Open-label, Phase 2 Study of Bevacizumab in Children and Young Adults With Neurofibromatosis 2 and Progressive Vestibular Schwannomas That Are Poor Candidates for Standard Treatment With Surgery or Radiation
Phase: PHASE2
Conditions: Neurofibromatosis Type 2, Progressive Vestibular Schwannomas
Sponsor: University of Alabama at Birmingham

 NCT01767792 
Phase 2 Study of Bevacizumab in Children and Young Adults With NF 2 and Progressive Vestibular 
Date Uploaded:  April 14, 2020  
Document  Date:  January 18, 2017 

Bevacizumab for children and adults with NF2 
Protocol Version Date:  May 13, 2016 Version 1.4 
Protocol Version Date: 
May 13, 2016 
Sponsor Information:   
USMRMC, Office of the Congressionally Directed Medical 
Research Programs (CDMRP), Department of Defense (DOD) 
and Genentech 
IND NUMBER:  
112096 
Title:  
Open-label, phase 2 study of bevacizumab in children and 
adults with neurofibromatosis 2 and progressive vestibular 
schwannomas that are poor candidates for standard 
treatment with surgery or radiation   
Principal Investigator: 
Scott R. Plotkin, MD, PhD 
Yawkey 9E, Massachusetts General Hospital 
55 Fruit Street 
Boston, MA  02114 
Phone: 617-726-3650 
E-mail address: splotkin@partners.org
Operations Center: 
Bruce R. Korf, MD, PhD, Operations Center PI 
University of Alabama, Birmingham 
1720 2nd Avenue South– Kaul 230  
Birmingham, AL  35294-0024 
Phone:  205-934-9411 
Fax: 205-934-9488 
E-mail address: bkorf@uabmc.edu
PDII:  Karen Cole-Plourde: kplourde@uab.edu
Co-Investigators: 
James Tonsgard, MD 
University of Chicago 
5841 South Maryland Avenue, MC 3055 
Chicago, IL  60637 
Phone:  773-702-6488 
tonsgard@midway.uchicago.edu 
Nicole Ullrich, MD, PhD 
Children’s Hospital Boston 
Department of Neurology 
300 Longwood Avenue 
Boston, MA 02115 
Phone:   617-355-3193 
nicole.ullrich@childrens.harvard.edu 

Bevacizumab for children and adults with NF2 
 
 
Protocol Version Date: May 13, 2016  Version 1.4   
 
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Elizabeth Schorry, MD  
Cincinnati Children’s Hospital Medical Center  
3333 Burnet Avenue – ML 4006 
Cincinnati, OH  45229-3039 
Phone:  513-636-4760 
Elizabeth.Schorry@cchmc.org 
 
Statistician:  
Gary Cutter, PhD 
 
Director, Dept. of Biostatistics 
School of Public Health 
Univ. of Alabama at Birmingham 
1665 University Boulevard, RPHB 410B 
Phone:  205-934-4937 
Fax: 205-975-2540 
Cutterg@uab.edu 
 
Joan E Hilner, MPH, MA 
Dept. of Biostatistics  
School of Public Health  
Univ. of Alabama at Birmingham 
1665 Univ. Blvd., RPHB 514D 
Phone:   205-934-4943 
Fax:  205-975-2500 
jhilner@uab.edu 
 
 
Operations Center  
Research Nurse Manager:  Liz Davis, RN, MPH, CCRC 
 
 
Dept. of Genetics 
 
 
Univ. of Alabama at Birmingham 
 
 
1720 2nd Avenue South, MCML 252 
 
Birmingham, AL  35294-0024 
 
Phone: 205-934-5376 
 
Fax:  205-934-3543 
 
lvdavis@uab.edu 
 
Operations Center  
Karen A. Cole-Plourde, BS 
Program Director: 
Dept. of Genetics 
 
Univ. of Alabama at Birmingham 
 
1720 2nd Avenue South, MCML 256 
 
Birmingham, AL  35294-0024 
 
Phone: 205-934-5140  
 
Fax: 205-934-3543 
 
kplourde@uab.edu 
 
 

Bevacizumab for children and adults with NF2 
 
 
Protocol Version Date: May 13, 2016  Version 1.4   
 
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Research Compliance   
Roy McDonald, MPH  
Manager:  
 
 
 
 
 
Dept. of Genetics  
 
 
 
 
 
 
 
 
 
 
Univ. of Alabama at Birmingham 
 
 
 
 
 
 
 
 
 
 
1720 2nd Avenue South, MCML 262A  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Birmingham, AL  35294-0024 
 
 
 
 
 
 
 
 
 
 
Phone: 205-975-4075 
     
 
 
 
 
 
 
 
 
Fax:  205-934-3543 
 
 
 
 
 
 
 
 
 
 
rmcdonald@uab.edu  
 
Central Pharmacy: 
Rebecca Quinn, PharmD 
Investigational Drug Service (IDS) Pharmacy 
UAB Hospital 
North Pavilion, room 3470 
1802 6th Avenue South 
Birmingham, AL  35249 
Phone: 205-934-719 
Fax: 205-975-6647 
UAB paging: 205-934-3411, pager 4295 
rquinn@uabc.edu  
 
Medical Monitor:  
 
 
Christopher Moertel, MD 
 
Medical Director, Neuro-oncology and   
 
 
Comprehensive Neurofibromatosis Clinics 
 
Professor of Pediatrics 
 
MMC 484 
 
420 Delaware Street SE 
 
Minneapolis, MN 55455 
 
moert001@umn.edu 
 
Agent(s):  Bevacizumab (NSC# 704865) – Supplier: Genentech 
 
Consortium Participating Sites 
 
Bruce Korf, MD, PhD 
University of Alabama at Birmingham 
1720 2nd Ave South -  KAUL 230 
Birmingham, Alabama  35294-0024 
Phone:  205-934-9411/Fax: 205-934-9488 
bkorf@uabmc.edu 
 
Elizabeth Schorry, MD  
Cincinnati Children’s Hospital Medical Center 
3333 Burnet Avenue - ML 4006 
Cincinnati, OH  45229 
Phone:  513-636-4760 
elizabeth.schorry@cchmc.org 
 
Michael Fisher, MD 
Children’s Hospital of Philadelphia 
34th Street & Civic Center Boulevard 
Philadelphia, PA 19096 
Phone:  215-590-2800/Lab: 215-590-2107 
fisherm@email.chop.edu 
James Tonsgard, MD 
University of Chicago 
5841 South Maryland Avenue, MC 3055 
Chicago, IL  60637 
Phone:  773-702-6488 
tonsgard@midway.uchicago.edu 

Bevacizumab for children and adults with NF2 
 
 
Protocol Version Date: May 13, 2016  Version 1.4   
 
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Roger Packer, MD 
Children’s National Medical Center 
111 Michigan Avenue, NW 
Washington, DC  20010 
Phone:  202-884-2120 
rpacker@cnmc.org 
David Viskochil, MD, PhD 
University of Utah 
50 North Medical Drive – 2C412 SOM 
Salt Lake City, UT  84132 
Phone:  801-581-8943 
dave.viskochil@hsc.utah.edu 
Wade Clapp, MD 
Indiana University  
1044 West Walnut Street  
Cancer Center, Room 402A  
Indianapolis, IN  46202 
Phone: 317-278-9290 
dclapp@iupui.edu 
 
David Gutmann, MD, PhD 
Washington University School of Medicine 
660 South Euclid Avenue – Box 811 
St. Louis, MO  63110 
Phone: 314-362-7379  
gutmannd@neuro.wustl.edu 
 
 
Tena Rosser, MD 
Children’s Hospital Los Angeles 
300 Medical Plaza Box 696824 
Los Angeles, CA  90095 
Phone: 323-361-2471 
trosser@chla.usc.edu 
 
Jeffrey Allen, MD 
New York Univ. Pediatrics 
160 E. 32nd Street – 2nd Floor 
Hassenfeld Children’s Center 
New York, NY 10016 
Phone: 212-263-9907 
Jeffrey.Allen@nyumc.org  
 
 

Bevacizumab for children and adults with NF2 
 
 
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Affiliate sites  
 
Massachusetts General Hospital (Ullrich; Plotkin) 
Dana Farber (Ullrich; Kieran) 
UCLA (Rosser; Silva) 
Johns Hopkins (Packer; Blakeley) 
Ohio State University  (Schorry) 
Northwestern University Hospital (Tonsgard; Listernick and Goldman) 
 
 
Data and Safety Monitoring Board (DSMB) Members  
 
Christopher Moertel, MD, Chair 
University of Minnesota 
Department of Pediatrics 
MMC 484 
420 Delaware Street S.E. 
Minneapolis, MN  55455 
Phone: (612) 625-3229 
Fax: (612) 626-2815 
Email: moert001@umn.edu 
 
Edwin Choy, MD, Member 
MGH, Dana Farber/Harvard Cancer Center 
Division of Hematology Oncology 
55 Fruit Street 
Boston MA 02114 
Phone: (617) 643-0230 
Fax: (617) 724-3166 
Email: echoy@partners.org 
 
Dr. Domenic Reda, PhD, Member (Statistician) 
Director, Cooperative Studies Program Coordinating Center  
Hines VA Hospital, CSPCC (151K) 
5000 South 5th Avenue, Building 1, Room B240,  
Hines, IL  60141-3030 
Phone: 708-202-5853 
Fax: 708-202-2116 
Email : domenic.reda@va.gov 
 
 
 

Bevacizumab for children and adults with NF2 
 
 
Protocol Version Date: May 13, 2016  Version 1.4   
 
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ABBREVIATIONS: 
 
AAO-HNS: American Academy of Otolaryngology, Head and Neck Surgery 
ASCO: American Society of Clinical Oncology 
ABI: auditory brainstem implant 
AST/ALT: alanine transaminase/alanine transaminase 
ATE: arterial thromboembolic events 
BAER: brainstem auditory evoked responses 
BMD: bone mineral density 
CHF: congestive heart failure 
CNS: central nervous system 
COV: coefficient of variation 
CRC: colorectal cancer 
CRF: case report form 
CTC: Common Terminology Criteria for Adverse Events  
CTCAE: Common Terminology Criteria for Adverse Events  
DBP: diastolic blood pressure 
DF/HCC: Dana Farber/Harvard Cancer Center 
DPOAE: distortion product otoacoustic emissions 
DMAC: Data Management and Analysis Center 
DSMB: Data and safety monitoring board 
EGFR: epidermal growth factor receptor 
FU/LV: fluorouracil/leucovorin 
HIV: human immunodeficiency virus 
HTN: hypertension 
LMWH: low molecular weight heparins 
IAC: internal auditory canal 
 
I.B.: investigator brochure 
IgG: immunoglobulin G 
IMP: investigational medicinal product 
IV: intravenous 
LVEF: left ventricular ejection fraction 
MAb: monoclonal antibody 
MLV: monitored live voice 
MTD: maximum tolerated dose 
NF2: neurofibromatosis 2 
NSCLC: non-small cell lung cancer 
OAE: otoacoustic emissions 
PDGFR: platelet derived growth factor receptor 
PI: Principal Investigator 
P.I.: package insert 
PK: pharmacokinetics 
PTA: pure-tone average 
RECIST: Response Evaluation Criteria in Solid Tumors 
RPLS:  Reversible Posterior Leukoencephalopathy Syndrome 
SAE: serious adverse event 

Bevacizumab for children and adults with NF2 
 
 
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SRT: speech reception threshold 
TE: thromboembolic 
TIA: transient ischemic attack 
ULN: upper limit of normal 
UPC: urine protein: creatinine 
VEGF: vascular endothelial growth factor 
VEGFR: vascular endothelial growth factor receptor 
VS(s): vestibular schwannoma(s) 
VTE: venous thromboembolism 
 

Bevacizumab for children and adults with NF2 
 
 
Protocol Version Date: May 13, 2016  Version 1.4   
 
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PRECIS 
 
Background 
 
• Bilateral vestibular schwannomas are the hallmark of neurofibromatosis 2 (NF2).  As these 
tumors enlarge, they cause sensorineural hearing loss and, ultimately, complete hearing loss.   
• Sporadic and NF2-related vestibular schwannomas express vascular endothelial growth 
factor (VEGF).   
• Bevacizumab is a humanized IgG1 monoclonal antibody (MAb) that binds all 
biologically active isoforms of human VEGF with high affinity. 
• The initial experience treating ten NF2 patients at risk for complete hearing loss with 
bevacizumab outside of a clinical trial showed promising results with 6/10 patients 
experiencing ≥ 20% reduction in tumor volume and 4/7 evaluable patients having 
significantly improved word recognition scores. 
 
Primary Objective 
 
• To determine the hearing response rate at 24 weeks after treatment with bevacizumab for 
symptomatic vestibular schwannomas (VS) in children and young adults with NF2. 
 
Eligibility 
 
• Patients  ≥ 6 years old with NF2 
• Subjects must have a target VS with the following qualities: 
o Not amenable to surgery due to patient preference or high risk for surgical 
complications  
o Associated with a word recognition score of < 85% and > 5% 
o Documented clinical progression defined as EITHER: 
• Progressive hearing loss (defined as a decline in word recognition score below 
the 95% critical difference interval from baseline score, Appendix A) related 
to VS.  
OR 
• Progressive tumor growth in the preceding 18 months, defined as ≥ 20% 
increase in volume. 
 
Design 
• Bevacizumab will be administered by IV infusion at a dose of 10 mg/kg every 2 weeks for 
24 weeks (induction therapy). 
• Clinical response will be assessed by audiology and MRI at weeks 12 and 24.  Subjects 
with hearing decline during induction therapy (defined as a decline in word recognition 
score below the 95% critical difference interval from baseline score, Appendix A) will be 
taken off of protocol (section 5.5).   
• At week 25, patients with a clinical response or stable disease (together comprising 
“clinical benefit”) will transition to maintenance therapy with bevacizumab.   
• During the maintenance phase, subjects will be treated with open-label bevacizumab 5 
mg/kg every 3 weeks for up to 72 weeks. 

Bevacizumab for children and adults with NF2 
 
 
Protocol Version Date: May 13, 2016  Version 1.4   
 
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• During maintenance therapy, subjects will be allowed to increase their bevacizumab dose 
to 10 mg/kg every 2 weeks if they experience hearing decline compared to their highest 
word recognition score during treatment.  Subjects will be taken off of study if their word 
recognition drops below the 95% critical difference (new hearing baseline defined as the 
word recognition score leading subject to receive 10 mg/kg dose every 2 weeks) after 
receiving bevacizumab 10 mg/kg every 2 weeks for at least 12 weeks (section 5.5).   
 
 
 
 
 
 
 
SCHEMA 
 
 
 
NF2 patients 
with 
progressive 
VS who are 
not good 
candidates 
for surgery 
or radiation
Bevacizumab
10 mg/kg IV q 
2 weeks 
for 6 months
Response 
evaluation
at months 3 
and 6
Hearing 
Improvement
Stable 
hearing
Hearing 
deterioration
Bevacizumab 
5 mg/kg IV q 
3 weeks for 
18 months
Off protocol
Response 
evaluation
every 3 months
Induction
Maintenance
N = 22 subjects
Accrual = 2 per month
Months 1-6
Months 7-24
Determine 
bevacizumab 
dose
Hearing 
Improvement 
or stable 
hearing
Hearing 
deterioration
< 10 mg/kg dose
Off protocol
10 mg/kg dose
Continue 
up to 18 
months
Increase 
bevacizumab 
dose per protocol

Bevacizumab for children and adults with NF2 
 
 
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TABLE OF CONTENTS 
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when you change the protocol document. To update the Table of Contents, put your cursor in the 
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the Table of Contents, always choose to update the Entire Table. 
PRECIS .................................................................................................................................................................... viii 
Background .............................................................................................................................................................. viii 
Primary Objective ................................................................................................................................................... viii 
Eligibility .................................................................................................................................................................. viii 
OR ............................................................................................................................................................................. viii 
Design ....................................................................................................................................................................... viii 
1. 
OBJECTIVES .................................................................................................................................................... 1 
1.1 
Study Design .................................................................................................................................................... 1 
1.2 
Primary Objectives .......................................................................................................................................... 1 
1.3 
Secondary Objectives ...................................................................................................................................... 1 
2. 
BACKGROUND ................................................................................................................................................ 1 
2.1 
Neurofibromatosis 2 ........................................................................................................................................ 1 
2.2 
Study Agent(s) ................................................................................................................................................. 5 
2.3 
Rationale ....................................................................................................................................................... 14 
2.4 
Correlative Studies Background.................................................................................................................... 14 
3. 
PARTICIPANT SELECTION ........................................................................................................................ 15 
3.1 
Eligibility Criteria ......................................................................................................................................... 15 
3.2 
Exclusion Criteria ...................................................................................................................................... 17 
3.3 
Inclusion of Women, Minorities and Other Underrepresented Populations ................................................. 19 
4. 
REGISTRATION PROCEDURES ................................................................................................................ 19 
4.1 
General Guidelines for NF Consortium Institutions ..................................................................................... 19 
4.2 
Registration Process for NF Consortium Institutions ............................................................................ 19 
4.3 
General Guidelines for all Participating Institutions ......................................................................... 20 
4.4 
Registration Process for All Participating Institutions ................................................................................ 20 
5. 
TREATMENT PLAN ...................................................................................................................................... 20 
5.1 
Pre-treatment Criteria ................................................................................................................................. 21 
5.2 
Bevacizumab Administration .................................................................................................................. 23 
5.3 
Definition of Dose-Limiting Toxicity ..................................................................................................... 23 
5.4 
General Concomitant Medication and Supportive Care Guidelines ............................................................. 23 

Bevacizumab for children and adults with NF2 
 
 
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5.5 
Duration of Therapy ....................................................................................................................................... 24 
5.6 
Duration of Follow-Up .................................................................................................................................. 25 
5.7 
Criteria for Removal from Study ................................................................................................................... 25 
6. 
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS .................................... 26 
6.1 
Anticipated Toxicities .................................................................................................................................... 27 
6.2 
Toxicity Management .................................................................................................................................... 29 
6.3 
Dose Modifications/Delays ........................................................................................................................... 29 
7. 
DRUG FORMULATION AND ADMINISTRATION ................................................................................. 33 
7.1 
Bevacizumab.................................................................................................................................................. 33 
8. 
CORRELATIVE/SPECIAL STUDIES .......................................................................................................... 38 
8.1 
Pharmacokinetic Studies ............................................................................................................................... 38 
8.2 
Pharmacodynamic Studies ............................................................................................................................ 38 
8.3 
Laboratory correlative markers .................................................................................................................... 38 
9. 
STUDY CALENDAR ...................................................................................................................................... 41 
10. 
MEASUREMENT OF EFFECT..................................................................................................................... 46 
10.1 
Antitumor Effect– Solid Tumors ............................................................................................................... 46 
10.2 
Antitumor Effect – Hematologic Tumors .................................................................................................. 50 
10.3 
Other Response Parameters: Hearing Response ...................................................................................... 50 
11. 
ADVERSE EVENT REPORTING REQUIREMENTS ............................................................................... 50 
11.1 
Definitions ................................................................................................................................................ 50 
11.2 
Methods and Timing for Assessing and Recording Safety Variable ......................................................... 52 
11.3 
Procedures for Eliciting, Recording, and Reporting Adverse Events ....................................................... 53 
11.4 
Adverse Event Reporting to the US Army ................................................................................................. 57 
11.5 
Reporting Requirements ........................................................................................................................... 57 
11.6 
Reporting to the Study Sponsor ................................................................................................................ 58 
11.7 
Reporting to the Institutional Review Board (IRB)................................................................................... 59 
11.8 
Reporting to the Food and Drug Administration (FDA) .......................................................................... 59 
11.9 
Reporting to the NIH Office of Biotechnology Activities (OBA) .............................................................. 61 
11.10 
Reporting to the Institutional Biosafety Committee (IBC) ........................................................................ 61 
11.11 
Reporting to Hospital Risk Management .................................................................................................. 61 
11.12 
Monitoring of Adverse Events and Period of Observation ....................................................................... 61 
12. 
DATA AND SAFETY MONITORING .......................................................................................................... 61 
12.1 
Data Reporting ......................................................................................................................................... 61 
12.2 
Safety Meetings ......................................................................................................................................... 63 

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12.3 
Monitoring ................................................................................................................................................ 63 
12.4 
Privacy ...................................................................................................................................................... 63 
12.5 
Confidentiality .......................................................................................................................................... 64 
13. 
REGULATORY CONSIDERATIONS .......................................................................................................... 64 
13.1 
Protocol Review and Amendments ........................................................................................................... 64 
13.2 
Informed Consent ..................................................................................................................................... 64 
13.3 
Ethics and Good Clinical Practice (GCP) ............................................................................................... 64 
13.4 
Study Documentation ................................................................................................................................ 66 
13.5 
Records Retention ..................................................................................................................................... 66 
13.6 
Multi-center Guidelines ............................................................................................................................ 66 
13.7 
Cooperative Research and Development Agreement (CRADA)/Clinical Trials Agreement (CTA) .......... 67 
14. 
STATISTICAL CONSIDERATIONS ............................................................................................................ 67 
14.1 
Study Design/Endpoints ............................................................................................................................ 67 
14.2 
Sample Size/Accrual Rate ......................................................................................................................... 67 
14.3 
Stratification Factors ................................................................................................................................ 67 
14.4 
Analysis of Secondary Endpoints .............................................................................................................. 67 
14.5 
Reporting and Exclusions ......................................................................................................................... 69 
15. 
PUBLICATION PLAN .................................................................................................................................... 69 
16. 
REFERENCES ................................................................................................................................................. 70 
17. 
APPENDICES .................................................................................................................................................. 74 
Appendix A: Hearing Response Guidelines ............................................................................................................ 74 
Appendix B:  NFTI-QOL (Neurofibromatosis 2 impact on quality of life) .......................................................... 76 
Appendix C: Performance Status Criteria .............................................................................................................. 79 
Appendix D:  Grading and management of hypertension for adults and for children 6 through 17 years old. 80 
Appendix E: Management of Bone Related Toxicity. ............................................................................................ 84 
Appendix F: Audiology Procedures ......................................................................................................................... 85 
Appendix G: MRI Protocols ..................................................................................................................................... 97 
Appendix H: Tinnitus Reaction Questionnaire (TRQ) a ...................................................................................... 106 

Bevacizumab for children and adults with NF2 
 
 
Protocol Version Date:  May 13, 2016 Version 1.4 
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1 
1. OBJECTIVES 
 
1.1 Study Design 
 
Subjects will be treated with open-label bevacizumab 10 mg/kg every 2 weeks for 24 weeks 
(induction therapy).  Clinical response will be assessed by audiology and MRI at weeks 12 
and 24.  Subjects with hearing decline at weeks 12 or 24 will be taken off of protocol.  At 
week 24, patients with a clinical response or stable disease (together comprising “clinical 
benefit”) will transition to maintenance therapy with bevacizumab.  During the maintenance 
phase, subjects will be treated with open-label bevacizumab 5 mg/kg every 3 weeks for up to 
72 weeks.  Subjects will be followed with audiology and MRI scans every 12 weeks.  The 
total time of the study will be 96 weeks (24 weeks induction + 72 weeks maintenance). 
   
Subjects will be allowed to increase their bevacizumab dose to 10 mg/kg every 2 weeks 
during maintenance therapy if they experience hearing decline during maintenance therapy 
(defined as decrease in word recognition score below the 95% critical difference compared 
with the word recognition score at baseline, Appendix A).  Subjects will be taken off of study 
if their word recognition score does not remain within the 95% critical difference after 
receiving bevacizumab 10 mg/kg every 2 weeks.   
 
1.2 Primary Objectives 
 
The primary objective of this study is to determine the hearing response rate at 24 weeks in 
children and young adults with neurofibromatosis 2 (NF2) treated with bevacizumab for 
symptomatic vestibular schwannomas.   
 
1.3 Secondary Objectives 
 
The secondary objectives are: (1) to determine the safety and tolerability of bevacizumab in 
this patient population; (2) to determine the radiographic response rate (defined as an 
decrease in VS volume by ≥ 20% compared to baseline) during bevacizumab treatment; (3) 
to determine the durability of hearing response, as measured by freedom from hearing loss 
from the time of hearing response (defined as a decrease in word recognition score below the 
upper limit of the 95% critical difference of the baseline word recognition score, Appendix 
A); (4) to determine the durability of radiographic response, as measured from the time of 
first response to tumor progression (defined as an increase in volume of > 20% compared to 
lowest tumor volume during treatment) (5) to determine changes in function of the auditory 
system during bevacizumab treatment; (6) to explore changes in tinnitus during treatment. 
 
2. BACKGROUND 
 
2.1 Neurofibromatosis 2 
 
An estimated 43,800 primary brain tumors were diagnosed in 2005 and 16,600 (38%) of these 
tumors were meningiomas or nerve sheath tumors.  Surprisingly, meningiomas and vestibular 
schwannomas (VSs) are as common as all types of gliomas combined.1 

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2 
 
Neurofibromatosis 2 (NF2) is a tumor suppressor syndrome characterized by multiple 
schwannomas, meningiomas, and ependymomas.  The birth prevalence is estimated to be 1 in 
25,000 births and NF2 affects more than 10,000 individuals in the United States.  The average 
age at onset of symptoms is 17 to 21 years.  
 
Despite the benign histology of schwannomas, meningiomas, and ependymomas, NF2 patients 
experience significant morbidity and mortality related to their disease.  Actuarial survival after 
diagnosis of NF2 is 85% at 5 years, 67% at 10 years, and 38% at 20 years.2  Bilateral VSs are the 
hallmark of NF2.  As these tumors enlarge, they cause sensorineural hearing loss and, ultimately, 
complete hearing loss.  In addition, half of all patients have intracranial meningiomas and 75% 
have spinal tumors (i.e., schwannomas, meningiomas, ependymomas).  Most patients require 
surgery during their lifetime and most patients have multiple procedures.  Morbidity related to 
NF2 is severe and includes early deafness, facial weakness, blindness, seizures, and hemiparesis.   
 
There are two forms of hearing loss in patients with NF2.  Gradual hearing loss is the rule, and it 
most commonly occurs with progression of tumor size over time.  Although there is a rough 
correlation with tumor size, gradual hearing loss can occur with tumors of any size.  Although 
surgical implantation of cochlear and auditory brainstem implants provides benefit for a small 
minority of patients, there is no widely effective treatment for this type of hearing loss.  In 
addition, some patients can experience episodes of sudden hearing loss superimposed on baseline 
hearing dysfunction.  Treatment with a short course of corticosteroids can often correct this acute 
hearing loss.  The mechanism of acute hearing loss is not clearly understood but probably 
involves compression of the auditory nerve from tumor mass and associated edema.  Previous 
studies of pressure within the internal auditory canal (IAC) of patients with VSs suggest that 
intracannalicular pressure is directly correlated with the amount of tumor in the IAC and may be 
inversely associated with preoperative hearing.3 Thus, therapies that reduce edema, a common 
cause of increased pressure in brain tumors, are a rational approach to treating hearing loss in 
NF2 patients. 
 
In patients with NF2, standard therapy involves surgery for progressive, symptomatic tumors.  
Due to the large number of tumors encountered in the brain and spinal cord, surgical removal of 
all tumors is not possible or advisable.  Iatrogenic morbidity after surgery for NF2-related lesions 
is, unfortunately, relatively common due to the intimate association between tumors and vital 
neurologic structures.  For example, complete surgical resection of VSs typically results in 
ipsilateral anacusis except in a minority of tumors that are smaller than 1.5 cm and smooth in 
outline. As well, facial palsy, spinal fluid leaks and infection are all common complications of 
VS resection.  
 
Radiation has been used in a subset of tumors that progress despite surgical treatment or in 
individuals who are considered high risk for surgical complications.  However, this modality 
should be used with caution since secondary malignancies after treatment have been reported.4  
In addition, many patients lose functional hearing after provision of radiation with hearing 
preservation rates of 73% at 1 year, 59% at 2 years, and 48% at 5 years after radiosurgery.5  
 

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3 
There are no known effective medical treatments for NF2-related tumors.  Given the limitations 
of surgery or radiation and the devastating impact of these tumors, medical treatments are 
desperately needed.  We have recently identified VEGF inhibition as a possible therapy. The 
initial experience treating ten NF2 patients at risk for complete hearing loss with bevacizumab 
outside of a clinical trial showed promising results with 6/10 patients experiencing ≥ 20% 
reduction in tumor volume and 4/7 evaluable patients having significantly improved word 
recognition scores .6  Trials of other targeted agents for treatment of NF2-related tumors are 
currently underway.  A phase 2 study of the VEGF inhibitor PTC299 for NF2-related vestibular 
schwannoma (NCT00911248) has completed stage 1 of accrual, and a phase 2 study of the 
HER1/HER2 inhibitor lapatinib for NF2-related tumors has completed enrollment 
(NCT00973739).  Other planned studies include trials of everolimus (NCT01490476, 
NCT01419639, NCT01345136). 
 
Hearing loss and NF2 
 
Hearing loss is a critical problem for patients with NF2. Unlike patients with sporadic VSs who 
can function with unilateral hearing loss, patients with NF2 are at risk for complete deafness. 
This hearing loss typically occurs during late adolescence or early adulthood and leads to social 
isolation and underemployment. Although hearing loss is related to VSs, the degree of hearing 
sensitivity (threshold) is only loosely correlated with tumor size. This dissociation may be due to 
direct compression of the auditory nerve, presence of intratumoral edema, disruption of blood 
flow to the cochlea, degeneration of certain cochlear structures, and distortion of auditory centers 
in the brainstem. There is evidence that the cochlea, as well as the 8th cranial nerve, is a site of 
both cell degeneration and the accumulation of precipitate in cases of VS.7 This means that sites 
anywhere along the auditory pathways—from the periphery to the brainstem—may contribute to 
the observed loss of hearing function. Thus, we will use the full range of audiologic diagnostic 
tools available to assess function of the pathway. 
 
Hearing is monitored in clinical practice by measuring pure tone thresholds, word recognition 
scores, brainstem auditory evoked responses (BAERs), and otoacoustic emissions (OAEs).   
 
Pure tone thresholds measure the minimum sound level that an ear can perceive.  Thresholds are 
typically measured at octaves and half-octaves from 250 Hz to 8000 Hz. An average of 
thresholds at 500, 1000, 2000 and 4000 Hz (PTA) is recommended as a standard outcome 
measure by the American Academy of Otolaryngology, Head and Neck Surgery (AAO-HNS) for 
reporting in cases of VS.   
 
Word recognition scores measure the ability to recognize (as opposed to detect) auditory 
information. Patients are presented a list of 50 words at a fully audible level and the percentage 
identified correctly is the score. This study will use full 50-item monosyllable lists and 
standardized recordings.  
 
Brainstem auditory evoked responses are small electrical voltage potentials recorded from the 
scalp in response to auditory stimuli (such as clicks). These signals originate from auditory 
structures (e.g., the cochlea, 8th cranial nerve, and auditory brainstem) and provide information 
about the synchronous conduction of auditory information to the brain. The latency (ms) and 

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amplitude of the peaks of waves I and V will be differentially evaluated to show the status of 
peripheral versus brainstem effects.   
 
Otoacoustic emissions (OAEs) are sounds that are generated from within the cochlea as it acts to 
amplify incoming sounds. OAEs are a sensitive measure of cochlear health and often disappear 
after the cochlea has been damaged. The presence (significantly above noise-floor) of measurable 
emissions, called distortion product otoacoustic emissions (DPOAEs) across frequencies from 
1000 to 8000 Hz will be used as an indicator of functioning cochlear regions. 
 
Because tumors associated with NF2 have benign histology, overall survival is not an appropriate 
endpoint for clinical trials in this condition. Instead, the goal of treatment is to minimize 
neurologic morbidity (including hearing loss) and to defer surgical treatments that may cause 
iatrogenic dysfunction. For this reason, hearing function is the most important way to monitor the 
activity of new agents designed to treat VSs.   
 
Word recognition is the measure most closely associated with daily hearing function since it 
measures the ability to comprehend speech (rather than “detect” it). If word recognition quality 
improves, the patient can converse successfully, even if a hearing aid is needed to make sounds 
sufficiently loud. Statistical methods have been developed to determine significant changes in 
this measure. Word recognition scores represent summary scores from a collection of binary 
endpoints (correct/incorrect responses) and thus follow a binomial distribution (e.g., non-
Gaussian distribution).  Although it is tempting to use a set change in word recognition score 
(e.g., fifteen percentage points) as a clinical response, this approach is inappropriate given the 
binomial model of variance.  A more rigorous approach involves the use of the 95% (p=0.05) 
critical difference table 8 (Appendix A).  The 95% critical differences for 50-word lists as 
proposed here have been used in previous studies9 and in clinical trials evaluating the effect of 
drug treatment on hearing. 
 
