). Together, these will assess attention capacity, working memory, and 
processing speed. Naming (NAM). This will assess confrontation naming and anomia. 
Design Construction (DES). This will assess spatial awareness and constructional praxis. List 
Learning (LL); Story Learning (SL); and Shape Leaming (ShL). These will assess auditory 
and visual episodic learning and memory retrieval and retention skills. Mazes (MZ); 
Categories (CAT); and Word Generation (WO). These will assess higher order executive 
functioning with regard to planning, conceptualization, and fluency. We expect the most 
significant effects to arise from assessment of processing speed, memory, and executive 
functioning. Each of these subtests will be administered at baseline, time 1, and time 2. The 
NAB was standardized with 2 alternate, equivalent forms, which will be connterbalanced 
across administration times while repeating one form per subject. 
Given the length of time 2 to time 3, practice effects across the three forms can be minimized. 
The tests will be administered as follows: 
Cognitive Domain 
Timel 
Time2 
Time3 
(Baseline) 
week following 
(3 months following 
treatment) 
treatment) 
Premorbid Intelligence 
WTAR 
Attention I Processing 
DF,DB,L&N 
DF,DB,L&N 
DF,DB,L&N 
Sneed 
Language 
NAM 
NAM 
NAM 
V isuospatial 
DES 
DES 
DES 
Learning and Memory 
LL, SL, ShL 
LL, SL, ShL 
LL, SL, ShL 
Executive Functioning 
MZ,CAT,WG 
MZ,CAT, 
MZ,CAT, WG 
WG 
10.3 Headache Correlate 
Patients with radiation necrosis often experience severe or intractable headaches. These 
headaches usually worsen during efforts to wean the patient off corticosteroids, leading to 
long-term steroid use and all its associated serious morbidities. Our preliminary experience 
indicates rapid and complete resolution of headaches following IA-bevacizumab treatment. 
All patients will be tested using a formal headache battery at baseline. The Headache Impact 
Test (HIT-6) which is a fixed-length 6-item, paper form version of the DYNHA Headache 
Impact Test will be filled out by the patient. MIDAS 5-item questionnaire will also be 
completed by the patient before treatment, as well as at 6 weeks, 3 mo, 6 mo, 9 mo, and 12 
mo. 
25 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
11. STUDY PARAMETERS AND CALENDAR 
Version3 
The tests and procedures found in the Study Flow Chart will be performed. Baseline 
evaluations are to be conducted within 2 weeks prior to start of protocol therapy. Scans and 
x-rays must be done 4 weeks prior to the start of therapy. 
Pre-
Day 
Day 
Week 
Month 
Month 
Month 
Studv 
0 
1 
6 
3 
6 
12 
Informed Consent 
R 
Demographics 
NR 
Medical History 
NR 
NR 
NR 
NR 
NR 
Concurrent Medication 
NR 
NR 
NR 
NR 
NR 
Physical Exam 
NR 
R 
R 
R 
R 
Neurological Exam 
NR 
R 
R 
R 
R 
Carotid Angiogram 
R 
Osmotic blood-brain-barrier 
R 
breakdown 
Avastin® 
R 
HIT - 6 Survey 
R 
R 
R 
R 
R 
( mav be via phone) 
MIDAS 
R 
R 
R 
R 
R 
(mav be via phone) 
N euroPsych Testing 
R 
R 
R 
KPS Functional Status 
R 
R 
R 
R 
Screening Lab tests1 
R 
ECG (if needed)2 
. 
R 
Adverse Event monitoring 
R 
R 
R 
R 
Urine Pregnancy Test 
R 
Brain MRI w & w/o contrast 
NR 
NR 
NR 
R=Research 
NR= non-research or standard of care 
1 = CBC with differential and platelets count, basic metabolic panel serum chemistry 
2= ECG will be done in patients >45 years old or in any patients with history of cardiac problems 
Physical Examination: All emolled participates will have an abbreviated physical examination 
and vital signs (heart rate, blood pressure and body weight) collected during screening and then 
again at Day 0, and 1, Month 3 and 12. 
Neurological Examination: 
All emolled participants will have a detailed neurological 
examination during screening and then again at Day 0, and 1, Month 3 and 12. 
26 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
Version 3 
Pregnancy Testing: It is not known whether study drug used in this study may cause side effects 
to pregnant women, to an unborn child, or to children of nursing women. Because of these 
unknown risks, all women of childbearing potential will be given a pregnancy test prior to receiving 
study drug. Testing will be performed either by urine or blood. 
Female participants will be 
informed that they must not become pregnant until 8 weeks following the last dose of study 
medication 
Karnofsky Performance Status Scale: Will be used to measure the functional status of the 
participant prior to and following study drug administration 
Brain MRI: All subject will undergo a Brain MRI prior to receive study medication (Pre-study) 
and then again at Months 3, and 12. 
CT Scan: Subject who cannot undergo a MRI for medical reasons will have undergo a head CT 
prior to receiving study medication (Pre-Study) and then again at Months 3 and 12. 
12. MEASUREMENT OF EFFECT 
12.1 Decrease in Cerebral Edema 
We will use pre-contrast axial and sagittal Tl with the axial with fat-sat, T2, FLAIR, 
DWI/ADC, susceptibility, post-contrast 3-plane FS Tl images, as well as brain 
perfusion to evaluate for progression. All scans will be done on a 1.5-3.0 Tesla MR. 
The scans will be performed within 4 weeks before the 1st treatment, at 3 months, and 
12 months, or as indicated for new clinical symptoms. 
A reduction in volume of 
cerebral edema of > 25% will constitute a positive response. 
12.2 Definitions 
Please use or modifY the following text as appropriate. 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their 
first treatment with Bevacizumab. 
Evaluable for objective response. Only those patients who have measurable disease 
present at baseline, have received one cycle of therapy, and have had their disease re-
evaluated will be considered evaluable for response. These patients will have their 
response classified according to the definitions stated below. (Note: Patients who 
exhibit objective disease progression treatment will also be considered evaluable.) 
12.3 Duration of Response 
Duration of overall response: The duration of overall response is measured from the 
time measurement criteria are met for CR or PR (whichever is first recorded) until the 
first date that recurrent or progressive disease is objectively documented (taking as 
reference for progressive disease the smallest measurements recorded since the 
treatment started). 
The duration of overall CR is measured from the time measurement criteria are first 
met for CR until the first date that recurrent disease is objectively documented. 
27 

Norton Healthcareillept of Neurosurgery 
LIBERTI 
Version 3 
Duration of stable disease: Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started. 
13. 
STATISTICAL CONSIDERATIONS 
13.l 
Study Design/Endpoints 
Two-stage design, Single-arm Phase II multi-center clinical trial. The participating 
centers are Norton Healthcare and University of Kentucky Healthcare. This study will 
determine efficacy of IA-bevacizumab after BBBD treatment for radiation necrosis. 
13.2 
Sample Size/Accrual Rate 
Stage 1: There will be a maximum of 10 patients accrued for stage 1 of this trial. In 
2013, there were a total of 5 patients seen and evaluated for medically refractory 
radiation necrosis at our center. Therefore, the accrual rate would be anticipated as 5 
patients per year. The accrual rates are expected to be 3-5 per year in other 
participating site. 
Stage 2: If 2:30% of patients have a positive response, then the number of patients 
in the trial will escalate to 46 patients. At that point, further participating sites will be 
considered. 
13.3 
Stratification Factors: None. 
13.4 
Analysis of Secondary Endpoints: Secondary endpoint findings will be compared 
to historical controls from published studies of IV-bevacizumab treatment for 
radiation necrosis. 
13.5 . OutcomeM_e;is.ures 
Prim11cy-Oufoome .Measure:.Decrease111radiationiiecrosfa••ill"l<Fcerebriile-dem~1~ 
after a single treatment ()flow.dose iiitrarterial beva()iiU111ab: Preconttast axial and 
sagittal Tl withthe axial with fatcsat;'f2, FLAIR, D_wl/ADC,·susceptibility,.post- .... 
contrast3~planeEST1 images, as well as brainperjusicu1 wiU b() used to evaluate fo~ 
ra.diation necrosis arid cerebral edema. All scans 'Nill be doile on a l.S.]_' esla or higher 
MR,: The scanswif! be performed before the•! st treatment, at] ll1onths;.and.12 
..• 
months,· or. as.indicatedfm newclirii<ial syiiiptoms.AllivlRI'sFill b.e sent on CDtQ 
Core.Lab afNortcm Healthcaietun. by br. Kadner (l>oaril-c()rtified neui:ocradiologistJ: 
If a.Patient cannot have ariMRI forlJ1idicalreqs.onsothen QT headwitli and with~ut 
contrast}Vill be used instead. 
Secondary Outc.0111e Measures: 
l, Decl"easeinsteroid us-age after asingfo;treatmeiitofJow d!is~illtrll.l;terfol. · 
bevadzrirnab: ·To asses§ the utility ofintra"arterial bevacizumab treattnentiri 
all owing decreased steroid usage, the quantity of steroid. use {measured as Il}g of 
J)eca_cleton per da)'}\Vill be noted a:t 1day, 3 months, and J2ri1()!1ths: 
2i Quarifffative 1m12rovemifotin heac!aclie after.II §ingle freatfu()nt ()fl<iw gose. _ .. 
. ··. 
intfarterial bevacizumab: Quarititativeiritprovementinheadachewi.Hbe asses_sed by 
pel-forIIiing The. FleE!Ql!Chelmpact Test{RIT~6)M']jjgh_is a fix_edcle11gth !Htem; fll!per 
28 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
Version3 
forffi.versiOn 9fthe·nYNHA-BeaaacheinipactTesfwin•oefi!Ie&.outby the.patieiif.. 