Quality of life and NF2 
 
NF2 is associated with decreased quality of life.  Recently, there have been efforts to develop a 
reliable and validated score to measure disease-specific quality of life (QOL) in NF2 patients.  
This effort has resulted in an 8-item scale that is called NFTI-QOL (Appendix B).10  The eight 
questions include items about balance, hearing, facial weakness, sight, mobility, functional role, 
pain, and mood.  In a sample of 50 subjects with NF2, NFTI-QOL score correlated with two 
established quality of life measures: the EuroQOL and the SF-36 (Pearson correlation, p≤0.001). 
In addition, there was a strong significant correlation with physician-ranked disease severity 
(Pearson correlation, p<0.001). 
 
Imaging vestibular schwannomas 
 
Although many clinicians believe that hearing loss related to VSs is irreversible, there are cases 
with transient hearing restoration after a course of corticosteroids or decompression of the 
auditory canal without removal of the tumor. Our preliminary observations indicate that 
neutralizing VEGF can reverse profound hearing loss and subsequently maintain hearing.   Based 
on these experiences, we hypothesize that the restoration of hearing function with bevacizumab is 

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in part due to reduction in intraneural edema that compresses the auditory nerve. In this proposal, 
we will investigate the mechanism(s) by which bevacizumab inhibits tumor growth and/or 
induces hearing recovery using advanced MRI techniques specifically designed to assess the 
vascular profile of tumors and the tumor environment.   
 
Internal auditory canal (IAC) imaging. The vestibular and auditory nerves together comprise 
the 8th cranial nerve. The nerve exits the lateral brainstem, travels through the subarachnoid 
space in the IAC to terminate in the cochlea (auditory nerve) and semicircular canals (vestibular 
nerve). Detailed imaging of the IAC is essential to identify and follow VSs in patients with NF2. 
MRIs must therefore include thin cuts through the IAC (3mm, no skip) in addition to the 
traditional pre- and post-contrast images (5 mm, 1 mm skip) that are performed for malignant 
brain tumors. 
 
Volumetric analysis. Traditionally, VSs have been measured using either 1-dimensional 
measurements (in the long axis) or 2-dimensional measurements (calculated by taking the square 
root of the product of the short axis * long axis measured to the plane perpendicular to the face of 
the temporal bone).11  However, the irregular shape of VSs, as determined by the unique anatomy 
of the IAC and cerebellopontine angle, makes it difficult for linear measurements to accurately 
and fully represent growth for the entire tumor. As a result, VS growth may be underestimated by 
linear measurement criteria. Semi-automated volumetric analysis overcomes these limitations 
since it uses data from 3 dimensions. The coefficient of variation (COV) ranges from 0.6% to 
6.8% and is generally below 5% for lesions greater than 1 cc.12  Volumetric analysis not only 
better reflects tumor size, but also allows accurate detection of smaller changes in tumor size 
compared to standard solid tumor response criteria (e.g., RECIST criteria). This ability to detect 
small changes in size is critical for tumors with slow growth rates such as VS, and, when used in 
clinical trials, helps limit exposure to potentially toxic and/or inactive agents. Trials for NF-
related tumors, such as plexiform neurofibromas, are now routinely using volumetric changes as 
the primary endpoint, typically choosing a 20% increase for progression and 20% decrease for 
radiographic response.13-15 
 
2.2 Study Agent(s) 
 
2.2.1 Bevacizumab (NSC #704865) 
 
Bevacizumab is a humanized IgG1 monoclonal antibody (MAb) that binds all 
biologically active isoforms of human vascular endothelial growth factor (VEGF, or 
VEGF-A) with high affinity (kd = 1.1 nM) (40).  The antibody consists of a human IgG1 
framework and the antigen-binding complementarity-determining regions from the 
murine anti-VEGF MAb A.4.6.1.16-18 
 
Mechanism of Action 
Of known proangiogenic factors, VEGF is one of the most potent and specific, and has 
been identified as a crucial regulator of both normal and pathological angiogenesis. 
VEGF is a secreted, heparin-binding protein that exists in multiple isoforms. Action of 
VEGF is primarily mediated through binding to the receptor tyrosine kinases, VEGFR-1 
(Flt-1) and VEGFR-2 (KDR/Flk-1). The biological effects of VEGF include endothelial 

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cell mitogenesis and migration, increased vascular permeability, induction of proteinases 
leading to remodeling of the extracellular matrix, and suppression of dendritic cell 
maturation. Neutralization of VEGF by A.4.6.1 or bevacizumab has been shown to 
inhibit the VEGF-induced proliferation of human endothelial cells in vitro, and decrease 
microvessel density and interstitial pressure in tumor xenografts in vivo. In patients, 
preliminary results from a neoadjuvant trial in rectal cancer demonstrated a decrease in 
blood perfusion/permeability and interstitial fluid pressure in tumors after one dose of 
bevacizumab.19 
 
Nonclinical Studies 
The murine parent MAb of bevacizumab, A4.6.1, has demonstrated potent growth 
inhibition in vivo in a variety of human cancer xenograft and metastasis models, 
including those for SK-LMS-1 leiomyosarcoma, G55 glioblastoma multiforme, A673 
rhabdomyosarcoma, Calu-6, and MCF-7 cell lines.16, 18, 20, 21  The antitumor activity was 
enhanced with the combination of A4.6.1 and chemotherapeutic agents compared to 
either agent alone.  Combined blockage of the VEGF and other growth factor pathways 
(e.g., EGFR or PDGFR) has also demonstrated additive effects in vivo.22, 23 Associated 
with the anti-tumor activity of anti-VEGF MAbs were findings of reduced intratumoral 
endothelial cells and microcapillary counts as well as reduced vascular permeability and 
interstitial pressure   
 
Nonclinical toxicology studies have examined the effects of bevacizumab on female 
reproductive function, fetal development, and wound healing. Fertility may be impaired 
in cynomolgus monkeys administered bevacizumab, which led to reduced endometrial 
proliferation and uterine weight as well as a decrease in ovarian weight and number of 
corpora lutea. Bevacizumab is teratogenic in rabbits, with increased frequency of fetal 
resorption, as well as specific gross and skeletal alterations. In juvenile cynomolgus 
monkeys with open growth plates, bevacizumab induced physeal dysplasia, which was 
partially reversible upon cessation of therapy.  Bevacizumab also delays the rate of 
wound healing in rabbits. This effect appeared to be dose-dependent and characterized by 
a reduction of wound tensile strength. 
 
Clinical Studies in Adults 
To date, over 7000 patients have been treated in clinical trials with bevacizumab as 
monotherapy or in combination regimens.17 
 
Pharmacokinetics 
The pharmacokinetics (PK) of bevacizumab have been characterized in several phase 1 
and phase 2 clinical trials, with doses ranging from 1 to 20 mg/kg administered weekly, 
every 2 weeks, or every 3 weeks. The estimated half-life of bevacizumab is 
approximately 21 days (range 11-50 days). The predicted time to reach steady state was 
100 days. The volume of distribution is consistent with limited extravascular distribution.   
  
Maximum Tolerated Dose 
The maximum tolerated dose (MTD) of bevacizumab has not been determined; however, 
the dose level of 20 mg/kg was associated severe headaches.24 The dose schedule of 

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either 10 mg/kg q2w or 15 mg/kg q3w is used in most phase 2 or 3 trials with only a few 
exceptions (e.g., the pivotal phase 3 trial in colorectal cancer, in which bevacizumab was 
given at 5 mg/kg q2w).25 
Bevacizumab has been studied in a multitude of Phase I, II, and III clinical trials in more 
than 5000 patients and in multiple tumor types. In addition, data are available from 3,863 
patients enrolled in two post-marketing studies in metastatic colorectal cancer (CRC).  
Approximately 130,000 patients have been exposed to bevacizumab as a marketed 
product or in clinical trials.  The following discussion summarizes bevacizumab’s safety 
profile and presents some of the efficacy results pertinent to this particular trial. Please 
refer to the bevacizumab Investigator Brochure for descriptions of all completed Phase I, 
II, and III trials reported to date. 
 
In a large phase III study (AVF2107g) in patients with metastatic colorectal cancer, the 
addition of bevacizumab, a monoclonal antibody directed against vascular endothelial 
growth factor (VEGF), to irinotecan/5-fluorouracil/leucovorin (IFL) chemotherapy 
resulted in a clinically and statistically significant increase in duration of survival, with a 
hazard ratio of death of 0.67 (median survival 15.6 vs. 20.3 months; p < 0.001).  Similar 
increases were seen in progression-free survival (6.2 vs. 10.6 months; p < 0.001), overall 
response rate (35% vs. 45%; p < 0.01) and duration of response (7.1 vs. 10.4 months; 
p < 0.01) for the combination arm versus the chemotherapy only arm.17 
 
Based on the survival advantage demonstrated in Study AVF2107g, bevacizumab was 
designated for priority review and was approved on 26 February 2004 in the United 
States for first-line treatment in combination with IV 5-FU−based chemotherapy for 
subjects with metastatic colorectal cancer.  
 
Additional data from Phase III trials in metastatic CRC (E3200), non−small cell lung 
cancer (NSCLC; E4599), and metastatic breast cancer (E2100) have also demonstrated 
clinical benefit from bevacizumab when added to chemotherapy.  In Study E3200, the 
addition of bevacizumab to FOLFOX chemotherapy resulted in improved overall survival 
compared with FOLFOX alone (13.0 vs. 10.8 months, respectively, HR = 0.75; p < 0.01) 
in a population of previously treated CRC patients.   
 
There was also improved overall survival in first-line NSCLC patients (E4599) treated 
with carboplatin/paclitaxel + bevacizumab compared with chemotherapy alone (12.3 vs. 
10.3 months, respectively; HR = 0.80; p = 0.003).  The results from this trial were the 
basis for FDA approval of bevacizumab for use in combination with 
carboplatin + paclitaxel as first-line treatment of patients with unresectable, locally 
advanced, recurrent or metastatic, non-squamous NSCLC in October 2006.  Finally, 
patients with untreated metastatic breast cancer (E2100) who received bevacizumab in 
combination with weekly paclitaxel had a marked improvement in PFS compared with 
chemotherapy alone (13.3 vs. 6.7 months, respectively; HR = 0.48; p < 0.0001) (see the 
Bevacizumab Investigator Brochure for additional details). 
 
 
 

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Clinical Studies in Children 
Compassionate-use and phase 1 trials of bevacizumab as single agent have been 
completed for children with refractory solid tumors.26, 27 In these studies, doses from 5 
mg/kg to 15 mg/kg every 2 weeks were well tolerated.  In the phase 1 study, eighteen of 
21 children completed ≥ 1 treatment cycle (median number of cycles 3, range 1-16 
cycles). No dose limiting toxicity was seen nor was hemorrhage/thrombosis noted.  
Interestingly, the typical adverse events seen in adults—hypertension, proteinuria, arterial 
thromboembolic events, hemorrhage, congestive heart failure (CHF), gastrointestinal 
perforations, wound healing complications, reversible posterior leukoencephalopathy 
syndrome and fistula formation—were not seen in children.28 Bony toxicity was not 
observed, but cumulative toxicity could not be evaluated given the fairly short treatment 
duration with bevacizumab. Based on these results, phase 2 studies at doses similar to 
adults were recommended. 
 
Additional studies of bevacizumab in combination with chemotherapy have been 
performed.29-32  In one study of 10 patients with recurrent low grade gliomas, durable 
objective responses (up to 22 months) to combination chemotherapy with improvement 
in clinical function.  No dose-limiting toxicity was reported.29  In a separate phase 2 study 
of 31 patients with recurrent malignant glioma and diffuse brainstem glioma, 
bevacizumab plus irinotecan was not effective; toxicity associated with chemotherapy 
included fatigue, hypertension, CNS hemorrhage (grade 1), and CNS ischemia (grade 4 
in 2 patients).30  In a retrospective study of 30 patients with a range of primary CNS 
tumors, bevacizumab was given with chemotherapy at a median dose of 9.5 mg/kg every 
2 weeks.  No hemorrhage or thrombosis was noted in this cohort.  The toxicity profile 
was consistent with other studies including hypertension, proteinuria, lymphopenia, and 
delayed wound healing.31 
 
Safety Profile 
 
Infusion-Related Reactions: Infusion reactions with bevacizumab were uncommon 
(<3%) and rarely severe (0.2%).  Infusion reactions may include rash, urticaria, fever, 
rigors, hypertension, hypotension, wheezing, or hypoxia. Currently, there is no adequate 
information on the safety of retreatment with bevacizumab in patients who have 
experienced severe infusion-related reactions.  
 
In the initial Phase I and II clinical trials, four potential bevacizumab-associated safety 
signals were identified: hypertension, proteinuria, thromboembolic events, and 
hemorrhage.  Additional completed Phase II and Phase III studies of bevacizumab as well 
as spontaneous reports have further defined the safety profile of this agent. Bevacizumab-
associated adverse events identified in phase III trials include congestive heart failure 
(CHF) primarily in metastatic breast cancer, gastrointestinal perforations, wound healing 
complications, and arterial thromboembolic events (ATE). These and other safety signals 
are described in further detail as follows and in the bevacizumab Investigator Brochure. 
 
Hypertension: An increased incidence of hypertension has been observed in patients 
treated with bevacizumab.  Grade 4 and 5 hypertensive events are rare. Clinical sequelae 

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of hypertension are rare but have included hypertensive crisis, hypertensive 
encephalopathy, and reversible posterior leukoencephalopathy syndrome (RPLS).33, 34  
 
There is no information on the effect of bevacizumab in patients with uncontrolled 
hypertension at the time of initiating bevacizumab therapy.  Therefore, caution should be 
exercised before initiating bevacizumab therapy in these patients.  Monitoring of blood 
pressure is recommended during bevacizumab therapy.  Optimal control of blood 
pressure according to standard public health guidelines is recommended for patients on 
treatment with or without bevacizumab.   
 
Temporary interruption of bevacizumab therapy is recommended in patients with 
hypertension requiring medical therapy until adequate control is achieved.  
If hypertension cannot be controlled with medical therapy, bevacizumab therapy should 
be permanently discontinued.  Bevacizumab should be permanently discontinued in 
patients who develop hypertensive crisis or hypertensive encephalopathy. 
 
Proteinuria:  An increased incidence of proteinuria has been observed in patients treated 
with bevacizumab compared with control arm patients.  In the bevacizumab-containing 
treatment arms of clinical trials (across all indications), the incidence of proteinuria 
(reported as an adverse event) was up to 38% (metastatic CRC Study AVF2192g). The 
severity of proteinuria has ranged from asymptomatic and transient events detected on 
routine dipstick urinalysis to nephrotic syndrome; the majority of proteinuria events have 
been grade 1. NCI-CTC Grade 3 proteinuria was reported in up to 3% of bevacizumab-
treated patients, and Grade 4 in up to 1.4% of bevacizumab-treated patients.  The 
proteinuria seen in bevacizumab clinical trials was not associated with renal impairment 
and rarely required permanent discontinuation of bevacizumab therapy.  Bevacizumab 
should be discontinued in patients who develop Grade 4 proteinuria (nephrotic 
syndrome). 
 
Patients with a history of hypertension may be at increased risk for the development of 
proteinuria when treated with bevacizumab.  There is evidence from the dose-finding, 
Phase II trials (AVF0780g, AVF0809s, and AVF0757g) suggesting that Grade 1 
proteinuria may be related to bevacizumab dose. 
 
Proteinuria will be monitored by urine protein:creatinine (UPC) ratio at least every 6 
weeks.  If the UPC ratio is not available, a dipstick urinalysis may be used to allow 
treatment to proceed. 
 
Thromboembolic Events: Both venous and arterial thromboembolic (TE) events, ranging 
in severity from catheter-associated phlebitis to fatal, have been reported in patients 
treated with bevacizumab in the colorectal cancer trials and, to a lesser extent, in patients 
treated with bevacizumab in NSCLC and breast cancer trials.  
 
Venous thromboembolism (including deep venous thrombosis, pulmonary  
embolism, and thrombophlebitis):  In the phase III pivotal trial in metastatic CRC, there 
was a slightly higher rate of venous TE events in patients treated with bevacizumab plus 

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chemotherapy compared with chemotherapy alone (19% vs. 16%).  
 
In Study AVF2107g, a Phase III, pivotal trial in metastatic CRC, VTE events, including 
deep venous thrombosis, pulmonary embolism, and thrombophlebitis, occurred in 15.2% 
of patients receiving chemotherapy alone and 16.6% of patients receiving 
chemotherapy + bevacizumab.  
 
The incidence of NCI-CTC Grade ≥ 3 venous VTE events in one NSCLC trial (E4599) 
was higher in the bevacizumab-containing arm compared to the chemotherapy control 
arm (5.6% vs. 3.2%).  One event (0.2%) was fatal in the bevacizumab-containing arm; 
not fatal events were reported in the carboplatin/paclitaxel arm (see Bevacizumab 
Investigator Brochure).  In metastatic CRC clinical trials, the incidence of VTE events 
was similar in patients receiving chemotherapy + bevacizumab and those receiving the 
control chemotherapy alone.  
 
In clinical trials across all indications the overall incidence of VTE events was 
2.8%−17.3% in the bevacizumab-containing arms compared with 3.2%−15.6% in the 
chemotherapy control arms.  The use of bevacizumab with chemotherapy does not 
substantially increase the risk of VTE event compared with chemotherapy alone.  
However, patients with metastatic CRC who receive bevacizumab and experienced a 
VTE event may be at higher risk for recurrence of VTE event. 
 
Arterial Thromboembotic Events:  An increased incidence of ATE events was observed 
in patients treated with bevacizumab compared with those receiving a control treatment.  
ATE events include cerebrovascular accidents, myocardial infarction, transient ischemic 
attacks (TIAs), and other ATE events.  In a pooled analysis of data from five randomized 
Phase II and III trials (mCRC [AVF2107g, AVF2192g, AVF0780g]; locally advanced or 
metastatic NSCLC [AVF0757g]; metastatic breast cancer [AVF2119g]), the incidence 
rate of ATE events was 3.8% (37 of 963) in patients who received 
chemotherapy + bevacizumab compared with 1.7% (13 of 782) in patients treated with 
chemotherapy alone.  ATE events led to a fatal outcome in 0.8% (8 of 963) of patients 
treated with chemotherapy + bevacizumab and 0.5% (4 of 782) of patients treated with 
chemotherapy alone.  Cerebrovascular accidents (including TIAs) occurred in 2.3% of 
patients treated with chemotherapy + bevacizumab and 0.5% of patients treated with 
chemotherapy alone.  Myocardial infarction occurred in 1.4% of patients treated with 
chemotherapy + bevacizumab compared with 0.7% of patients treated with chemotherapy 
alone. (See the Bevacizumab Investigator Brochure for additional details.) 
 
Aspirin is a standard therapy for primary and secondary prophylaxis of arterial 
thromboembolic events in patients at high risk of such events, and the use of aspirin ≤ 
325 mg daily was allowed in the five randomized studies discussed above. Use of aspirin 
was assessed routinely as a baseline or concomitant medication in these trials, though 
safety analyses specifically regarding aspirin use were not preplanned. Due to the 
relatively small numbers of aspirin users and arterial thromboembolic events, 
retrospective analyses of the ability of aspirin to affect the risk of such events were 
inconclusive. However, similarly retrospective analyses suggested that the use of up to 

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325 mg of aspirin daily does not increase the risk of grade 1-2 or grade 3-4 bleeding 
events, and similar data with respect to metastatic colorectal cancer patients were 
presented at ASCO 2005.35 Further analyses of the effects of concomitant use of 
bevacizumab and aspirin in colorectal and other tumor types are ongoing. 
 
Gastrointestinal perforation:  Patients with metastatic carcinoma may be at increased 
risk for the development of gastrointestinal perforation and fistula when treated with 
bevacizumab and chemotherapy. Bevacizumab should be permanently discontinued in 
patients who develop gastrointestinal perforation. A causal association of intra-abdominal 
inflammatory processes and gastrointestinal perforation to bevacizumab  treatment has 
not been established. Nevertheless, caution should be exercised when treating patients 
with intra-abdominal inflammatory processes with bevacizumab. Gastrointestinal 
perforation has been reported in other trials in non-colorectal cancer populations (e.g., 
ovarian, renal cell, pancreas, breast, and NSCLC) and may be higher in incidence in some 
tumor types. 
 
Fistula:  Bevacizumab use has been associated with serious cases of fistulae including 
events resulting in death.  Fistulae in the GI tract are common (1%–10% incidence) in 
patients with metastatic CRC, but uncommon (0.1%−1%) or rare (0.01%–0.1%) in other 
indications.  In addition, fistulae that involve areas of the body other than the GI tract 
(e.g., tracheoesophageal, bronchopleural, urogenital, biliary) have been reported 
uncommonly (0.1%–1%) in patients receiving bevacizumab in clinical studies and 
postmarketing reports.  Events were reported at various time points during treatment, 
ranging from 1 week to > 1 year following initiation of bevacizumab, with most events 
occurring within the first 6 months of therapy. 
 
Permanently discontinue bevacizumab in patients with tracheoesophageal fistulae, new 
gastrointestinal fistula (any grade), or any Grade 4 fistula.  Limited information is 
available on the continued use of bevacizumab in patients with other fistulae.  In cases of 
internal fistula not arising in the GI tract, discontinuation of bevacizumab should be 
considered. 
 
Wound healing complications: Wound healing complications such as wound dehiscence 
have been reported in patients receiving bevacizumab. In an analysis of pooled data from 
two trials in metastatic colorectal cancer, patients undergoing surgery 28-60 days before 
study treatment with 5-FU/LV plus bevacizumab did not appear to have an increased risk 
of wound healing complications compared to those treated with chemotherapy alone.36 
Surgery in patients currently receiving bevacizumab is not recommended. No definitive 
data are available to define a safe interval after bevacizumab exposure with respect to 
wound healing risk in patients receiving elective surgery; however, the estimated half life 
of bevacizumab is 21 days. Bevacizumab should be discontinued in patients with severe 
wound healing complications. 
 
If patients receiving treatment with bevacizumab require elective major surgery, it is 
recommended that bevacizumab be held for 4–8 weeks prior to the surgical procedure.  
Patients undergoing a major surgical procedure should not begin or restart bevacizumab 

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until 4 weeks after that procedure. In the case of high-risk procedures (such as liver 
resection, thoracotomy, or neurosurgery), it is recommended that chemotherapy be 
restarted no earlier than 6 weeks and bevacizumab no earlier than 8 weeks after surgery. 
 
Hemorrhage: Overall, grade 3 and 4 bleeding events were observed in 4.0% of 1132 
patients treated with bevacizumab in a pooled database from eight phase I, II, and III 
clinical trials in multiple tumor types.17 The hemorrhagic events that have been observed 
in bevacizumab clinical studies were predominantly tumor-associated hemorrhage (see 
below) and minor mucocutaneous hemorrhage.  
 
Tumor-Associated Hemorrhage:  Major or massive pulmonary hemorrhage or 
hemoptysis has been observed primarily in patients with NSCLC.  Life-threatening and 
fatal hemoptysis was identified as a bevacizumab-related adverse event in NSCLC trials.  
These events occurred suddenly and presented as major or massive hemoptysis.  Among 
the possible risk factors evaluated (including squamous cell histology, treatment with 
anti-rheumatic/anti-inflammatory drugs, treatment with anticoagulants, prior 
radiotherapy, bevacizumab therapy, previous medical history of atherosclerosis, central 
tumor location, and cavitation of tumors during therapy), the only variables that showed 
statistically significant correlations with bleeding were bevacizumab therapy and 
squamous cell histology. 
 
GI hemorrhages, including rectal bleeding and melena have been reported in patients 
with CRC, and have been assessed as tumor-associated hemorrhages. 
 
Tumor-associated hemorrhages were also seen rarely in other tumor types and locations, 
including a case of CNS bleeding in a patient with hepatoma with occult CNS metastases 
and a patient who developed continuous oozing of blood from a thigh sarcoma with 
necrosis. 
 
Mucocutaneus Hemorrage:  Across all bevacizumab clinical trials, mucocutaneous 
hemorrhage has been seen in 20%-40% of patients treated with bevacizumab. These were 
most commonly NCI-CTC Grade 1 epistaxis that lasted less than 5 minutes, resolved 
without medical intervention and did not require any changes in bevacizumab treatment 
regimen.  
 
There have also been less common events of minor mucocutaneous hemorrhage in other 
locations, such as gingival bleeding and vaginal bleeding.  
 
Reversible Posterior Leukoencephalopathy Syndrome (RPLS):  There have been rare 
reports of bevacizumab-treated patients developing signs and symptoms that are 
consistent with RPLS, a rare neurologic disorder that can present with the following signs 
and symptoms (among others):  seizures, headache, altered mental status, visual 
disturbance, or cortical blindness, with or without associated hypertension.  Brain 
imaging is mandatory to confirm the diagnosis of RPLS.  In patients who develop RPLS, 
treatment of specific symptoms, including control of hypertension, is recommended along 
with discontinuation of bevacizumab.  The safety of reinitiating bevacizumab therapy in 

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patients previously experiencing RPLS is not known.33, 34   
 
Congestive heart failure (CHF):  In clinical trials CHF was observed in all cancer 
indications studied to date, but predominantly in patients with metastatic breast cancer.  
In the Phase III clinical trial of metastatic breast cancer (AVF2119g), 7 (3%) 
bevacizumab-treated patients experienced CHF, compared with two (1%) control arm 
patients.  These events varied in severity from asymptomatic declines in left ventricular 
ejection fraction (LVEF) to symptomatic CHF requiring hospitalization and treatment.  
All the patients treated with bevacizumab were previously treated with anthracyclines 
(doxorubicin cumulative dose of 240−360 mg/m2).  Many of these patients also had prior 
radiotherapy to the left chest wall.  Most of these patients showed improved symptoms 
and/or left ventricular function following appropriate medical therapy.37 
 
In a randomized, Phase III trial of patients with previously untreated metastatic breast 
cancer (E2100), the incidence of LVEF decrease (defined as NCI-CTC Grade 3 or 4) in 
the paclitaxel + bevacizumab arm was 0.3% versus 0% for the paclitaxel alone arm  
 
No information is available on patients with preexisting CHF of New York Heart 
Association (NYHA) Class II−IV at the time of initiating bevacizumab therapy, as these 
patients were excluded from clinical trials. 
 
Prior anthracyclines exposure and/or prior radiotherapy to the chest wall may be possible 
risk factors for the development of CHF.  Caution should be exercised before initiating 
bevacizumab therapy in patients with these risk factors. 
 
A Phase II trial in patients with refractory acute myelogenous leukemia reported 5 cases 
of cardiac dysfunction (CHF or LVEF decrease to < 40%) among 48 patients treated with 
sequential cytarabine, mitoxantrone, and bevacizumab.  All but 1 of these patients had 
significant prior exposure to anthracyclines as well.38  
 
Other studies in patients with various tumor types and either a history of anthracycline 
exposure or concomitant use with bevacizumab are ongoing.  
 
Patients receiving concomitant anthracyclines or with prior exposure to anthracyclines 
should have a baseline MUGA scans or echocardiograms (ECHOs) with a normal LVEF. 
 
Neutropenia:  Increased rates of severe neutropenia, febrile neutropenia, or infection 
with severe neutropenia (including some fatalities) have been observed in patients treated 
with some myelotoxic chemotherapy regimens plus bevacizumab in comparison to 
chemotherapy alone.39 
 
Fertility and Pregnancy. Clinical data are lacking regarding the immediate or long-term 
effect of bevacizumab on fertility and pregnancy. However, bevacizumab is known to be 
teratogenic and detrimental to fetal development in animal models. In addition, 
bevacizumab may alter corpus luteum development and endometrial proliferation, 
thereby having a negative effect on fertility. As an IgG1, it may also be secreted in 

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human milk. Therefore, fertile men and women on bevacizumab studies must use 
adequate contraceptive measures and women should avoid breast feeding.  The duration 
of such precautions after discontinuation of bevacizumab should take into consideration 
the half-life of the agent (average 21 days, ranging from 11 to 50 days). 
 
Immunogenicity. As a therapeutic protein, there is a potential for immunogenicity with 
bevacizumab. With the currently available assay with limited sensitivity, high titer human 
anti-bevacizumab antibodies have not been detected in approximately 500 patients treated 
with bevacizumab. 
 
Additional Adverse Events:  See the bevacizumab Investigator Brochure for additional 
details regarding the safety experience with bevacizumab. 
 
2.3 Rationale 
 
Patients with NF2 develop multiple tumors, including bilateral vestibular schwannomas, 
meningiomas, and ependymomas.  As bilateral VS enlarge, they cause sensorineural hearing loss 
and, ultimately, complete deafness. Disease-specific mortality is extremely high for NF2 with 
greater than 90% of NF2 patients dying from their disease or from complications in the 
immediate post-operative period.40 Standard treatment options for VS include surgery or 
radiation, which often cause hearing loss or cranial nerve dysfunction.  Sporadic and NF2-related 
vestibular schwannomas express vascular endothelial growth factor (VEGF).  Bevacizumab is an 
antibody that binds VEGF with high affinity and is approved for treatment of multiple cancers 
including glioblastoma.  Our initial experience treating ten NF2 patients at risk for complete 
hearing loss or brainstem compression with bevacizumab on compassionate-care basis showed 
promising results with 6/10 patients experiencing ≥ 20% tumor volume reduction and 4/7 
experiencing significantly improved hearing.6  The proposed trial is designed to confirm the 
clinical response rate of bevacizumab in a larger cohort of pediatric patients with NF2 treated at 
multiple centers.  Because patients with NF2 have long life expectancy, the optimum duration of 
treatment with bevacizumab is an important question to address.  An exploratory aim of this 
study is to determine the durability of clinical response to bevacizumab in subjects with 
progressive vestibular schwannomas who either respond to therapy or experience stable disease 
after initial treatment. 
  
2.4 
Correlative Studies Background 
 
Our study and others suggest that there are dose- and time-dependent increases in soluble 
VEGF and PlGF and decreases in soluble VEGFR following treatment with anti-angiogenic 
agents 19, 41, 42. Our studies have also shown that circulating biomarkers can help predict 
tumor progression. For example, progression of glioblastoma during treatment with 
AZD2171 is associated with significant increases in basic fibroblast growth factor (b-FGF) 
and stromal cell-derived factor 1 alpha (SDF-1α), whereas progression in hepatocellular 
carcinoma after sunitinib is correlated with increases in IL-6 and SDF-1α. Finally, we found 
that baseline sVEGFR1 concentration in plasma may predict response to bevacizumab 
therapy in rectal cancer patients 41. 
 

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There is no published data on molecular biomarkers for anti-VEGF agents in patients with 
NF2 and this study proposes to analyze baseline biomarkers with respect to outcomes 
(response) as well as the possible effect of bevacizumab on biomarker levels over time (see 
section 8.3.1). 
 
3. PARTICIPANT SELECTION 
 
3.1 
Eligibility Criteria 
 
Participants must meet the following criteria on screening examination to be eligible to 
participate in the study: 
3.1.1 Patients must have a confirmed diagnosis of neurofibromatosis 2 by fulfilling 
National Institute of Health (NIH) criteria or Manchester criteria, or by detection of 
a causative mutation in the NF2 gene.     
 
 
The NIH criteria43 includes presence of: 
• Bilateral vestibular schwannomas, OR 
• First-degree relative with NF2 and EITHER unilateral eighth nerve mass 
OR two of the following: neurofibroma, meningioma, glioma, 
schwannoma, juvenile posterior subcapsular lenticular opacity. 
 
 
 
The Manchester criteria44 includes presence of: 
• Bilateral vestibular schwannomas, OR 
• First-degree relative with NF2 and EITHER unilateral eighth nerve mass 
OR two of the following: neurofibroma, meningioma, glioma, 
schwannoma, juvenile posterior subcapsular lenticular opacity, OR 
• Unilateral vestibular schwannoma AND any two of: neurofibroma, 
meningioma, glioma, schwannoma, juvenile posterior subcapsular 
lenticular opacity, OR 
• Multiple meningiomas (two or more) AND unilateral vestibular 
schwannoma OR any two of: schwannoma, glioma, neurofibroma, 
cataract. 
3.1.2 Patients must have measurable disease, defined as at least one VS  > 0.4 ml (on 
volumetric analysis) that can be accurately measured by contrast-enhanced cranial 
MRI scan with fine cuts through the internal auditory canal (3 mm slices, no skip). 
 
3.1.3 Age  ≥ 6 years on day 1 of treatment.   
 
3.1.4 Life expectancy of greater than 1 year. 
 
3.1.5 Karnofsky performance status ≥ 70 (see Appendix C). 
  
3.1.6 Participants must have normal organ and marrow function as defined below: 
• Leukocytes > 3,000/mcL 

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• Absolute neutrophil count > 1,500/mcL 
• Platelets > 100,000/mcL 
• Total bilirubin within normal institutional limits 
• AST (SGOT)/ALT (SGPT) < 2.5 X institutional upper limit of normal 
• Patients must have a creatinine clearance or radioisotope GFR 
≥60ml/min/1.73 m2 or a normal serum creatinine based on age/gender 
described in the table below:     
 
Age 
 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
6 to < 10 years 
1 
1 
10 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
 
The threshold creatinine values in this Table were derived 
from the Schwartz formula for estimating GFR (Schwartz 
et al. J. Peds, 106:522, 1985) utilizing child length and 
stature data published by the CDC. 
 
3.1.7 Subjects must have a target VS with the following qualities: 
• Not amenable to surgery due to patient refusal, high risk for surgical 
complications (e.g., damage to lower cranial nerve function, tumor size > 3 
cm in longest diameter, or multilobulated tumor appearance on MRI scan). 
• Associated with a word recognition score of < 85% and > 5% 
• Documented clinical progression defined as EITHER:  
• Progressive hearing loss (defined as a decline in word recognition score 
below the 95% critical difference interval from baseline score (Appendix A) 
related to VS (i.e., not due to prior interventions such as surgery or 
radiation)  
 
OR  
• Progressive tumor growth in the preceding 18 months, defined as ≥ 20% 
increase in volume  
3.1.8 The effects of bevacizumab on the developing human fetus are unknown. For this 
reason and because bevacizumab agents are known to be teratogenic, women of 
child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence; surgical sterilization) prior 
to study entry and for the duration of study participation. Should a woman become 

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pregnant or suspect she is pregnant while participating in this study, she should 
inform her treating physician immediately. 
 
 
 
3.1.9 Ability to understand and the willingness to sign written informed consent and 
assent documents. 
 
3.1.10 Must have established relationship with primary care physician and provide contact 
information 
 
3.2 
Exclusion Criteria 
 
Participants who exhibit any of the following conditions at screening will not be 
eligible for admission into the study. 
 
3.2.1 Patients who have had chemotherapy within 4 weeks (6 weeks for nitrosoureas or 
mitomycin C) prior to entering the study or those who have not recovered from 
adverse events due to agents administered more than 4 weeks earlier.  Prior 
radiation treatment to the target vestibular schwannoma is allowed if provided 3 
years prior to participation in the clinical trial.  Prior radiation treatment to non-
target tumors is allowed.   
 
3.2.2 Participants may not be receiving any other study agents. 
 
3.2.3 Patients with nervous system tumors associated with NF2 (e.g., schwannomas, 
meningiomas, ependymomas, or gliomas) will not be excluded from this clinical 
trial unless (in the opinion of the investigator) these tumors are growing and are 
likely to require treatment during the clinical trial. 
 
3.2.4 History of allergic reactions attributed to compounds of similar chemical or 
biologic composition to bevacizumab. 
 
3.2.5 Patients with known hypersensitivity of Chinese hamster ovary cell products, 
other recombinant human antibodies, or compounds of similar chemical or 
biologic composition to bevacizumab. 
 
3.2.6 Inability to tolerate periodic MRI scans or gadolinium contrast. 
 
3.2.7 Uncontrolled intercurrent illness including, but not limited to ongoing or active 
infection, unstable angina pectoris, or psychiatric illness/social situations that 
would limit compliance with study requirements. 
 
3.2.8 History of arterial/myocardial disease. 
 
3.2.9 Clinically significant cardiovascular disease, such as: 

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• Inadequately controlled HTN (for adults: SBP > 160 mmHg and/or DBP > 
90 mmHg despite antihypertensive medication; for children: please refer to 
Appendix D for age-appropriate values indicating ≥ Grade 2) 
• History of CVA within 12 months 
• Myocardial infarction or unstable angina within 12 months 
• New York heart association grade II or greater congestive heart failure  
• Serious and inadequately controlled cardiac arrhythmia 
• Significant vascular disease (e.g., aortic aneurysm, history of aortic 
dissection) 
• Clinically significant peripheral vascular disease  
 
3.2.10 Pregnant women are excluded from this study because bevacizumab is an anti-
angiogenic agent with the potential for teratogenic or abortifacient effects. Because 
there is an unknown but potential risk of adverse events in nursing infants 
secondary to treatment of the mother with bevacizumab, breastfeeding should be 
discontinued if the mother is treated with bevacizumab. These potential risks may 
also apply to other agents used in this study. 
  
3.2.11 HIV-positive patients or cancer survivors are eligible for this study if they fulfill all 
other eligibility criteria. 
 
3.2.12 Concurrent use of anti-coagulant drugs (not including prophylactic doses), history 
of coagulopathy, or evidence of bleeding diathesis or coagulopathy. 
 
3.2.13 Imaging (CT or MRI) evidence of hemorrhage deemed significant by the treating 
physician (> grade 1).  Subjects with history of CNS hemorrhage are not eligible. 
 
3.2.14 Urine protein should be screened by urine analysis for Urine Protein Creatinine 
(UPC) ratio.  For UPC ratio > 0.5, 24-hour urine protein should be obtained and the 
level should be <1000 mg for patient enrollment. NOTE: UPC ratio of spot urine is 
an estimation of the 24-urine protein excretion. A UPC ratio of 1 is roughly 
equivalent to a 24-hour urine protein of 1 gm.  UPC ratio is calculated using one of 
the following formulas: 
•  [urine protein]/[urine creatinine] – if both protein and creatinine are 
reported in mg/dL 
•  [(urine protein) x0.088]/[urine creatinine] – if urine creatinine is reported 
in mmol/L 
3.2.15 Serious or non-healing wound, ulcer or bone fracture. 
3.2.16 History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess 
within 6 months prior to Day 1.  
3.2.17 Invasive procedures defined as follows: 
• Major surgical procedure, open biopsy or significant traumatic injury within 
28 days prior to Day 1 therapy 

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• Brain biopsy within 28 days prior to day 1 of therapy (wounds must be fully 
healed from brain biopsies performed more than 28 days prior to Day 1 of 
therapy) 
• Anticipation of need for major surgical procedures during the course of the 
study 
• Core biopsy within 7 days prior to Day 1 of therapy 
3.2.18 Prior treatment with bevacizumab. 
3.3 
Inclusion of Women, Minorities and Other Underrepresented Populations 
 
Both men and women, and members of all races and ethnic groups are eligible for this 
trial.   
 
4. REGISTRATION PROCEDURES 
   
4.1 
General Guidelines for NF Consortium Institutions 
 
Institutions will register eligible participants through a web-based data entry 
system created for that purpose by the NF Consortium Data Management and 
Analysis Center (DMAC). Registration must occur prior to the initiation of therapy. 
Any participant not registered to the protocol before treatment begins will be 
considered ineligible and registration will be denied.  
 
A physician on the study team will confirm eligibility criteria and complete the 
protocol-specific eligibility checklist. 
  
Following registration, participants may begin protocol treatment. Issues that 
would cause treatment delays should be discussed with the protocol Principal 
Investigator (PI).  
 
4.2 
Registration Process for NF Consortium Institutions 
 
The registration procedures are as follows: 
 
1. 
Obtain written informed consent from the participant prior to the performance 
of any study related procedures or assessments. 
 
2. Complete the protocol-specific eligibility checklist using the eligibility 
assessment documented in the participant’s medical/research record. To be 
eligible for registration to the study, the participant must meet each 
inclusion and exclusion criteria listed on the eligibility checklist. 
 
3. Enrollment and exclusion criteria will be entered through the NF Consortium’s 
web-based data entry system after receiving email confirmation from the 
Protocol PI (or his designee) that consented subject is eligible for study entry. 
 

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4. NF Consortium’s web-based data entry system will send enrollment 
confirmation via automated email alerts to study protocol team, Operations 
Center, site PI and site study coordinator. 
 
4.3 General Guidelines for all Participating Institutions 
 
The required forms for subject registration can be found on the UAB online entry 
system. 
 
Following registration, participants should begin protocol treatment within 28 days. 
Issues that would cause treatment delays should be discussed with the Principal 
Investigator. If a participant does not receive protocol therapy following registration, 
the participant’s protocol status must be changed. The Research Nurse Manager 
(Operations Center) should be notified of participant status changes as soon as 
possible by email. 
 
Each participating institution will order the study agent from the UAB Research 
Pharmacy. A participating site may order the agent only after the initial IRB approval 
for the site has been forwarded by the Operations Center. 
 
4.4 
Registration Process for All Participating Institutions 
 
To register a participant, the following documents should be completed and information 
entered online by the study coordinator or designee:  
• 
CBC, Chemistry-12, urinalysis, urine protein:creatinine ratio  
• 
Confirmation of signed study consent form 
• 
Confirmation of HIPAA authorization form 
• 
Confirmation of acceptability of baseline audiology by clinical research team 
in Principal Investigator’s office (Dr. Scott Plotkin) or Dr. Chris Halpin 
(Massachusetts Eye and Ear Infirmary)  
• 
Confirmation of baseline MRI scan including internal auditory canal 
protocol (3 mm slices, 0 mm gap)  
• 
Completion of Inclusion/Exclusion, Eligibility Checklist, and 
Registration forms located on the  UAB  web-based data entry system. 
 
NOTE: Registration with NF Consortium’s web-based data entry system can be 
conducted anytime, but the DMAC support can only be provided during the business 
hours of 8am – 5pm CST Monday through Friday.  Study sites are responsible for 
arranging initial and follow-up study treatments.  
 
5. TREATMENT PLAN  
 
Treatment will be administered on an outpatient basis. Expected toxicities and potential 
risks as well as dose modifications for bevacizumab are described in Section 6 (Expected 
Toxicities and Dosing Delays/Dose Modification).  Reported adverse events and potential 
risks are described in Section 2.1.  No investigational or commercial agents or therapies 

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other than those described below may be administered with the intent to treat the 
participant’s malignancy. 
 
Bevacizumab is administered by IV infusion at a dose of 10 mg/kg every 2 weeks for 24 
weeks (induction therapy, see Schema).  One cycle lasts 28 days and includes two infusions 
of bevacizumab.  Clinical response will be assessed by audiology and MRI at weeks 13 and 
25.  Subjects with hearing decline at weeks 13 and 25 will be taken off of protocol.  After 
week 25, patients with a clinical response or stable disease (together comprising “clinical 
benefit”) will transition to maintenance therapy with bevacizumab.  During the maintenance 
phase, subjects will be treated with open-label bevacizumab 5 mg/kg every 3 weeks for up 
to 72 weeks.  Subjects will be followed with audiology and MRI scans every 12 weeks.  The 
total time of the study will be 96 weeks (24 week induction + 72 weeks maintenance). 
   
During maintenance therapy, subjects will be allowed to increase their bevacizumab dose to 
10 mg/kg every 2 weeks if they experience hearing decline (defined as decrease in word 
recognition score below the 95% critical difference compared with the word recognition 
score at baseline, Appendix A) compared with the highest word recognition score during 
treatment.  Subjects will be taken off of study if their word recognition drops below the 95% 
critical difference (new hearing baseline defined as the word recognition score leading 
subject to receive 10 mg/kg dose every 2 weeks) after receiving bevacizumab 10 mg/kg 
every 2 weeks for at least 12 weeks.   
 
The planned treatment duration will be 96 weeks, but continued therapy on study will be 
allowed at the study chair’s discretion based on individual risk-benefit assessment. The 
consequence of treatment interruption/discontinuation in subjects who respond to treatment 
is not known. For example, discontinuation of VEGF receptor inhibitors has been associated 
with rebound edema in some patients with recurrent glioblastoma.45   
 
5.1 
Pre-treatment Criteria 
 
5.1.1 Cycle 1, Day 1 
 
 
 
Patients must have organ and marrow function as defined below: 
 
• leukocytes 
>3,000/mcL 
• absolute neutrophil count 
>1,500/mcL 
• platelets 
>100,000/mcL 
• creatinine  
< 1.5 ULN for age 
• total bilirubin 
≤2 X institutional ULN 
• AST(SGOT)/ALT(SGPT) 
≤2.5 X institutional ULN  
• urine protein:creatinine ratio 
≤ 1 
 
 
 
 

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5.1.2 Subsequent Cycles, Day 1 
 
 
Patients must have organ and marrow function as defined below: 
 
• leukocytes 
>3,000/mcL 
• absolute neutrophil count 
>1,500/mcL 
• platelets 
>100,000/mcL 
• creatinine  
< 1.5 ULN for age 
• total bilirubin 
≤2 X institutional ULN 
• AST(SGOT)/ALT(SGPT) 
≤2.5 X institutional ULN  
• urinary dipstick/urinalysis 
≤ 2+ protein 
• urine protein:creatinine ratio 
< 3.5 (if urine dipstick > 2+) 
 
Special Precautions/Safety Issues 
Prior to each treatment, the patient should be carefully assessed with special attention to 
blood pressure, proteinuria, bleeding and cardiovascular events, as well as symptoms or 
signs of bowel perforation and RPLS.  Decisions for retreatment or dose 
modification/interruption should follow the dose modification guidelines in Section 6.3. 
 
Patients who have an ongoing study agent-related serious adverse event upon study 
completion or at discontinuation from the study will be contacted by the investigator or 
his/her designee periodically until the event is resolved or determined to be irreversible. 
 
Infusional reactions. Routine premedication is not required for the first dose of 
bevacizumab. If infusional reactions occur, acetaminophen, diphenhydramine, steroids or 
other medications may be given for symptom control and for premedication as needed. 
Anaphylactic precautions should be observed during bevacizumab administration. 
 
Hypertension. Patients should have BP monitored prior to each infusion of bevacizumab. 
Hypertensive medication should be initiated or increased for optimal BP control 
according to Appendix D. Specific guidelines for the management of hypertension are 
provided for children 6 through 17 years old enrolled on this trial (Sections 6.3 and 
Appendix D). 
 
Proteinuria. Proteinuria should be monitored by urine protein: creatinine (UPC) ratio and 
dipstick as indicated in study calendar.  If urine dipstick ≤ 2+ protein, bevacizumab can 
be infused.  If urine dipstick > 2+, infusion can be provided once the UPC ratio is 
reported to be < 3.5. 
 
Surgery and wound complication issues. The appropriate interval from discontinuation 
of bevacizumab to subsequent elective surgery required to reduce the risk of impaired 
wound healing has not been determined. Decision on such an interval should take into 
consideration the half-life of bevacizumab. It is generally recommended that 
bevacizumab should be discontinued at least 4-8 weeks prior to major elective surgery. In 
addition, bevacizumab should not be restarted until at least 4 weeks after major surgery 
provided that the wound has adequately healed; in cases of high-risk procedures such as 

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liver resection, thoracotomy or neurosurgery, it is recommended that bevacizumab be 
resumed no earlier than 8 weeks after surgery.  NOTE: If bevacizumab is interrupted for 
ANY reasons for > 12 weeks, the patient should discontinue bevacizumab therapy on 
protocol. 
 
Bony toxicity. Children 6 through 17 years old will be carefully monitored for the 
development of bony toxicity (Sections 6.3 and Appendix E). 
 
For patients with open growth plates on tibial radiographs at baseline, measurements of 
stature (height) will be measured at visits on weeks 13, 25, 49, 73, and 91.  Bevacizumab 
will be discontinued if: 
 
• <1 cm growth is noted prior to week 25  
• <2.5 cm growth is noted prior to week 49 
• Subsequently, <2cm/year annualized growth velocity noted every 24 weeks (for 
patients with open growth plates only) 
 
5.2 Bevacizumab Administration  
 
Bevacizumab is administered by IV infusion at a dose of 10 mg/kg every 2 weeks 
(dose level +1) for 24 weeks (induction therapy) followed by a dose of 5 mg/kg every 3 
weeks (dose level 0) for 72 weeks (maintenance therapy).  During induction therapy, 
one cycle lasts 28 days and includes two infusions of bevacizumab; during 
maintenance therapy, one cycle lasts 42 days and includes two infusions.  The dose 
should be based on the patient’s actual body weight.   The first dose of bevacizumab 
should be given over 90 minutes.  If well-tolerated, the second dose can be given over 
60 minutes. If this dose is well tolerated, then all subsequent infusions can be 
administered over 30 minutes. If an infusion reaction occurs, subsequent doses of 
bevacizumab should be administered over the shortest period that was well tolerated.   
 
5.3 
Definition of Dose-Limiting Toxicity 
 
N/A 
 
5.4 
General Concomitant Medication and Supportive Care Guidelines 
 
There is no known interaction of bevacizumab with other concomitantly administered 
drugs. Prophylactic low-dose (81 mg or 325 mg/day) acetylsalicylic acid and systemic 
anticoagulation is allowed (LMWH preferred relative to warfarin). Other medication 
considered necessary for the subject’s safety and well being may be given at the 
discretion of the investigator. 
 
Prolonged systemic corticosteroid treatment should not be given during the study, 
except for topical applications (e.g., rash), inhaled sprays (e.g., obstructive airways 
diseases), eye drops or local injections (e.g., intra-articular). A short duration (≤ 15 

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days) of systemic corticosteroids is allowed (e.g., for sudden hearing loss, chronic 
obstructive pulmonary disease, or as an anti-emetic).  
 
Cases of sudden hearing loss during treatment (defined as hearing loss with onset over 
a period of less than 72 hours) may be treated with a short course of high dose 
glucocorticoids (e.g., prednisone 60 mg daily for 10 days followed by a taper of 10 mg 
every day).  These patients should have repeat audiology performed during the episode 
at the discretion of the treating physician to document hearing function (see section 5.5 
for guidance on continuing therapy). 
 
5.5 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue for 2 
years (96 weeks) or until one of the following criteria applies (whichever occurs first): 
 
 
• Hearing decline at the 10 mg/kg every 2 week dose during induction 
therapy.  NOTE: Patients with episodes of sudden hearing loss (Section 5.4) or 
hearing loss related to other causes (e.g., otitis media, allergic symptoms, or other 
infectious causes) should remain on treatment provided their word recognition 
score returns to the 95% critical difference compared with baseline [Appendix A] 
within 14 days of the start of the event.) 
• Hearing decline at the 10 mg/kg every 2 week dose during maintenance 
therapy (hearing decline is defined as a decline in word recognition score below 
the 95% critical difference interval from word recognition score leading subject to 
receive 10 mg/kg dose [Appendix A] ) after receiving bevacizumab 10 mg/kg 
every 2 weeks for at least 12 weeks.  NOTE: Patients with episodes of sudden 
hearing loss (Section 5.4) or hearing loss related to other causes (e.g., otitis media, 
allergic symptoms, or other infectious causes) should remain on treatment 
provided their word recognition score returns to the 95% critical difference 
compared with baseline [Appendix A] within 14 days of the start of the event.) 
• Radiographic progression of NF2-associated tumors (target VS, contralateral VS, 
meningiomas, or ependymomas) that require additional or alternate therapies 
(Section 10.1.4); (NOTE: Growth of NF2-associated tumors that is consistent 
with the natural history of the disease is not a criterion for discontinuing protocol 
therapy.) 
• Intercurrent illness that prevents further administration of treatment; 
• Unacceptable adverse event(s), including, but not limited to: 
o Grade 4 hypertension or Grade 3 hypertension not controlled with 
medication 
o Nephrotic syndrome 
o Grade ≥ 2 pulmonary or CNS hemorrhage; any Grade 4 hemorrhage 
o ≥ Grade 2 venous thromboembolic event 
o Any grade arterial thromboembolic event 
o ≥ Grade 2  congestive heart failure 
o Gastrointestinal perforation or new gastrointestinal fistula (any Grade) 
o Tracheoesophageal fistula (any grade) or Grade 4 fistula 

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o Grade ≥ 2 bowel obstruction  
o Wound dehiscence requiring medical or surgical intervention 
o Pregnancy during the study period (for female participants) 
o All Grade 4 events thought to be related to bevacizumab by the 
investigator (NOTE: Patients who have an ongoing bevacizumab-
related Grade 4 or serious adverse event at the time of discontinuation 
from study treatment will continue to be followed until resolution of 
the event or until the event is considered irreversible [See Section 
7.1.3].) 
• Participant decides to withdraw from the study; or 
• General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the opinion of the treating investigator. 
 
Withdrawal of full consent for a study means that the subject does not wish to receive 
further investigational treatment and does not wish to or is unable to continue further 
study participation; subject data up to withdrawal of consent will be included in the 
subject’s study data. Any subject may withdraw full consent to participate in the study 
at any time during the study. The investigator will discuss with the subject appropriate 
procedures for withdrawal from the study. 
 
Withdrawal of partial consent means that the subject does not wish to take 
protocol-specified product any longer but is still willing to collaborate in providing 
further data by continuing on study (eg, participate in any or all subsequent study visits or 
procedures). Subjects may decline to continue receiving protocol-specified product at any 
time during the study. If this occurs, the investigator will discuss with the subject 
appropriate procedures for withdrawal from protocol-specified therapy. These subjects, as 
well as those who have stopped receiving protocol-specified product(s) for other reasons 
(eg, investigator or sponsor concern) should continue the schedule of study observations 
at the discretion of the principal investigator. 
 
NOTE: A course of high dose glucocorticoids (typically prednisone 60 mg daily for 10 
days followed by a taper of 10 mg every day) is permitted at the discretion of the treating 
physician in cases of sudden hearing loss during treatment (defined as hearing loss with 
onset over a period of less than 72 hours). 
 
5.6 
Duration of Follow-Up  
 
Participants will be followed in person or by telephone for 12 weeks after 
removal from study. Participants removed from study for unacceptable adverse 
events will be followed until resolution or stabilization of the adverse event. 
  
5.7 
Criteria for Removal from Study  
 
Participants will be removed from study when any of the criteria listed in Section 
5.5 applies. The reason for study removal and the date the participant was 

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removed must be documented in the data entry system. Alternative care options 
will be discussed with the participant. 
 
In the event of unusual or life-threatening complications, participating investigators 
must immediately notify the Principal Investigator (or Protocol Chair), Scott 
Plotkin, MD, PhD at 617-726-2000 (pager #34635) and Bruce Korf, MD, PhD, at 
205-934-9411 (UAB Operations Center Office) or Liz Davis at 205-934-5376 
(Research Nurse Manager) or email: nfconsortium@uab.edu. 
 
6. EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS  
 
A number of measures will be taken to ensure the safety of patients participating in this trial.  
These measures will be addressed through exclusion criteria (see Section 3.2) and routine 
monitoring as follows. 
Patients enrolled in this study will be evaluated clinically and with standard laboratory tests 
before and at regular intervals during their participation in this study.  Safety evaluations 
will consist of medical interviews, recording of adverse events, physical examinations, 
blood pressure, and laboratory measurements.  Patients will be evaluated for adverse events 
(all grades), serious adverse events, and adverse events requiring study drug interruption or 
discontinuation at each study visit for the duration of their participation in the study.  
Patients discontinued from the treatment phase of the study for any reason will be evaluated 
~30 days (28–42 days) after the decision to discontinue treatment (see Section 5.5).   
Specific monitoring procedures are as follows: 
• Hypertension will be monitored through routine evaluation of blood pressure prior to 
each bevacizumab treatment.  Optimal control of blood pressure is recommended for 
patients on treatment with or without bevacizumab. Blood pressure monitoring during 
study drug administration should be performed according to institutional guidelines. 
• Proteinuria will be monitored by urine protein:creatinine (UPC) ratio and 
urinalysis/dipstick at least every 6 weeks.  
• If patients on treatment with bevacizumab require major surgery, it is recommended 
that bevacizumab be held for 4-8 weeks prior to the surgical procedure. Patients 
undergoing a major surgical procedure should not begin/restart bevacizumab until 4 
weeks after that procedure. In the case of high risk procedures (such as liver 
resection, thoracotomy, or neurosurgery), it is recommended that chemotherapy be 
restarted no earlier than 6 weeks and bevacizumab no earlier than 8 weeks after 
surgery. 
 
Dose delays and modifications will be made using the following recommendations. Toxicity 
assessments will be done using the CTEP Version 4.03 of the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) which is identified and located on the CTEP website 
at: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
 

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Dose Level 
Bevacizumab  Dose 
-2 
3 mg/kg IV every 3 weeks 
-1 
4 mg/kg IV every 3 weeks 
0 
5 mg/kg IV every 3 weeks 
+1 
10 mg/kg IV every 2 weeks 
If possible, symptoms should be managed symptomatically. In the case of toxicity, 
appropriate medical treatment should be used (including anti-emetics, anti-diarrheals, etc.). 
 
All adverse events experienced by participants will be collected from the time of the first 
dose of study treatment, through the study and until the final study visit. Participants 
continuing to experience toxicity at the off study visit may be contacted for additional 
assessments until the toxicity has resolved or is deemed irreversible. 
 
6.1 
Anticipated Toxicities 
  
Toxicities with a possible association to bevacizumab treatment include: 
 
Frequent (Chance of 10-50% that this will happen) 
• Fatigue 
• Headaches 
• High blood pressure, with increased risk of heart problems, headache and stroke.  
• Pain 
• Abdominal pain 
• Shortness of breath 
• Mouth sores  
• Weakness 
• Upper respiratory infection  
• Chills  
• Loss of appetite 
• Bleeding (including in stomach or intestines) 
• Runny nose or increase in tears in your eyes  
• Kidney damage, found by testing your urine 
• Irregular menstrual period or loss of menstrual period 
• Loss of function of the ovaries (female sex glands), that can lead to menopause.  
Studies in humans have shown a decrease in the function of ovaries during 
treatment with bevacizumab with chemotherapy.  This condition results in 
difficulty becoming pregnant.  In some participants, the function of the ovaries 
returned to normal after treatment with bevacizumab and chemotherapy was 
stopped.  
 
Occasional (Chance of 5-10% that this will happen) 

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• Hoarseness 
• Nosebleeds 
• Low levels of potassium in the blood (can cause an irregular heartbeat) 
• Hair loss  
• Dry Skin 
• Hole in your intestine; requires hospitalization and/or surgery; could be fatal. 
• Blood clots in your veins and arteries.  These can cause chest pain, heart attack, or 
stroke.  A blood clot in your eye might cause vision loss.  Clots can be serious and 
life threatening.  
• Allergic reaction when infusion is given.  Serious allergic reaction may result in 
death.  
• Slowed growth in height and development (for children and young adults who are 
still growing).  Laboratory studies have shown a decreased in growth during 
treatment with bevacizumab .   
 
Rare (Chance < 5% that this will happen) 
• Congestive heart failure (fluid that builds up in your lungs because your heart isn’t 
working properly). 
• Bevacizumab might affect the ability of your wounds to heal.  This can lead to 
infections, hospitalization, or could possibly be fatal. 
• A very rare problem in your brain that may cause confusion, blindness, and coma 
has been seen in some patients that were given Bevacizumab.  This is associated 
with very high blood pressure and is not thought to be a permanent condition. 
• Confusion 
• Abdominal abscess or infection in your abdomen 
• Fistula or hole in your bowel.  This is an abnormal connection between two 
different organs and may lead to life threatening complications including serious 
infections, bleeding, or dysfunction of the organs. 
• Dehydration 
• Abnormal bleeding in your body or from the tumor, which may be fatal. 
• Laboratory studies of bevacizumab showed abnormal bone growth.  These and 
other effects of bevacizumab could possibly cause problems with growth and 
development.  Abnormal changes in the bones after treatment with bevacizumab 
have been seen in young children with growing bones.  This side effect appeared to 
be reversible after the drug was stopped, but has not been studied with long-term 
use of the drug.  All participants in this study who receive bevacizumab and are still 
growing will be monitored for changes to bones by the use of x-rays performed 
throughout the study treatment. 
• Fistula or hole in your gallbladder (part of the intestines that helps with digestion).  
This may require surgery and be serious or life threatening. 
• Osteonecrosis of the jaw.  A severe bone disease in which the jaw bone becomes 
visible (exposed) inside the mouth. This can be associated with pain and infection. 
 
 
 

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6.2 
Toxicity Management 
 
 
Any toxicities associated or possibly associated with bevacizumab treatment should be 
managed according to standard medical practice. Discontinuation of bevacizumab will 
have no immediate therapeutic effect. Bevacizumab has a terminal half-life of 21 days; 
therefore, its discontinuation results in slow elimination over several months. There is 
no available antidote for bevacizumab.  
 
6.3 
Dose Modifications/Delays 
  
A list of the adverse events and potential risks associated with the agents administered 
in this study appear below. 
NOTE 1: Treatment should be interrupted or discontinued for certain adverse events, 
as described below. Doses missed while recovering from toxicity will not be made up.  
The AEs will be defined based on CTCAE term (AE description) and grade.  The 
descriptions and grading scales found in the CTEP Version 4.03 of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) will be utilized for AE reporting.  
The CTEP Version 4.03 of the CTCAE is identified and located on the CTEP website 
at: http://ctep.cancer.gov/.  All appropriate treatment areas will have access to a copy of 
the CTEP Version 4.03 of CTCAE.  Details of actions to be taken based on a particular 
AE (using the most active CTCAE version) are provided below.  
 
NOTE 2: If bevacizumab is interrupted for ANY reasons for > 12 weeks, the patient 
should discontinue bevacizumab therapy on protocol. 
 
NOTE 3: Subjects will be allowed to increase their bevacizumab dose to 10 mg/kg 
every 2 weeks during maintenance therapy if they experience hearing decline during 
maintenance therapy (defined as decrease in word recognition score below the 95% 
critical difference compared with the word recognition score at baseline, Appendix A).  
Subjects will be taken off of study if their word recognition score does not remain 
within the 95% critical difference (determined from word recognition score leading 
subject to receive 10 mg/kg dose) after receiving bevacizumab 10 mg/kg every 2 weeks 
for at least 3 months.   
 
Subjects should be assessed clinically for toxicity prior to, during, and after each 
infusion. If unmanageable toxicity occurs because of bevacizumab at any time during 
the study (Table 1), treatment with bevacizumab should be discontinued.  
 
Infusion Reaction: Infusion of bevacizumab should be interrupted for subjects who 
develop dyspnea or clinically significant hypotension. Subjects who experience a NCI 
CTCAE v. 4.3 Grade 3 or 4 allergic reaction / hypersensitivity, adult respiratory 
distress syndrome, or bronchospasm (regardless of grade) will be discontinued from 
bevacizumab treatment. 
 
The infusion should be slowed to 50% or less or interrupted for subjects who 
experience any infusion-associated symptoms not specified above. When the subject’s 

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symptoms have completely resolved, the infusion may be continued at no more than 
50% of the rate prior to the reaction and increased in 50% increments every 30 
minutes if well tolerated. Infusions may be restarted at the full rate during the next 
cycle.  
 
Adverse events requiring delays, dose reductions, or permanent discontinuation of 
bevacizumab are listed in Table 1.  
 
 
Table 1:  Bevacizumab Dose Management Due to Adverse Events 
 
Event 
Action to be Taken 
Hypertension (in adults only) 
No dose modifications for grade 1 or 2 events 
Grade 3 
If not controlled to 150/100 mmHg with medication, reduce 
one dose level.  For second occurrence, reduce a second 
dose level.  For third occurrence, discontinue bevacizumab. 
Grade 4 (including 
hypertensive 
encephalopathy) 
Discontinue bevacizumab. 
*Specific guidelines for the management of hypertension are provided for adults and children 6 
through 17 years (Appendix D).  
Hemorrhage 
No dose modifications for grade 1or 2 non-pulmonary and non-CNS events 
  Grade 3   
  Non-pulmonary 
and 
    non-CNS 
hemorrhage 
Subjects who are also receiving full-dose anticoagulation 
will be discontinued from receiving bevacizumab.   
All other subjects will have bevacizumab held until all of 
the following criteria  are met: 
• The bleeding has resolved and hemoglobin is stable. 
• There is no bleeding diathesis that would increase the risk 
of therapy. 
• There is no anatomic or pathologic condition that 
significantly increases the risk of hemorrhage recurrence. 
Subjects who experience a repeat Grade 3 hemorrhagic 
event will be discontinued from receiving bevacizumab. 
  Grade 4  
     non-pulmonary 
or  
    non-CNS 
hemorrhage 
Discontinue bevacizumab. 

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   Grade 1 
pulmonary or CNS 
hemorrhage 
Subjects who are also receiving full-dose anticoagulation 
will be discontinued from receiving bevacizumab.   
All other subjects will have bevacizumab held until all of 
the following criteria  are met: 
• The bleeding has resolved and hemoglobin is stable. 
• There is no bleeding diathesis that would increase the risk 
of therapy. 
• There is no anatomic or pathologic condition that 
significantly increases the risk of hemorrhage recurrence. 
 
Grade 2, 3, or 4 
pulmonary or CNS 
hemorrhage 
Discontinue bevacizumab. 
Venous Thrombosis 
No dose modifications for grade 1 events 
 
Grade 2, 3, or 4 
Discontinue bevacizumab. 
 