MIDASS"item questionnaire will also be completed by thepatientbefoi:~ treatment! 
as well as at6 weeks,3 mp, 61no,9 mo, and.l2mo> 
3. ·Neurocognitiveimprovemelifiifter a single treatment()ffow dose inttarteria1 
bevae~utnab:··m·ordertoinvestigatetheimme(liate·andnosEop.erative 
neurocogriitivesequelae of.intra-arterial beva.Cizumab, patients wno conseritlo:a . ... -
formalneuropsychological battery will be tested at baseline(priortoIAbevacizumab 
adfilinistration),3_and12 J:llonths. postoperative follow-up: Subtests from the~J\.;6 
(Neuropsychological Assessment B.attery, Stem c\'cWliite,l'ARlnc,)have been ·. 
_ 
chosen for brevity,serisitixfty,!(ndd.ueto the.wide range cifayailiiblel1oflllative diita 
(ages 18091). 11la,ddition;the W:echslerTest of Adult Reading (WTAR, Pearson Inc.) 
willbeachninisteredto provide_an estiinate ofpremorbiqpogtiitive funptioning. ; 
4: .•Safety of.a single treatment pf low.dose intial'terial bevacizumiib:-Safetys1fintra~ 
arterialbevaciZUlliab will be assessed by noting the number ot'pariicjp<!Jits With 
treatinent:related_ adverse•events a:s asses§ed by GTCAEy,tO. · 
5; Neurological improvement after a single tr()atmentof!ow do-se intrarterial _ 
bevacizumab:ObJectiveimproyemenf inneurolQgicaleX:am wiU]je asse~sed by 
performing ·serial neurological exaifis at baseline, 1·. day, 3 moj)t}1s; artdl.2 iu61itl1s: 
Also,··quantitative.improvementinfcinctional:itat\ls.will[Jeassessedbyperforming 
Kamofaky Performance Statris· Scale (KI'S)• at baseline,J day; 3im5.nth~, and 1 i 
months. 
0th.er Pre.:spedfied Outcome Measures:· .. Cosfanalysis ofa singletreatineJ1t of 
low.doseihtrart~rial beyaciZUffiab compared to collventionalI\Z:-bevaciz.um&b .. 
regiment:· Collfanalysisofasingle~tteatment oflow .. do tie fo.tri\r1:erial bevaci.zurnab ·.· 
after osmot[C:J)loOd-brain"barrier.disruptionascol'nparedtocorivehtiqnali:ntrayerioiis 
bevaiiqma.15 Use for radiation necrosis. ('Z:S mg/kgJV 0Beyaci~!Jfalf()'1el:y3weeks .. for 
4 cyc:lesJ. . 
- -
--
-
29 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
14. References 
Version3 
1. Levin VA, Bidaut L, Hou P, et al. Randomized double-blind placebo-controlled trial of 
bevacizumab therapy for radiation necrosis of the central nervous system. International Journal of 
radiation Oncology, Biology, Physics 2011;79:1487-95. 
2. Nonoguchi N, Miyatake S, Fukumoto M, et al. The distribution of vascular endothelial 
growth factor-producing cells in clinical radiation necrosis of the brain: pathological 
consideration of their potential roles. Journal of neuro-oncology 2011; 105:423-31. 
3. Dashti SR, Spalding A, Kadner RJ, et al. Targeted intraarterial anti-VEGF therapy for 
medically refractory radiation necrosis in the brain. J Neurosurg Pediatr 2015; 15 :20-5. 
4. Monaco EA, 3rd, Niranjan A, Kano H, Flickinger JC, Kondziolka D, Lunsford LD. 
Management of adverse radiation effects after radiosurgery for arteriovenous malformations. 
Progress in neurological surgery 2013;27:107-18. 
5. Williamson R, Kondziolka D, Kanaan H, Lunsford LD, Flickinger JC. Adverse radiation 
effects after radiosurgery may benefit from oral vitamin E and pentoxifylline therapy: a pilot 
study. Stereotactic and functional neurosurgery 2008;86:359-66. 
6. Levin VA, Bidaut L, Hou P, et al. Randomized double-blind placebo-controlled trial of 
bevacizumab therapy for radiation necrosis of the central nervous system. Int J Radiat Oncol Biol 
Phys 2011;79:1487-95. 
7. Li J, Gupta M, Jin D, Xin Y, Visich J, Allison DE. Characterization of the long-term 
pharmacokinetics of bevacizumab following last dose in patients with resected stage II and III 
carcinoma of the colon. Cancer chemotherapy and pharmacology 2013;71 :575-80. 
8. Takano M, Kikuchi Y, Kato M, Yoshikawa T, Kita T. Bowel perforation associated with 
bevacizumab therapy in recurrent ovarian cancers without bowel obstruction or bowel 
involvement]. Gan To Kagaku Ryoho 2008;35:1981-4. 
9. Heinzerling JH, Huerta S. Bowel perforation from bevacizumab for the treatment of 
metastatic colon cancer: incidence, etiology, and management. Curr Surg 2006;63:334-7. 
10. 
Abbrederis K, Kremer M, Schuhmacher C. [Ischemic anastomotic bowel perforation during 
treatment with bevacizumab 10 months after surgery]. Chirurg 2008;79:351-5. 
11. 
Suenaga M, Mizunuma N, Kobayashi K, et al. Management of venous thromboembolism in 
colorectal cancer patients treated with bevacizumab. Med Oncol;27:807-14. 
12. 
Grivas AA, Trafalis DT, Athanassiou AE. Implication ofbevacizumab in fatal arterial 
thromboembolic incidents. J BUON 2009;14:115-7. 
13. 
Vredenburgh JJ, Desjardins A, Kirkpatrick JP, et al. Addition ofBevacizumab to Standard 
Radiation Therapy and Daily Temozolomide Is Associated with Minimal Toxicity in Newly 
Diagnosed Glioblastoma Multiforme. Int J Radiat Oncol Biol Phys. 
14. 
Chamberlain MC, Johnston S. Salvage chemotherapy with bevacizumab for recurrent 
alkylator-refractory anaplastic astrocytoma. J Neurooncol 2009;91 :359-67. 
15. 
Gobin YP, Cloughesy TF, Chow KL, et al. Intraarterial chemotherapy for brain tumors by 
using a spatial dose fractionation algorithm and pulsatile delivery. Radiology 2001;218:724-32. 
16. 
Namba H, Kobayashi S, Iwadate Y, et al. Assessment of the brain areas perfused by 
superselective intra-arterial chemotherapy using single photon emission computed tomography 
with technetium-99m-hexamethyl-propyleneamine oxime--technical note. Neurol Med Chir 
(Tokyo) 1994;34:832-5. 
17. 
Neuwelt EA, Frenkel EP, D'Agostino AN, et al. Growth of human lung tumor in the brain 
of the nude rat as a model to evaluate antitumor agent delivery across the blood-brain barrier. 
Cancer Res 1985;45:2827-33. 
18. 
Armstrong BK, Robinson PJ, Rapoport SI. Size-dependent blood-brain barrier opening 
demonstrated with [14C]sucrose and a 200,000-Da [3H]dextran. Exp Neurol 1987;97:686-96. 
19. 
Ziylan YZ, Robinson PJ, Rapoport SI. Differential blood-brain barrier permeabilities to 
[14C]sucrose and [3H]inulin after osmotic opening in the rat. Exp Neurol 1983;79:845-57. 
20. 
Bullard DE, Bigner DD. Applications of monoclonal antibodies in the diagnosis and 
30 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
Version 3 
treatment of primary brain tumors. JNeurosurg 1985;63:2-16. 
21. 
Zalutsky MR, Moseley RP, Benjamin JC, et al. Monoclonal antibody and F(ab')2 fragment 
delivery to tumor in patients with glioma: comparison of intracarotid and intravenous 
administration. Cancer Res 1990;50:4105-10. 
22. 
Epenetos AA, Courtenay-Luck N, Pickering D, et al. Antibody guided irradiation of brain 
glioma by arterial infusion ofradioactive monoclonal antibody against epidermal growth factor 
receptor and blood group A antigen. Br Med J (Clin Res Ed) 1985;290:1463-6. 
23. 
Zalutsky MR, Moseley RP, Coakham HB, Coleman RE, Bigner DD. Pharmacokinetics and 
tumor localization of 13 ll-labeled anti-tenascin monoclonal antibody 81 C6 in patients with 
gliomas and other intracranial malignancies. Cancer Res 1989;49:2807-13. 
24. 
Neuwelt EA, Barnett PA, Hellstrom KE, Hellstrom I, McCormick CI, Ramsey FL. Effect of 
blood-brain barrier disruption on intact and fragmented monoclonal antibody localization in 
intracerebral lung carcinoma xenografts. J Nucl Med 1994;35:1831-41. 
25. 
Lee YS, Bullard DE, Zalutsky MR, et al. Therapeutic efficacy of antiglioma mesenchymal 
extracellular matrix 13 ll-radiolabeled murine monoclonal antibody in a human glioma xenograft 
model. Cancer Res 1988;48:559-66. 
26. 
Dahlborg SA, Henner WD, Crossen JR, et al. Non-AIDS primary CNS lymphoma: first 
example of a durable response in a primary brain tumor using enhanced chemotherapy delivery 
without cognitive loss and without radiotherapy. The cancer journal from Scientific American 
1996;2:166-74. 
27. 
Doolittle ND, Miner ME, Hall WA, et al. Safety and efficacy of a multicenter study using 
intraarterial chemotherapy in conjunction with osmotic opening of the blood-brain barrier for the 
treatment of patients with malignant brain tumors. Cancer 2000;88:637-47. 
28. 
Neuwelt EA. Mechanisms of disease: the blood-brain barrier. Neurosurgery 2004;54: 131-
40; discussion 41-2. 
29. 
Boockvar JA, Tsiouris AJ, Hofstetter CP, et al. Safety and maximum tolerated dose of 
superselective intraarterial cerebral infusion ofbevacizumab after osmotic blood-brain barrier 
disruption for recurrent malignant glioma. J Neurosurg. 
30. 
Rajappa P, Krass J, Riina HA, Boockvar JA, Greenfield JP. Super-selective basilar artery 
infusion ofbevacizumab and cetuximab for multiply recurrent pediatric ependymoma. 
Interventional neuroradiology : journal of peritherapeutic neuroradiology, surgical procedures 
and related neurosciences 2011; 17 :459-65. 