Arterial Thromboembolic event 
(New onset, worsening, or unstable angina, myocardial infarction, transient ischemic attack, 
cerebrovascular accident, and any other arterial thromboembolic event) 
 Any grade 
Discontinue bevacizumab. 
Congestive Heart Failure (Left ventricular systolic dysfunction) 
No dose modifications for grade 1 events 
Grade 2, 3, and 4 
Discontinue bevacizumab. 
Proteinuria 
No dose modifications for grade 1/2 events 
Grade 3 
(UPC> 3.5, urine 
collection > 3.5 g/24 
hr)   
 
Hold bevacizumab treatment until ≤ Grade 2, as determined by 
either UPC ratio ≤ 3.5 or 24 hr collection ≤ 3.5 g, and reduce by 
one dose level.  For second occurrence, reduce by a second dose 
level.  For third occurrence, discontinue bevacizumab. 
 
Grade 4 (nephrotic 
syndrome) 
Discontinue bevacizumab. 
GI Perforation 
 
Discontinue bevacizumab. 
Fistula  
 
Any grade (TE or 
gastrointestinal 
fistula) 
Discontinue bevacizumab. 
Grade 4 fistula 
Discontinue bevacizumab. 
Bowel Obstruction 
Grade 1 
 
Continue patient on study for partial obstruction NOT requiring 
medical intervention. 
 
 

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Grade 2, 3, or 4 
Discontinue bevacizumab. 
 
Wound dehiscence 
Any grade 
(requiring medical 
or surgical therapy) 
Discontinue bevacizumab. 
Reversible Posterior LeukoencephalopathySyndrome (RPLS)  
Any grade 
(confirmed by MRI) 
Discontinue bevacizumab. 
Ovarian function 
Follicle stimulating 
hormone (FSH) > 
20 Units/L 
Hold bevacizumab and refer patient to qualified practitioner 
(eg., reproductive endocrinology specialist) to assess ovarian 
function.  Subject should have measurement of anti-Mullerian 
hormone (AMH) and ultrasound of ovaries for determination of 
antral follicle count by qualified practitioner. If assessment 
reveals evidence of premature ovarian failure, consider 
discontinuation of bevacizumab after discussion with subject, 
medical monitor, and study PI.  No additional actions are 
required for subsequent occurrences. 
Other Unspecified Bevacizumab-Related Adverse Events 
Grade 3 
Grade 4 
Hold bevacizumab until recovery to ≤ Grade 1 
Discontinue bevacizumab. 
 
Hypertension in children aged 6 - 17 years: 
Any patient with a diastolic blood pressure greater than 25 mmHg above the 95th% for age 
and gender (Appendix D) confirmed by repeated measurements will result in reduction of 
one dose level.  For a second occurrence, discontinue bevacizumab. (See Appendix D for 
assessment of blood pressure recordings and for management.) 
   
In children on antihypertensive therapy, a diastolic blood pressure ≥25 mmHg above the 95th 
% for age and gender for >14 days will result in reduction of one dose level.  For a second 
occurrence, discontinue bevacizumab (see Appendix D).   
 
Dose limiting bony changes in children aged 6 - 17 years 
 
Children 6 - 17 years old will be carefully monitored for the development of bony toxicity 
(Sections 6.3 and Appendix E). 
 
For patients with open growth plates on tibial radiographs at baseline, measurements of 
stature (height) will be measured at weeks 13, 25, 49, 73, and 91.  Bevacizumab will be 
discontinued if: 
 
• <1 cm growth is noted prior to week 25  
• <2.5 cm growth is noted prior to week 49 
• Subsequently, <2cm/year annualized growth velocity noted every 24 weeks for patients 
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7. DRUG FORMULATION AND ADMINISTRATION  
 
7.1 
Bevacizumab 
 
7.1.1 Description 
 
Other Names. rhuMAb VEGF, Avastin® 
 
Classification. Recombinant humanized monoclonal antibody 
 
Molecular Weight. Approximate molecular weight is 149,000 daltons 
 
Mode of Action. Bevacizumab blocks the binding of vascular endothelial growth 
factor (VEGF) to its receptors resulting in inhibition of angiogenesis. 
 
Description. Bevacizumab is a recombinant humanized anti-VEGF monoclonal 
antibody consisting of 93% human and 7% murine amino acid sequences. The 
agent is composed of human IgG framework and murine antigen-binding 
complementarity-determining regions 
 
Route of Administration. Intravenous 
 
Terminal half-life.  21 days 
 
For further details and molecule characterization, see the bevacizumab 
Investigator Brochure. 
 
7.1.2 Form 
 
Bevacizumab is a clear to slightly opalescent, colorless to pale brown, sterile 
liquid concentrate for solution for intravenous (IV) infusion.  Bevacizumab may 
be supplied in 5-cc (100-mg) and 20-cc (400-mg) glass vials containing 4 mL or 
16 mL bevacizumab, respectively (all at 25 mg/mL).  Vials contain bevacizumab 
with phosphate, trehalose, polysorbate 20, and Sterile Water for Injection 
(SWFI), USP.  Vials contain no preservative and are suitable for single use only. 
 
7.1.3 Storage and Stability 
 
Upon receipt of the study drug, vials are to be refrigerated at 2°C–8°C  
(36°F–46°F) and should remain refrigerated until just prior to use.  DO NOT 
FREEZE.  DO NOT SHAKE.   Vials should be protected from light. 
Opened vials must be used within 8 hours.  VIALS ARE FOR SINGLE USE 
ONLY.  Vials used for 1 subject may not be used for any other subject.  Once 
study drug has been added to a bag of sterile saline, the solution must be 
administered within 8 hours. 
  

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7.1.4 Compatibility 
 
Bevacizumab will be diluted in a total volume of 100mL of 0.9% Sodium 
Chloride Injection, USP. 
7.1.5 Handling 
 
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and 
safe disposal of the chemotherapeutic agent in a self-contained and protective 
environment. 
 
7.1.6 Availability 
 
Distribution:  Bevacizumab will be supplied free of charge by Genentech, Inc. 
and will be distributed to investigators by a designated central pharmacy (UAB 
Pharmacy).  
 
7.1.7 Preparation 
 
Bevacizumab will be diluted in a total volume of 100mL of 0.9% Sodium 
Chloride Injection, USP.  Opened vials must be used within 8 hours.  VIALS 
ARE FOR SINGLE USE ONLY.  Vials  used for 1 patient may not be used for 
any other patient.  Once study drug has been added to a bag of sterile saline, the 
solution must be administered within 8 hours.   
  
7.1.8 Administration 
 
Anaphylaxis precautions should be observed during study drug administration.   
The initial dose will be delivered over 90±15 minutes.  If the first infusion is 
tolerated without infusion-associated adverse events (e.g., fever and/or chills), 
the second infusion may be delivered over 60±10 minutes.  If the 60-minute 
infusion is well tolerated, all subsequent infusions may be delivered over 
30±10 minutes.  If a subject experiences an infusion-associated adverse event 
with the 60-minute infusion, all subsequent doses should be given over 
90±15 minutes.  Similarly, if a subject experiences an infusion-associated 
adverse event with the 30-minute infusion, all subsequent doses should be given 
over 60±10 minutes.   
 
If a subject experiences an infusion–associated adverse event, he or she may be 
premedicated for the next study drug infusion; however, the infusion time may 
not be decreased for the subsequent infusion.  If the next infusion is well 
tolerated with premedication, the subsequent infusion time may then be 
decreased by 30±10 minutes as long as the subject continues to be premedicated.   

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It is not necessary to correct dosing based on ideal weight. 
 
To insure complete delivery of bevacizumab, flush the IV infusion line with 0.9% 
sodium chloride. The following are two recommended methods for flushing the 
bevacizumab IV infusion line: 
 
• When the bevacizumab infusion is complete, add an additional 50mL of 0.9% 
sodium chloride for injection to the bevacizumab infusion bag. Continue the 
infusion until a volume equal to that of the volume contained in the tubing has 
been administered. 
 
• Replace the empty bevacizumab infusion bag with a 50mL bag of 0.9% 
sodium chloride for injection and infuse a volume equal to the volume 
contained in the tubing. NOTE: the flush is not included in the total 
recommended infusion times. 
 
7.1.9 Ordering 
 
(See Appendix B for Bevacizumab Supply Request Form) 
 
Initial Shipments (new patients registered to study) 
When a site has received Sponsor IRB approval and has identified potential 
patients to screen, the study site will complete a ‘Drug Order Request Form’ 
and submit this request to UAB Pharmacy.   
 
After faxing to the request, study site will:  
• Place a call UAB Pharmacy confirming the faxed order was received, and 
confirm estimated day and time of arrival for the study drug.   
• UAB will pack and ship the required number of bevacizumab vials to the 
site for the patient to complete treatment for 24 weeks based on the 
patient’s weight (kg).  Initially, 20 vials will be sent. 
 
Subsequent Shipments (active patients requiring additional bevacizumab 
supply) 
When additional bevacizumab is required for a subject, the study site will 
complete a ‘Bevacizumab Supply Request’ and submit to UAB by calling 205-
975-6647.  
 
After faxing to UAB, site will:  
• Place a call to UAB to confirm the order was received, and arrange day and 
time of arrival for the study drug.   
• UAB will pack and ship the required number of bevacizumab vials to the 
site. 
• UAB Pharmacy will pack and ship the additional vials of bevacizumab 
vials for 24 weeks based on the subject’s weight (kg). 
 

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For all drug shipments from UAB: 
 
• Bevacizumab will be shipped in original manufacturers packaging.   Boxes 
are placed in a ZipLock bag.  Subject-specific labeling will be added at the 
clinical study site. 
 
• A complete accountability record (including date of dispense, site name, 
quantity dispensed, and balance forward) will be recorded.  Study 
accountability records are documented in electronic 21 CFR format and are 
kept in a secured area for duration of the study. 
 
• Require a Pharmacist review; a licensed pharmacist checks off package for 
accuracy of contents, authorizing order via 21 CFR compliant trial 
accountability log. 
 
• Each shipment includes the following information: 
• Study number  
• IND caution statement and/or local regulatory statements 
• Drug identification 
• Lot number and expiration 
• Storage conditions 
• Dosing instructions (Take as Directed per Protocol) 
(Subject ID number, initials and date dispensed will be provided 
by the study site pharmacy.) 
 
• Enclose a packing slip that includes the quantity of drug provided with a 
section to be completed once received by the site coordinator. This section 
includes confirmation of drug receipt, verification of package contents, and 
instruction to fax the completed packing slip to UAB.   
 
• Process and ship authorized and completed orders “same day” of patient 
randomization if received  Monday through Thursday. Authorized and 
completed orders received after 12N CST Thursday, will be sent on the 
following Monday or Tuesday if Monday is a Holiday.  Orders will be 
processed and shipped the next business morning.  
 
All drug orders are shipped via FedEx for Priority Overnight delivery. 
Bevacizumab is shipped with a gel pack to maintain temperature stability.   
 
Packages are tracked until confirmed delivered and delivery exceptions are 
managed with the highest level of urgency to ensure therapy start date 
adherence.  Packing slips with the shipment tracking number included will be 
faxed to the designated site coordinator for all shipments. 
 
 
 

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Once study drug is received at the clinical trial site: 
 
• The designated site coordinator or Investigational pharmacy representative 
validates that contents of package matches information provided on 
packing slip, signs off on the packing slip, and contacts UAB to validate 
shipment has been received and is accurate.  
 
The order transaction is completed by entering the receipt confirmation and 
signed packing slip into the study file. 
 
Drug Destruction and Transfer of Study Drug 
Sites will be instructed to destroy unused/returned drug per institution policy 
and note in the accountability record after site Pharmacy Drug Destruction 
Policy is sent to Operations Center and policy is placed in the regulatory files. 
Drug destruction policy should also be maintained in Pharmacy. 
 
Since study drug vials are sent to study sites, Bevacizumab may be used for all 
consented subjects. Use of all study drug vials will be documented on study 
drug accountability records. 
 
Central Pharmacy – UAB 
Rebecca Quinn, PharmD 
Senior Pharmacist -Investigational Drug Service 
UAB Hospital 
North Pavilion, room 3470 
1802 6th Avenue South 
Birmingham, AL  35249 
205-934-7191 (phone) 
205-975-6647 (fax) 
UAB paging: 205-934-3411, pager 4295 
 
7.1.10 Accountability 
 
The investigator, or a responsible party designated by the investigator, must 
maintain a careful record of the inventory and disposition of the agent 
(investigational or free of charge) using the NCI Drug Accountability Record or 
another comparable drug accountability form. (See the CTEP website at 
http://ctep.cancer.gov/protocolDevelopment  for the “Policy and Guidelines for 
Accountability and Storage of Investigational Agents” or to obtain a copy of the 
drug accountability form.) 
 
Sites will be required to send site drug accountability records to Operations 
Center on a quarterly basis.  The site study drug accountability records will be 
checked against UAB Pharmacy study drug administration data accountability 
records.  
 

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Drug accountability records should be submitted quarterly to UAB: 
 
Roy McDonald, MPH 
Research Compliance Manager  
Department of Genetics  
University of Alabama at Birmingham 
1720 20th Street South, MCML 262A  
Birmingham, AL  35294-0024 
 
 
 
 
 
205-975-4075 (phone) 
 
 
 
 
 
205-975-3543 (fax) 
 
 
 
 
 
Email: rmcdonald@uab.edu  
 
 
7.1.11 Destruction and Return 
 
At the end of the study, unused supplies of bevacizumab should be destroyed 
according to institutional policies. Destruction will be documented in the Drug 
Accountability Record Form. 
8. CORRELATIVE/SPECIAL STUDIES  
8.1 
Pharmacokinetic Studies 
 
N/A 
8.2 
Pharmacodynamic Studies 
 
N/A 
8.3 
Laboratory correlative markers 
8.3.1 Markers of angiogenesis and tumor growth 
 
Recent development in understanding the molecular basis of cancer has 
dramatically advanced the field in cancer drug discovery and development. Now 
it is clear that the translation of molecularly targeted cancer therapy into useful 
and practical therapeutic approaches is highly complex. The discovery of 
mechanism-based biomarkers can facilitate the efficient development of new anti-
tumor medicines and potentially serve as true intermediate or surrogate end point 
biomarkers for future clinical trials. Biomarkers can also help guiding rational 
selection of therapeutic agents for patient likely to respond to therapy. Two recent 
studies show that collagen IV structure was modified after VEGFR2 blockade. 
These data together with other data on different biomarkers indicate that it is 
important to include measurement on the serum levels of biomarkers in future 
clinical practices. 
 

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To measure numerous biomarkers simultaneously with exceptional sensitivity but 
only small amount of plasma proteins, the MSD (Meso Scale Discovery, Maryland) 
platform will be used. MSD technology utilizes electrochemiluminescence 
detection to detect binding events on patterned arrays.  By customizing the Multi-
Array, multiple serum molecules can be tested. We will collect blood samples from 
the patients before and during the course of treatment (see study table). Analysis 
will be performed for VEGF-A, VEGF-C, sVEGFR1, sVEGFR2, sVEGFR3, Col 
IV, SDF1a, IL-1beta, IL-6, IL-8, TNFalpha, G-CSF, Ang1, Ang2, sTie2, s-cKIT, 
MMP-1, MMP-2, MMP-3, MMP-9, MMP-10, PlGF, and bFGF using the Meso-
Scale Discovery multiplex array reader and custom multiplex plates and R&D 
Systems ELISA kits for collagen IV and SDF1α. This assay provides a sensitivity 
of 0.001 ng/mL and low variability. The level of these biomarkers during treatment 
with bevacizumab will be compared to the baseline level. 
8.3.2 Collection of specimen(s) 
 
Sample Collection Time Points 
 
Blood samples will be obtained for protein analysis of potential biomarkers 
for anti-angiogenic therapy ~3 hours prior to bevacizumab infusion (i.e., when 
baseline labs are drawn) at the following time points: 
• Prior to initiating therapy 
•Weeks 3, 5, and 25 
 
Blood collection (needed for each time point sample) 
 
o Collect 16 ml of blood in 2 polypropylene tubes (8 mL in each tube) 
containing the anticoagulant EDTA. Tubes should be pre-cooled in an 
ice bath. 
 SARSTEDT Monovette® EDTA KE (9 ml), Part # 02.1333.001 
or 
 Becton-Dickinson VacutainerTM K2E (10 ml), Part # 367525 
or 
 Greiner Bio-One Vacuette® K3E EDTA K3 (9 ml), Part 
455036 
o Blood tubes must be gently inverted several times after collection to 
ensure thorough mixing of EDTA with the sample to prevent clotting. 
o Cool all tubes in an ice bath immediately after collection. 
o Glass tubes MUST NOT be used as they may break during transport 
and freeze-thaw cycles. 
Heparin must not be used as an anticoagulant as it may interfere 
with downstream genotyping methodology. 
8.3.3 Handling of specimens 
Centrifuge tubes collected at 700 G for 20 minutes at 4C° with no breaks 
within 30 minutes of collection. 
 

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Prepare two labels each printed with Study-No., patient ID, initials and 
day/time of sample collection (24-hour clock format, i.e., 6:30 pm = 18:30). A 
label example is provided below: 
 
 
Study-No.:  NFCTC104 
Investigator:   
Patient-ID:  
Sample Type:  Plasma  
Date of sampling: (mm/dd/yy) 
Time of Sampling:  (hh:mm) (24-hr format) 
 
• 
Plasma is pipetted in 1 ml aliquots into two red-labeled Nalgene 
cryovials. 
• 
Clearly label tubes as “plasma” and store at -80°C.  
• 
When samples from all time-points have been collected (after the 
patient goes off trial) the plasma samples should be shipped to the 
Steele Laboratory at Massachusetts General Hospital on DRY ICE in a 
Styrofoam box (Thermo Safe shippers, Fisher Scientific, cat# :11-676-
14; 12/case; $122.30). If a deep freezer is not available on site, the 
plasma sample should be kept and shipped on dry ice on the same day. 
• 
Specimens should be shipped Monday to Wednesday only by 
overnight FedEx to the Testing Core Facility. 
 
8.3.4 Shipping and analysis of specimen(s) 
 
Ship all specimens to the following Testing Core Facility address: 
 
Attn : Julia Kahn or Anna Khachatryan or Ms. Sylvie Roberge 
100 Blossom St. 
MGH, Cox-734 
Boston, MA 02114 
Tel. (617) 724-1353 
Fax (617) 724-5841 
Pager 14082 (617-726-2000) 
 
 
On the day of shipment, the study coordinator will notify the Testing Core Facility via 
email: jakahn@partners.org or AKHACHATRYAN@PARTNERS.ORG or 
Sylvie@steele.mgh.harvard.edu to expect the upcoming shipment and include the 
estimated date of arrival and FedEX tracking number.  
 
All analysis will be performed within the Steele Laboratory under the direction of Dr. 
Dan Duda. The Steele Laboratory has 6 years experience in analyzing and 
understanding variation in circulating angiogenic markers in various clinical trials 19, 
45, 46.  

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8.3.5 Future use of specimen(s) 
Blood specimens will be stored for future use in NF studies approved by the IRB. 
Specimens will be labeled as noted above (see 8.3.3) and stored indefinitely in the 
Steele Laboratory at MGH.  Neither cell lines nor commercial products will be 
developed from the blood specimens.  Specimens will be banked under the current 
study protocol.  Access to specimen samples will be limited to research personnel 
approved by the IRB.  Subjects who wish to have their samples removed from storage 
(e.g., withdraw consent for biomarker storage)  should contact the study PI who will 
work with  the Steele Laboratory to have the sample destroyed. 
 
9.  STUDY CALENDAR 
Baseline evaluations are to be conducted within 2 weeks prior to start of protocol 
therapy. Scans must be done <4 weeks prior to the start of therapy. In the event that the 
participant's condition is deteriorating, laboratory evaluations should be repeated within 
48 hours prior to initiation of the next cycle of therapy. 
Appropriate study assessments must be performed prior to administration of study 
medication. All study assessments should be administered within + 7 days of the 
protocol-specified date, unless otherwise noted.  Audiology and MRI scans should be 
performed on day 1 of appropriate cycles (see table below).  Bevacizumab should be 
provided on days 1 and 15 of each induction cycle and on days 1 and 22 of each 
maintenance cycle (window: -1 to +3 days).

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42 
 
Induction Therapy 
Cycle = 4 weeks 
Maintenance Therapy 
Cycle = 6 weeks 
 
 
Study week 
Pre-
Study 1 
3 
5 
9 
13 
17 
21 
25 
31 
37 
43 
49 
55 
 
61 
 
67 
 
73 
 
79 
 
85 
 
91 
Off 
Studyf 
 
Cycle number 
Pre-
Study 1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
13 
 
14 
 
15 
 
16 
 
17 
 
18 
Off 
Studyf 
 
Bevacizumab 
 
X 
X--------------------------------X a 
X -------------------------------------------------------------------------X b 
 
 
 
Informed consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
  Interval history 
 
X 
X ----------------------------------------------------------------------------------------------------------- X 
 
X 
 
Physical exam 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Vital signs 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Weight 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Performance 
status 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
CBC w/diff, plts  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Coagulation 
studies 
(PT/PTT/INR) 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Serum 
chemistryc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysisd 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
EKG  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Adverse event 
evaluation 
 
X 
X ----------------------------------------------------------------------------------------------------------- X 
 
X 
 
B-HCG e 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
FSHi 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
Radiologic 
evaluation j 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
Tumor volume 
measurements 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
Hearing 
assessmentg 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
Tinnitus 
Assessmentsh 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
NFTI-QOLk 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
Plasma 
biomarkers  
 
 
 
 X 
 
X 
 X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a: Bevacizumab 10 mg/kg by vein (IV) every 2 weeks.  Doses should be provided on days 1 and 15 of each cycle (window: -1 to +3 days). 
b:    Bevacizumab 5 mg/kg by vein (IV) every 3 weeks starting on week 25.  Doses should be provided on days 1 and 22 of each cycle (window: 
-1 to +3 days).  For subjects on dosing every 2 weeks (dose level +1), doses should be provided on days 1, 15, and 29 of each 6 week cycle 
(window: -1 to +3 days). 
c: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, total 
protein, SGOT[AST], SGPT[ALT], sodium. 
d:   Proteinuria will be monitored by urine dipstick and by urine protein:creatinine (UPC) ratio at least every cycle. If urine dipstick ≤ 2+ 
protein, bevacizumab can be infused.  If urine dipstick > 2+, infusion can be provided once the UPC ratio is reported 
to be < 3.5. If UPC ratio is > 2, collection of 24 hour urine for measurement of urine protein level is recommended but not required.   
UPC ratio of spot urine is an estimation of the 24 urine protein excretion – a UPC ratio of 1 is roughly equivalent to a 24-hour urine 
protein of 1 gm.  UPC ratio is calculated using one of the following formulas: 
- 
[urine protein]/[urine creatinine] – if both protein and creatinine are reported in mg/dL 
- 
[(urine protein) x0.088]/[urine creatinine] – if urine creatinine is reported in mmol/L 
e: Serum pregnancy test (women of childbearing potential). 
f:     Off-study evaluation.  Patients who have an on-going study agent-related serious adverse event upon study completion or at discontinuation 
from the study should be contacted by the investigator or his/her designee periodically until the event is resolved or determined to be 

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irreversible.  Patients who continue with off-label bevacizumab after completion of the study will be contacted by the investigator or his/her 
designee for 30 days after removal from the study.  Adverse events during this time period will be assessed as part of the study.  Patients 
who do not receive off-label bevacizumab after completion of the study will be be contacted by the investigator or his/her designee for 12 
weeks after removal from study.  Adverse events during this time period will be assessed as part of the study.   
g:  Audiology will include measurement of pure tone thresholds and determination of word recognition scores as described in Appendix F .  
Audiograms should be performed on day 1 of each  designated cycle (window: -5 days to day of infusion).  Audiograms must be reviewed 
prior to bevacizumab infusion. 
h:  Tinnitus reaction questionnaire is given in Appendix H.  Children 11 and younger on day 1 of the protocol should not complete NFTI-QOL 
during trial participation. 
i:    Follicle stimulating hormone (FSH) should be measured in post-pubescent/pre-menopausal women only.  The day of the menstrual cycle 
(the onset of menses is day 1) on which the labs are drawn should be recorded (if the subject is menstruating).  Off-study levels should be 
drawn 30 days (+/-2 days) after discontinuing bevacizumab (can be drawn locally). 
j:   MRI scans should be performed on day 1 of each designated cycle (window: -5 days to day of infusion). 
k:  See Appendix B for NFTI-QOL questionnaire.  Children 11 and younger on day 1 of the protocol should not complete NFTI-QOL during 
trial participation. 
 
 
 
 

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Additional Evaluations for Bony Toxicity for Children only (ages 6 to 17) 
 
 
Induction Therapy 
Cycle = 4 weeks 
Maintenance Therapy 
Cycle = 6 weeks 
 
 
Study week 
Pre-
Study 1 
3 
5 
9 
13 
17 
21 
25 
31 
37 
43 
49 
55 
 
61 
 
67 
 
73 
 
79 
 
85 
 
91 
Off 
Studyb 
 
Cycle number 
Pre-
Study 1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
13 
 
14 
 
15 
 
16 
 
17 
 
18 
Off 
Studyb 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
 
Radiograph of 
tibial growth 
plate  
 
X 
 
 
 
 
 
 
 
 
 
X a 
 
 
 
 
 
X a 
 
 
 
 
 
 
X a 
 
 
 
 
X a 
 
 
X a 
 
X a 
a:      Radiographs of tibial growth plates will be repeated if growth plates are open at baseline.   
b:     Off-study evaluation.  Patients who have an on-going study agent-related serious adverse event upon study 
completion or at discontinuation from the study should be contacted by the investigator or his/her designee periodically 
until the event is resolved or determined to be irreversible.  Patients who continue with off-label bevacizumab after 
completion of the study will be contacted by the investigator or his/her designee for 30 days after removal from the 
study.  Adverse events during this time period will be assessed as part of the study.  Patients who do not receive off-
label bevacizumab after completion of the study will be be contacted by the investigator or his/her designee for 12 
weeks after removal from study.  Adverse events during this time period will be assessed as part of the study.   
 
 
 

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10. MEASUREMENT OF EFFECT  
10.1 Antitumor Effect– Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 
12 weeks.  Response and progression will be evaluated in this study using the 
criteria proposed by Widemann and colleagues15 for neurofibromatosis-associated 
lesions. Response and progression will not be evaluated using the Response 
Evaluation Criteria in Solid Tumors (RECIST)47 or by MacDonald Criteria48, since 
they may underestimate progression in these irregularly shaped tumors. However, 
linear measurements will be collected as part of the trial for comparison with 
volumetric measurements. 
10.1.1 Definitions 
 
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 received at 
least 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.   
10.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be 
accurately measured using volumetric analysis of cranial MRI scans.  All study 
MRI scans should include standard brain imaging sequences as well as fine cuts 
through the internal auditory canal (3 mm slice, no gaps) to image small 
tumors.  In patients who have had surgery for tumors in the cerebellopontine 
angle, fat-saturation should be performed with the post-contrast sequences to 
compensate for the possible presence of post-operative fat packing.    
 
NOTE:  Tumor lesions that are situated in a previously irradiated area are 
considered measurable.   
 
Non-measurable disease.  Non-measurable lesions include skull-base lesions 
that are obscured by artifact from auditory brainstem implants (ABIs) or lesions 
whose margins are completely obscured by neighboring tumors (i.e., 
“collision” tumors).  
  
Target lesions.   Investigators should identify a single target lesion in all 
subjects. The target lesion in this study is the progressive VS (e.g., the lesion 
that is enlarging or is associated with hearing loss) that led to enrollment in the 
protocol. In cases where subjects have a single ear with hearing, the target 
lesion should be the enlarging VS ipsilateral to the hearing ear.  In cases where 
subjects have hearing in both ears, the target lesion should be the tumor 
associated with word recognition score < 85% and is growing the fastest or is 
causing the most rapid hearing loss.  In rare cases where both VSs are 

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associated with word recognition < 85% and progressing equally rapidly, the 
target lesion should be the larger of the two tumors on imaging. Target lesions 
should be identified at baseline and measured using volumetric analysis of the 
baseline MRI scan. The baseline volumetric MRI scan will be used as reference 
for comparison of all future MRI scans to characterize the objective tumor 
response. 
 
Non-target lesions.  Non-target lesions in this study include VSs contralateral to 
the target lesion (if present).  The baseline contralateral VS will be used as 
reference by which to characterize the objective tumor response.   
 
NOTE: Histologic confirmation of tumor type is not required. Designation of 
tumor type will be determined by the radiographic appearance by the study 
radiologist. 
10.1.3 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation [i.e., cubic 
centimeters (cm3) and in millimeters (or decimal fractions of centimeters)] for 
linear measures.  All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 8 weeks before the 
beginning of the treatment. 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-
up.  
Cranial MRI.  Volumetric analysis of MRI scans should be performed on 
sequences with fine cuts through the internal auditory canal (3 mm slices, no 
gap; Appendix G). 
10.1.4 Response Criteria  
10.1.4.1 Evaluation of Target Lesions 
 
For the purpose of this study, radiographic response will be defined by 
the change in tumor volume compared to baseline, as previously 
defined in previous studies in NF1.15   Hearing will be measured in 
standardized fashion as described in Appendix F.  Hearing response 
(Section 10.3) will be defined by the change in word recognition scores, 
taking as reference the baseline word recognition score (Appendix A 
and Section 10.3). 
 
Radiographic Response (RR): At least a 20% decrease in the volume of 
the target lesions, taking as reference the 
baseline volume. 
 
Progressive Disease (PD): 
At least a 20% increase in the volume of 
the target lesion, taking as reference the 
lower volume during treatment 

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Stable Disease (SD): 
Does not meet criteria for radiographic 
response or for progressive disease.   
Unknown (UN): Assessment of target lesions cannot be made due to 
insufficient or unevaluable data.  In this case, a concise explanation 
must be given. 
10.1.4.2 Evaluation of Non-Target Lesions 
 
 
Radiographic evaluations should be calculated separately for non-target 
lesions (contralateral VS).   
 
Radiographic  Response (RR):At least a 20% decrease in the non- target 
lesions, taking as reference the baseline 
volumes. 
 
Stable Disease (SD): 
Does not meet criteria for radiographic 
response or progressive disease. 
 
Progressive Disease (PD): 
At least a 20% increase in the volume of 
the non-target lesions, taking as reference 
the baseline volume 
Although a clear progression of “non-target” lesions only is exceptional, 
the opinion of the treating physician should prevail in such 
circumstances, and the progression status should be confirmed at a later 
time by the review panel (or Principal Investigator). 
10.1.4.3 Evaluation of Best Overall Response 
 
The best overall response is the best response for the target vestibular 
schwannoma recorded from the start of the treatment until disease 
progression (taking as reference for progressive disease the hearing 
measurements recorded at baseline and the minimal tumor volume 
during treatment).   
 
Note:  Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease 
progression at that time should be reported as “symptomatic 
deterioration”.  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
10.1.5 Duration of Response 
 
Hearing evaluations should be performed for non-target (contralateral) VS if 
present and if hearing is present in the ipsilateral ear. 
 
Duration of hearing response:  The duration of hearing response (HR) is 
measured from the time that measurement criteria are met for HR until the first 

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date that the word recognition score decreases beneath the upper limit of the 
95% critical difference of the baseline word recognition score.. 
 
Duration of stable hearing:  Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the word 
recognition score recorded at baseline.  
 
Duration of radiographic response:  The duration of radiographic response is 
measured from the time measurement criteria are met for RR until the first date 
that progressive disease is objectively documented (taking as reference for 
progressive disease the lowest tumor volume during treatment). 
 
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 
measurements recorded at baseline.  
10.1.6 Progression-Free Survival: Freedom from hearing loss and freedom from tumor 
progression 
 
The proportion of patients alive and free from progressive hearing loss at 24, 
48, 72, and 96 weeks from the start of treatment will be determined.  The 
proportion of patients alive and free from progressive tumor growth at 24, 48, 
72, and 96 weeks from the start of treatment will be determined.   
10.1.7 Response Review 
Central review of audiologic and radiologic data will be performed at 
MGH/MEEI.  Audiograms collected during the study period will be sent to the 
Operations Center and then forwarded to the team at MGH/MEEI for analysis.  
A study member (under the guidance of lead study audiologist Chris Halpin, 
PhD) will extract data for review by the Principal Investigator and lead 
audiologist.  The expected time to review audiologic data is ≤ 2 business days 
once it is received at MGH/MEEI. 
MRI images from enrolled subjects will transmitted by the “MedCommons On 
Demand” platform to the Dana-Farber/Harvard Cancer Center Tumor Imaging 
Metric Core (TIMC) for central analysis of tumor volume.    The procedure for 
clinical sites to upload MRI scans are provided in Appendix G.  MedCommons 
On Demand is a HIPAA-compliant and customizable web service that 
provides secure communications for document management and storage of 
medical images. The application allows users to conveniently upload DICOM 
CDs to cloud standards. The system requirements to launch MedCommons 
include 1) Windows, Mac, or Linux system with access to the internet 2) 
modern web browsers such as Internet Explorer, Firefox, Safari, or Chrome 
and 3) Java. All activities are monitored by MedCommons and full support 
team is available for problem resolution. 
Enhancing lesions will be outlined using a volumetric approach that includes 
outlining each enhancing voxel on post-contrast scans and then summing the 
voxels to calculate an overall lesion volume.  A report will be generated and 

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then sent to the Principal Investigator at each study site within 2 business days 
of receiving the files. 
10.2 Antitumor Effect – Hematologic Tumors 
N/A 
10.3 Other Response Parameters: Hearing Response 
 
Hearing Response (HR): Improvement in word recognition score above the 95% 
critical difference, taking as reference the baseline word recognition score 
(Appendix A).  
 
Stable Hearing (SH): Persistence of word recognition score within the 95% critical 
difference, taking as reference the baseline word recognition score (Appendix A). 
 
Progressive Hearing Loss (PHL):  Decline in word recognition score below the 
95% critical difference, taking as reference the baseline word recognition score 
(Appendix A). 
11. ADVERSE EVENT REPORTING REQUIREMENTS 
11.1 Definitions 
11.1.1 Specification of Safety Variables 
Safety assessments will consist of monitoring and reporting adverse events (AEs) 
and serious adverse events (SAEs) that are considered related to bevacizumab, all 
events of death, and any study specific issue of concern. 
11.1.2 Adverse Events 
 
An AE is any unfavorable and unintended sign, symptom, or disease 
temporally associated with the use of an investigational medicinal product 
(IMP) or other protocol-imposed intervention, regardless of attribution. 
 
This includes the following: 
• AEs not previously observed in the subject that emerge during the protocol-
specified AE reporting period, including signs or symptoms associated with 
neurofibromatosis 2 that were not present prior to the AE reporting period. 
• Complications that occur as a result of protocol-mandated interventions 
(e.g., invasive procedures such as cardiac catheterizations). 
• If applicable, AEs that occur prior to assignment of study treatment 
associated with medication washout, no treatment run-in, or other protocol-
mandated intervention. 
• Preexisting medical conditions (other than the condition being studied) 
judged by the investigator to have worsened in severity or frequency or 
changed in character during the protocol-specified AE reporting period. 
 

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Abnormal laboratory values or diagnostic test results constitute adverse events 
only if they  are accompanied by clinical symptoms, result in a change in study 
treatment or require a medical intervention, or are considered to be clinically 
significant in the investigators judgment.   
 
Abnormal vital signs constitute adverse events only if they are accompanied by 
clinical symptoms, results in a change in study treatment, or require a medical 
intervention, or are considered to be clinically significant in the investigators 
judgment.  
 
In the event of an adverse event the first concern will be for the safety of the 
subject. 
11.1.3 Serious Adverse Event (SAE) 
 
Investigators are required to report to Operations Center ANY serious treatment 
emergent adverse event as soon as possible.  Operations Center will report 
ANY serious treatment emergent adverse to Genentech Drug Safety and the 
Protocol Chair.  
 
An AE should be classified as an SAE if the following criteria are met: 
• It results in death (i.e., the AE actually causes or leads to death). 
• It is life threatening (i.e., the AE, in the view of the investigator, places 
the subject at immediate risk of death. It does not include an AE that, 
had it occurred in a more severe form, might have caused death.). 
• It requires or prolongs inpatient hospitalization. 
• It results in persistent or significant disability/incapacity (i.e., the AE 
results in substantial disruption of the subject’s ability to conduct 
normal life functions). 
• It results in a congenital anomaly/birth defect in a neonate/infant born to 
a mother exposed to the IMP. 
• It is considered a significant medical event by the investigator based on 
medical judgment (e.g., may jeopardize the subject or may require 
medical/surgical intervention to prevent one of the outcomes listed 
above). 
 
Events not considered to be serious adverse events are hospitalizations for: 
• routine treatment or monitoring of the studied indication, not associated 
with any deterioration in condition, or for elective procedures; 
• elective or pre-planned treatment for a pre-existing condition that did 
not worsen; 
• emergency outpatient treatment for an event not fulfilling the serious 
criteria outlined above and not resulting in inpatient admission; and/or 
• respite care 
11.1.4 Expectedness 
 
Adverse events can be 'Expected' or 'Unexpected.'  

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11.1.4.1 Expected adverse event 
 
Expected adverse events are those that have been previously identified 
as resulting from administration of the agent. For the purposes of this 
study, expected adverse events are those adverse events that are listed 
or characterized in the Package Insert or current Investigator 
Brochure. 
 
Refer to Section 6.1 for a listing of expected adverse events 
associated with the study agent(s). 
11.1.4.2 Unexpected adverse event 
 
 
For the purposes of this study, unexpected adverse events are those not 
listed in the Package Insert (P.I.) or current Investigator Brochure 
(I.B.) or not identified. This includes adverse events for which the 
specificity or severity is not consistent with the description in the P.I. 
or I.B. For example, under this definition, hepatic necrosis would be 
unexpected if the P.I. or I.B. only referred to elevated hepatic enzymes 
or hepatitis. 
11.2 Methods and Timing for Assessing and Recording Safety Variable 
 
The investigator is responsible for ensuring that all AEs and SAEs that are observed 
or reported during the study, are collected and reported to the FDA, appropriate 
IRB(s), and Genentech, Inc. in accordance with CFR 312.32 (IND Safety Reports) 
and with the most recent approved protocol document. 
11.2.1 Adverse Event Reporting Period 
 
The study period during which all AEs and SAEs must be reported begins after 
informed consent is obtained and initiation of any study procedures and ends 30 
days following the last administration of study treatment or study 
discontinuation/termination, whichever is earlier. After this period, 
investigators should only report SAEs that are attributed to prior study 
treatment. 
11.2.2 Assessment of Adverse Events 
 
All AEs and SAEs whether volunteered by the subject, discovered by study 
personnel during questioning, or detected through physical examination, 
laboratory test, or other means will be reported in the participant’s medical 
record and on the appropriate study-specific case report forms and entered into 
the NF Consortium’s web-based data entry system.  Each reported AE or SAE 
will be described by its duration (i.e., start and end dates), regulatory 
seriousness criteria if applicable, suspected relationship to the bevacizumab 
(see following guidance), and actions taken. 
 
To ensure consistency of AE and SAE causality assessments, investigators 
should apply the following general guideline: 

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Yes:  There is a plausible temporal relationship between the onset of the AE 
and administration of bevacizumab; and the AE cannot be readily explained by 
the subject’s clinical state, intercurrent illness, or concomitant therapies; and/or 
the AE follows a known pattern of response to bevacizumab; and/or the AE 
abates or resolves upon discontinuation of the bevacizumab or dose reduction 
and, if applicable, reappears upon re-challenge. 
 
No : Evidence exists that the AE has an etiology other than the bevacizumab 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, or 
concomitant medication); and/or the AE has no plausible temporal relationship 
to bevacizumab administration (e.g., cancer diagnosed 2 days after first dose of 
study drug). 
11.3 Procedures for Eliciting, Recording, and Reporting Adverse Events 
11.3.1 Eliciting Adverse Events 
A consistent methodology for eliciting AEs at all subject evaluation time points 
should be adopted. Examples of non-directive questions include:  
 
 
• “How have you felt since your last clinical visit?” 
 • “Have you had any new or changed health problems since you were 
last here?”  
 
11.3.2 Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting 
AEs or SAEs. Avoid colloquialisms and abbreviations.  The descriptions and 
grading scales found in the CTEP Version 4.03 of the NCI Common 
Terminology Criteria for Adverse Events (CTCAE v. 4.03) will be utilized for 
AE reporting. The CTEP Version 4.03 of the CTCAE is identified and located 
on the CTEP website at:  
 
http://ctep.cancer.gov/ 
 
All appropriate treatment areas should have access to a copy of the CTEP 
Version 4 of CTCAE. 
11.3.2.1 Diagnosis vs. Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather 
than individual signs and symptoms (e.g., record only liver failure or 
hepatitis rather than jaundice, asterixis, and elevated transaminases). 
However, if a constellation of signs and/or symptoms cannot be 
medically characterized as a single diagnosis or syndrome at the time 
of reporting, it is ok to report the information that is currently 
available. If a diagnosis is subsequently established, it should be 
reported as follow-up information. 
11.3.2.2 Deaths 
All deaths that occur during the protocol-specified AE reporting 
period, regardless of attribution, will be reported to the appropriate 
parties. When recording a death, the event or condition that caused or 

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contributed to the fatal outcome should be reported as the single 
medical concept. If the cause of death is unknown and cannot be 
ascertained at the time of reporting, report “Unexplained Death”. 
11.3.2.3 Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the 
study. Such conditions should be reported as medical and surgical 
history. A preexisting medical condition should be re-assessed 
throughout the trial and reported as an AE or SAE only if the 
frequency, severity, or character of the condition worsens during the 
study. When reporting such events, it is important to convey the 
concept that the preexisting condition has changed by including 
applicable descriptors (e.g., “more frequent headaches”). 
11.3.2.4 Hospitalizations for Medical or Surgical Procedures 
Any AE that results in hospitalization or prolonged hospitalization 
should be documented and reported as an SAE. If a subject is 
hospitalized to undergo a medical or surgical procedure as a result of 
an AE, the event responsible for the procedure, not the procedure 
itself, should be reported as the SAE. For example, if a subject is 
hospitalized to undergo coronary bypass surgery, record the heart 
condition that necessitated the bypass as the SAE. 
 
 
 
 
Hospitalizations for the following reasons do not require reporting: 
• Hospitalization or prolonged hospitalization for diagnostic or 
elective surgical procedures for preexisting conditions; 
• Hospitalization or prolonged hospitalization required to allow 
efficacy measurement for the study; or 
• Hospitalization or prolonged hospitalization for scheduled therapy 
of the target disease of the study. 
11.3.2.5 Pregnancy 
If a female subject becomes pregnant while receiving investigational 
therapy or within 30 days after the last dose of study drug, a report 
should be completed and expeditiously submitted to the Genentech, 
Inc as an SAE. Follow-up to obtain the outcome of the pregnancy 
should also occur. Abortion, whether accidental, therapeutic, or 
spontaneous, should always be classified as serious, and expeditiously 
reported as an SAE. Similarly, any congenital anomaly/birth defect in 
a child born to a female subject exposed to the bevacizumab should be 
reported as an SAE. 
11.3.2.6 Post-Study Adverse Events 
The investigator should expeditiously report any SAE occurring after 
a subject has completed or discontinued study participation if 
attributed to prior bevacizumab exposure. If the investigator should 
become aware of the development of cancer or a congenital anomaly 
in a subsequently conceived offspring of a female subject who 
participated in the study, this should be reported as an SAE. 
 

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11.3.2.7 Reconciliation/Genentech 
The Sponsor agrees to conduct reconciliation for the product.  
Genentech and the Sponsor will agree to the reconciliation periodicity 
and format, but agree at minimum to exchange monthly line listings of 
cases received by the other party.  The responsible individuals for each 
party shall handle the matter on a case-by-case basis until satisfactory 
resolution. 
 
11.3.2.8 AEs of Special Interest (AESIs)/Genentech 
AEs of Special Interest are defined as a potential safety problem, 
identified as a result of safety monitoring of the product. The Avastin 
AESIs are: 
• Hypertension ≥ Gr 3 
• Proteinuria ≥ Gr 3 
• GI Perforation, abscesses and fistulae (any grade) 
• Wound healing complications ≥ Gr 3 
• Hemorrhage ≥ Grade 3 (any grade CNS bleeding;  > Gr 2 
hemoptysis 
• Arterial thromboembolic events (any grade) 
• Venous thromboembolic events ≥ Gr 3 
• RPLS (any grade) 
• CHF ≥ Gr 3 
• Non-GI fistula or abscess ≥ Gr 2 
 
11.3.2.9 SAE Reporting/Genentech 
All SAEs should be recorded on a MedWatch 3500a Form and SAE 
CRF and sent to NF Consortium Operations Center (Attn: Research 
Nurse Manager) within 24 hours. 
   
The NF Consortium Operations Center must report all SAEs reported 
by a clinical site and entered into the electronic data entry system to 
Genentech within the timelines described below. The completed 
MedWatch/case report should be faxed immediately upon completion 
to Genentech Drug Safety at:  (650) 225-4682 or (650) 225-5288. 
 
• Relevant follow-up information should be submitted to 
Genentech Drug Safety as soon as it becomes available.   
• Serious AE reports that are related to bevacizumab will be 
transmitted to Genentech within fifteen (15) calendar days of 
the Awareness Date.   
• Serious AE reports that are unrelated to the bevacizumab will 
be transmitted to Genentech within thirty (30) calendar days of 
the Awareness Date.  

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• Serious AE reports that are related to the study drug and AEs 
of Special Interest (regardless of causality) will be transmitted 
to Genentech within fifteen (15) calendar days of the 
Awareness Date. 
 
  
The Operations Center will complete Genentech Drug Safety fax 
cover sheet with contact information for appropriate follow-up.  
 
The NF Consortium is also responsible for notifying the NF 
Consortium IRB, DSMB and appropriate Regulatory agencies.  
Because this is an IND study, the IND holder, Dr. Bruce Korf, will 
submit the report to the FDA. 
 
 
MedWatch 3500a Reporting Guidelines: 
 
In addition to completing appropriate patient demographic and 
suspect medication information, the report should include the 
following information within the Event Description (Section 5) of the 
MedWatch 3500a form: 
 
• Treatment regimen (dosing frequency, combination therapy) 
• Protocol description (and number, if assigned) 
• Description of event, severity, treatment, and outcome, if known 
• Supportive laboratory results and diagnostics 
• Investigator’s assessment of the relationship of the adverse event to 
each investigational product and suspect medication 
 
Follow-up information:   
 
Additional information may be added to a previously submitted report 
by any of the following methods: 
 
• Adding to the original MedWatch 3500a report and submitting it as 
follow-up; 
• Adding supplemental summary information and submitting it as 
follow-up with the original MedWatch 3500a form; or 
• Summarizing new information and faxing it with a cover letter 
including subject identifiers (i.e., D.O.B. initials, subject number), 
protocol description and number, if assigned, suspect drug, brief 
adverse event description, and notation that additional or follow-up 
information is being submitted.  (The subject identifiers are important 
so that the new information is added to the correct initial report.) 
 
Occasionally Genentech may contact the reporter for additional 
information, clarification, or current status of the subject for whom 
and adverse event was reported. For questions regarding SAE 
reporting, you may contact the Genentech Drug Safety representative 

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noted above or the MSL assigned to the study. Relevant follow-up 
information should be submitted to Genentech Drug Safety as soon as 
it becomes available and/or upon request. 
 
MedWatch 3500A (Mandatory Reporting) form is available at: 
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM048334.pdf 
  
Additional reporting requirements  
 
 All pregnancies whether reported by the participant, discovered during questioning, 
directly observed, or detected by physician examination, laboratory test(s) or by other 
means, will be recorded in the participant’s medical records and on the appropriate 
study-specific case report form and entered into the data-base subject record.  The 
pregnancy will also be recorded on a MedWatch 3500a Form and SAE CRF and the 
NF Consortium Operations Center will be notified within 24 hours.  The NF 
Consortium Operations Center is responsible for notifying Genentech of any reports 
of pregnancy following the start of administration with bevacizumb will be 
transmitted to Genentech within thirty (30) calendar days of the Awareness Date. The 
NF Consortium Operations Center is also responsible for notifying the NF 
Consortium IRB (UAB and the DOD), DSMB, the FDA, and all other appropriate 
regulatory agencies. 
11.4 Adverse Event Reporting to the US Army 
 
This trial receives funding by a Grant of the U.S. Army. Per US Army request, 
adverse events will therefore also be reported by the NF Consortium Operations 
Center to the US Army as follows: All adverse events, which require prompt 
reporting (as defined in Section 10.5), will be immediately reported by telephone to 
the USAMRMC Deputy Chief of Staff for Regulatory Compliance and Quality 
(301-619-2165) (non-duty hours call 301-619-2165, email or by facsimile to (301-
619-7803).  A written report will follow the initial contact within three working 
days to the NF Consortium Operations Center.  The NF Operations Center will 
notify all appropriate study regulatory personnel and send a written report to the 
U.S. Army Medical Research and Materiel Command within seven working days of 
the initial contact to ATTN: MCMR-RCQ, 504 Scott Street, Fort Detrick, Maryland 
21702-5012 or email.  
11.5 Reporting Requirements 
 
The study must be conducted in compliance with FDA regulations, local safety 
reporting requirements, and reporting requirements of the Principal Investigator.  
 
Each investigative site will be responsible for reporting SAEs that occur at that 
institution to their respective IRB. It is the responsibility of the Operations Center to 
report serious adverse events (SAEs) to the study sponsor and/or others as previously 
described and according to the schedule below.  
 
 
 

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11.6 Reporting to the Study Sponsor 
11.6.1 Serious Adverse Event Reporting 
All serious adverse events that occur after the initial dose of study treatment, 
during treatment, or within 30 days of the last dose of treatment must be 
reported to the NF Consortium Research Nurse Manager using the appropriate 
SAE reporting forms, MedWatch Form 3500a. This includes events meeting 
the criteria outlined in Section 11.1.2, as well as the following: 
 
• Grade 2 (moderate) and Grade 3 (severe) events that are unexpected and 
at least possibly related/associated with the intervention. 
• All Grade 4 (life-threatening or disabling) events that are unexpected or 
not specifically listed in the protocol as not requiring reporting. 
• All Grade 5 (fatal) events while the participant is enrolled and actively 
participating in the trial OR when the event occurs within 30 days of the 
last study intervention.  
 
Note: If the participant is in long term follow up, report the death at the 
time of continuing review.  
 
Participating investigators must report each serious adverse event to the NF 
Consortium Operations Center Research Nurse Manager (Liz Davis) within 24 
hours of learning of the occurrence. In the event that the participating 
investigator does not become aware of the serious adverse event immediately 
(e.g., participant sought treatment elsewhere), the participating investigator is 
to report the event within 24 hours after learning of it and document the time of 
his or her first awareness of the adverse event. Report serious adverse events by 
email to: 
 
NF Consortium Operations Center Research Nurse Manager 
Attn: Liz Davis, RN, MPH, CCRC 
Email: lvdavis@uab.edu 
 
and 
 
 
 
Scott R. Plotkin, MD, PhD 
 
 
Telephone: 617-724-8770  
 
 
 
Email: splotkin@partners.org  
 
 
Fax: 617-724-8769 
 
Within the following 24-48 hours, the participating investigator must provide 
follow-up information on the serious adverse event. Follow-up information 
should describe whether the event has resolved or continues, if and how the 
event was treated, and whether the participant will continue or discontinue 
study participation. 
 
 
 

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11.6.2 Non-Serious Adverse Event Reporting  
 
Non-serious adverse events will be reported to the NF Consortium via the UAB 
web-based data entry system on the adverse event screen(s).  All non-serious 
adverse events will be forwarded, at most, on a quarterly report to Genentech. 
11.7 Reporting to the Institutional Review Board (IRB) 
 
All participating study sites will report all serious adverse events directly to their 
institutional regulatory agencies according to their institutional policies and 
procedures.  
 
A copy of the submitted institutional SAE documentation should be forwarded to: 
 
NF Consortium Operations Center  
Attn: Roy McDonald  
Phone: (205) 975-4075 
Email: rmcdonald@uab.edu 
 
All SAE reports will be reported to Study PI by the Operations Center. 
11.8 Reporting to the Food and Drug Administration (FDA) 
 
For Investigator-Sponsored IND Studies, some additional reporting requirements for 
the FDA apply in accordance with the guidance set forth in 21 CFR § 600.80. 
 
All related adverse events that are both serious and unexpected will be sent to the 
FDA on Form FDA 3500A MedWatch Form 
(http://www.fda.gov/medwatch/getforms.htm) by Dr. Bruce Korf and the Operations 
Center.  MedWatch Form will be sent by mail or fax to: 
 
MedWatch 
5600 Fishers Lane 
Rockville, MD 20852-9787 
Fax: 1-800-FDA-0178 
 
Events meeting the following criteria need to be submitted to the Food and Drug 
Administration (FDA) as expedited IND Safety Reports by Dr. Bruce Korf according 
to the following guidance and timelines: 
• 7 Calendar Day via Telephone or Fax Report 
The IND-holder is required to notify the FDA of any fatal or life-
threatening adverse event that is unexpected and assessed by the 
investigator to be possibly related to the use of bevacizumab. An 
unexpected adverse event is one that is not already described in the 
bevacizumab Investigator Brochure. Such reports are to be telephoned or 
faxed to the FDA and Genentech within 7 calendar days of first learning 
of the event. 
• 15 Calendar Day via Written Report 
The IND-holder with support of Protocol Chair is also required to notify 
the FDA and all participating investigators, in a written IND Safety 

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Report, of any serious, unexpected AE that is considered reasonably or 
possibly related to the use of bevacizumab. An unexpected adverse event 
is one that is not already described in the bevacizumab investigator 
brochure. 
 
Written IND Safety Reports should include an Analysis of Similar Events in 
accordance with regulation 21 CFR § 312.32. All safety reports previously filed by 
the investigator with the IND concerning similar events should be analyzed and the 
significance of the new report in light of the previous, similar reports commented on. 
 
Written IND safety reports with Analysis of Similar Events are to be submitted to the 
FDA, Genentech, and all participating investigators within 15 calendar days of first 
learning of the event. The FDA prefers these reports on a MedWatch 3500 form, but 
alternative formats are acceptable (e.g., summary letter).   
 
 
 FDA Fax number for IND Safety Reports:  
1 (800) FDA 0178 
 
All written IND Safety Reports submitted to the FDA by the Investigator must 
also be faxed to Genentech Drug Safety at:   
 
(650) 225-4682 or (650) 225-5288 
 
  
and to the Site IRBs:  (see contact information about Consortium Participating Sites at 
the beginning of the document) 
 
  
 
 For questions related to safety reporting, please contact Genentech Drug Safety: 
Tel: (888) 835-2555 
Fax: (650) 225-4682 or (650) 225-5288 
 
IND Annual Report 
 
Copies to Genentech:  All IND annual reports submitted to the FDA by the 
Sponsor-Investigator should be copied to Genentech. Copies of such reports should 
also be faxed to Genentech Drug Safety: 
 
Fax: (650) 225-4682 or (650) 225-5288 

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11.9 Reporting to the NIH Office of Biotechnology Activities (OBA) 
 
N/A  
11.10 Reporting to the Institutional Biosafety Committee (IBC) 
 
N/A. 
11.11 Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any 
subject safety reports or sentinel events that require reporting according to 
institutional policy. 
11.12 Monitoring of Adverse Events and Period of Observation 
 
All adverse events attributable to study drug, both serious and non-serious, and 
deaths that are encountered from initiation of study intervention, throughout the 
study, and within 30 days of the last study intervention should be followed to their 
resolution, or until the participating investigator assesses them as stable, or the 
participating investigator determines the event to be irreversible, or the participant is 
lost to follow-up. The presence and resolution of AEs and SAEs (with dates) should 
be documented on the appropriate written or electronic case report form and recorded 
in the participant’s medical record to facilitate source data verification.  
 
For some SAEs, the study sponsor or designee may follow-up by telephone, fax, 
and/or monitoring visit to obtain additional case details deemed necessary to 
appropriately evaluate the SAE report (e.g., hospital discharge summary, consultant 
report, or autopsy report).  
 
Participants should be instructed to report any serious post-study event(s) that might 
reasonably be related to participation in this study. Participating investigators should 
notify the Study PI and Operations Center and their respective IRB of any 
unanticipated death or adverse event occurring after a participant has discontinued or 
terminated study participation that may reasonably be related to the study.   
12. DATA AND SAFETY MONITORING 
12.1 Data Reporting 
12.1.1 Method  
The NF Consortium Data Management and Analysis Center (DMAC) will 
collect, manage, and monitor data for this study.  
 
DMAC Director: Gary Cutter, PhD  
Phone: 205-975-5048 
Email: cutterg@ms.soph.uab.edu 
 

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DMAC Deputy Director: Joan Hilner, MPH, MA 
Phone:  205-934-4943 
Email:  jhilner@uab.edu 
 
DMAC Program Manager: Steve Powell, PhD 
Phone: 205-934-6741 
powells@uab.edu 
 
DMAC Fax:  205-975-2540 
12.1.2 Data Submission  
The schedule for completion and submission of electronic case report forms 
(paper or electronic) to the NF Consortium via a web-based data entry system as 
follows: 
 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration and 
enrollment with NF DMAC 
On Study Form 
Within 14 days of registration 
Baseline Assessment Form 
Complete prior to enrollment 
Treatment Form 
Within 10 days of the last day of the 
treatment 
Adverse Event Report Form 
Within 10 days of the last day of the 
evaluation 
Serious Adverse Event 
Reporting 
Initial reporting within 24 hours of 
awareness of occurrence 
Response Assessment Form 
(i.e., audiology and MRI 
assessment forms) 
Within 10 days of the completion of the 
cycle required for response evaluation 
Off Treatment/Off Study 
Form 
Within 14 days of completing treatment or 
being taken off study for any reason 
Follow up/Survival Form 
Within 14 days of the protocol defined 
follow up visit date or call 
The NF Consortium DMAC is responsible for compiling and providing the 
data to the Principal Investigator for review. 

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12.2 Safety Meetings 
 
The trial PI and clinical coordinator will review the study progress regularly. Patients 
entered on the trial and adverse events will be reviewed to ensure that the study is 
implemented as outlined in the protocol. Monthly reports will be generated by the 
NF Consortium to assess completeness and timeliness of data. There will be monthly 
phone conferences between the NF Consortium and the Principal Investigator to 
address QA issues.  A Data Safety Monitoring Board has been established for the 
purpose of ensuring data compliance and regular monitoring of this trial.  
 
A medical monitor has been selected for this study (Dr. Christopher Moertel, see 
roster at beginning of protocol). The medical monitor is a qualified physician and is 
not associated with this particular protocol.  The monitor will work closely with the 
DSMB and Protocol Chair to monitor the participants’ treatment while on this study. 
 
The medical monitor is required to review all unanticipated problems involving risk 
to subjects or others, serious adverse events and all subject deaths associated with the 
protocol and provide an unbiased written report of the event.  At a minimum, the 
medical monitor should comment on the outcomes of the event or problem, and in 
the case of a serious adverse event or death, comment on the relationship to 
participation in the study.  The medical monitor should also indicate whether he/she 
concurs with the details of the report provided by the study investigator.  Reports for 
events determined by either the investigator or medical monitor to be possibly or 
definitely related to participation and reports of events resulting in death should be 
promptly forwarded to the USAMRMC ORP HRPO. 
12.3  Monitoring  
Involvement in this study as a participating investigator implies acceptance of 
potential audits or inspections, including source data verification, by representatives 
designated by the Protocol Chair or NF Consortium Operations Center. The 
purpose of these audits or inspections is to examine study-related activities and 
documents to determine whether these activities were conducted and data were 
recorded, analyzed, and accurately reported in accordance with the protocol, 
institutional policy, Good Clinical Practice (GCP), and any applicable regulatory 
requirements and to ensure subject safety.  
 
All data will be monitored for timeliness of submission, completeness, and 
adherence to protocol requirements.  
 
12.4 Privacy 
Data provided must be treated in strictest confidence.  No information provided 
from individual subject’s records may be discussed with anyone other than those 
individuals mentioned in the collaborative research agreement.  Data may not be 
released in any form except as provided in the agreement. 
 
 
 

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12.5 Confidentiality 
Each subject enrolled will, from that point forward, be identified by a unique 
identifier (study number).  This study number will also be used for any research 
specimens collected and shipped to analysts outside of the NF Consortium. All 
records generated will be stored in a locked office area, only accessible to study 
personnel.  Clinical information will be accessed, according to HIPAA 
requirements, by study personnel to complete study documents, as needed. For 
standard of care procedure reimbursement, clinical information may be shared with 
insurers. 
 
13. REGULATORY CONSIDERATIONS 
13.1 Protocol Review and Amendments 
This protocol, the proposed informed consent and all forms of participant 
information related to the study (e.g., advertisements used to recruit participants) 
and any other necessary documents must be submitted, reviewed and approved by 
a properly constituted IRB governing each study location.  
Any changes made to the protocol must be submitted as amendments and must be 
approved by the DSMB, Genentech, and the UAB IRB prior to implementation. 
Any changes in study conduct must be reported to the IRB. The NF Consortium 
Operations Center will disseminate protocol amendment information to all 
participating investigators.  
All decisions of the IRB concerning the conduct of the study must be made in 
writing. 
13.2 Informed Consent 
 
All participants must be provided a consent form describing this study and 
providing sufficient information for participants to make an informed decision 
about their participation in this study. The formal consent of a participant, 
using the IRB approved consent form, must be obtained before the participant 
is involved in any study-related procedure. The consent form must be signed 
and dated by the participant or the participant’s legally authorized 
representative, and by the person obtaining the consent. The process of informed 
consent should also be documented in the subject research record. The 
participant must be given a copy of the signed and dated consent document. 
The original signed copy of the consent document must be retained in the 
medical record or research file.  
13.3 Ethics and Good Clinical Practice (GCP) 
This study is to be conducted according to the following considerations, which 
represent good and sound research practice: 

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• 
E6 Good Clinical Practice: Consolidated Guidance 
www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM129515.p
df  
• 
US Code of Federal Regulations (CFR) governing clinical study conduct 
and ethical principles that have their origin in the Declaration of Helsinki 
o Title 21 Part 11 – Electronic Records; Electronic Signatures 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr11_02.html 
o Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html  
o Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html  
o Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html  
o Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html  

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State laws 
It is understood that deviations from the protocol should be avoided, except when 
necessary to eliminate an immediate hazard to a research participant. In such 
case, the deviation must be reported to the IRB according to the local reporting 
policy.  
13.4 Study Documentation 
 
The investigator must prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each 
research participant, including all protocol deviations. This information enables the 
study to be fully documented and the study data to be subsequently verified.  
 
Original source documents supporting entries in the electronic data entry system 
include but are not limited to hospital records, clinical charts, laboratory and 
pharmacy records, recorded data from automated instruments, microfiches, 
photographic negatives, microfilm or magnetic media, and/or x-rays. To standardize 
data collection and entry, study staff can complete a hard copy of the eCRFs prior to 
entry into the web-based data collection system. 
13.5 Records Retention 
 
All study-related documents must be retained for the maximum period required by 
applicable federal regulations and guidelines or institutional policies.  
13.6 Multi-center Guidelines 
This protocol will adhere to the policies and requirements of NF Consortium IRB 
and the Sponsor. The specific responsibilities of the Protocol Chair, NF 
Consortium Coordinating Center, and Participating Institutions are presented in the 
Multi-Center Data and Safety Monitoring Plan. 
• The Protocol Chair and NF Consortium Coordinating Center are responsible 
for distributing all IND Action Letters or Safety Reports to all participating 
institutions for submission to their individual IRBs for action as required. 
• Mechanisms will be in place to ensure quality assurance, protocol compliance, 
and adverse event reporting at each site.  
• Except in very unusual circumstances, each participating institution will order 
the agent from a licensed drug distribution vendor. A participating site 
may order the agent(s) only after the initial IRB approval for the site has been 
forwarded to the drug distribution center at UAB.   

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13.7 Cooperative Research and Development Agreement (CRADA)/Clinical Trials 
Agreement (CTA)  
 
N/A 
 
14. STATISTICAL CONSIDERATIONS  
 
14.1 Study Design/Endpoints 
 
The primary endpoint for the study is hearing response at 24 weeks, defined as an 
improvement in word recognition score above the 95% critical difference, taking as 
reference the baseline word recognition score (Appendix A). We will use a Simon 
two stage MinMax design with a one sided significance level of .05 and 90% power 
for a null response rate of .03 vs. an alternative of .23.  This design calls for accruing 
14 patients in the first stage.  If none respond, the study will be terminated with the 
conclusion that bevacizumab is not effective.  Otherwise we will accrue 8 additional 
patients for a total of 22.  Bevacizumab will be considered effective if and only if 3 
or more of the 22 respond.   
14.2 Sample Size/Accrual Rate 
 
 A maximum of 22 evaluable subjects will be accrued into the trial.  Allowing for 
10% inevaluable, we may need to accrue a total of 24.  We believe this 10% rate is 
reasonable since no patients discontinued treatment due to toxicity in the previous 
study using bevacizumab.  Similarly, no patients have discontinued treatment in an 
ongoing study of PTC299 in adult patients with NF2.  The estimated accrual rate is 2 
subjects per month with an expected accrual period will be about 12 months. 
 