31. 
Riina HA, Burkhardt JK, Santillan A, Bassani L, Patsalides A, Boockvar JA. Short-term 
clinico-radiographic response to super-selective intra-arterial cerebral infusion ofBevacizumab 
for the treatment of vestibular schwannomas in Neurofibromatosis type 2. Interventional 
neuroradiology : journal of peritherapeutic neuroradiology, surgical procedures and related 
neurosciences 2012;18:127-32. 
32. 
Riina HA, Knopman J, Greenfield JP, et al. Balloon-assisted superselective intra-arterial 
cerebral infusion of bevacizumab for malignant brainstem glioma. A technical note. 
Interventional neuroradiology: journal of peritherapeutic neuroradiology, surgical procedures 
and related neurosciences 2010;16:71-6. 
31 

Norton Healthcareillept of Neurosurgery 
LIBERTI 
Version3 
STUDY TITLE: Low-dose Intra-arterial Bevacizumab for Edema and Radiation necrosis 
Therapeutic Intervention (LIBERTI) 
Participating Centers: 
Norton Healthcare 
University of Kentucky Healthcare 
Sponsor/Principal Investigator:Shervin R. Dashti, MD, PhD 
4950 Norton Healthcare Blvd. #205 
Louisville, KY 40241 
Telephone: 502-394-6390 
Fax: 502-394-6388 
Shervin. dashti@nortonhealthcare.org 
Version 3 
Date: 20 June 2016 
CONFIDENTIAL STATEMENT 
This document contains confidential information, which should not be copied, referred to , 
released or published without written approval from Shervin Dashti, MD or Norton Heathcare. 
Investigators are cautioned that the information is this protocol might be subject to change and 
revision. Any conclusion regarding efficacy and safety must be considered provisional. 
I 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
SCHEMA 
Version 3 
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 
blood-brain-barrier disruption using 25% Mannitol at 4-12 ml/sec for 30 seconds. 
INTRA-ARTERIAL DOSING SCHEMA 
Dose NUMBER 
Agent 
Dose#!: Day 0 
2.5 mg/kg X 1 dose 
2 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
INVESTIGATOR'S STATEMENT AND SIGNATURE 
Version3 
I have read and understand this protocol, attachments, and (name of study drug). I agree to 
conduct the study as outlined in the protocol and to comply with all the terms and conditions set 
out therein. I confirm that I will conduct the study in accordance with ICH GCP guidelines and 
the ethical principles of the Helsinki Declaration. 
Sponsor/Principal Investigator: 
Signature: _____________ _ 
Date: _______ _ 
Printed Name: ________________ _ 
3 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
Version3 
CONTACT DETAILS OF KEY PERSONNEL 
Role 
Name 
Contact Information 
4950 Norton Healthcare Blvd. #205 
Sponsor/Principal 
Shervin R. Dashti, MD, 
Louisville, KY 40241 
Telephone: 502-394-6390 
Investigator 
PhD 
Fax: 502-394-6388 
Shervin. dashtiffllnortonhealthcare. orv 
UK Medical Center 
Department of Neurosurgery 
Principal Investigator 
Justin Fraser, MD 
Medical Science Building Room MS 108A 
Lexington, KY 40536-0298 
Telephone: (859) 323-0616 
Jfi·235ffliukv.edu 
UK Center for Clinical and Translational 
Science 
800 Rose Street, Pavilion H, Room C300 
Sponsor Project Manager 
Elodie Elayi 
Lexington KY, 40536 
Telephone: (859) 323-7939 
Fax: (859) 257-9560 
Elodie. elay_i@ukv.edu 
Bluegrass Research Consultants, Inc. 
8020 Sea Hero Run 
Sponsor Study Monitor 
Karen Bowen, RN 
Versailles, KY 403 83 
Phone: (859)396-4655 
FAX: 
(859)873-9963 
Bowen 7 3 ffllwindstream. net 
4950 Norton Healthcare Blvd. #205 
Shervin R. Dashti, MD, 
Louisville, KY 40241 
SAE Reporting 
PhD 
Telephone: 502-394-6390 · 
Fax: 502-394-6388 
Shervin. dashtifnl nortonhealthcare. or<' 
4 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
Version 3 
1.0 
BACKGROUND ......................................................................... . 
1.1 
Radiation Necrosis 
1.2 
Bevacizumab 
1. 3 
Preclinical Data 
1.4 
Clinical Data 
Case Study 1 
.............................................................. .. 
Case Study 2 
............................................................... . 
1.5 
Clinical Pharmacokinetics ..................................................... . 
1.6 
Rationale ........................................................................ . 
1. 7 
Safety of cerebral intra-arterial bevacizumab treatment .................. . 
2.0 
OBJECTIVES 
2.1 
Primary Objective ................................................................ . 
2.2 
Secondary Objective(s) ........................................................ .. 
2.3 
Tertiary Objective(s) ........................................................... .. 
3.0 
STUDY DESIGN ....................................................................... .. 
Page 
7 
8 
10 
11 
12 
13 
13 
14 
14 
14 
4.0 
PATIENT SELECTION 
4.1 
Inclusion Criteria .. .. .. .. .. . .. .. .. .. .. .. .. .. .. . .. .. .. .. . .. . .. .. .. .. .. .. . .. . .. .. . .. . 
14 
4.2 
Exclusion Criteria ... ..................... ... ... .................. ............... ... 15 
5.0 
REGISTRATION ... ... ............ ............ ......... ................................... 15 
5.1 
General Guidelines 
5.2 
Registration Process 
6.0 
TREATMENT PLAN ..................................................................... 16 
6.1 
Vascular Access, Cerebral Angiogram, and Osmotic Blood Brain Barrier Disruption 
6.2 
Intra-Arterial Bevacizumab Administration 
6.3 
Post-Operative Care .. . .. .. .. .. .. .. .. . .. .. .. .. . .. .. .. .. .. .. . .. .. .. .. .. .. .. .. .. .. .. .. 17 
6.4 
General Concomitant Medications and Supportive Care Guidelines 
6.5 
Duration of Therapy 
6.6 
Duration of Follow Up 
6.7 
Definition of Dose-Limiting Toxicity 
6.8 
Criteria for Removal from Study 
7.0 
DOSE MODIFICATIONS .... .. ......... ... .. .... .. .. .. ... .. .. .. ... . .. ... .. .. .. . .. .. . .... 17 
8.0 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
8.1 
Adverse Events and Potential Risks . .. .. .. . .. .. . .. . .. .. .. .. .. .. . .. .. .. .. . .. .. .. .. 17 
8.2 
Definitions .. . .. . .. .. .. .. .. .. .. . .. .. .. . .. .. . .. . .. . .. .. . .. . .. .. .. .. .. .. . .. .. .. .. .. . .. .. 20 
8.2.1 
Adverse Events ............................................................. 21 
8.2.2 Significance of an Adverse Event 
8.2.3 
Serious Adverse Events 
8.2.4 Expectedness 
8.2.5 Attribution 
8.3 
Reporting Procedures for All Adverse Events ................................... 22 
8.4 
Serious Adverse Events Reporting Procedure 
8.5 
Data Safety and Toxicity Committee 
9.0 
PHARMACEUTICAL INFORMATION ... .. .... . .. .. .. .. .. . ... .. .... ... ..... .. .. .. .. 23 
5 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
Version 3 
10.0 
CORRELATIVE I SPECIAL STUDIES ... . .. . . . . .. .. .. .. .. . . .. . . . . . . . .. .. . ......... 24 
10.1 
Imaging Correlate 
10.2 
Neurocognitive correlate 
10.3 
Headache Correlate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 
11.0 
STUDY PARAMETERS AND CALENDAR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 
12.0 
MEASUREMENT OF EFEECT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 
12.1 
Decrease in Cerebral Edema 
13.0 
12.2 
Definitions 
12.3 
Duration of Response 
STATISTICAL CONSIDERATIONS· ............................................ . 
13 .1 
Study design/Endpoints 
13.2 
Sample Size/Accrual Rate 
13.3 
Stratification Factors 
13 .4 
Analysis of secondary Endpoints 
13.5 
Outcome Measures 
28 
14.0 
REFERENCES .. . . . . ... .. . .. . .. . .. . . . . .. . . .. . . . . .. . . . . . . . . . . . . .. . . . . .. . . . . . . . . . . .. . .... 
30 
6 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
1. BACKGROUND 
Version 3 
1.1. Radiation Necrosis: Stereotactic radiosurgery has become integral in treatment of brain 
tumors and arteriovenous malformations (A VM). 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. 
1.2. 
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 tumors'. 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. 
1.3. Preclinical 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 immunohistochemistry2• It is postulated that radiation causes micro vascular 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. 
1.4. 
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 tumors'. 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. 
We 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 oflife 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, we used intra-arterial Mannitol to 
disrupt the blood-brain barrier immediately prior to targeted intra-arterial drug 
administration. 
7 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
Version3 
Case 1: A 12-year-old right handed female presented with severe headaches. MRI of 
the brain showed a 3 .2 cm left posterior frontal arteriovenous malformation (Spetzler-
Martin Grade III) with mild surrounding vasogenic edema. There were no signs of 
hemorrhage. She was initially treated with a 2-week course of steroids with significant 
improvement in headaches along with decreased edema on MRI. After considering 
treatment options including observation, endovascular embolization and/or surgical 
resection, the patient and her family chose stereotactic radiosurgery. She underwent SRS 
with a dose of 21 Gy prescribed to the A VM with a volume of 9 .9 cm3. 
Eight months later, the patient presented with severe headaches and focal seizures 
affecting the right arm and leg. MRI of the brain at this time demonstrated increasing 
T2 FLAIR signal as well as new Gadolinium signal on the Tl sequences. She was treated 
with anti-epileptics for her seizures and oral steroids for presumed radiation necrosis. 
Her seizure episodes resolved, but her severe headache persisted. She was initially 
started on 24 mg per day of dexamethasone tapering over 3 weeks. Because of worsening 
headache and progressively worsening right hemiparesis, repeated attempts to reduce 
dexamethasone dose below 6 mg daily proved unsuccessful over the ensuing 9 months. 