If the true response rate for bevacizumab is .03 then the probability of stopping after 
only 14 patients is .65 and the expected sample size is 16.78.   
14.3 Stratification Factors 
 
None 
14.4 Analysis of Secondary Endpoints 
 
The secondary endpoints include:  
 
• Frequency of adverse events (possibly, probably, or definitely) related to 
bevacizumab use in this patient population;  
• Proportion of patients with a radiographic response at 24, 48, 72, and 96 weeks; 
• Proportion of patients with a hearing response at weeks 48, 72, and 96  
(response defined as a statistically significant improvement in word recognition 
score compared with baseline score—Appendix A);  
• Proportion of patients free from progressive hearing loss at 24, 48, 72, and 96 
weeks (response defined as a statistically significant decline in word 
recognition score compared with baseline score); 

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• Proportion of patients free from tumor progression at weeks 24, 48, 72, and 96  
(progression defined as an increase in VS volume by ≥ 20%);  
• Durability of hearing response in patients with a hearing response at 24 weeks, 
as measured freedom from hearing loss at weeks 48, 72, and 96  (progression 
defined as a decrease in word recognition score below the 95% critical 
difference compared with values at 24 weeks, Appendix A);  
• Durability of radiographic response in patients with a radiographic response at 
24 weeks, as measured by freedom from tumor progression at weeks 48, 72, 
and 96  (progression defined as an increase in VS volume by ≥ 20% compared 
with volume at 24 weeks, Appendix A);  
• Change in 4-tone pure tone average compared to baseline.  The proportions 
above will be estimated from our data and exact 95% confidence intervals will 
be constructed.  Changes in 4-tone pure tone average will be described 
descriptively by means, medians, and standard deviations.    
• Change in tinnitus as measured by the Tinnitus Questionnaire (Appendix H).  
The proportions above will be estimated from our data and exact 95% 
confidence intervals will be constructed.  Changes in tinnitus will be described 
descriptively by means, medians, and standard deviations.    
 
Radiographic response rate 
The secondary endpoint of change in target tumor size will be assessed by 
volumetric analysis of MRI scans.  In a longitudinal study of plexiform 
neurofibromas in 49 patients, no patients experienced spontaneous tumor 
regression, as assessed by volumetric MRI scanning.49  Similarly, the proportion of 
patients with spontaneous tumor regression of vestibular schwannoma in the 
international Natural History of NF2 Study was < 5%.50  The radiologic response 
rate will be reported for all patients in the study and for all patients who complete 
at least 12 weeks of treatment.  Radiologic response rates will be reported with 
exact 95% confidence limits.  The durability of radiographic response over time 
will estimated using the Kaplan-Meier method.  The median of the duration of 
response time with 95% confidence limits will be reported.  The proportion of 
patients free from tumor progression at weeks 24, 48, 72, and 96 will be reported 
with 95% confidence limits. 
 
Audiometric outcomes 
Secondary endpoints will include changes in word recognition scores, pure-tone 
averages (PTAs), and tinnitus questionnaire scores.  These tests will be performed 
at baseline and every 24 weeks. 
 
o Word recognition score:  A hearing response will be defined as 
improvement in word recognition score above the 95% critical difference 
(Appendix A) in the affected ear.  The hearing response rate will be 
reported for all patients in the study and for all patients who complete at 
least 12 weeks of treatment.  Hearing response rates at weeks 24, 72, and 96 
will be reported with exact 95% confidence limits.  The durability of 
hearing response over time will be estimated using the Kaplan-Meier 
method.  The median time with 95% confidence limits will be reported.  
The proportion of patients free from hearing decline at weeks 24, 48 72, 
and 96 will be reported with 95% confidence limits. 

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69 
o Pure tone average: A 12 dB change in 4-frequency Pure Tone Average will 
be considered clinically significant. The proportion with this change will be 
estimated and an exact 95% confidence interval computed.  
o Tinnitus:  In the analysis of the Tinnitus Questionnaire data, compliance 
with questionnaire administration (defined as the proportion of 
questionnaires actually received out of the expected number) will be 
calculated. Questionnaires will be scored as recommended in the user 
manual for the instrument.  
 
14.5 Reporting and Exclusions 
 
14.5.1 Evaluation of toxicity.  All patients will be evaluable for toxicity from the time 
of their first treatment with bevacizumab. 
 
14.5.2 Evaluation of response.  Only those patients who have received at least one 
cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for response.  Each participant should be assigned one of the following 
categories: 1) hearing response, 2) stable hearing, 3) progressive hearing loss, 4) 
early death from NF2-related condition, 5) early death from toxicity, 6) early 
death because of other cause, or 9) unknown (not assessable, insufficient data). 
By arbitrary convention, category 9 usually designates the "unknown" status of 
any type of data in a clinical database. 
 
All of the participants who met the eligibility criteria (with the possible 
exception of those who received no study medication) should be included in the 
main analysis of the response rate. Participants in response categories 5-9 should 
be considered to have a treatment failure (disease progression). Thus, an 
incorrect treatment schedule or drug administration does not result in 
exclusion from the analysis of the response rate.  
 
All conclusions should be based on all eligible participants. Subanalyses 
may then be performed on the basis of a subset of participants, excluding 
those for whom major protocol deviations have been identified (e.g., early death 
due to other reasons, early discontinuation of treatment, major protocol 
violations, etc.). However, these subanalyses may not serve as the basis for 
drawing conclusions concerning treatment efficacy, and the reasons for 
excluding participants from the analysis should be clearly reported. The 95% 
confidence intervals should also be provided. 
15. PUBLICATION PLAN 
The results of this study will be made public within 24 months of the end of data 
collection. If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International 
Committee of Medical Journal Editors. A full report of the outcomes should be made 
public no later than three (3) years after the end of data collection.  
 

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16. REFERENCES  
 
Reference List 
 
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schwannomas in patients with neurofibromatosis type 2: an analysis of tumor control, 
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 12.  Harris GJ, Plotkin SR, MacCollin M et al. Three-dimensional volumetrics for tracking 
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 13.  Solomon J, Warren K, Dombi E, Patronas N, Widemann B. Automated detection and 
volume measurement of plexiform neurofibromas in neurofibromatosis 1 using magnetic 
resonance imaging. Comput Med Imaging Graph 2004;28(5):257-265. 

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71 
 14.  Babovic-Vuksanovic D, Ballman K, Michels V et al. Phase II trial of pirfenidone in 
adults with neurofibromatosis type 1. Neurology 2006;67(10):1860-1862. 
 15.  Dombi E, Solomon J, Gillespie AJ et al. NF1 plexiform neurofibroma growth rate by 
volumetric MRI: relationship to age and body weight. Neurology 2007;68(9):643-647. 
 16.  Presta LG, Chen H, O'Connor SJ et al. Humanization of an anti-vascular endothelial 
growth factor monoclonal antibody for the therapy of solid tumors and other disorders. 
Cancer Res 1997;57(20):4593-4599. 
 17.  Avastin™ (bevacizumab) Investigator's Brochure. 2007 
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angiogenesis suppresses tumour growth in vivo. Nature 1993;362(6423):841-844. 
 19.  Willett CG, Boucher Y, di Tomaso E et al. Direct evidence that the VEGF-specific 
antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 
2004;10(2):145-147. 
 20.  Borgstrom P, Gold DP, Hillan KJ, Ferrara N. Importance of VEGF for breast cancer 
angiogenesis in vivo: implications from intravital microscopy of combination treatments 
with an anti-VEGF neutralizing monoclonal antibody and doxorubicin. Anticancer Res 
1999;19(5B):4203-4214. 
 21.  Kabbinavar F, Wong JT, Ayala RE. The effect of antibody to vascular endothelial 
growth factor and cisplatin on the growth of lung tumors in nude mice. 
Proc.Am.Assoc.Cancer Res. 36, A488. 1995.  
Ref Type: Abstract 
 22.  Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D. Benefits of targeting both 
pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin 
Invest 2003;111(9):1287-1295. 
 23.  Shaheen RM, Ahmad SA, Liu W et al. Inhibited growth of colon cancer carcinomatosis 
by antibodies to vascular endothelial and epidermal growth factor receptors. Br J Cancer 
2001;85(4):584-589. 
 24.  Cobleigh MA, Langmuir VK, Sledge GW et al. A phase I/II dose-escalation trial of 
bevacizumab in previously treated metastatic breast cancer. Semin Oncol 2003;30(5 
Suppl 16):117-124. 
 25.  Allegra CJ, Yothers G, O'Connell MJ et al. Phase III trial assessing bevacizumab in 
stages II and III carcinoma of the colon: results of NSABP protocol C-08. J Clin Oncol 
2011;29(1):11-16. 
 26.  Glade Bender JL, Adamson PC, Reid JM et al. Phase I trial and pharmacokinetic study 
of bevacizumab in pediatric patients with refractory solid tumors: a Children's Oncology 
Group Study. J Clin Oncol 2008;26(3):399-405. 

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72 
 27.  Benesch M, Windelberg M, Sauseng W et al. Compassionate use of bevacizumab 
(Avastin) in children and young adults with refractory or recurrent solid tumors. Ann 
Oncol 2008;19(4):807-813. 
 28.  Bender JL, Adamson PC, Reid JM et al. Phase I trial and pharmacokinetic study of 
bevacizumab in pediatric patients with refractory solid tumors: a Children's Oncology 
Group Study. J Clin Oncol 2008;26(3):399-405. 
 29.  Packer RJ, Jakacki R, Horn M et al. Objective response of multiply recurrent low-grade 
gliomas to bevacizumab and irinotecan. Pediatr Blood Cancer 2009;52(7):791-795. 
 30.  Gururangan S, Chi SN, Young PT et al. Lack of efficacy of bevacizumab plus irinotecan 
in children with recurrent malignant glioma and diffuse brainstem glioma: a Pediatric 
Brain Tumor Consortium study. J Clin Oncol 2010;28(18):3069-3075. 
 31.  Reismuller B, Azizi AA, Peyrl A et al. Feasibility and tolerability of bevacizumab in 
children with primary CNS tumors. Pediatr Blood Cancer 2010;54(5):681-686. 
 32.  Narayana A, Kunnakkat S, Chacko-Mathew J et al. Bevacizumab in recurrent high-grade 
pediatric gliomas. Neuro Oncol 2010;12(9):985-990. 
 33.  Ozcan C, Wong SJ, Hari P. Reversible posterior leukoencephalopathy syndrome and 
bevacizumab. N Engl J Med 2006;354(9):980-982. 
 34.  Glusker P, Recht L, Lane B. Reversible posterior leukoencephalopathy syndrome and 
bevacizumab. N Engl J Med 2006;354(9):980-982. 
 35.  Hambleton J, Skillings JR, Kabbinavar F, Bergsland E, Holmgren E, Holden SN. Safety 
of low-dose aspirin (ASA) in a pooled analysis of 3 randomized, controlled trials (RCTs) 
of bevacizumab (BV) with chemotherapy (CT) in patients (pts) with metastatic 
colorectal cancer (mCRC). Journal of Clinical Oncology 23[Suppl 16s], 3554. 2005.  
Ref Type: Abstract 
 36.  Scappaticci FA, Fehrenbacher L, Cartwright T et al. Surgical wound healing 
complications in metastatic colorectal cancer patients treated with bevacizumab. J Surg 
Oncol 2005;91(3):173-180. 
 37.  Miller KD, Wang M, Gralow J, Dickler M. E2100: a randomized phase III trial of 
paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or 
metastatic breast cancer. Journal of Clinical Oncology 23. 2005.  
Ref Type: Abstract 
 38.  Karp JE, Gojo I, Pili R et al. Targeting vascular endothelial growth factor for relapsed 
and refractory adult acute myelogenous leukemias: therapy with sequential 1-beta-d-
arabinofuranosylcytosine, mitoxantrone, and bevacizumab. Clin Cancer Res 
2004;10(11):3577-3585. 
 39.  Sandler A, Gray R, Perry MC et al. Paclitaxel-carboplatin alone or with bevacizumab for 
non-small-cell lung cancer. N Engl J Med 2006;355(24):2542-2550. 

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73 
 40.  Baser ME, Friedman JM, Aeschliman D et al. Predictors of the risk of mortality in 
neurofibromatosis 2. Am J Hum Genet 2002;71(4):715-723. 
 41.  Duda DG, Willett CG, Ancukiewicz M et al. Plasma soluble VEGFR-1 is a potential 
dual biomarker of response and toxicity for bevacizumab with chemoradiation in locally 
advanced rectal cancer. Oncologist 2010;15(6):577-583. 
 42.  Willett CG, Duda DG, Xu L et al. Correlation of blood and physiologic markers with 
effect of bevacizumab (BV) with chemoradiation therapy in rectal cancer (RC). Journal 
of Clinical Oncology 26[May 20 suppl.], 202s. 2008.  
Ref Type: Abstract 
 43.  Mulvihill JJ, Parry DM, Sherman JL, Pikus A, Kaiser-Kupfer MI, Eldridge R. NIH 
conference. Neurofibromatosis 1 (Recklinghausen disease) and neurofibromatosis 2 
(bilateral acoustic neurofibromatosis). An update. Ann Intern Med 1990;113(1):39-52. 
 44.  Baser ME, Friedman JM, Wallace AJ, Ramsden RT, Joe H, Evans DG. Evaluation of 
clinical diagnostic criteria for neurofibromatosis 2. Neurology 2002;59(11):1759-1765. 
 45.  Batchelor TT, Sorensen AG, di Tomaso E et al. AZD2171, a pan-VEGF receptor 
tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in 
glioblastoma patients. Cancer Cell 2007;11(1):83-95. 
 46.  Willett CG, Boucher Y, Duda DG et al. Surrogate markers for antiangiogenic therapy 
and dose-limiting toxicities for bevacizumab with radiation and chemotherapy: 
continued experience of a phase I trial in rectal cancer patients. J Clin Oncol 
2005;23(31):8136-8139. 
 47.  Therasse P, Arbuck SG, Eisenhauer EA et al. New guidelines to evaluate the response to 
treatment in solid tumors. European Organization for Research and Treatment of Cancer, 
National Cancer Institute of the United States, National Cancer Institute of Canada. J 
Natl Cancer Inst 2000;92(3):205-216. 
 48.  Macdonald DR, Cascino TL, Schold SC, Jr., Cairncross JG. Response criteria for phase 
II studies of supratentorial malignant glioma. J Clin Oncol 1990;8(7):1277-1280. 
 49.  Dombi E, Solomon J, Gillespie AJ et al. NF1 plexiform neurofibroma growth rate by 
volumetric MRI: relationship to age and body weight. Neurology 2007;68(9):643-647. 
 50.  Slattery WH, III, Fisher LM, Iqbal Z, Oppenhiemer M. Vestibular schwannoma growth 
rates in neurofibromatosis type 2 natural history consortium subjects. Otol Neurotol 
2004;25(5):811-817. 
 51.  Kopke RD, Hoffer ME, Wester D, O'Leary MJ, Jackson RL. Targeted topical steroid 
therapy in sudden sensorineural hearing loss. Otol Neurotol 2001;22(4):475-479. 
 52.  Sorensen AG, Patel S, Harmath C et al. Comparison of diameter and perimeter methods 
for tumor volume calculation. J Clin Oncol 2001;19(2):551-557. 
 
 

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17. APPENDICES  
Appendix A: Hearing Response Guidelines 
 
Clinical criteria for definition of hearing response based on a 50-word hearing test.  Upper and 
lower limits for the 95% critical differences for percentage scores are adapted from Thornton.8 
 
Baseline word 
recognition 
score (%) 
95% critical  
difference (%) 
Hearing 
Response (%) 
Progressive 
hearing loss (%) 
0 
0–4 
≥ 6 
n/a 
2 
0–10 
≥ 12 
n/a 
4 
0–14 
≥ 16 
n/a 
6 
2–18 
≥ 20 
0 
8 
2–22 
≥ 24 
0 
10 
2–24 
≥ 26 
0 
12 
4–26 
≥ 28 
≤ 2 
14 
4–30 
≥ 32 
≤ 2 
16 
6–32 
≥ 34 
≤ 4 
18 
6–34 
≥ 36 
≤ 4 
20 
8–36 
≥ 38 
≤ 6 
22 
8–40 
≥ 42 
≤ 6 
24 
10–42 
≥ 44 
≤ 8 
26 
12–44 
≥ 46 
≤ 10 
28 
14–46 
≥ 48 
≤ 12 
30 
14–48 
≥ 50 
≤ 12 
32 
16–50 
≥ 52 
≤ 14 
34 
18–52 
≥ 54 
≤ 16 
36 
20–54 
≥ 56 
≤ 18 
38 
22–56 
≥ 58 
≤ 20 
40 
22–58 
≥ 60 
≤ 20 
42 
24–60 
≥ 62 
≤ 22 
44 
26–62 
≥ 64 
≤ 24 
46 
28–64 
≥ 66 
≤ 26 
48 
30–66 
≥ 68 
≤ 28 
50 
32–68 
≥ 70 
≤ 30 
52 
34–70 
≥ 72 
≤ 32 
54 
36–72 
≥ 74 
≤ 34 
56 
38–74 
≥ 76 
≤ 36 
58 
40–76 
≥78 
≤ 38 
60 
42–78 
≥ 80 
≤ 40 
62 
44–78 
≥ 80 
≤ 42 
64 
46–80 
≥ 82 
≤ 44 
66 
48–82 
≥ 84 
≤ 46 
68 
50–84 
≥ 86 
≤ 48 
70 
52–86 
≥ 88 
≤ 50 
72 
54–86 
≥ 88 
≤ 52 

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75 
74 
56–88 
≥ 90 
≤ 54 
76 
58–90 
≥ 92 
≤ 56 
78 
60–92 
≥ 94 
≤ 58 
80 
64–92 
≥ 94 
≤ 62 
82 
66–94 
≥ 96 
≤ 64 
84 
68–94 
≥ 96 
≤ 66 
86 
70–96 
≥ 98 
≤ 68 
88 
74–96 
≥ 98 
≤ 72 
90 
76–98 
100 
≤ 74 
92 
78–98 
100 
≤ 76 
94 
82–98 
100 
≤ 80 
96 
86–100 
n/a 
≤ 84 
98 
90–100 
n/a 
≤ 88 
100 
96–100 
n/a 
≤ 94 
 
 
 
 

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Appendix B:  NFTI-QOL (Neurofibromatosis 2 impact on quality of life) 
 
SUBJECT IDENTIFIER: _____________________________________ 
 
 
INSTRUCTIONS FOR COMPLETING THE NFTI-QOL 
 
Please complete the following information: 
 
Age:              years 
 
Gender: Male     1   Female    2           (please tick) 
 
 
For each of the questions on the next page, please tick the one box that 
describes how you feel today 
 
Usual activities include: work; housework; study; sport; social; family or leisure 
activities 
 
 
Guy’s NFTI-QOL 
 
Q1. Do balance or dizziness problems stop you performing your usual activities? 
No balance problems or dizziness                                          □0 
Balance or dizziness problems but no difficulties                 □1 
Balance or dizziness problems cause me some difficulties   □2 
Balance or dizziness problems stop my usual activities        □3 
 
Q2. Do hearing problems stop you performing your usual activities? 
No hearing problems                                                              □0 
Hearing problems but no difficulty                                        □1 
Hearing problems cause me some difficulty                          □2 
Hearing problems stop my usual activities                            □3 
 
 
Q3. Does facial weakness stop you performing your usual activities? 
No facial weakness                                                                □0 
Facial weakness, but no difficulty                                         □1 
Facial weakness causes some difficulty                                 □2 
Facial weakness stops my usual activities                             □3 
 
 
 
 

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Q4. Do problems with your sight stop you performing your usual activities? 
No problems with sight                                                          □0 
Sight problems, but no difficulty                                           □1 
Sight problems cause me some difficulty                              □2 
Sight problems stop my usual activities                                 □3 
 
Q5. Do you have any problems in mobility and walking? 
No problems in mobility and walking                                   □0 
Some difficulty but can manage on my own                         □1 
Unable to walk around without some help                            □2 
Unable to walk at all                                                              □3 
 
Q6. Has your medical condition affected your role and outlook on life? 
(e.g., confidence, vulnerability, relationships, caring for family, career, having children) 
No effect or positive effect                                                    □0 
Small negative effect                                                              □1 
Moderately negative effect                                                    □2 
Large negative effect                                                              □3 
 
Q7. Pain; throughout our lives, most of us have had pain from time to time such as mild 
headaches, sprains and toothaches. Have you had pain other than this in the last week? 
None                                                                                       □0 
Mild pain                                                                                □1 
Moderate pain                                                                        □2 
Severe pain                                                                             □3 
 
Q8. Do you currently suffer from anxiety or depression? 
No                                                                                           □0 
Mild anxiety or depression                                                     □1 
Moderate anxiety or depression                                             □2 
Extreme anxiety or depression                                               □3 

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Guy's NFTI-QOL 
 
If you have any further comments regarding the impact of NF2 on your quality 
of life, please write them here: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
You have now completed the  NFTI-QOL. Thank you for your input. 

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Appendix C: Performance Status Criteria 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Description 
Percent 
Description 
0 
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
2 
In bed < 50% of the time. 
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities. Up and about more 
than 50% of waking hours. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care 
and assistance. 
30 
Severely disabled, 
hospitalization indicated. Death 
not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any self-
care. Totally confined to bed or 
chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly.  
5 
Dead. 
0 
Dead. 
 

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 Appendix D:  Grading and management of hypertension for adults and for children 6 
through 17 years old. 
 
 
Suggested management of hypertension for adults 
 
Hypertension* 
 
Treat with anti-hypertensive medication as needed.  The goal of BP control should be 
consistent with general medical practice, including confirming that BP is elevated across 
three separate measurements on three separate days and all other contributing factors have 
been addressed (i.e., pain, anxiety). 
    Grade 1 
(SBP 120-139 mmHg or 
DBP80-89 mm Hg) 
Consider increased BP monitoring; start anti-hypertensive 
medication, if appropriate. 
Grade 2 asymptomatic 
(SBP 140-159 mmHg or 
DBP 90-99 mm Hg) 
Begin anti-hypertensive therapy and continue bevacizumab. 
   Grade 3 
(> SBP 160 mmHg or > 
DBP 100 mmHg 
If not controlled to 150/100 mmHg with medication, reduce 
one dose level.  For second occurrence, discontinue 
bevacizumab. 
Grade 4 
Discontinue bevacizumab. 
 
 
Grading of hypertension for children 6 through 17 years old 
 
 
Diastolic blood pressure levels for BOYS aged 6-17 years   
 
1 
2 
3 
4 
Age 
(years) 
ULN* 
DBP 
mmHg  
DBP ≤10 
mmHg above 
ULN 
DBP >10 or ≤25 
mmHg above ULN 
DBP>25 
mmHg 
above ULN 
6 
73 
74-83 
84-98 
99 
7 
75 
76-85 
86-100 
101 
8 
77 
78-87 
88-102 
103 
9 
78 
79-88 
89-103 
104 
10 
79 
80-89 
90-104 
105 
11 
79 
80-89 
90-104 
105 
12 
80 
81-90 
91-105 
106 
13 
80 
81-90 
91-105 
106 
14 
81 
82-91 
92-106 
107 
15 
82 
83-92 
93-107 
108 
16 
83 
84-93 
94-108 
109 
17 
86 
85-94 
95-111 
112 
* ≤95th percentile for age and 50% height percentile 
 
 
 
 

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Diastolic blood pressure levels for GIRLS aged 6-17 years  
 
1 
2 
3 
4 
Age 
(years) 
ULN* 
DBP 
mmHg  
DBP ≤10 
mmHg above 
ULN 
DBP>10 or ≤25 
mmHg above ULN 
DBP>25 
mmHg 
above ULN 
6 
73 
74-83 
84-98 
99 
7 
74 
75-84 
85-99 
100 
8 
75 
76-85 
86-100 
101 
9 
76 
77-86 
87-101 
102 
10 
77 
78-87 
88-102 
103 
11 
78 
79-88 
89-103 
104 
12 
79 
80-89 
90-104 
105 
13 
80 
81-90 
91-105 
106 
14 
81 
82-91 
92-106 
107 
15 
82 
83-92 
93-107 
108 
16 
83 
84-93 
94-108 
109 
17 
83 
84-93 
94-108 
109 
* ≤95th percentile for age and 50% height percentile 
 
These charts list DBP levels within the ULN (1), within 10 mmHg above the ULN (2), within 
11-25 mmHg above the ULN (3), and >25 mmHg above the ULN (taken from “The Fourth 
Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and 
Adolescents” PEDIATRICS Vol. 114 No. 2 August 2004, pp. 555-576).  
 
Instructions for using this BP chart: 
1. Measure the patient’s blood pressure using an appropriate size cuff. 
2. Select appropriate chart for a female or male patient.  Age should be rounded to the 
nearest year. 
3. Using the “age” row determine if the DBP is within the ULN (1) or elevated (2, 3, 4).  
4. See Section 6 for definition of dose limiting hypertension.  
 
Management of Bevacizumab-related Hypertension in Children  
The algorithm outline below will be used to grade and manage bevacizumab-related 
hypertension. A diastolic blood pressure (DBP) equal to the 95th % for age and gender will be 
defined as the upper limit of normal (ULN).   
 
Patients with elevated DBP at any time should have blood pressure measurements performed 
twice weekly until DBP is within the ULN.  
 

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Monitor DBP†
DBP† >25 mm Hg 
above ULN§for age 
or Grade 4 HTN*
10< DBP† ≤25 mm Hg 
above ULN§for age
Discontinue 
drug
Continue drug 
at same dose
DBP† ≤ULN§
for age
DBP ≤ULN for 
age within 14d
DBP >25 mm Hg 
above ULN for 
age*
DBP ≤25 mm Hg 
above ULN for 
age for >14d*
Start anti-HTN therapy
† Elevated diastolic blood pressure (DBP) measurements should be repeated on the same day to confirm the elevation
§ ULN (Upper Limit of Normal) is a DBP ≤the 95th percentile from age and gender-appropriate normal values (Appendix G)
* If DBP >25 mm Hg above ULN for age (verified) or grade 4 HTN at any time, discontinue drug.  Antihypertensive agents can be 
used to control hypertension as clinically indicated after study drug is discontinued.
Hold drug; continue 
anti-HTN until DBP 
<10 mm Hg above 
ULN for age x 2; 
then discontinue 
anti-HTN
DBP† ≤10 mm Hg 
above ULN§for age
Continue drug at same 
dose; recheck BP 
within 72 h
DBP ≤ULN 
for age on 
recheck
DBP† >ULN§
on recheck
Arm 1
Arm 2
Arm 3
Arm 4
Grade 4 HTN*

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Arm 1 of algorithm: 
• If DBP ≤95% for age and gender, continue bevacizumab at the same dose.   
Arm 2 of algorithm: 
• If DBP ≤10 mm Hg above the ULN for age and gender, continue bevacizumab at same 
dose. 
• If the DBP ≤ 95% for age and gender on recheck, continue bevacizumab at same dose. 
• If the DBP remains above the ULN for age and gender on recheck, then start single agent 
antihypertensive therapy (consider a calcium channel blocker such as amlodipine or 
nifedipine) and follow arm 3 of the algorithm from the point that anti-hypertensive 
therapy is started. 
Arm 3 of algorithm: 
• If DBP is 11 to 25 mm Hg above the 95% for age and gender on ≥2 of 3 measurements, 
start single agent anti-hypertension therapy (consider a calcium channel blocker such as 
amlodipine or nifedipine), continue bevacizumab at the same dose and monitor blood 
pressure at least every 3 days.  
o If the DBP remains elevated ≤25 mm Hg above 95% for age and gender for more 
than 14 days after the institution of single agent anti-hypertensive therapy, reduce 
bevacizumab one dose level and continue the antihypertensive agent until the 
DBP is ≤10 mm Hg above the 95% for age and gender on 2 measurements at least 
3 days apart.   If the DBP remains elevated ≤25 mm Hg above 95% for age and 
gender for more than 56 days after the institution of single agent anti-hypertensive 
therapy, discontinue bevacizumab. 
o If the DBP increases to ≥25 mm Hg above the 95% for age and gender despite 
antihypertensive therapy or the participant develops grade 4 hypertension 
(CTCAE ), discontinue bevacizumab permanently, but continue the 
antihypertensive agent until the DBP is ≤10 mm Hg above the 95% for age and 
gender on 2 measurements at least 3 days apart.  
Arm 4 of algorithm: 
• If DBP is >25 mm Hg above the 95% for age and gender or the participant develops a 
grade 4 hypertension (CTCAE), discontinue bevacizumab permanently and monitor 
blood pressure at least every 3 days.  Antihypertensive agents can be used until the DBP 
is <10 mm Hg above the 95% for age and gender on 2 measurements at least 3 days 
apart. 
• The cycle remains 28 consecutive days in patients who have dose interruptions.   
 

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Appendix E: Management of Bone Related Toxicity. 
 
Potential bone related toxicity is of great concern for this study based on pre-clinical data and 
because bevacizumab will be used in a pediatric population.   Therefore, we will carefully 
monitor for it, utilizing multiple serial measurements of height (in patients with open growth 
plates at baseline).   
 
For patients with open growth plates on tibial radiographs at baseline, measurements of stature 
(height) will be measured at weeks 13, 25, 49, 73, and 91.  Bevacizumab will be discontinued if: 
 
• <1 cm growth is noted prior to week 25  
• <2.5 cm growth is noted prior to week 49 
• Subsequently, <2cm/year annualized growth velocity noted every 24 weeks for patients 
with open growth plates only 
 
 
 

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 Appendix F: Audiology Procedures 
 
1.0    INTRODUCTION 
The purpose of this appendix is twofold: In the first section, procedures for local 
audiologists will be outlined. In the second section, procedures for transfer of the audiometric 
data from the local audiogram to the data form will be specified. 
 
2.0   AUDIOLOGY PERSONNEL  
The primary source of reliability and validity will be the qualifications of the clinical 
audiologists performing the tests, and their adherence to standard practices.  These practices will 
be specified in this section.  A secondary source of reliability and validity will be the oversight of 
the local Lead Audiologist appointed for each clinical site.  The Lead Audiologist will compile 
information assuring standard calibration, installation of reference-calibrated equipment, etc. 1  
The local Lead Audiologist will also act as a stable contact on behalf of their center.  Finally, the 
Senior Study Audiologist (MEEI) will provide a final layer of assurance by developing and 
updating the procedures in this manual in response to any problems and by maintaining regular 
contact with each site's Lead Audiologist. 
 
2.1 Lead Audiologist 
Each Clinical Site will designate a Lead Audiologist who will be the contact for 
study-related issues with the Senior Study Audiologist.  This audiologist will oversee local 
audiology operations and also communicate with the site PI.  The lead audiologist may 
train other audiologists at the site for testing.  
2.2 Qualifications 
Each evaluation will be performed by a fully qualified audiologist.  The precise 
definition of qualification can vary from state to state depending on licensure laws, etc.  For 
the purposes of this study, full qualification is defined as the highest local level of 
qualification, certification or licensure. Basic requirements for Lead Audiologist will be no 
different, but only one audiologist per center will be designated for this duty.  
2.3 Training 
Each site's Lead Audiologist will be responsible for local training of any audiologist 
performing assessments for this protocol.  This training will be based on this appendix, and 
the appendix will remain available to all trained audiologists as a resource. All Lead 
Audiologists will be contacted in advance of the initiation of participant enrollment at the 
site, and the Senior Study Audiologist will discuss and demonstrate the procedures 
contained in this Appendix.  These will include personnel, test protocols, data cross 
checking, procedures for correcting or completing evaluations, and reporting results. 
  2.4 Contacts 
A system of regular contact between the Senior Study Audiologist and each Lead 
Audiologist will be initiated before any participant's enrollment.  This will take place 

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primarily by e-mail, with documents faxed as necessary.  As audiologic issues arise, the 
local audiologists will be asked to contact the Lead Audiologist, who will act as liaison 
with the Senior Study Audiologist.  Other local issues are expected to be addressed by 
contact among the clinical site PIs, their Lead Audiologists, and the CRCs.  
 
3.0 AUDIOLOGY FILES 
Each clinical site's Lead Audiologist will, at the commencement of the study, create a filing 
system for audiology facility records and correspondence. System features will be at the 
discretion of the Lead Audiologist, incorporating the local filing protocols.  However, at 
minimum this system will contain three recognizable sections: general information, 
correspondence, and worksheets. 
3.1 
General Information Section 
This section will include site-specific information as to the identification of the PI, the 
Lead Audiologist, Senior Study Audiologist, and others associated with the study, along 
with extensive contact and coverage information. This section will also include the local 
location of this appendix, and the data reporting protocol along with copies of calibrations 
and other equipment records sufficient to document validity. Finally, the general section 
will include a comment log, in which dated and initialed entries by any audiologist may 
make note of any events or concerns. 
3.2 
Correspondence Section 
This section will include records of conference calls and other correspondence 
regarding procedural issues, changes in equipment or personnel, and any adverse events. 
3.3 
Audiogram Section 
This section will include audiograms generated for each audiologic evaluation related 
to this study.  
 