Courses of pentoxiphylline, vitamin E, and hyperbaric oxygen were all administered per 
study protocols without success4•5. Despite these interventions, she declined to 4/5 
strength in the proximal right upper and lower extremities and 0/5 strength in her right 
hand and foot. She experienced a 60-pound weight gain with severe cushingoid features. 
She complained of constant severe (10 on the 10-point scale) headache. She also 
experienced severe emotional lability, causing her to withdraw from school. 
Given the progressive neurological decline and the lack of alternative therapies, the 
option ofIV-bevacizumab treatment was initially explored. However, this proved to be 
not available for our pediatric patient population. Hence, the option of low dose intra-
arterial (IA) bevacizumab treatment was considered. Our rational for this approach was 
to use a smaller dose ofbevacizumab in a more directed fashion (IA-administration after 
BBB disruption), in order to maintain efficacy while reducing systemic toxicity6. 
The 
off-label uses of the medication, as well as the risks, including intracranial hemorrhage, 
were reviewed in detail. An informed written consent was signed by the parents, and 
assent was provided by the patient. We performed intra-arterial infusion of 2.5 mg/kg 
bevacizumab after hyperosmotic blood-brain-barrier breakdown. There were no acute 
complications from the procedure. 
Within 12 hours of IA-bevacizumab administration, the patient experienced complete 
resolution (0 on the IO-point scale) of her previously intractable headaches. She also felt 
subjectively stronger on her right side. She was started on a long steroid taper under 
supervision of the Endocrine Service. Two months later, MRI of the brain revealed an 
82% decrease in FLAIR signal and a 6% decrease in contrast.enhancement (Figures IA 
and lB, middle panel). There was an associated markedly reduced mass effect. MRI of 
the brain at 5 months revealed 78% decreased FLAIR signal and 22% decreased contrast 
enhancement (Figures 1). MRI of the brain 5 months and 11 months later showed 
relative stability of the radiographic improvement, despite active weaning of steroids. 
At 18 months clinical follow-up, the patient had made a progressive and prominent 
improvement in her proximal right arm and leg strength. She was able to walk long 
distances with the help of an electronic drop-foot unit. She has continued to lose weight 
(50 pounds so far). She experiences occasional moderate (5-6 on a IO-point scale) 
headaches that would last several hours, but not the constant very severe headaches 
she was experiencing before treatment. Her emotional lability resolved and she was able 
8 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
to go back to school. 
Figure 1: 
before treatment 
3 months after 
treatment 
5 months after 
treatment 
11 months after 
treatment 
Version 3 
9 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
Version3 
Case 2: An 11-year-old right-handed female presented with right hemiparesis, 
headache, nausea and vomiting. CT of the head revealed intraparenchymal and 
intraventricular hemorrhage and hydrocephalus. She required temporary external 
ventricular drainage. MRI imaging demonstrated a Spetzler-Martin Grade II A VM of 
the corpus callosum. She underwent embolization with only partial obliteration of the 
A VM 2 months later. She then underwent stereotactic radiosurgery to the residual 
A VM nidus with a dose of 18Gy prescribed to the A VM with a volume of 4.3 cm3. 
She developed moderate headache within the first month after treatment, which 
responded to a 2-week course of steroids. Six-months after stereotactic radiosurgery, 
the patient developed mild to moderate headaches, which initially responded to 
ibuprofen. MRI showed evidence of mild vasogenic edema surrounding the A VM site. 
Eight months after radiosurgery, she then developed intractable headaches that were 
associated with nausea and vomiting. Repeat MRI demonstrated worsening cerebral 
edema with new contrast enhancement consistent with radiation necrosis in the left 
frontal lobe. There were no associated motor or sensory symptoms. A 21-day steroid 
course starting with 24 mg per day ofDexamethasone was initiated. This steroid taper 
could not however, be weaned below 8 mg of Dexamethasone daily over the ensuing 
3 months secondary to recurrent severe headache, nausea and vomiting. Courses of 
p'entoxiphylline and vitamin E were tried without success. Over time, she developed 
significant steroid related symptoms. The patient also required a hospitalization for 
fluid overload. In less than 3 months, the patient gained over 30 pounds and had a BMI 
of25.5. As a result of her symptoms she too had to withdraw from school. 
Based on the initial experience with Case # 1, we discussed the option of intra-arterial 
bevacizumab treatment. The off-label uses of the medication as well as the risks 
including intracranial hemorrhage were reviewed in detail. An informed written 
consent was signed by the parents, and the patient provided assent. 
The patient underwent intra-arterial infusion of 2.5 mg/kg bevacizumab into the left 
internal carotid artery after hyperosmotic blood-brain-barrier breakdown. There were 
no complications. 
Immediately after IA-bevacizumab administration, the patient experienced complete 
resolution of her intractable headache and she was successfully weaned off steroids 
within 4 weeks. MRI of the brain 3 months later revealed 74% decrease in FLAIR 
signal volume and a 33.6% decrease in contrast enhancement (Figure 2). MRI of the 
brain 10 months later showed even further decrease in cerebral edema, which was in 
fact completely resolved. At 16 months clinical follow-up, the patient was headaches 
free and was back in school. She lost 30 pounds and was back at her baseline weight. 
10 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
Figure 2: 
before 
treatment 
3 months 
after 
treatment 
10 months 
after 
treatment 
1.5. 
Clinical Pharmacokinetics: 
Version 3 
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. VEGF is a tyrosine kinase that plays an important 
role in angiogenesis and modulation of vascular permeability. VEGF-A binds with high 
11 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
Version 3 
specificity to VEGF-receptor-1 (VEGFR-1) and VEGF-receptor-2 (VEGFR-2) on 
vascular endothelial cells. These modulate down-stream signaling pathways affecting 
various cellular processes. VEGF has recently been implicated in the pathophysiology 
of radiation necrosis. Reactive astrocytes immediately surrounding the necrotic core in 
RN are strongly VEGF-positive by immunohistochemistry2. 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. The elimination half-life 
of bevacizumab is 19 days 7• 
1.6. Rationale: 
Current IV bevacizumab regimen for RN and its associated morbidity 
Current IV-bevacizumab regimens use a dose of7.5 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 s-14. 
These 
complications are common to the anti-angiogenic class of drugs and reflect systemic 
exposure to bevacizumab. In our initial clinical experience, we 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 ofbevacizumab. We 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. We 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 inflannnation. Therefore, 
IA-bevacizumab may result in more effective and durable control of radiation necrosis 
compared to traditional IV-bevacizumab treatment. 
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 15, 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 16. 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. We will infuse bevacizumab in the artery that 
supplies the territory affected by RN, such as cervical internal carotid artery and/or 
12 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
cervical vertebral artery. 
Version 3 
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 17•18 19. Several tumor clinical trials have shown that 
localization of monoclonal antibodies to the brain is ;oor without BBB disruption 
(0.0006%-0.0043% of the injected dose/g of tumor) 20-2 24 21•25. There is also evidence 
of a 20-fold increase in petmeability to immunoreactive IgM Mab with BBB disruption 
in rats24. We believe that using blood-brain-barrier disruption significantly increases 
delivery of Bevacizumab to the affected brain. We Will use the protocol described by 
Neuwelt and colleagues, using infusion of 25% Mannitol over 30 seconds26. 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 infusion27•28• 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 tlte 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. 
1. 7 Safety of cerebral intra-arterial bevacizumab treatment 
Safety ofIA-Bevacizumab treatment after hyperosmotic BBBD was recently 
established in a series of malignant glioma patients29• 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, 
ependym?ma, and 1!1alignant bra!n~tem ~lioma have also demonstrated good safety 
profile with no obv10us neurotox1c1ty3°-3 . 
2. OBJECTIVES 
2.1. Primary Objective: To assess the efficacy of intra-arterial (IA) bevacizumab for the 
treatment of radiation necrosis. 
13 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
2.2. 
Secondary Objective: 
Version 3 
• 
To assess the degree of clinical and radiographic response to a single treatment 
• 
To assess the durability of response to a single treatment 
• 
To assess time to steroid independence 
• 
To assess neurocognitive improvement 
2.3. Tertiary Objective: Cost analysis of a single treatment of low dose intrarterial 
bevacizumab as compared to conventional intravenous bevaizumab use for radiation 
necrosis (7.5 mg/kg IV-Bevacizumab every 3 weeks for 4 cycles) 
3. STUDY DESIGN: Single Ann Phase II clinical trial 
4. PATIENT SELECTION 
4.1. Inclusion Criteria 
Patients must have radiation necrosis based on radiographic evidence defined as: 
• Increased Tl 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 :C::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 0::70%. 
• Life expectancy of greater than 3 months. 
• Patients must have normal organ and marrow function as defined below: 
leukocytes :C::l,500/mcL 
platelets 
:C::85, 000/mcL 
creatinine Sl.8 mg/di 
• 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. 
14 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
4.2. Exclusion Criteria 
Version3 
• 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 5:28 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 ifthe mother is treated with Bevacizumab. 
• HIV-positive patients on combination antiretroviral therapy are ineligible because 
of the potential for pharmacokinetic interactions with Bevacizumab. 
5. REGISTRATION 
5.1. General Guidelines: Eligible patients will be entered into the study at the participating 
site by the Study Coordinator at that site. Patients must enroll in the study within 4 weeks 
following registration. Patients should begin protocol treatment within 4 weeks of 
enrollment. Issues that would cause treatment delays should be discussed with the 
Principal Investigator. 
If a patient does not receive protocol therapy following 
registration, the patient's registration on the study may be canceled. 
The Study 
Coordinators should be notified of cancellations as soon as possible. 
5.2. Registration Process: To register a patient, the following documents should be 
completed by the research nurse or data manager: 
• 
Copy of required laboratory tests 
• 
Signed patient consent form 
• 
HIP AA authorization form 
• 
Other appropriate forms (e.g., Eligibility Screening Worksheet, Registration Form). 
• 
Assign a patient study number 
• 
Register the patient in the study 
15 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
6. TREATMENT PLAN 
Version3 
Treatment will be administered on an outpatient basis. Reported adverse events and potential 
risks are described in Section 7. 
6.1. Vascular Access, Cerebral Angiogram, and Osmotic Blood-Brain-Barrier 
Disruption: 
We will use the protocol described by Neuwelt and colleagues, using infusion of 25% 
Mannitol over 30 seconds26. The safety of this protocol has been established in more than 
6000 patients treated worldwide with BBBD for intra-arterial chemotherapy infusion27•28• 
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 Cl-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 
C0) 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. 
*It is important to warm the 25% Mannitol for adequate amount of time to prevent 
crystallization. Filtering with 5-micron filter is important because of the propensity of 
Mannitol to crystalize at such high concentrations. 
**Dexamethasone is given for its anti-inflammatory effect 
* * *Keppra and Valium are given to increase seizure threshold because a small risk of 
seizure has been observed with osmotic BBBD. This was in the setting of IA-delivery of 
highly toxic chemotherapy agents in patient with malignant brain tumors such as CNS 
lymphoma. 
* * * * Atropine is given because of very small potential risk ofbradycardia associated with 
stimulating the carotid bulb during injection of Mannitol. 
6.2. 
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 ofMannitol 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. 
16 

Norton Healthcareillept of Neurosurgery 
LIBERTI 
Version3 
Angiogram of the femoral artery will then be performed. The femoral sheath will be 
removed and hemostasis will be achieved using a closure device and/or digital pressure 
for 20 minutes according to the surgeon's preference. 
6.3. 
Post-Operative Care: The patient is then monitored in the recovery unit with Q 15 min 
neurological exam and continuous heart rate and pulse-oximetric measurement for 2-4 
hours. The patient will then be observed overnight in TCU. The patient will be discharged 
home the following morning if clinically stable. 
6.4. General Concomitant Medication and Supportive Care Guidelines: Because there is 
a potential for interaction of Bevacizumab with other concomitantly administered drugs, 
the case report form must capture the concurrent use of all other drugs, over-the-counter 
medications, or alternative therapies. 
6.5. Duration of Therapy: One treatment drug dose only 
6.6. Duration of Follow-Up: Patients will be followed for 1 year. Patients with adverse 
events will be followed until resolution or stabilization of the adverse event. 
6.7. Definition of Dose-Limiting Toxicity: Development of Grade 3 or 4 major adverse event 
as described in section 8.2. 
*Management and dose modifications associated with the above adverse events are 
outlined in Section 7. 
6.8. Criteria for Removal from the Study: Patients will be removed from study upon request 
from the patient. The reason for study removal and the date the patient was removed must 
be documented in the Case Report Form. 
7. 
DOSE MODIFICATION: None 
8. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
8.1 
Adverse Events and Potential Risks List 
17 

Norton Healthcareillept of Neurosurgery 
LIBERTI 
BevacJzunu1b. 
---
--
-
Coteg<iry •· -
Adverse Eventu'!ilh Possible ·_-
. (Bndy -
· R~JatiO.nshiP. to_Bevaclzumab · 
-• SY~lem} 
- - {CTCAE113.0'Teffi1l. 
AUt!'rg!-c re-a¢tJoflihyp€'rs~n-sitivify (including drug fever) 
H 
tEnsion 
Fatigue {asthen!a, 
ma!aist>) 
-
-FeVer on-the abs-ence of neutr-openia, whiie 
_f)~_l_!~fl~I}~~ !!_~!7tf_iood as ANC < 1.0 x __ 1o:lb:) ___ _ 
Ri 
rsich<lls 
Rashl-<.tesquam.)ticm 
Diarrhea 
Fi:Stu!a, Gl: ~ Seleot 
il@-US (funetional obstn..1ct1-0-n of bowe-1. Le,. 
neurocons{i iltionJ 
l.~Jk {including anastOnlOtl¢}, GI; large. bowel 
~hrccsitiMston1atitis (funcllcnaffsyniptomatJc) - Select 
18 
Version 3 
Version 1.2 June 19 
'A~en1·s~~clfieA<JverseE~eflfii~r 
. • 
lASA!Ol.l 
. 
-
. -
Atlergi<; reaction/hypersensitivity (including drug 
fever 
Cardiac ischerol~n[a_[_ction 
H 
ertenslcn 
Fatigue- (as Urenia, 
y1 rualaise} 
Fever jlii the absence of neutfOPenla, where 
neutro --~nlli!_defmed a.s ANC <1.Q x 101/LJ _ 
orslchUls 
Consti_ation 
l)Jarrhea 
Mu<:o$Ulfifston1atili.s (fut1oticnaMsyn1ptomatio} -
Select 

Norton Healthcareillept of Neurosurgery 
LIBERTI 
categQry 
c ll'!ody 
. SyiiternJ 
.Adver11<> Eveltts\Vltti Poll1'ible 
· Reta!JonsliJJ>fo ae.vaciiumob 
CCTCAE.vJ,0 Jerml 
. 
Pefforiltmn, GI • Sele.et 
Vomilir; 
Infection \\'1Th norrnal 
or Grado!:> 1 Ol' .2: n~n.Jtrop.h!ts 
-S~!#Ct 
_ 
lnfee!lon wi!h ncut'!.s! ANC or Grad-e 1 or 2 tH1u!roplllls--
• S~ac:t {peJ>1is. pedtcooaJ ca•1!ty. rttCt\lrn, scrotum. 
skin. wound 
AST. SGOi (s-arum glutam\e oxaloae-e-tk -
ttan~aminils~) 
Gillrubfn (hyperbllirvbtnen1f3} 
Creatin!ne 
Prote-inuria 
Version3 
'Agent.specmc_A_<Jvers~Eventl.is.1'.- · 
- -· 
(ASAEl..)c_ 
. 
. . 
Alkaffne hos hatase 
ALT SGPT .s.eron1 alutan1ic 
ruvic tranf.anlinits~ 
AST1 SGOT (~~rum g_liJi~Q1lt; Q~;Jloacetic­
tr.f4n~ilroio~~e __ 
Billrubln 
Cou h 
D s nE"a (shOrlne-&s of breath 
tlasal c.avit h aranasaf sinus reaction-$ 
Voice changes!dy.$-arthria (e.g., ho<JrGen-es$, lo:5~ or 
alteration in vole~ la n ills 
'This lab!e will be updated as the toxicity proftl" of the agent Is revised. Updates wm be distributed to all Principal 
1nvesti9ators a! !he time ot revlslon. The eurrent version can be obtained by contacting AQEEESMR@tech-
re-s.cc-rn. Your narne 1 the non1e of the investig~tor, the protocol and the a.gent should be Included in the e--n1aiL 
19 

Norton Healthcareillept of Neurosurgery 
LIBERTI 
8.2 Adverse Event Definitions: 
Version 3 
CTCAE term (AE description) and grade: The descriptions and grading Events 
(CTCAE) version 4.0 will be utilized for AE reporting. All appropriate treatment areas 
should have access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 
4.0 can be downloaded from the CTEP web site (http://ctep.cancer.gov). 
Significance of an Adverse Event 
Grades 1 are mild adverse events. (e.g., minor event requiring no specific medical 
intervention; asymptomatic laboratory findings only; marginal clinical relevance) 
Grades 2 are moderate adverse events (e.g., minimal intervention; local intervention; 
non-invasive 
intervention; 
transfusion; 
elective 
interventional 
radiological 
procedure; therapeutic endoscopy or operation). 
Grades 3 are severe and undesirable adverse events (e.g., significant symptoms 
requiring hospitalization or invasive intervention; transfusion; elective interventional 
radiological procedure; therapeutic endoscopy or operation). 
Grades 4 are life threatening or disabling adverse events (e.g., complicated by acute, 
life-threatening metabolic or cardiovascular complications such as circulatory 
fuilure, hemorrhage, sepsis; life-threatening physiologic consequences; need for 
intensive care or emergent invasive procedure; emergent interventional radiological 
procedure, therapeutic endoscopy or operation). 
G d 
5 
ra es 
are f; al d 
1. 
. d th 
at a verse event resu tmg m ea 
Grades 
Grade I 
Grade 2 
Gradel 
Grade3 
Grade3 
4&52 
Unexpected 
Expected 
Unexpected 
Unexpected 
Un ex-
with 
! without 
with 
' 
without 
pected 
Expected 
and 
and Expected 
Hospitali- : Hospitali-
Hospitali- j Hospitali-
Expected 
zation 
' 
zation 
zation 
' 
zation 
JO 
' 
JO 
; 
24-Hour; 
Unrelated 
Not 
Not 
Not 
: 
Not 
Not 
Calendar : R 
. d 
Calendar 
5 Calendar 
Unlikely 
Required 
Required Required 
D 
, 
equ1re 
Days 
Required 
Days 
ays 
: 
' 
Possible 
JO 
24-Hour; i 24-Hour; 
JO 
; 
24-Hour; 
Not 
Not 
' 
Not 
Probable 
Calendar 
5 Calendar: 5 Calendar Calendar i 
5 Calendar 
Definite 
Required 
Days 
Required 
Days 
' 
Days 
Days 
' Required 
Days 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the last 
dose of treatment with an agent under a CTEP IND require reporting as follows: 
AdEERS 24-hour notification followed by complete report within 5 calendar days for: 
• Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
• Grade 4 unexpected events 
• Grade 5 expected events and unexpected events 
2 Although an AdEERS 24-hour notification is not required for death clearly related to progressive disease, a full report 
is required as outlined in the table. 
December 15, 2004 
Note: All deaths on study require both routine and expedited reporting 
regardless of causality. Attribution to treatment or other cause must be 
provided. 
20 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
8.2.1 
Serious Adverse Events: 
• 
Results in death. 
Version3 
• 
Is a life-threatening adverse experience. The term life threatening in 
the definition of serious refers to an adverse event in which the subject was at 
risk of death at the time of the event. It does not refer to an adverse event 
which hypothetically might have caused death if it were more severe. 