4.0 AUDIOLOGY TESTING PROTOCOL OVERVIEW  
Participants will be referred for each evaluation by the local site PI or CRC, who will 
determine the timing of return visits. At minimum, the referral will include designation of the 
target ear.  When the participant arrives for each test, the audiologist will greet the participant 
and accompanying persons and briefly and privately discuss progress if the participant wishes. 
Study questions may be referred to the local PI or CRC.  Audiologists will not be formally 
blinded to any aspect of the study.  
The audiologist will seat the participant in a sound-treated room. 2 No more than one 
person will be allowed to accompany the participant to this area and this person will not be 
allowed to sit in the booth or to be in the line of sight of the participant.  As much as possible, 
light levels in the participant and the tester sides will be adjusted to provide a good view of the 
participant and a poorer view of the audiologist (i.e.,  participant side bright, tester side dark). 
The participant should be seated perpendicular to the audiologist to minimize cues.  The room 
door will be fully closed.  The participant will be asked to respond by hand raise or by button 
push, whichever is customary at the clinical site. 

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The Lead Audiologist at each site will ensure that threshold tests are performed in the 
standard manner.  This includes the Hughson-Westlake bracketing procedure 3, 4. A 200 ms.  ON 
versus 200 ms.  OFF duty cycle for tone presentation is recommended with an opportunity to 
appreciate 4 tones per trial.  Narrow band noises or FM modulated tones will not be substituted 
for standard pure tones.  Thresholds will be transcribed on the Clinical Site’s standard 
audiogram, using standard symbols.5  At the conclusion of the evaluation, the audiologist may 
briefly discuss the result with the participant and accompanying persons, again referring most 
study questions to the PI or CRC where possible.  Discussion of helpful strategies and devices as 
indicated by the case is expected.   
4.1 The Sound Pathway 
The testing audiologist will perform a visual inspection of both ears using an 
otoscope.  If there is sufficient access to the tympanic membrane to allow testing, the 
audiologist will proceed. If there are concerns as to cerumen or other factors, the 
audiologist may elect to perform tympanometry.  When complete, the outcome of 
tympanometry will be noted on the audiogram in the customary manner for that site. If  
occluding cerumen or similar factors cannot be resolved, testing will not proceed. The local 
PI has overall responsibility to ensure unoccluded ears if referrals are required. 
4.2 Pure Tone Thresholds 
Pure tone thresholds will be found in the standard manner by bone conduction at 250, 
500, 1000, 2000 and 4000 Hz. Air conduction thresholds will be found at 250,500, 1000, 
2000, 3000, 4000 and 8000 Hz. Masking will be used in any case where it is considered 
necessary to establish which ear is responding.6 Air-bone gaps larger than 10 dB will be 
masked. For air conduction, masking will be applied for each threshold where the 
possibility of crossover exists. The possibility of overmasking will be evaluated by the 
audiologist and may be addressed, for example, by using insert phones. A masking plateau 
procedure will be performed at the discretion of the audiologist.7 The local audiologists 
have discretion to test other frequencies or to repeat testing to ensure validity. In addition, 
further testing (Stenger’s test; SRT; OAE) is at the discretion of the local audiologist to 
ensure validity. Auditory brainstem response testing is not indicated in these patients 
because their retrocochlear diagnosis is established prior to entry.  
4.2.1 Transducer 
Air conduction thresholds may be evaluated using both standard headphones 
(TDH-39, 49, 50) or calibrated insert phones (Etymotic ER-3A), as long as specific 
correction factors are in place.8 The transducer type (i.e., TDH-49, ER 3-A) should be 
entered on the local clinical audiogram form reflecting the method by which the final 
recorded threshold was obtained.   
4.3 Vibrotactile and Responses at Limits 
Vibrotactile responses will never be reported as thresholds. On discussing the nature 
of the percept with the participant and determining that they are vibrotactile, the audiologist 
will mark the response as “out at limits” at the vibrotactile response level. Other “out at 
limits” responses will be noted at the highest actual stimulus level with the standard “down 
arrow” notation. None of the study frequencies should ever be left blank.  
  

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4.4 Word Recognition  
Speech intelligibility will be evaluated for each ear using standard word recognition 
of monosyllables.9 All tests will use recorded lists (CID-W22, Ira Hirsh recording, 
Q/MASS v 2)  from a compact disk supplied by the Senior Study Audiologist, 10 including 
standardized score sheets. Each disk contains a calibration reference 1 KHz tone (track 1) 
which will be used to set the input sensitivity (V.U. meter) to “0” before each set of tests. 
The recording and list must be noted on the clinical audiogram. This is necessary to verify 
the list used in all cases when the report of this study is made.  Since the results are 
analyzed as repeated measures, a participant may be evaluated using English materials if 
the local audiologist decides that the results reasonably reflect comparative (test to test) 
performance.  In such a case, the participant may be instructed to produce the sounds of the 
words, even if they do not necessarily recognize the meaning. All lists will be recorded (no 
live voice tests) and 50 items always given. 
4.4.1 Setting the “High” and “Low” speech test levels 
The principal guiding the initial level setting for speech tests is: The level 
should be set where maximum performance is expected for each ear.  Performance 
has been shown to exhibit “rollover” in some NF2 cases,11,51 so an empirical search 
using at least two levels will also be used. These will be designated the “High” and 
the “Low ” levels. The “High ” level will be the level calculated for maximum 
audibility, as in the standard method for level setting in non-tumor cases. The “Low” 
level will be the maximum level minus 10-15 dB as chosen by the audiologist to 
reflect a level with less chance of rollover. 
  Fletcher’s Articulation Index12 will be used to assist in calculation of the initial 
(“High”) presentation level.  This formula can be used to draw a cumulative (ogive) 
optimum performance/intensity (P/I) function for any audiogram (Figure 1, below).  
If rollover was not a factor, the maximum performance would be expected at levels  
Figure 1.  Cumulative optimum performance/intensity (P/I) function.  
 

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on the asymptote of the curve. 13 Using software developed for this purpose14, Table 1 
was created for setting “High” speech levels: 
 
Table 1.  High Speech Level Settings:  
 
PTA2 
Monosyllable level 
30 
- 
35 
- 
40 
70 
45 
75 
50 
80 
55 
85 
60 
90 
65 
95 
 
 
The PTA2 parameter designates Fletcher’s 2-frequency average. 15  PTA2 is the 
average of the two best (lowest) thresholds of the set 500 Hz, 1 KHz and 2 KHz.  This 
value is easy to calculate and delivers better performance predicting speech reception 
threshold (SRT) and other speech level values than the more inclusive PTAs.16  The 
levels were developed Monte Carlo fashion by submitting a representative sample of 
audiograms to the P/I function generator and relating the PTA2 to the lower levels of 
the asymptotic portion of the curve.  The step size is 5 dB.  Smaller gradations are 
available on some audiometers and may be used at the discretion of the audiologist.  
No “High” level list will ever be given lower than 70 dB HL.  The advantage of this 
minimum level is that normal, mild, and moderate loss cases can all be tested at the 
same physical level.17 
Table 1 is designed to replace rule-based level setting schemes since they may 
not be optimal, especially given severe losses (PTA ≥ 50 dB HL).  For example, a 
common rule requires a further test (SRT) to allow levels set at SRT + 40 dB.  While 
this provides reasonable maximum performance for milder cases, with severe losses 
the dynamic range is reduced below the 40 dB constant.  On the other hand, no rule or 
table can replace good clinical sense when very high levels are required. In 
abandoning the table values, the audiologist will be asked to decrease levels 
minimally below the participant’s Uncomfortable Level (UCL) rather than set the 
level at a determined Most Comfortable Level (MCL).  No levels should exceed 95 
dB HL. 
As described above, after performing a word list at the “High” level, the 
Audiologist will reduce the intensity by 10-15 dB and present a 50-item list at the 
“Low ” level.  If the speech stimulus exceeds most frequencies at a level 15 dB below 
the “High” level then that level should be used. If, on the other hand, many important 
frequencies are no longer audible, then the level 10 dB below should be used. This 
procedure will be used for the target and the contralateral ear, with the exception that 
the “High” level may be used alone for the contralateral ear if there is no vestibular 
schwannoma on that side. 

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4.4.2 Participant responses 
Participants with poor speech intelligibility are expected to initially report no 
intelligibility (i.e., “I can’t get it”).  The audiologist is required to explain that 
guessing is very helpful and that, in order for the test to proceed, the participant must 
guess a monosyllable each time the carrier phase is heard.  Instead of reporting no 
recognition, a “wild guess” should be substituted.  This strategy will optimize 
responses in cases of low speech intelligibility and is surprisingly effective with 
participants who are really only uncertain.  Dropped plurals are to be scored wrong.  
If the participant responds with several options, the first one said will be scored.  
Items will not be repeated.  Small variations in regional dialect (i.e., vowel 
boundaries) are scored at the discretion of the audiologist.  Fifty items will be given 
unless the audiologist is convinced that the participant has no speech-like percept at 
all.  Fifty wrong guesses will be scored as 0% and this represents an optimal test by 
both the participant and the audiologist.  If there is no speech-like percept at all, the 
test can be scored CNT (could not test).  Skipping the word recognition test and 
entering the notation “DNT” (did not test) is never acceptable. The audiology 
evaluation will be considered incomplete if the notation DNT appears.  Under no 
circumstances will half-lists or screening lists be accepted. 
4.4.3 Masking for word recognition 
Masking will be applied to the contralateral ear during speech tests if there exists 
a possibility of significant contribution due to crossover. 18 To facilitate this 
application for this study, the Articulation Index was again used to calculate the 
maximum score possible by crossover given the difference in PTA2 and the effective 
masking required to reduce this contribution to zero19 (Table 2). 
Table 2.  Calculation/Crossover Scores 
 
Speech Level minus 
Non-test PTA2 
Speech Noise TDH 
Speech Noise Inserts 
50 
15 
- 
55 
20 
- 
60 
25 
- 
65 
30 
- 
70 
35 
10 
75 
40 
15 
80 
45 
20 
85 
50 
25 
90 
55 
30 
95 
60 
35 
100 
65 
40 
 
Table 2 includes values based on published interaural attenuation values for both 
TDH phones20 and insert phones.21  Standard speech-shaped noise is assumed in this 
calculation and will be the masker used at the study centers. 

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4.5 Validity  
If the audiologist determines that the test is valid she/he will indicate this in the 
space used for this purpose on the local audiogram form and need not enter any further 
information regarding validity.  If the audiologist decides to perform other tests (for 
example SRT, to rule out functional loss) this will be noted along with the outcome in the 
text section. In most cases, the principles and procedures outlined above will allow 
reliable and valid data.  One example of an exception requiring different tests would be 
when functional hearing loss (pseudohypoacusis) is suspected.  Hesitant threshold 
responses or a history of litigation for loss are some of the many warning signs 
audiologists use to initiate tests to rule out functional loss.  In this study, audiologists, 
supported by their local Lead Audiologist will rule out functional loss on a case-by-case 
basis.  For example, SRTs may be done to evaluate the match with the pure tones. 22 
Stenger’s test 23 may be performed.  The text section of the local audiogram will also be 
used to convey any testing issues such as participant cooperation, noise, equipment 
issues, etc., which might adversely affect validity.   
4.6 The Target Ear 
  
All referrals to the local audiologist from the local investigator site must include a 
designation of the target ear. Designation of the target ear is noted to occur redundantly 
on many forms of documentation in this study. The local audiologist will ensure that the 
special “High” and “Low” level word recognition testing is performed on the target ear at 
minimum during the evaluation. This strategy should also be applied to the contralateral 
ear if that ear is known to have a vestibular schwannoma or its status is unknown. The 
audiologist will specify the target ear on their audiogram at every evaluation.   
4.7 Example Audiogram 
  
Figure 2 shows an example audiogram which satisfies the needs of this study 
protocol. It is for example only and local variation is expected. 
 
 
 
 
 
 
 
 
 
 
 
 

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5.0 
DATA CROSS CHECKS 
This section will describe data cross check activities performed by the testing audiologist 
and the Lead Audiologist, as well as the mechanism for reporting unforeseen problems or 
concerns.   
5.1 Testing Audiologist 
The primary data cross checks will be the responsibility of the testing audiologist.  
Specifically, equipment and training will be maintained which will allow such procedures 
as masking plateau verification, tympanometry, SRT, Stenger’s test, etc.  These tests will 
be applied at the discretion of the testing audiologist to verify results and to rule out 
functional or retrocochlear hearing loss.  None of these tests will be used as data, but will 
be noted on the local audiogram form along with the overall judgment of the audiologist as 
to validity.   
5.2 Lead Audiologist 
The audiogram will then be given to the Lead Audiologist or placed in the study 
“Audiograms” file section for data awaiting review.  The Lead Audiologist will verify the 
audiologic aspects of the data.  The Lead Audiologist will verify validity and completeness, 
or will contact the CRC for rescheduling for other testing if necessary.  The completed 
form will be faxed or emailed (scanned) to the NF Consortium Operations Center.  
5.3 Problems and Concerns 
The Senior Study Audiologist will be responsible for resolution of problems in 
audiology data interpretation.  If these arise at the office of the PI, they will be 
communicated to the Senior Study Audiologist (i.e., not the local Lead Audiologist 
directly), who will have discretion as to resolution study-wide or site-specific.  If problems 
arise at an individual site, they will be communicated by the local Lead Audiologist to the 
Senior Study Audiologist, who will again be responsible for resolution either study-wide or 
site-specific.  The anticipated mechanism for resolution of study-wide issues will be 
communication with all local Lead Audiologists and changes or additions to this Appendix.  
The Senior Study Audiologist will be responsible for informing and receiving advice and 
approval from the Study Chair as appropriate.   
 
6.0  AUDIOGRAM ACCEPTANCE 
After the audiogram is faxed (or emailed) to the NF Consortium Operations Center, it 
will be forwarded to the Senior Audiologist in the office of the overall study PI for review 
and approval for use in the study. This is particularly critical in the case of the initial 
audiometric evaluation. All subsequent evaluations and outcomes will be compared to this 
initial audiometric evaluation and, following intent-to-treat principles, patients will not be 
removed from the study after the fact if the audiogram is found to be invalid. If the 
audiogram is not accepted, it must be re-scheduled by the study local PI’s office, re-done 
and re-submitted for acceptance. The Senior Study Audiologist will be responsible for 
providing any required materials and advice in order to ensure audiogram acceptance 
before the fact. It is necessary that each site make contact with the Senior Study 
Audiologist (C. Halpin, chris_halpin@meei.harvard.edu,  617-573-3266) when they are 

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contacted by referral sites in order to initiate this support. The following sections will 
describe some factors which will cause the audiogram not to be accepted.  
6.1 Improper Referral 
If a patient arrives at the audiologist’s office without that office being previously 
contacted about the study, or provided full materials and adequate time to have questions 
addressed, this evaluation is not expected to be possible and the result will be a request by 
the Senior Audiologist and the Study PI to the referring center for adequate referral 
procedures. 
 
6.2 Ear Occluded With Cerumen 
If the audiologist finds the ear occluded with cerumen (it is recommended that this be 
confirmed using tympanometry), the patient’s audiologic evaluation cannot be performed 
and the patient should be returned to the referral source for remediation if the cerumen 
cannot be managed in the audiologists’ office. If a notation is found that either ear was 
occluded with cerumen, the audiogram will not be accepted. 
 6.3 Word Recognition 
If word recognition is recorded as “DNT” (Did Not Test) on either side, the 
patient’s audiologic evaluation cannot be accepted. This is also true if a half (25-item) or 
screening list was given, or if the word recognition test was delivered using monitored live 
voice (MLV). Word recognition must be positively noted as having been done using the 
provided CD, 50 items and done at high and low levels as described in section 5.6.1 in 
order to be accepted. The software used to create Table 2 may be used to evaluate the 
potential for influence of the contralateral ear, though significant crossover is unlikely. 
6.4 Pure Tone Thresholds 
If pure tone thresholds do not include all frequencies specified in section 5.4, for 
example if bone conduction was not done, the audiogram cannot be accepted. With regard 
to masking, thresholds may be input to the Harvard Audiometry software for evaluation of 
crossover. If significant chance that the non-test ear was responding is found, the 
audiogram cannot be accepted. 
 
7.0 EQUIPMENT 
The following section contains specifications for equipment used in this study. 
7.1 
Sound-treated Enclosure 
A single- or double-walled sound-treated enclosure that meets American National 
Standard Criteria for Maximum Permissible Ambient Noise Levels for Audiometric Test 
Rooms shall be used to conduct pure tone air and bone conduction thresholds and word 
recognition testing.   
An illuminated otoscope is used to examine a participant’s ear canals.   If any 
possible contraindications to audiometric testing (such as excess cerumen, eardrum 
abnormalities, etc.) are detected, the participant must be referred for medical evaluation 
before audiometric testing can proceed. 

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7.2 
Audiometer 
Audiometers that meet the American National Standard Specifications for 
Audiometers1 and have two channels are used to conduct pure tone air and bone conduction 
threshold, SRT and word recognition testing.  One channel of the audiometer generates and 
delivers the test signals, either pure-tones or prerecorded speech.   The second channel 
delivers narrow-band or speech-band masking noise simultaneously with the test signal, but 
to the non-test ear whenever necessary.  The audiometer must have an input jack for 
external equipment such as a compact disc player or tape player, which will be used to 
present speech stimuli for word recognition testing. 
7.3 
Audiometer Transducers 
Earphones mounted in supra-aural cushions and calibrated according to the American 
National Standard Specification for Audiometers1 are used to deliver the test material from 
the audiometer to the participant.  The earphones are designated as “right” and “left” and 
will be placed comfortably over the participant’s right and left ears, respectively.  Bone 
vibrators calibrated according to the same standards are used to obtain bone conduction 
thresholds.   During the testing, the bone vibrator is positioned over the mastoid area of the 
participant’s test ear, taking care that it is not in contact with the posterior part of the pinna. 
7.4 Compact Disc Player 
A compact disc player must be used to deliver pre-recorded speech material to the 
audiometer and subsequently to the transducers positioned over the participant’s ears.  A 
cable extends between the output jack of the compact disc player and the input jack of the 
audiometer. 
7.5 Acoustic Immittance Equipment 
Immitance is not required by this study protocol, but may be used at the audiologists’ 
discretion. An immittance device that meets the American National Standard Specifications 
for Instruments to Measure Aural Acoustic Impedance and Admittance is used to conduct 
tympanometry and acoustic reflex threshold testing.   Test results will be printed directly 
from the immittance device or recorded manually at the conclusion of testing on each ear.  
Probe tips must be appropriate in size to seal the participant’s ear canal tightly during 
tympanometry and acoustic reflex testing.   Clinical centers must have an adequate variety 
of sizes of probe tips to accommodate ear canals of varying dimensions. 
7.6 
Maintenance 
Each clinical center is responsible for the proper operation and maintenance of its 
audiometric equipment.   Responsibility for proper maintenance is assumed by the Lead 
Audiologist, and all staff are instructed to report promptly any real or suspected equipment 
problems to that person.   All checks, inspections, and repairs are documented and recorded 
by date in a permanent log.  The Study PI and Study Senior Audiologist may review this 
log at periodic site visits.  All study test equipment including audiometers and acoustic 
immittance devices must be calibrated according to the American National Standards 
Institute. Listening checks may help to identify problems that could influence participants’ 
test behavior and audiometric results in between scheduled physical calibrations.   Study 
audiologists should perform a listening check on any day when a participant enrolled in the 
protocol will be tested. 

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8.0 Data Reporting 
Audiograms done using the procedures described above will be faxed or emailed 
from the NF Consortium Operations Center to the office of the Senior Study Audiologist 
(C. Halpin, PhD) and the Principal Investigator. The Senior Study Audiologist and others at 
the PI’s office, will have direct access to the eCRF software used for data collection in the 
study. The clinical audiograms will be checked and the data transferred to the study eCRF 
system. The PI’s office (Senior Study Audiologist) will keep copies of each of the study 
audiograms and records of the transfer process.  
 
 
 

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Appendix G: MRI Protocols 
 
Image Acquisition 
Each patient will be scanned on the same MRI system. Each scanning session must include the 
following sequences (although additional sequences can be performed per institutional protocol):  
1) Scout sequence 
2) T2-weighted imaging 
3) Fluid-attenuated inversion recovery (FLAIR) imaging 
4) T1-weighted pre-contrast imaging 
5) Diffusion weighted imaging (DWI) 
6) Post-contrast T1-weighted imaging (including post-contrast T1 weighted imaging    
with fine cuts through the internal auditory canal) 
 
NOTE:  The post-contrast T1 weighted imaging with fine cuts through the internal auditory 
canal (3 mm slices, no skip) and volumetric analysis will be used to assess the endpoint of 
radiographic response (defined as ≥ 20% decrease in tumor volume by MRI scan).  The total 
scan time for the required images for the primary endpoint is roughly 10 minutes.   
 
Image Analysis 
Enhancing lesions will be quantitatively analyzed by an experienced neuroradiologist blinded to 
the order of the scans, patient identity and treatment status of the patients. Bi-dimensional 
diameters will be created and outlined using electronic calipers in accordance with the 
Macdonald criteria 48. The lesions will also be outlined using a volumetric approach described 
previously 52 that includes outlining each enhancing voxel on post-contrast scans and then 
summing the voxels to calculate an overall lesion volume.   
 
Secure File Transfer  
The procedure for uploading MRI scans to the Tumor Imaging Metrics Core are listed below. 
 MRI images from enrolled subjects should be de-identified and will be transmitted 
electronically to the Dana-Farber/Harvard Cancer Center Tumor Imaging Metric Core (TIMC) 
under the direction of Dr. Gordon Harris for central analysis of tumor volume. (see section 
10.1.7). 
 
Welcome to the TIMC 
The TIMC provides standardized measurement of imaging scans for oncology clinical trials. 
TIMC’s web-based system ensures easy ordering and access with exceptionally fast 
turnaround. Tumor response assessment criteria include RECIST, RECIST 1.1, Cheson, 
irRC, SUV, and 3D volume. 
 
Getting Started 
This document provides step-by-step instructions to help you use the TIMC website. Topics 
covered include: 

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• New User Registration 
• Patient Registration 
• Scan Assessment Requests 
• Results Reporting 
• Resources 
 
Please contact the TIMC help desk at timc@nmr.mgh.harvard.edu for any questions or 
concerns that are not addressed below. 
 
New User Registration: 
1. Please email the TIMC help desk at timc@nmr.mgh.harvard.edu and provide the 
following information: 
• User Full name 
• Home institution 
• Study role 
• Disease group affiliation 
2. After account set-up, TIMC will notify you via email with your username and 
temporary password. Please go to www.tumormetrics.org and click Client Login or 
go to www.timclogin.org to directly access the login page.  
3. Login with your TIMC username and password. The password can be changed by 
going to Main Menu → My Profile → Edit. You will be required to enter your 
current password and new password (alphanumeric, case sensitive, 6-10 characters). 
Click OK.  
 
Patient Registration: 
1. After login, click on the link for the appropriate protocol number (12-466). 
2. Select Patient Registration from the Protocol Menu pull-down.  
 
3. Click Add New Record to register a new research subject.  
 

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Subject ID 
• Enter the PID1 upon initial registration. Once the PID2 is issued, 
edit this field to reflect the PID2.  
Sponsor Prefix 
• Enter your site’s code according to the chart below: 
CHLA, Children’s Hospital Los Angeles 
CLA 
CHOP, Children’s Hospital of Philadelphia 
CHP 
CHB, Children’s Hospital Boston 
CHB 
UAB, University of Alabama at Birmingham 
UAB 
MGH 
MGH 
CNMC, Children’s National Medical Center 
CHN 
UChicago, University of Chicago 
UCH 
LCH, Lurie Children’s Hospital 
LCH 
WU, Washington University 
WAU 

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NYUMC, New York University Medical Center NYU 
JHU, Johns Hopkins University 
JHU 
CCHMC, Cincinnati Children’s Medical Center CCH 
IU, Indiana University 
INU 
Primary Disease 
• Select Patient’s primary disease from pull-down.  
• Please email timc@nmr.mgh.harvard.edu if the patient’s primary 
disease is not included in the list. 
Date Registered 
• This date will auto-populate with the date the patient is registered 
in the system. 
Date Off 
Protocol 
• Leave Date off Protocol field blank at this time.  
• Date off Protocol will auto-populate with the date of response 
assessment progression.  
• Please manually fill in Date Off Protocol if the patient comes off 
study for another reason (i.e., toxicity, etc). 
Failed Screening 
• Failed Screening should be checked if the patient does not meet 
enrollment criteria per imaging assessment. 
 
4. Click Submit. 
 
 
Making Changes: 
TIMC website has an audit trail which requires users to enter a reason for the change before 
they can edit. 
1. Please select the reason to change the data from the pull-down highlighted in 
yellow near the top right hand side of the browser window.  
 
2. Click Edit to make changes to data entry.  
 
Scan Assessment Requests: 
1. Click on the appropriate protocol number. (is automatically prepopulated) 

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2. Select Order Entry from the Protocol Menu pull-down. 
 
3. Click Add New Order. 
 
 
 
Protocol 
• Automatically populates the protocol for which the 
patient is registered to (12-466).  
Patient  
• Select the patient from the Patient pull-down.  
• Only registered patients will appear in this list. 

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Scan Institution 
• Select the institution where the scan was performed. 
Radiation Date 
• Select whether the patient has received radiation 
recently.  If yes, enter the date of radiation.  
Scan Date 
• Enter date as MM/DD/YY or click the calendar button 
to select the scan date. 
Scan Time 
• Round time to the nearest 30 minutes. 
Time Point 
• Choose screening, baseline, or follow-up. 
Imaging Modality 
• Select the scan modality from the pull-down (i.e., CT, 
MR, PT). 
Imaging Source 
PACS 
• Select PACS if the scans were uploaded into the 
hospital’s imaging archive (PACS). 
CD 
• Select CD if the scan is from an outside institution and 
needs to be uploaded manually. 
Due Date 
• Enter date as MM/DD/YY or click the calendar button 
to select the scan date. 
Due Time 
• Round time to the nearest 30 minutes. 
Order Comment 
• Indicate if left and/or right schwannoma should be 
assessed. 
• Enter information about the scan (i.e., scans to include 
in the assessment, lesion(s) of interest, etc). 
Reason for Urgent 
Request 
• Select a reason for urgent request from the Reason 
pull-down. 
• This field is required for urgent scans. 

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Treating Physician Email 
• Enter the treating physician’s email address 
• This field is required for urgent scans 
Notify by Email Upon 
Assessment Completion 
• Check the box if you would like to be notified by 
email when the scan assessment has been completed. 
• Add up to 3 additional email addresses to receive 
notifications 
Status 
This field is not editable and refers to the scan assessment 
status. 
• Ordered = Scan request has been made by trial staff 
• Inquiry = Inquiry initiated by TIMC; email response 
required by trial staff. 
• Processed = TIMC has started scan analysis. 
• Complete = Preliminary results are complete but scan 
has not been reviewed by a radiologist. 
• Final = Radiologist has reviewed and approved the 
scan assessment. 
 
4. Click Submit. 
Note: The online system has an audit trail. To change data, please select the reason 
to change the data from the pull-down highlighted in yellow near the top right hand 
side of the browser window. Once a reason has been selected, click on ‘Edit’ to edit 
the patient information. 
 
Results Reporting: 
• Click on the appropriate protocol. 
• From the Patient List page, click on the 
appropriate patient link. 
• Compare image captures across time 
points by clicking the lesion location 
link (left box).  
• View annotated images for a specific 
scan date by clicking on the measurement link (right box). 

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• Click the Next Lesion button located near the top right hand side of the screen to 
view the image capture for the next lesion or select the lesion of interest from the 
Select Lesion pull-down located under the patient information. 
• Click the Next Scan button located to the right hand side of the image capture (on 
the right) to go to the next scan or select the desired scan date from the pull-downs 
located above the image captures.  
 
 
 
• Select Patient Summary from the Patient Menu pull-down to go back to results 
 
Longitudinal Graphs: 
• Click the graph button 
 to view graphs. This button is located near the bottom 
left hand side of the screen on the Patient Summary page, or Select Response 
Graph from the Patient Menu pull-down 
• Compare time point and individual lesion measurement data to baseline, nadir (scan 
with the lowest measurement total), and prior scans. 

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Request Re-Review: 
 
If the central review is felt to be discordant with the clinical assessment, trial staff has the option 
to request a re-review of the scan.   
 
• Click on the appropriate protocol. 
• From the Patient List page, click on the appropriate patient link. 
• Click the Request Re-review button. 
• Populate all fields in the email template. 
Resources: 
 
Click on the Resources button at the top right hand side of the website to go to our Resources 
website. This website provides: 
• 
Tutorials on imaging assessment criteria for clinical trials 
• 
Documents to incorporate imaging metrics in study protocols 
• 
Service and workflow requirement policies 
• 
"How to" documents for navigating the TIMC website 
• 
Imaging specific manuals and policies, only accessible to core staff 
For additional information about our services, please visit www.tumormetrics.org. 
 
 

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Appendix H: Tinnitus Reaction Questionnaire (TRQ) a 
 
SUBJECT IDENTIFIER :   ______________________________ 
 
 
 
Number 
Item 
Scoresb 
1 
My tinnitus has made me unhappy. 
 0 
 1 
 2 
 3 
 4 
2 
My tinnitus has made me feel tense. 
 0 
 1 
 2 
 3 
 4 
3 
My tinnitus has made me feel irritable. 
 0 
 1 
 2 
 3 
 4 
4 
My tinnitus has made me feel angry. 
 0 
 1 
 2 
 3 
 4 
5 
My tinnitus has led me to cry. 
 0 
 1 
 2 
 3 
 4 
6 
My tinnitus has led me to avoid quiet situations. 
 0 
 1 
 2 
 3 
 4 
7 
My tinnitus has made me feel less interested in going out. 
 0 
 1 
 2 
 3 
 4 
8 
My tinnitus has made me feel depressed. 
 0 
 1 
 2 
 3 
 4 
9 
My tinnitus has made me feel annoyed. 
 0 
 1 
 2 
 3 
 4 
10 
My tinnitus has made me feel confused. 
 0 
 1 
 2 
 3 
 4 
11 
My tinnitus “driven me crazy”. 
 0 
 1 
 2 
 3 
 4 
12 
My tinnitus interfered with my enjoyment of life. 
 0 
 1 
 2 
 3 
 4 
13 
My tinnitus made it hard for me to concentrate. 
 0 
 1 
 2 
 3 
 4 
14 
My tinnitus has made it hard for me to relax. 
 0 
 1 
 2 
 3 
 4 
15 
My tinnitus has made feel distressed. 
 0 
 1 
 2 
 3 
 4 
16 
My tinnitus has me feel helpless. 
 0 
 1 
 2 
 3 
 4 
17 
My tinnitus has made me feel frustrated with things. 
 0 
 1 
 2 
 3 
 4 
18 
My tinnitus has interfered with my ability to work. 
 0 
 1 
 2 
 3 
 4 

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19 
My tinnitus has led me to despair. 
 0 
 1 
 2 
 3 
 4 
20 
My tinnitus has led me to avoid noisy situations. 
 0 
 1 
 2 
 3 
 4 
21 
My tinnitus has led me to avoid social situations. 
 0 
 1 
 2 
 3 
 4 
22 
My tinnitus has made me feel hopeless about the future. 
 0 
 1 
 2 
 3 
 4 
23 
My tinnitus has interfered with my sleep. 
 0 
 1 
 2 
 3 
 4 
24 
My tinnitus led me to think about suicide. 
 0 
 1 
 2 
 3 
 4 
25 
My tinnitus has made me feel panicky. 
 0 
 1 
 2 
 3 
 4 
26 
My tinnitus has made me feel tormented. 
 0 
 1 
 2 
 3 
 4 
a 
From Wilson et al, 1991 
b 
0 = not at all, 1 = a little of the time, 2 = some of the time, 3 = a good deal of the time, and 4 = almost all of the time. 
 
  

Research Consent Form 
NF Consortium                
 NF 2 Trial Protocol Version 1.4 dated  May 13, 2016    
Revised: January 30, 2017 
Page 1 of 17 
 
 
 
Protocol Title:  Open-label, Phase 2 study of bevacizumab in children and adults with 
neurofibromatosis 2 and progressive vestibular schwannomas that are poor candidates for 
standard treatment with surgery or radiation   
IND Number: 112096 
SITE IRB Protocol Number:   
Sponsor: US Army, Dept. of Defense and Genentech  
Principal Research Doctor/Institution:  SITE PI 
                                                                         
If you are a parent or guardian of a child under 19 years old, the word “you” refers to 
your child.  You, the parent, will be asked to read and sign this document to give 
permission for your child to participate.   
 
INTRODUCTION 
 
You are invited to take part in a clinical trial, a type of research study. You are invited to 
take part because you have neurofibromatosis type 2 (NF2) and a tumor on your hearing 
nerve (vestibular schwannoma) that is causing you to lose hearing.  At this time, you may 
have been told that surgery to remove the tumor or radiation treatments are not favorable 
options.  This research study is a way of gaining new knowledge about vestibular 
schwannomas. If you decide to take part, you will be known as a “participant” rather than 
a “patient”.  This research study is evaluating a drug called bevacizumab as a possible 
treatment for vestibular schwannoma. 
 