• 
Requires inpatient hospitalization or prolongation of existing 
hospitalization. Any adverse event leading to hospitalization or prolongation 
of hospitalization will be considered as Serious, UNLESS at least one of the 
following expectations is met: 
o The admission results in a hospital stay ofless than 12 hours OR 
o The admission is pre-planned (i.e., elective or scheduled surgery 
arranged prior to the start of the study) OR 
o The admission is not associated with an adverse event (e.g., social 
hospitalization for purposes ofrespite care. 
However it should be noted that invasive treatment during any 
hospitalization may fulfill the criteria of "medically important" and as 
such may be reportable as a serious adverse event dependant on clinical 
judgment. 
In addition where local regulatory authorities specifically 
require a more stringent definition, the local regulation takes precedent. 
• 
Results in persistent or significant disability/incapacity. 
The 
definition of disability is a substantial disruption of a person's ability to 
conduct normal life's functions. 
• 
Is a congenital anomaly /birth defect. 
• 
Is an important medical event. Important medical events that may not 
result death, be life-threatening, or require hospitalization may be considered 
, a serious adverse experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical 
or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood disease 
or disorders, or convulsions that do not result in inpatient hospitalization, or 
the development of drug dependency or drug abuse. 
8.2.2 Expectedness: Adverse Events can be Expected or Unexpected. 
• 
An expected adverse event is an event previously known or anticipated to 
result from participation in the research study or any underlying disease, 
disorder, or condition of the subject. The event will be listed in the consent 
form and research protocol. 
• 
An unexpected adverse event is an adverse event not previously known or 
anticipated to result from the research study or any underlying disease, 
disorder, or condition of the subject. 
8.2.3 Attribution 
Definite - The AE is clearly related to the study treatment. 
Probable - The AE is likely related to the study treatment. 
Possible - The AE may be related to the study treatment. 
Unlikely - The AE is doubtfally related to the study treatment. 
Unrelated - The AE is clearly NOT related to the study treatment. 
21 

Norton HealthcareIDept of Neurosurgery 
LIBERTI 
8.3 
Reporting Procedures for all Adverse Events 
Version 3 
All participating investigators will assess the occurrence of AEs throughout the subject's 
participation in the study. Subjects will be followed for toxicity for 30 days after treatment 
has been discontinued or until death, whichever occurs first. The clinical course of each 
event will be followed until resolution, stabilization, or until it has been determined that 
the study treatment or participation is not the cause. 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject which occur after the subject has signed the 
informed consent are fully recorded in the subject's case report form, subject's medical 
records, and/or any other institutional requirement. Source documentation must be 
available to support all adverse events. 
A laboratory test abnormality considered clinically relevant (e.g., causing the subject to 
withdraw from the study), requiring treatment or causing apparent clinical manifestations, 
or judged relevant by the investigator, should be reported as an adverse event. 
The investigator will provide the following for all adverse events: 
• 
Description of the event 
• 
Date of onset and resolution 
• 
Grade of toxicity 
• 
Attribution ofrelatedness to the investigational agent 
• 
Action taken as a result of the event 
• 
Outcome of event 
In this study, descriptions and grading scales found in the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 available at http://ctep.cancer.gov will 
be utilized for AE reporting. 
Investigative sites will report adverse events to their respective IRB according to the local 
IRB' s policies and procedures in reporting adverse events. 
8.4 
Serious Adverse Event Reporting Procedures 
Serious adverse events that occur beginning with the signing of the informed consent form, 
during treatment, or within 30 days of the last dose of treatment must be reported to the 
Norton Healthcare Principal Investigator. Investigative sites will report serious adverse 
events to their respective IRB according to the local IRB 's policies and procedures in 
reporting serious adverse events. 
8.5 
Data Safety Toxicity Committee 
It is the Norton Healthcare's Principal Investigator's responsibility to ensure that ALL 
serious adverse events are reported to the Norton Healthcare's Data Safety Toxicity 
Committee. This submission is simultaneous with submission to the Sponsor or other 
Regulatory body. 
22 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
9. PHARMACEEUTICAL INFORMATION 
Version3 
A list of the adverse events and potential risks associated with bevacizumab administered in this 
study can be found in Section 8.0 
Name of Agent 
Chemical Name: 
bevacizumab 
Other Names: 
Avastin 
Classification: 
anti-angiogenic 
Molecular Formula: Avastin (bevacizumab) is a recombinant humanized monoclonal lgG 1 
antibody that binds to and inhibits the biologic activity of human vascular endothelial growth 
factor (VEGF) in in vitro and in vivo assay systems. Bevacizumab contains human framework 
regions and the complementarity-determining regions of a murine antibody that binds to VEGF. 
Avastin has an approximate molecular weight of 149 kD. Bevacizumab is produced in a 
mammalian cell (Chinese Hamster Ovary) expression system in a nutrient medium containing the 
antibiotic gentamicin. Gentamicin is not detectable in the final product. 
Mode of Action: Bevacizumab binds VEGF and prevents the interaction ofVEGF to its receptors 
(Flt-I and KDR) on the surface of endothelial cells. The interaction of VEGF with its receptors 
leads to endothelial cell proliferation and new blood vessel formation in in vitro models of 
angiogenesis. Administration of bevacizumab to xenotransplant models of colon cancer in nude 
( athymic) mice caused reduction of micro vascular growth and inhibition of metastatic disease 
progression. 
Metabolism: The pharmacokinetic profile of bevacizumab was assessed using an assay that 
measures total serum bevacizumab concentrations (i.e., the assay did not distinguish between free 
bevacizumab and bevacizumab bound to VEGF ligand). Based on a population pharmacokinetic 
analysis of 491 patients who received 1 to 20 mg/kg of Avastin weekly, every 2 weeks, or every 3 
weeks, the estimated half-life ofbevacizumab was approximately 20 days (range 11-50 days). The 
predicted time to reach steady state was 100 days. The accumulation ratio following a dose of 10 
mg/kg ofbevacizumab every 2 weeks was 2.8. 
The clearance of bevacizumab varied by body weight, gender, and tumor burden. After correcting 
for body weight, males had a higher bevacizumab clearance (0.262 L/day vs. 0.207 L/day) and a 
larger Ve (3.25 L vs. 2.66 L) than females. Patients with higher tumor burden (at or above median 
value of tumor surface area) had a higher bevacizumab clearance (0.249 L/day vs. 0.199 L/day) 
than patients with tumor burdens below the median. In Study 1, there was no evidence of lesser 
efficacy (hazard ratio for overall survival) in males or patients with higher tumor burden treated 
with A vastin as compared to females and patients with low tumor burden. The relationship between 
bevacizumab exposure and clinical outcomes has not been explored. 
Product description: 
-100 mg per 4 mL single-use vial 
-400 mg per 16 mL single-use vial 
23 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
Version 3 
Solution preparation: Use appropriate aseptic technique. Parenteral drug products should be 
inspected visually for particulate matter and discoloration prior to administration, whenever 
solution and container permit. Withdraw necessary amount of Avastin and dilute in a total volume 
of 100 mL of 0.9% Sodium Chloride Injection, USP. Discard any unused portion left in a vial, as 
the product contains no preservatives. 
DO NOT ADMINISTER OR MIX WITH DEXTROSE SOLUTION. 
Storage requirements: Avastin vials [100 mg (NDC 50242-060-01) and 400 mg (NDC 50242-
061-01 )] are stable at 2-8°C (36-46°F). Avastin vials should be protected from light. Do not freeze 
or shake. 
Stability: Diluted Avastin solutions may be stored at 2-8°C (36-46°F) for up to 8 hours. Store in 
the original carton until time of use. No incompatibilities between Avastin and polyvinylchloride 
or polyolefin bags have been observed. 
Route of administration: 
In this study we will be performing intra-arterial infusion over a 14-minute period. 
Drug Procurement: Bevacizumab must be obtained from commercial sources. 
Drug Accountability: The investigator or designated study personnel are responsible for 
maintaining accurate dispensing records of the study drug. All study drugs must be accounted for, 
including study drug accidentally or deliberately destroyed. Under no circumstances will the 
investigator allow the investigational drug to be used other than as directed by the protocol. If 
appropriate, drug storage, drug dispensing, and drug accountability may be delegated to the 
pharmacy section of the investigative site. 
10. CORRELATIVE I SPECIAL STUDIES 
10.1 Imaging correlate 
Previous studies have shown that the use of bevacizumab alters the ability of gadolinium to 
produce enhancement in RN. Bevacizumab also decreases T2 FLAIR signal. In this Pilot 
Study, precontrast axial and sagittal Tl with the axial with fat-sat, T2, FLAIR, DWI/ADC, 
susceptibility, post-contrast 3-plane FS Tl images, as well as brain perfusion will be used to 
evaluate for radiation necrosis and cerebral edema. All scans will be done on a 1.5-Tesla or 
higher MR. The scans will be performed before the 1st treatment, at 3 months, and 12 months, 
or as indicated for new clinical symptoms. All MRI's will be sent on CD to Core Lab at 
Norton Healthcare run by Dr. Kadner (board-certified neuro-radiologist). 
If a patient cannot have an MRI for medical reasons, then CT head with and without contrast 
will be used instead. 
10.2 Neuro-cognitive correlate 
In order to investigate the immediate and post-operative neurocognitive sequelae of 
bevacizumab, patients who consent to a formal neuropsychological battery will be tested at 
baseline (prior to IA bevacizumab administration), 3 and .12 months postoperative follow-up. 
The test battery was selected by a board certified neuropsychologist in order to thoroughly 
assess multiple cognitive domains and to be brief enough for patients to complete within one 
hour at each testing session. The neuropsychologist will conduct appropriate training sessions 
24 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
Version 3 
with an identified research assistant or nurse at each study site until inter-rater reliability is 
established (total ICC>.85) to assure both standardized administration and reduction of 
method error. Subtests from the NAB (Neuropsychological Assessment Battery, Stem & 
White, PAR Inc.) have been chosen for brevity, sensitivity, and due to the wide range of 
available normative data (ages 18-97). Subtests of the NAB can be administered alone or as 
part of the entire battery without loss of appropriate normative data, as each test across forms 
was administered to the same individuals in the standardization sample. Administration of 
the entire battery can take up to 4 hours, thus a subset of requisite performance measures was 
selected for inclusion in this study. In addition, the Wechsler Test of Adult Reading (WTAR, 
Pearson Inc.) will be administered to provide an estimate ofpremorbid cognitive functioning. 