It is expected that about 22 people will take part in this research study.  At SITE, we will 
enroll 2 to 5 participants.  Some research studies are supported in some way by an outside 
organization. Genentech, Inc. and the US Army, Department of Defense (DOD) are 
supporting this research study by providing bevacizumab (Genentech) and by providing 
funds (DOD and Genentech) to cover the costs of running this clinical trial. 
 
This research consent form explains why this research study is being done, what is 
involved in participating in the research study, the possible risks and benefits of the 
research study, alternatives to participation, and your rights as a research participant.  The 
decision to participate is yours.  If you decide to participate, please sign and date at the 
end of this form. We will give you a copy so that you can refer to it while you are 
involved in this research study. If you choose not to participate in this research study, the 
research doctors will discuss other treatment options with you and/or refer you back to 
your regular doctor.  
 
We encourage you to take some time to think this over, to discuss it with other people 
and your doctor, and to ask questions now and at any time in the future. 
 

Research Consent Form 
NF Consortium                
 NF 2 Trial Protocol Version 1.4 dated  May 13, 2016    
Revised: January 30, 2017 
Page 2 of 17 
 
 
 
 
WHY IS THIS RESEARCH STUDY BEING DONE?  
 
This research study is a Phase II clinical trial.  Phase II clinical trials test the effectiveness 
of an investigational drug to learn whether it works in treating a specific tumor.  
“Investigational” means that bevacizumab is still being studied in NF2 and that research 
doctors are trying to find out more about it(such as the safest dose to use), the side-effects 
it may cause, and if it is effective for treating different types of tumors.  Bevacizumab is 
an investigational agent that has been approved by the U.S. Food and Drug 
Administration (FDA) for use in cancers of the colon, breast, brain, pancreas, and 
kidneys.  However, bevacizumab is not approved to treat vestibular schwannomas. 
 
The purpose of this study is to find out what effects, good and/or bad, bevacizumab has 
on you and your vestibular schwannoma.  Bevacizumab acts by preventing the growth of 
new blood vessels in tumors.  Because tumors need new blood vessels to grow and 
spread, bevacizumab may stop blood vessel growth and slow or reverse the growth of the 
vestibular schwannoma or improve your hearing.    
 
WHAT OTHER OPTIONS ARE THERE? 
 
Taking part in this research study is voluntary. Instead of being in this research study, 
you have other options which may include the following: 
 
• Radiation treatments to your vestibular schwannoma 
• Surgery to remove your vestibular schwannoma 
• Participate in another research study 
• No therapy specific to your tumor 
• Comfort care, also called palliative care.  This type of care may help to reduce 
pain, tiredness, appetite problems and other problems caused by the tumor.  It 
does not treat the tumor directly, but instead tries to treat the symptoms  
 
The study doctor will discuss with you alternate procedures or courses of treatment. 
Please talk to the research doctor about your options before you decide whether you want 
to take part in this research study. 
 
WHAT IS INVOLVED IN THE RESEARCH STUDY? 
 
Sometimes it is hard to keep track of all of the details and procedures that are part of a 
research study. We will describe them in this consent form and you can refer to this at 
any time during the research study.  The study doctor will discuss with you your 
responsibilities as a participant.  
 
Before the research starts (screening):  After signing this consent form, you will be 
asked to undergo some screening tests or procedures to find out if you can be in the 
research study.  Many of these tests and procedures are likely to be part of regular cancer 
care and may be done even if it turns out that you do not take part in the research study.   
 

Research Consent Form 
NF Consortium                
 NF 2 Trial Protocol Version 1.4 dated  May 13, 2016    
Revised: January 30, 2017 
Page 3 of 17 
 
 
 
If you have had some of these tests or procedures recently, they may or may not have to 
be repeated.   
 
• 
Physical exam, including measurement of vital signs (temperature, heart rate 
and blood pressure) 
• 
Medical history, including questions about your health, current medications, 
and any allergies  
• 
Blood tests. Blood will be drawn (about 4 tablespoons) for tests to monitor 
your health, including blood counts and clotting studies, chemistry, and liver 
and kidney function   
• 
Urine test to measure the amount of protein 
• 
Pregnancy test.  If you are a woman who can have children, you will have a 
blood pregnancy test.  (If you are pregnant, you will not be able to participate 
in this research study) 
• Electrocardiogram (EKG). The function of your heart will be checked with 
an EKG, which traces the electrical activity of your heart 
• 
MRI scan of the brain to measure the size of your tumor 
• 
Hearing assessment to measure your ability to hear sounds and words 
• 
Questionnaires to measure any effect your treatment may have on your 
tinnitus (“ringing” in the ears) and other symptoms that affect quality of life 
• 
For participants less than 18 years of age: X-rays of the leg to determine 
whether you are still growing 
 
If these tests show that you are eligible to participate in the research study, you will begin 
the study treatment.  If you do not meet the eligibility criteria, you will not be able to 
participate in this research study. 
 
After the screening procedures confirm that you are eligible to participate in the 
research study:   
 
If you take part in this research study, you will come to the outpatient clinic for all of 
your evaluations and procedures over the course of 24 months.  All participants will 
receive treatment for 6 months (the induction phase).  Participants who benefit from 
treatment will continue receiving treatment for an additional 18 months (the maintenance 
phase).  Participants who do not benefit from treatment by 6 months will not be allowed 
to continue receiving treatment. 
 
Treatment will be divided into time periods called cycles. Each cycle is 4 weeks (28 
days) during the first 6 months. You will come to clinic every 2 weeks to receive 
bevacizumab by vein. After the first 6 months, you will come to clinic every 3 weeks to 
receive bevacizumab by vein as long as your hearing is stable or improving. Each cycle 
after the first 6 months is 6 weeks as long as your hearing is stable or improves.   If your 
hearing gets worse, then you will come to the clinic every 2 weeks to receive 
bevacizumab by vein. 
 
 

Research Consent Form 
NF Consortium                
 NF 2 Trial Protocol Version 1.4 dated  May 13, 2016    
Revised: January 30, 2017 
Page 4 of 17 
 
 
 
The following tests and procedures are part of regular tumor care and will be done 
throughout the study: 
• 
Physical exam, including measurement of vital signs (height, weight, 
temperature, heart rate and blood pressure) 
• 
Questions about how you are able to perform activities of daily living 
(performance status assessment) 
• 
Blood tests. Blood will be drawn (about 4 tablespoons) for tests to monitor 
your health, including blood counts, chemistry, and liver and kidney function 
• 
MRI scan to measure the size of your tumor 
 
You will need the following tests and procedures repeated throughout the study.  These 
tests are part of regular tumor care, but are being done more often because you are in this 
study: 
• 
Urine test to measure the amount of protein 
• 
Hearing assessment to measure your ability to hear sounds and words 
• 
Pregnancy test.  If you are a female who can have children, you will have 
occasional blood pregnancy test  
• 
Blood tests for hormone levels.  If you are a woman who has reached puberty, 
blood will be drawn (about 1 tablespoon) for tests to monitor the function of 
your ovaries 
•  Questionnaires to measure any effect your treatment may have on your 
tinnitus (“ringing” in the ears) and other symptoms that affect quality of life 
 
The following procedures will be done as part of the research trial to see how the study 
treatment is affecting your body: 
 
• 
Questionnaires to measure any effect your treatment may have on your 
tinnitus and other symptoms that affect quality of life 
• 
For participants less than 18 years of age that are still growing: X-rays of the 
leg to determine the effect of treatment on your growth 
• Blood samples (about 5 teaspoons) will also be collected to test if you have     
any biomarkers or special measurements to see if bevacizumab is working to 
preventing the growth of blood vessels into your tumor. This collection is 
done prior to the first treatment, at week 3, week 5 and week 25. 
 
The chart below shows what will happen to you during Cycle 1 and future treatment 
cycles, as previously explained.  The left-hand column shows the day in the cycle and the 
right-hand column tells you what to expect on that day. 
 
 
 

Research Consent Form 
NF Consortium                
 NF 2 Trial Protocol Version 1.4 dated  May 13, 2016    
Revised: January 30, 2017 
Page 5 of 17 
 
 
 
 
Cycle 1 
 
Day 
 
      Tests/Procedures 
 
Day 1 
• Routine blood tests (about 2 tablespoons), urine test, and exams: 
• Medical History 
• Physical exam 
• Vital signs, height and weight 
• Performance status. 
• Receive first treatment of bevacizumab 
Day 15 
• Routine blood tests (about 2 tablespoons), urine test, and exams: 
• Physical exam 
• Vital signs and weight 
• Research blood samples (about 5 teaspoons) will also be collected to test for 
biomarkers during week 3 
• Receive second treatment of bevacizumab 
Day 28 
• Cycle 1 ends.  Return to clinic the following day (day 1 of cycle 2) for next 
infusion of bevacizumab 
 
 
 
Cycles 2 to 6 
 
Day 
 
Tests/Procedures 
 
Day 1 
• Urine test and physical exams every cycle (more if your doctor tells you to). 
• Routine blood tests (about 2 tablespoons)  
• Brain MRI scan and hearing assessments during cycle 4 
• Tinnitus Questionnaire and Quality of Life questionnaire during cycle 4 
• For participants under the age of 18 who are still growing: x-ray of the leg during 
cycle 4 
• Research blood samples (about 5 teaspoons) will also be collected to test for 
biomarkers during week 5 (cycle 2) 
• Receive treatment of bevacizumab 
Day 15 
• Receive treatment of bevacizumab 
Day 28 
• Cycle ends.  Return to clinic the following day (day 1 of next cycle) for infusion 
of bevacizumab 
 
 
 
 
 
 

Research Consent Form 
NF Consortium                
 NF 2 Trial Protocol Version 1.4 dated  May 13, 2016    
Revised: January 30, 2017 
Page 6 of 17 
 
 
 
 
Future cycles – after the first 6 months   
 
Day 
 
Tests/Procedures 
 
Day 1 
• Urine test and physical exams every cycle (more if your doctor tells you to) 
• Routine blood tests (about 2 tablespoons)  
• Brain MRI scan and hearing assessments during cycles 7, 9, 11, 13, 15, and 17. 
• Tinnitus Questionnaire and Quality of Life questionnaire during cycles 7, 11, and 
15 
• For participants under the age of 18 who are still growing: x-ray of the leg during 
cycles 7, 11, and 15 
• Research blood samples (about 5 teaspoons) will also be collected to test for 
biomarkers at week 25 (cycle 6) 
• Receive treatment of bevacizumab 
Day 22 
• Receive treatment of bevacizumab 
Day 42 
• Cycle ends.  Return to clinic (day 1 of next cycle) for infusion of bevacizumab 
 
After the final dose of the study drug:  After the final dose of bevacizumab, you will 
have tests and procedures including urine test, physical exam, routine blood tests (about 2 
tablespoons), performance status, brain MRI, hearing assessment, tinnitus Questionnaire 
and Quality of Life questionnaire, research blood tests for biomarkers (about 5 
teaspoons), and x-ray of the leg (for participants under the age of 18 who are still 
growing).  Afterwards, you will resume standard care for your neurofibromatosis 2 and 
vestibular schwannomas.  No research tests are scheduled after the final round of testing 
noted above.  However, we would like to keep track of your medical condition 12 weeks 
after you finish taking bevacizumab.  We would like to do this by calling you on the 
telephone once a year to see how you are doing.   
 
HOW LONG WILL I BE IN THIS RESEARCH STUDY? 
 
You will be asked to take bevacizumab for 2 years or until your tumor grows or your 
hearing gets worse.  After you are finished taking bevacizumab, the study doctor will ask 
you to visit the office or follow-up by telephone for at least 12 weeks.   
 
The research doctor may decide to take you off the research study for many reasons 
including if: 
• It is considered to be in your best interest 
• The study treatment or procedures are found to be unsafe or ineffective 
• There is any problem with following study treatments and procedures 
• Your condition worsens 
• Or for other unforeseen reasons that make it necessary to stop your participation 
in the research study 
 
 

Research Consent Form 
NF Consortium                
 NF 2 Trial Protocol Version 1.4 dated  May 13, 2016    
Revised: January 30, 2017 
Page 7 of 17 
 
 
 
If you are removed from the research study, the research doctor will explain to you why 
you were removed.  In addition, you can stop participating in the research study at any 
time. If you decide to stop participating in this research study, e it is very important that 
you talk to the research doctor and your regular doctor first. 
 
In addition, you can stop participating in the research study at any time; however, the 
FDA requires that any information collected up to the point of your withdrawal cannot be 
removed from the study.  If you decide to stop participating in this research study, we 
encourage you to talk to the research doctor and your regular doctor first. 
 
WHAT ARE THE RISKS OR DISCOMFORTS OF THE RESEARCH STUDY? 
 
There are risks to taking part in any research study. One risk is that you may get a drug 
that does not help treat your disease or that makes your condition or disease worse.  
Another risk is that there may be side-effects.   
 
All chemotherapy drugs have side-effects, which can range from mild and reversible to 
severe, long lasting and possibly life-threatening.  There is a wide range of side-effects 
between different drugs and between individuals.  For investigational drugs, not all of the 
risks are known at this time. You need to tell your doctor or a member of the study 
team immediately if you experience any side-effects.  
 
Since many drugs used to treat tumors are designed to cause the rapidly dividing tumor 
cells in your body to slow down or die, these drugs can also cause other rapidly dividing 
normal cells in your body to slow down or die.  These include the blood cells that help to 
fight infection (white blood cells), the blood cells that help the blood clot (platelets), and 
the blood cells that carry oxygen in your body (red blood cells).  When anticancer drugs 
cause a decrease in these blood cells, it is called bone marrow suppression.  While you 
are participating in this research study, your blood cell levels will be monitored closely.  
 
Please notify your doctor if any of the following occur: 
 
• A fever of 100.5 or above.   
This could be a sign of an infection.  If you have a low white blood cell 
count, this can be serious, life-threatening or fatal. You may have to take 
antibiotics or be admitted to the hospital. 
 
• Low energy or shortness of breath. 
This could be a sign of anemia (not enough red blood cells).  If this 
becomes severe, you may need to come into the clinic or hospital to have a 
transfusion of red blood cells.   
 
• You bruise easily, or, when injured, you do not stop bleeding. 
This could be a sign that your platelets (blood cells that help with clotting) 
are low.  This can be serious or life-threatening.  You may need to come 
into the clinic or hospital for a transfusion of platelets. 
 

Research Consent Form 
NF Consortium                
 NF 2 Trial Protocol Version 1.4 dated  May 13, 2016    
Revised: January 30, 2017 
Page 8 of 17 
 
 
 
Many cancers are associated with an increased risk of blood clots forming that could lead 
to swelling in the legs and arms.  These clots may travel to the lungs causing shortness of 
breath or to the brain causing a stroke.  This may become serious and life threatening.  
Some cancer drugs can increase this risk.  It is important to let your doctor know if you 
have increased shortness of breath or difficulty breathing.  
 
Everyone in the research study will be watched carefully for side-effects.  You will be 
monitored during your chemotherapy to keep track of your blood counts and organ 
function, particularly your kidney and liver function.  If you experience side-effects, they 
may go away after you stop taking the study drug.  Some side-effects can be mild; but 
others can be long lasting and may never go away.  Some may be life-threatening or fatal.  
 
Since the effect of the study drug(s) taken with other medications may not be known, it is 
important that you tell the research doctor about all prescription and non-prescription 
drugs, herbal preparations and nutritional supplements that you are taking or planning to 
take. There may also be some foods that you should avoid while on this research study 
and your research doctor will review this information with you. 
 
During the research study, you will be notified of newly discovered side-effects or 
significant findings, which may affect your health or willingness to participate.  You may 
be asked to sign a new consent form that shows that you have been informed of new 
information relating to this research study. 
 
Risks Associated with Bevacizumab: 
 
Frequent (Chance of 10-50% that this will happen) 
• 
Fatigue 
• 
Headaches 
• 
High blood pressure, with increased risk of heart problems, headache and 
stroke.  
• 
Pain 
• 
Abdominal pain 
• 
Shortness of breath 
• 
Mouth sores  
• 
Weakness 
• 
Upper respiratory infection  
• 
Chills  
• 
Loss of appetite 
• 
Bleeding (including in stomach or intestines) 
• 
Runny nose or increase in tears in your eyes  
• 
Kidney damage, found by testing your urine 
• 
Loss of function of the ovaries (female sex glands), that can lead to 
menopause.  Studies in humans have shown a decrease in the function of 
ovaries during treatment with bevacizumab with chemotherapy.  This 
condition results in difficulty becoming pregnant.  In some participants, the 

Research Consent Form 
NF Consortium                
 NF 2 Trial Protocol Version 1.4 dated  May 13, 2016    
Revised: January 30, 2017 
Page 9 of 17 
 
 
 
function of the ovaries returned to normal after treatment with bevacizumab 
and chemotherapy was stopped.  
• 
Changes in menstrual period, including abnormally heavy menstrual bleeding, 
decreased menstrual bleeding, absent menstrual bleeding, or irregularity in 
time between the menstrual periods 
 
Occasional (Chance of 1-10% that this will happen) 
• 
Hoarseness 
• 
Nosebleeds 
• 
Low levels of potassium in the blood (can cause an irregular heartbeat) 
• 
Hair loss  
• 
Dry Skin 
• 
Hole in your intestine; requires hospitalization and/or surgery; could be fatal. 
• 
Blood clots in your veins and arteries.  These can cause chest pain, heart 
attack, or stroke.  A blood clot in your eye might cause vision loss.  Clots can 
be serious and life threatening.  
• 
Allergic reaction when infusion is given.  Serious allergic reaction may result 
in death.  
• 
Slowed growth in height and development (for children and young adults who 
are still growing).  Laboratory studies have shown a decreased in growth 
during treatment with bevacizumab.  
 
Rare (Chance of less than 5% that this will happen) 
• 
Congestive heart failure (fluid that builds up in your lungs because your heart 
isn’t working properly). 
• 
Bevacizumab might affect the ability of your wounds to heal.  This can lead to 
infections, hospitalization, or could possibly be fatal. 
• 
A very rare problem in your brain that may cause confusion, blindness, and 
coma has been seen in some patients that were given Bevacizumab.  This is 
associated with very high blood pressure and is not thought to be a permanent 
condition. 
• 
Confusion 
• 
Abdominal abscess or infection in your abdomen 
• 
Fistula or hole in your bowel.  This is an abnormal connection between two 
different organs and may lead to life threatening complications including 
serious infections, bleeding, or dysfunction of the organs. 
• 
Dehydration 
• 
Abnormal bleeding in your body or from the tumor, which may be fatal. 
• 
Laboratory studies of bevacizumab showed abnormal bone growth.  These 
and other effects of bevacizumab could possibly cause problems with growth 
and development.  Abnormal changes in the bones after treatment with 
bevacizumab have been seen in young children with growing bones.  This side 
effect appeared to be reversible after the drug was stopped, but has not been 
studied with long-term use of the drug.  All participants in this study who 
receive bevacizumab and are still growing will be monitored for changes to 
bones by the use of x-rays performed throughout the study treatment. 

Research Consent Form 
NF Consortium                
 NF 2 Trial Protocol Version 1.4 dated  May 13, 2016    
Revised: January 30, 2017 
Page 10 of 17 
 
 
 
• 
Fistual or hole in your gallbladder (part of the intestines that helps with 
digestion).  This may require surgery and be serious or life threatening. 
• 
Osteonecrosis of the jaw.  A severe bone disease in which the jaw bone 
becomes visible (exposed) inside the mouth. This can be associated with pain 
and infection.  
• 
Pulmonary hypertension.  Abnormally high blood pressure in the blood 
vessels in the lungs, which makes it harder to pump blood into the lungs.  May 
cause fatigue, shortness of breath, chest pain, and ankle swelling.  Can lead to 
loss of consciousness and could be serious and life threatening.  
 
 
Cancer research often included biopsies, scans, x-rays that are also provided as routine 
care.  The following describes the side effects of procedures down only for the purposes 
or research.  
  
Reproductive Risks:  
 
Because the drug in this study can possibly affect an unborn baby and infants, you should 
not become pregnant or father a baby or breast feed while you are on this study.  Also, 
because bevacizumab remains in your body for weeks to months, you should continue to 
use adequate contraceptive measures and avoid nursing a baby for at least 6 months after 
your last dose of bevacizumab, although the optimal or the maximal time required for 
drug clearance cannot be precisely predicted.  Let your doctor know immediately if you 
become pregnant or find out that you are going to be the father of a child. We can provide 
counseling about preventing pregnancy for either male or female study participants.  In 
addition, the effect of the study drug on the ability have children in the future is 
uncertain.  The study drug may make it more difficult or impossible to have children in 
the future.  
 
NON-PHYSICAL RISKS  
 
Because of side-effects or the time required for tests and clinic visits while you are on 
this research study, you may be unable to keep up with your normal daily activities.  
 
Questionnaires 
 
The questionnaires used in this study may be upsetting. If you find the questionnaires 
upsetting, you may speak with the research doctor or ask to be referred for additional 
emotional support. 
 
WHAT ARE THE BENEFITS OF THE RESEARCH STUDY? 
 
Taking part in this research study may or may not make your health better.  We hope the 
information learned from this research study will help doctors learn more about 
bevacizumab as a treatment for vestibular schwannomas in the future.   
 

Research Consent Form 
NF Consortium                
 NF 2 Trial Protocol Version 1.4 dated  May 13, 2016    
Revised: January 30, 2017 
Page 11 of 17 
 
 
 
CAN I STOP BEING IN THE RESEARCH STUDY AND WHAT ARE MY RIGHTS? 
 
You have the right to choose not to sign this form.  If you choose not to participate in this 
research study, do not sign this form. If you decide not to sign this form, you cannot 
participate in this research study.  
 
You can stop being in the research study at any time.  Tell the research doctor if you are 
thinking about stopping or decide to stop.  He or she will tell you how to stop.  Leaving 
the research study will not affect your medical care outside of the research study.   
 
If you choose not to participate, are not eligible to participate, or withdraw from this 
research study, this will not affect your present or future care and will not cause any 
penalty or loss of benefits to which you are otherwise entitled.   
 
It is important to tell the research doctor if you are thinking about stopping so your 
research doctor can evaluate the risks from stopping the study treatment with 
bevacizumab.  In some cases, the abrupt stopping of a drug can have risks in itself. 
Another reason to tell your research doctor that you are thinking about stopping is to 
discuss what follow-up care and testing could be most helpful for you. 
 
WHO IS CONDUCTING THE RESEARCH STUDY? 
 
The study is being conducted here at SITE as part of the Neurofibromatosis Consortium.  
This group is dedicated to the treatment of NF-related tumors and other problems 
resulting from NF. It is made up of thirteen clinical centers within the United States and 
Australia and an Operations Center (University of Alabama at Birmingham, AL). The 
Neurofibromatosis Consortium is a clinical cooperative group (a network of hospitals 
working together) funded by the Department of Defense (DoD). Each clinical site has NF 
specialists, health care providers, nurses, and other scientists who are dedicated to the 
development of new treatments and cures for the tumors of infants, children, adolescents, 
and young adults with NF. We also conduct research on the causes, prevention and 
treatment of tumors, and the long-term effects of treatment on patients.  
 
This research study is also being supported by an outside organization called Genentech, 
Inc. They are supporting this research study by providing the study drug and modest 
monetary support. 
  
WILL I BE PAID TO TAKE PART IN THIS RESEARCH STUDY? 
 
You will not be paid as part of this research study.   
 
We may use your samples and information to develop a new product or medical test to be 
sold.  The sponsor, hospital, and researchers may benefit if this happens. There are no 
plans to pay you if your samples are used for this purpose.  

Research Consent Form 
NF Consortium                
 NF 2 Trial Protocol Version 1.4 dated  May 13, 2016    
Revised: January 30, 2017 
Page 12 of 17 
 
 
 
 
WHAT ARE THE COSTS? 
 
Taking part in this research study might lead to added costs to you or your insurance 
company. The costs of your standard medical care will be billed to you and/or your 
insurance company in the usual manner.  
 
You will not be charged for bevacizumab. 
 
You or your insurance company will be charged for portions of your care during this 
research study that are considered standard care. Typical standard care for NF2 patients 
includes MRI scans and hearing tests.  You may be responsible for co-payments and 
deductibles that are typical for your insurance coverage. 
 
If you have questions about your insurance coverage, or the items you might be required 
to pay for, please call financial services for information.  The contact information for 
financial services are:   
 
• SITE: SITE PHONE NUMBER 
 
The National Cancer Institute provides an online resource to help people participating in 
cancer clinical trials understand which services their insurance company is required by 
law to pay.  This can be found at the website below or can be provided by the study team: 
 
http://www.cancer.gov/clinicaltrials/learning/insurance-coverage 
 
WHAT HAPPENS IF I AM INJURED OR SICK BECAUSE I TOOK PART IN THIS RESEARCH STUDY? 
 
We will offer you the care needed to treat injuries directly resulting from taking part in 
this research.  We may bill your insurance company or other third parties, if appropriate, 
for the costs of the care you get for the injury, but you may also be responsible for some 
of them. 
 
The SITE, Department of Defense and the Neurofibromatosis Consortium has made no 
provision for monetary compensation in the event of injury from the research, and in the 
event of such injury, treatment will be provided, but is not free of charge. 
 
The Principal Investigator or his/her designee will assist you and your child in obtaining 
appropriate medical treatment if it is required.  If you have any questions, please discuss 
this issue thoroughly with the Principal Investigator or his/her designee before you enroll 
in this study.  This is not a waiver or release of your legal rights.   
 
What about confidentiality? 
 
We will take measures to protect the privacy and security of all your personal 
information, but we cannot guarantee complete confidentiality of study data.  

Research Consent Form 
NF Consortium                
 NF 2 Trial Protocol Version 1.4 dated  May 13, 2016    
Revised: January 30, 2017 
Page 13 of 17 
 
 
 
 
Medical information created by this research study may become part of your hospital 
medical record and may be forwarded to your primary doctor. Information that does not 
become part of your medical record will be stored in your study file.  It may also become 
part of a SITE research database.  Representatives of the Department of Defense, the 
outside organization that is partly funding the study, are authorized to review research 
records.  
 
The results of this research study may be shared with the sponsors and published. You 
will not be identified in publications without your permission.   
 
Your information may also be shared with outside individuals or entities that have a need 
to access this information to perform functions relating to the conduct of this research.  
This may include, but not limited to, other research doctors and medical centers 
participating in this research, labs, insurance agencies, Federal and state regulatory 
agencies and safety monitoring boards.  
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law.  This Web site will not include information that can identify you. 
At most, the Web site will include a summary of the results. You can search this Web site 
at any time. 
 
WHOM DO I CONTACT IF I HAVE QUESTIONS ABOUT THE RESEARCH STUDY? 
 
If you have questions about the study, please contact the research doctor, SITE PI at  
SITE PHONE NUMBER .  She will be glad to answer any of your questions.  After 
hour number to call are: SITE PHONE NUMBER.  You may also use these numbers if 
you have questions about any part of this study or consent form either now or at any time in 
the future or if you believe you have been injured as a result of being in this study 
 
If you have any questions or concerns about your rights as a research participant, or 
concerns or complaints about the research, you may contact The SITE Office of the IRB 
(OIRB) at  SITE PHONE NUMBER.  Regular hours for the Office of the IRB are 8:00 
a.m. to 5:00 p.m. Central Time Zone, Monday through Friday.  You may also call this 
number in the event the research staff cannot be reached or you wish to talk to someone 
else. 
 
Storage of Specimens for Future Use  
 
We will try to collect the blood used for this research at the same time as blood is drawn 
to monitor your health during your study treatment and at follow-up visits, in order not to 
increase the number of times you will have blood drawn.  If you agree, any blood sample 
that is left over after the research for this study is complete will be stored for future use.  
Please read each sentence below and think about your choice.  After reading each 
sentence, circle “yes” or “no” for each type of specimen and write your initials.  Then 
sign your name at the bottom of this section.  If you have any questions, please talk to 

Research Consent Form 
NF Consortium                
 NF 2 Trial Protocol Version 1.4 dated  May 13, 2016    
Revised: January 30, 2017 
Page 14 of 17 
 
 
 
your doctor or nurse, or call the Principal Investigator for this study (SITE PI at  SITE 
PHONE NUMBER). 
  
No matter what you decide to do, it will not affect your care.  
 
You may request at any time that your research samples be removed from storage and not 
be used for future research.  If you decide you want your samples removed, you may  
contact SITE PI at  SITE PHONE NUMBER.  Once your request is received, and if your 
samples have not already been used for other research, they will be destroyed.  If you do 
not make such a request, your specimens will be stored indefinitely or until used.   
 
1. My blood specimens may be kept for use in future research to learn about, 
prevent, or treat neurofibromatosis 2: 
 
 
 
⁪ Yes  
⁪ No ___________________________    ___________ 
 
 
 
 
Signature 
 
 
 
Date 
 
 
2. My blood specimens may be kept for use in future research to learn about, 
prevent, or treat other health problems (for example, diabetes, Alzheimer’s 
disease, or heart disease): 
 
 
 
⁪ Yes  
⁪ No ___________________________    ___________ 
 
 
 
Signature 
 
 
 
Date 
 
 
3. Someone may contact me in the future to ask me to take part in more research: 
 
 
 
⁪ Yes  
⁪ No ___________________________    ___________  
 
 
 
Signature 
 
 
 
Date  
 
 
 
 
 
 
 
 
 
 

Research Consent Form 
NF Consortium                
 NF 2 Trial Protocol Version 1.4 dated  May 13, 2016    
Revised: January 30, 2017 
Page 15 of 17 
 
 
 
 
Document of Assent 
 
Signature of participant between age of 14 and 17: The person doing this research 
study has explained what will happen to me if I take part in this research study.  My 
signature below means that I want to be in this research study.  I can decide not to take 
part in this research study if I do not want to and nothing will happen to me if I decide I 
do not want to participate.   
 
 
 
____________________________________ 
__________________ 
Signature of Participant 
 
 
 
Date 
 
Document of Consent  
 
My signature below indicates that I agree to participate in this study.  I am aware that I 
will receive a copy of this signed agreement: 
 
• I have had enough time to read the consent and think about participating in 
this study; 
• I have had all of my questions answered to my satisfaction; 
• I am willing to participate in this study; 
• I have been told that my participation is voluntary and I can withdraw at any 
time 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Participant 
 
 
 
Date 
Or Legally Authorized Representative   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relationship of Legally Authorized Representative to Participant   
 
 
___________________________________  
______________________________ 
Signature of Witness   
 
 
 
Date  
 
 
 
 
 
 
 
 
 

Research Consent Form 
NF Consortium                
 NF 2 Trial Protocol Version 1.4 dated  May 13, 2016    
Revised: January 30, 2017 
Page 16 of 17 
 
 
 
 
Waiver of Assent  
 
The assent of ______________________________ (name of child/minor) was waived 
because of: 
 
Age _________ 
Maturity ________ 
Psychological state of the child ________ 
 
 
To be completed by person obtaining consent: 
 
The consent discussion was initiated on   
 (date). 
 A copy of this signed consent form will be given to the participant or legally 
authorized representative, or, where the participant is a minor, the participant’s parent 
or legal guardian. 
For Adult Participants 
 The participant is an adult and provided consent to participate.  
 
 The participant is a non-English speaker and signed the translated Short Form in 
lieu of English consent document 
 The participant is an adult who lacks capacity to provide consent and his/her legally 
authorized representative: 
 gave permission for the adult participant to participate  
 did not give permission for the adult participant to participate  
or 
For Minor Participants 
 The parent or legally authorized representative gave permission for the minor to 
participate.  
 
 parent or legally authorized representative is a non-English speaker and signed 
the translated Short Form in lieu of English consent document 
 The parent or legally authorized representative did not give permission for the minor 
to participate 
 
 
Signature of Individual obtaining consent:  
 
 
Printed name of above:  
 
 
Date:  
 
 
 
 

Research Consent Form 
NF Consortium                
 NF 2 Trial Protocol Version 1.4 dated  May 13, 2016    
Revised: January 30, 2017 
Page 17 of 17 
 
 
 
 
 
Medical Release of Information 
 
Permission is hereby given: 
 
______________________________________ 
Name  
 
______________________________________ 
Address 
 
______________________________________ 
City   
State  
Zip  
 
 
To release to the SITE, any and all medical information contained in the record of: 
 
______________________________________ 
Name of Patient  
 
______________________________________ 
Address 
 
______________________________________ 
City   
State   
Zip 
 
______________________________________ 
Date  
 
 
 
 
 
 
Signed:  
______________________________ 
 
 
 
 
 
 
 
Patient  
 
 
 
 
 
 
Signed: 
______________________________ 
 
 
 
 
 
 
 
Witness  
 
 
 
 
 
 
__________________________________________ 
 
 
 
 
 
Address  
 
 
 
 
 
 
__________________________________________ 
 
 
 
 
 
City   
 
State  
Zip