Subtests chosen from the NAB include: Digits Forwards (DF); Digits Backwards (DB); Letter 
and Numbers (L&N). Together, these will assess attention capacity, working memory, and 
processing speed. Naming (NAM). This will assess confrontation naming and anomia. 
Design Construction (DES). This will assess spatial awareness and constructional praxis. List 
Learning (LL); Story Learning (SL); and Shape Learning (ShL). These will assess auditory 
and visual episodic learning and memory retrieval and retention skills. Mazes (MZ); 
Categories (CAT); and Word Generation (WG). These will assess higher order executive 
functioning with regard to planning, conceptualization, and fluency. We expect the most 
significant effects to arise from assessment of processing speed, memory, and executive 
functioning. Each of these subtests will be administered at baseline, time I, and time 2. The 
NAB was standardized with 2 alternate, equivalent forms, which will be counterbalanced 
across administration times while repeating one form per subject. 
Given the length of time 2 to time 3, practice effects across the three forms can be minimized. 
The tests will be administered as follows: 
Cognitive Domain 
Time 1 
Time2 
Time3 
(Baseline) 
week following 
(3 months following 
treatment) 
treatment) 
Premorbid Intelligence 
WTAR 
Attention I Processing 
DF,DB,L&N 
DF,DB,L&N 
DF,DB,L&N 
Speed 
Language 
NAM 
NAM 
NAM 
Visuospatial 
DES 
DES 
DES 
Learning and Memory 
LL,SL,ShL 
LL, SL,ShL 
LL, SL, ShL 
Executive Functioning 
MZ,CAT, WG 
MZ,CAT, 
MZ,CAT, WG 
WG 
10.3 Headache Correlate 
Patients with radiation necrosis often experience severe or intractable headaches. These 
headaches usually worsen during efforts to wean the patient off corticosteroids, leading to 
long-term steroid use and all its associated serious morbidities. Our preliminary experience 
indicates rapid and complete resolution of headaches following IA-bevacizumab treatment. 
All patients will be tested using a formal headache battery at baseline. The Headache Impact 
Test (HIT-6) which is a fixed-length 6-item, paper form version of the DYNHA Headache 
Impact Test will be filled out by the patient. MIDAS 5-item questionnaire will also be 
completed by the patient before treatment, as well as at 6 weeks, 3 mo, 6 mo, 9 mo, and 12 
mo. 
25 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
11. STUDY PARAMETERS AND CALENDAR 
Version3 
The tests and procedures found in the Study Flow Chart will be performed. 
Baseline 
evaluations are to be conducted within 2 weeks prior to start of protocol therapy. Scans and 
x-rays must be done 4 weeks prior to the start of therapy. 
Pre-
Day 
Day 
Week 
Month 
Month 
Month 
Study 
0 
1 
6 
3 
6 
12 
Informed Consent 
R 
Demographics 
NR 
Medical History 
NR 
NR 
NR 
NR 
NR 
Concurrent Medication 
NR 
NR 
NR 
NR 
NR 
Physical Exam 
NR 
R 
R 
R 
R 
Neurological Exam 
NR 
R 
R 
R 
R 
Carotid Angiogram 
R 
Osmotic blood-brain-barrier 
R 
breakdown 
Avastin® 
R 
HIT - 6 Survey 
R 
R 
R 
R 
R 
(may be via ohone) 
MIDAS 
R 
R 
R 
R 
R 
(may be via ohone) 
NeuroPsych Testing 
R 
R 
R 
KPS Functional Status 
R 
R 
R 
R 
Screening Lab tests1 
R 
ECG (if needed)2 
R 
Adverse Event monitoring 
R 
R 
R 
R 
Urine Pregnancy Test 
R 
Brain MRI w & w/o contrast 
NR 
NR 
NR 
R=Research 
NR= non-research or standard of care 
1 =CBC with differential and platelets count, basic metabolic panel serum chemistry 
2= ECG will be done in patients >45 years old or in any patients with history of cardiac problems 
Physical Examination: All enrolled participates will have an abbreviated physical examination 
and vital signs (heart rate, blood pressure and body weight) collected during screening and then 
again at Day 0, and 1, Month 3 and 12. 
Neurological Examination: 
All enrolled participants will have a detailed neurological 
examination during screening and then again at Day 0, and 1, Month 3 and 12. 
26 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
Version3 
Pregnancy Testing: It is not known whether study drug used in this study may cause side effects 
to pregnaut women, to au unborn child, or to children of nursing women. Because of these 
unknown risks, all women of childbearing potential will be given a pregnaucy test prior to receiving 
study drug. Testing will be performed either by urine or blood. 
Female participants will be 
informed that they must not become pregnant until 8 weeks following the last dose of study 
medication 
Karnofsky Performance Status Scale: Will be used .to measure the functional status of the 
participant prior to and following study drug administration 
Brain MRI: All subject will undergo a Brain MRI prior to receive study medication (Pre-study) 
and then again at Months 3, and 12. 
CT Scan: Subject who cannot undergo a MRI for medical reasons will have undergo a head CT 
prior to receiving study medication (Pre-Study) and then again at Months 3 and 12. 
12. MEASUREMENT OF EFFECT 
12.1 Decrease in Cerebral Edema 
We will use pre-contrast axial aud sagittal Tl with the axial with fat-sat, T2, FLAIR, 
DWI/ADC, susceptibility, post-contrast 3-plaue FS Tl images, as well as brain 
perfusion to evaluate for progression. All scaus will be done on a 1.5-3.0 Tesla MR. 
The scaus will be performed within 4 weeks before the 1st treatment, at 3 months, aud 
12 months, or as indicated for new clinical symptoms. 
A reduction in volume of 
cerebral edema of > 25% will constitute a positive response. 
12.2 Definitions 
Please use or modify the following text as appropriate. 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their 
first treatment with Bevacizumab. 
Evaluable for objective response. Only those patients who have measurable disease 
present at baseline, have received one cycle of therapy, aud have had their disease re-
evaluated will be considered evaluable for response. These patients will have their 
response classified according to the definitions stated below. (Note: Patients who 
exhibit objective disease progression treatment will also be considered evaluable.) 
12.3 Duration of Response 
Duration of overall response: The duration of overall response is measured from the 
time measurement criteria are met for CR or PR (whichever is first recorded) until the 
first date that recurrent or progressive disease is objectively documented (taking as 
reference for progressive disease the smallest measurements recorded since the 
treatment started). 
The duration of overall CR is measured from the time measurement criteria are first 
met for CR until the first date that recurrent disease is objectively documented. 
27 

Norton HealthcareIDept of Neurosurgery 
LIBERTI 
Version 3 
Duration of stable disease: Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started. 
13. STATISTICAL CONSIDERATIONS 
13.1 
Study Design/Endpoints 
Two-stage design, Single-arm Phase II multi-center clinical trial. The participating 
centers are Norton Healthcare and University of Kentucky Healthcare. This study will 
determine efficacy ofIA-bevacizumab after BBBD treatment for radiation necrosis. 
13.2 
Sample Size/Accrual Rate 
Stage 1: There will be a maximum of 10 patients accrued for stage 1 of this trial. In 
2013, there were a total of 5 patients seen and evaluated for medically refractory 
radiation necrosis at our center. Therefore, the accrual rate would be anticipated as 5 
patients per year. The accrual rates are expected to be 3-5 per year in other 
participating site. 
Stage 2: If ?:30% of patients have a positive response, then the number of patients 
in the trial will escalate to 46 patients. At that point, further participating sites will be 
considered. 
13.3 
Stratification Factors: None. 
13.4 
Analysis of Secondary Endpoints: Secondary endpoint findings will be compared 
to historical controls from published studies of IV-bevacizumab treatment for 
radiation necrosis. 
13.5 
Outcome Measures 
Primary Outcome Measure: Decrease in radiation necrosis and cerebral edema 
after a single treatment oflow dose intrarterial bevacizumab: Precontrast axial and 
sagittal Tl with the axial with fat-sat, T2, FLAIR, DWI/ADC, susceptibility, post-
contrast 3-plane FS Tl images, as well as brain perfusion will be used to evaluate for 
radiation necrosis and cerebral edema. All scans will be done on a 1.5-Tesla or higher 
MR. The scans will be performed before the 1st treatment, at 3 months, and 12 
months, or as indicated for new clinical symptoms. All MRI's will be sent on CD to 
Core Lab at Norton Healthcare run by Dr. Kadner (board-certified neuro-radiologist). 
If a patient carmot have an MRI for medical reasons, then CT head with and without 
contrast will be used instead. 
Secondary Outcome Measures: 
1. Decrease in steroid usage after a single treatment of low dose intrarterial 
bevacizumab: To assess the utility of intra-arterial bevacizumab treatment in 
allowing decreased steroid usage, the quantity of steroid use (measured as mg of 
Decaderon per day) will be noted at 1 day, 3 months, and 12 months. 
2. Quantitative improvement in headache after a single treatment of low dose 
intrarterial bevacizumab: Quantitative improvement in headache will be assessed by 
performing The Headache Impact Test (HIT-6) which is a fixed-length 6-item, paper 
28 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
Version 3 
form version of the DYNHA Headache Impact Test will be filled out by the patient. 
MIDAS 5-item questionnaire will also be completed by the patient before treatment, 
as well as at 6 weeks, 3 mo, 6 mo, 9 mo, and 12 mo. 
3. Neurocognitive improvement after a single treatment oflow dose intrarterial 
bevacizumab: In order to investigate the immediate and post-operative 
neurocognitive sequelae of intra-arterial bevacizumab, patients who consent to a 
formal neuropsychological battery will be tested at baseline (prior to IA bevacizumab 
administration), 3 and 12 months postoperative follow-up. Subtests from the NAB 
(Neuropsychological Assessment Battery, Stern & White, PAR Inc.) have been 
chosen for brevity, sensitivity, and due to the wide range of available normative data 
(ages 18-97). In addition, the Wechsler Test of Adult Reading (WTAR, Pearson Inc.) 
will be administered to provide an estimate of premorbid cognitive functioning. 
4. Safety of a single treatment oflow dose intrarterial bevacizumab: Safety of intra-
arterial bevacizumab will be assessed by noting the number of participants with 
treatment-related adverse events as assessed by CTCAE v4.0. 
5. Neurological improvement after a single treatment of low dose intrarterial 
bevacizumab: Objective improvement in neurological exam will be assessed by 
performing serial neurological exams at baseline, 1 day, 3 months, and 12 months. 
Also, quantitative improvement in functional status will be assessed by performing 
Karnofsky Performance Status Scale (KPS) at baseline, 1 day, 3 months, and 12 
months. 
Other Pre-specified Outcome Measures: Cost analysis of a single treatment of 
low dose intrarterial bevacizumab compared to conventional IV-bevacizumab 
regiment: Cost analysis of a single treatment of low dose intrarterial bevacizumab 
after osmotic blood-brain-barrier disruption as compared to conventional intravenous 
bevaizumab use for radiation necrosis (7.5 mg/kg IV-Bevacizumab every 3 weeks for 
4 cycles). 
29 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
14. References 
Version3 
1. Levin VA, Bidaut L, Hou P, et al. Randomized double-blind placebo-controlled trial of 
bevacizumab therapy for radiation necrosis of the central nervous system. International Journal of 
radiation Oncology, Biology, Physics 2011;79:1487-95. 
2. Nonoguchi N, Miyatake S, Fukumoto M, et al. The distribution of vascular endothelial 
growth factor-producing cells in clinical radiation necrosis of the brain: pathological 
consideration of their potential roles. Journal of neuro-oncology 2011; 105 :423-31. 
3. Dashti SR, Spalding A, Kadner RJ, et al. Targeted intraarterial anti-VEGF therapy for 
medically refractory radiation necrosis in the brain. J Neurosurg Pediatr 2015; 15 :20-5. 
4. Monaco EA, 3rd, Niranjan A, Kano H, Flickinger JC, Kondziolka D, Lunsford LD. 
Management of adverse radiation effects after radiosurgery for arteriovenous malformations. 
Progress in neurological surgery 2013;27:107-18. 
5. Williamson R, Kondziolka D, Kanaan H, Lunsford LD, Flickinger JC. Adverse radiation 
effects after radiosurgery may benefit from oral vitamin E and pentoxifylline therapy: a pilot 
study. Stereotactic and functional neurosurgery 2008;86:359-66. 
6. Levin VA, Bidaut L, Hou P, et al. Randomized double-blind placebo-controlled trial of 
bevacizumab therapy for radiation necrosis of the central nervous system. Int J Radiat Oncol Biol 
Phys 2011;79:1487-95. 
7. Li J, Gupta M, Jin D, Xin Y, Visich J, Allison DE. Characterization of the long-term 
pharmacokinetics of bevacizumab following last dose in patients with resected stage II and III 
carcinoma of the colon. Cancer chemotherapy and pharmacology 2013;71 :575-80. 
8. Takano M, Kikuchi Y, Kato M, Yoshikawa T, Kita T. Bowel perforation associated with 
bevacizumab therapy in recurrent ovarian cancers without bowel obstruction or bowel 
involvement]. Gan To Kagaku Ryoho 2008;35:1981-4. 
9. Heinzerling JH, Huerta S. Bowel perforation from bevacizumab for the treatment of 
metastatic colon cancer: incidence, etiology, and management. Curr Surg 2006;63:334-7. 
10. 
Abbrederis K, Kremer M, Schuhmacher C. [Ischemic anastomotic bowel perforation during 
treatment with bevacizumab 10 months after surgery]. Chirurg 2008;79:351-5. 
11. 
Suenaga M, Mizunuma N, Kobayashi K, et al. Management of venous thromboembolism in 
colorectal cancer patients treated with bevacizumab. Med Oncol;27:807-14. 
12. 
Grivas AA, Trafalis DT, Athanassiou AE. Implication ofbevacizumab in fatal arterial 
tlrromboembolic incidents. J BUON 2009;14:115-7. 
13. 
Vredenburgh JJ, Desjardins A, Kirkpatrick JP, et al. Addition ofBevacizumab to Standard 
Radiation Therapy and Daily Temozolomide Is Associated with Minimal Toxicity in Newly 
Diagnosed Glioblastoma Multiforme. Int J Radiat Oncol Biol Phys. 
14. 
Chamberlain MC, Johnston S. Salvage chemotherapy with bevacizumab for recurrent 
alkylator-refractory anaplastic astrocytoma. J Neurooncol 2009;91 :359-67. 
15. 
Gobin YP, Cloughesy TF, Chow KL, et al. Intraarterial chemotherapy for brain tumors by 
using a spatial dose fractionation algorithm and pulsatile delivery. Radiology 2001;218:724-32. 
16. Namba H, Kobayashi S, Iwadate Y, et al. Assessment of the brain areas perfused by 
superselective intra-arterial chemotherapy using single photon emission computed tomography 
with technetium-99m-hexamethyl-propyleneamine oxime--technical note. Neurol Med Chir 
(Tokyo) 1994;34:832-5. 
17. 
Neuwelt EA, Frenkel EP, D'Agostino AN, et al. Growth of human lung tumor in the brain 
of the nude rat as a model to evaluate antitumor agent delivery across the blood-brain barrier. 
Cancer Res 1985;45:2827-33. 
18. 
Armstrong BK, Robinson PJ, Rapoport SL Size-dependent blood-brain barrier opening 
demonstrated with [14C]sucrose and a 200,000-Da [3H]dextran. Exp Neurol 1987;97:686-96. 
19. 
Ziylan YZ, Robinson PJ, Rapoport SL Differential blood-brain barrier permeabilities to 
[14C]sucrose and [3H]inulin after osmotic opening in the rat. Exp Neurol 1983;79:845-57. 
20. 
Bullard DE, Bigner DD. Applications of monoclonal antibodies in the diagnosis and 
30 

Norton Healthcare/Dept of Neurosurgery 
LIBERTI 
treatment of primary brain tumors. J Neurosurg 1985;63:2-16. 
Version 3 
21. 
Zalutsky MR, Moseley RP, Benjamin JC, et al. Monoclonal antibody and F(ab')2 fragment 
delivery to tumor in patients with glioma: comparison of intracarotid and intravenous 
administration. Cancer Res 1990;50:4105-10. 
22. 
Epenetos AA, Courtenay-Luck N, Pickering D, et al. Antibody guided irradiation of brain 
glioma by arterial infusion of radioactive monoclonal antibody against epidermal growth factor 
receptor and blood group A antigen. Br Med J (Clin Res Ed) 1985;290:1463-6. 
23. 
Zalutsky MR, Moseley RP, Coakham HB, Coleman RE, Bigner DD. Pharmacokinetics and 
tumor localization of 1311-labeled anti-tenascin monoclonal antibody 81 C6 in patients with 
gliomas and other intracranial malignancies. Cancer Res 1989;49:2807-13. 
24. Neuwelt EA, Barnett PA, Hellstrom KE, Hellstrom I, McCormick CI, Ramsey FL. Effect of . 
blood-brain barrier disruption on intact and fragmented monoclonal antibody localization in 
intracerebral lung carcinoma xenografts. J Nucl Med 1994;35: 1831-41. 
25. 
Lee YS, Bullard DE, Zalutsky MR, et al. Therapeutic efficacy of antiglioma mesenchymal 
extracellular matrix 1311-radiolabeled murine monoclonal antibody in a human glioma xenograft 
model. Cancer Res 1988;48:559-66. 
26. 
Dahlborg SA, Henner WD, Crossen JR, et al. Non-AIDS primary CNS lymphoma: first 
example of a durable response in a primary brain tumor using enhanced chemotherapy delivery 
without cognitive loss and without radiotherapy. The cancer journal from Scientific American 
1996;2:166-74. 
27. 
Doolittle ND, Miner ME, Hall WA, et al. Safety and efficacy of a multicenter study using 
intraarterial chemotherapy in conjunction with osmotic opening of the blood-brain barrier for the 
treatment of patients with malignant brain tumors. Cancer 2000;88:637-47. 
28. 
Neuwelt EA. Mechanisms of disease: the blood-brain barrier. Neurosurgery 2004;54: 131-
40; discussion 41-2. 
29. 
Boockvar JA, Tsiouris AJ, Hofstetter CP, et al. Safety and maximum tolerated dose of 
superselective intraarterial cerebral infusion of bevacizumab after osmotic blood-brain barrier 
disruption for recurrent malignant glioma. J Neurosurg. 
30. 
Rajappa P, Krass J, Riina HA, Boockvar JA, Greenfield JP. Super-selective basilar artery 
infusion ofbevacizumab and cetuximab for multiply recurrent pediatric ependymoma. 
Interventional neuroradiology : journal of peritherapeutic neuroradiology, surgical procedures 
and related neurosciences 2011;17:459-65. 
31. 
Riina HA, Burkhardt JK, Santillan A, Bassani L, Patsalides A, Boockvar JA. Short-term 
clinico-radiographic response to super-selective intra-arterial cerebral infusion of Bevacizµmab 
for the treatment of vestibular schwannomas in N eurofibromatosis type 2. Interventional 
neuroradiology : journal of peritherapeutic neuroradiology, surgical procedures and related 
neurosciences 2012;18:127-32. 
32. 
Riina HA, Knopman J, Greenfield JP, et al. Balloon-assisted superselective intra-arterial 
cerebral infusion of bevacizumab for malignant brainstem glioma. A technical note. 
Interventional neuroradiology : journal of peritherapeutic neuroradiology, surgical procedures 
and related neurosciences 201O;16:71-6. 
31