Open-label, Phase 2 Clinical Trial of Crizotinib for Children and Adults With Neurofibromatosis Type 2 and Progressive Vestibular Schwannomas
Phase: PHASE2
Conditions: Neurofibromatosis 2, Progressive Vestibular Schwannoma (VS)
Sponsor: University of Alabama at Birmingham

NF110: Open-label, Phase 2 Clinical Trial of Crizotinib for 
Children and Adults with Neurofibromatosis Type 2 and 
Progressive Vestibular Schwannomas 
 
 
Study Protocol & Statistical Analysis Plan 
 
NCT04283669 
 
 
September 15, 2023 
 
 
Girish Dhall, MD 
University of Alabama at Birmingham 
Birmingham, AL 35294 
 

 
 
 
Protocol Version Date:  9/15/2023 Version 1.7 
Protocol Version Date:   
9/15/2023 
 
Sponsor Information:   
U.S. Army Medical Research and Development Command 
(USAMRDC), Department of Defense (DOD)  
                                                                              
Supported by: 
 
 
 
 
Pfizer 
 
IND NUMBER:    
 
 
EXEMPT 
 
Title:  
NF110: Open-label, Phase 2 Clinical Trial of Crizotinib for 
Children and Adults with Neurofibromatosis Type 2 and 
Progressive Vestibular Schwannomas   
 
Principal Investigator 
Matthias A. Karajannis, MD, MS 
Memorial Sloan Kettering Cancer Center 
1275 York Ave, Box 234 
New York, NY 10065 
Phone: 212-639-3171 
Fax: 212-717-3239 
karajanm@mskcc.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 
 
bkorf@uabmc.edu 
 
 
 
  
 
Co-Chair:  
 
 
Phioanh [Leia] Nghiemphu, MD 
UCLA Neuro-Oncology Program  
The Ronald Reagan UCLA Medical Center  
710 Westwood Plaza, Reed Bldg RM 1-230 
Los Angeles CA 90095 
Phone: 310-825-5321 
Fax: 310-825-0644 
E-mail address: 
PNghiemphu@mednet.ucla.edu 
Co-Investigator: 
 
Scott R. Plotkin, MD, PhD 
Massachusetts General Hospital 
55 Fruit Street, Yawkey 9E 
Boston, MA  02114 
Phone: 617-726-3650 
splotkin@partners.org  
 
 
 
  
 
 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
3 
Statistician:  
Yimei Li, PhD 
3501 Civic Center Blvd 
Colket Translational Research Building Room 4032 
Philadelphia, PA 19104-3820 
 
LiY3@chop.edu 
 
Operations Center  
 
 
Lauren Baldwin, BS 
Clinical Research 
University of Alabama at Birmingham 
Manager: 
 
Department of Genetics 
1720 2nd Avenue South– Kaul 230  
 
Birmingham, AL  35294-0024 
lahaynes@uabmc.edu   
 
Operations Center  
Karen A. Cole-Plourde, BS 
Program Director: 
 
University of Alabama at Birmingham 
Department of Genetics 
1720 2nd Avenue South– Kaul 230  
 
Birmingham, AL  35294-0024 
 
kplourde@uab.edu 
 
Operations Center         
Juliette Southworth, BS, CCRP   
Research Compliance 
 
University of Alabama at Birmingham 
Manager: 
 
Department of Genetics 
1720 2nd Avenue South– Kaul 230  
 
Birmingham, AL  35294-0024 
 
 
 
 
 
 
 
 
 
 
jsouthworth@uab.edu 
 
Central Pharmacy: 
Chris Chapleau, PharmD, PhD, MBA   
Investigational Drug Service (IDS) Pharmacy 
UAB Hospital 
North Pavilion, room 3470 
1802 6th Avenue South 
Birmingham, AL  35249 
Phone: 205-934-7191 
cchapleau@uabmc.edu 
 
Study Audiologist: 
Kerri O’Connor, AuD, CCC-A 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue, 4th Floor, Suite 7  
New York, New York 10065 
Phone: 212-639-5358 
Fax: 212-717-3302 
oconnok7@mskcc.org 
 
 
 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
4 
Study Radiologist: 
Sofia Haque, MD 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue  
New York, New York 10065 
Phone: 212-639-7170 
Fax: 212-717-3325 
 
 
 
haques@mskcc.org 
 
Research Monitor: 
 
 
Diana Osorio, MD, MPH  
Nationwide Children’s Hospital 
700 Children’s Drive 
Columbus, Ohio 43205 
Phone: 614-722-4087 
Fax: 614-722-3369 
diana.osorio@nationwidechildrens.org 
 
Agent(s):    
 
 
 
 
 
Crizotinib (NSC# 749005) – Supplier: Pfizer, Inc. 
 
 
 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
5 
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 
 
Peter de Blank, MD 
Cincinnati Children’s Hospital Medical 
Center 
240 Albert Sabin Way, T6. Suite 505 
Cincinnati, OH  45229 
Phone:  513-517-2068 
Peter.deBlank@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 
 
Miriam Bornhorst, MD 
Children’s National Medical Center 
111 Michigan Avenue, NW 
Washington, DC  20010 
Phone:  202-545-2772 
MBornhorst@childrensnational.org 
Amy Armstrong, MD 
Washington University School of Medicine 
660 South Euclid Avenue – Box 8116 
St. Louis, MO  63131 
Phone: 314-454-6018 
armstrongae@wustl.edu  
 
Steven Rhodes, MD 
Indiana University  
705 Riley Hospital Drive Room 5867 
Indianapolis, IN  46202 
Phone: 317-944-4034 
sdrhodes@iupui.edu 
Kaleb Yohay, MD 
New York Univ. Pediatrics 
160 E. 32nd Street – 2nd Floor 
Hassenfeld Children’s Center 
New York, NY 10016 
Phone: 212.263.7744 
kaleb.yohay@nyumc.org 
 
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 
 
Dusica Babovic-Vuksanovic, M.D 
The Mayo Clinic 
200 First St. SW 
Rochester, MN 55905 
Phone: 507-284-3215 
DBabovic@Mayo.edu 
Nicole Ullrich, MD, PhD 
Children’s Hospital Boston – Dept. of 
Neurology 
300 Ongwood Avenue – Fegan 11 
Boston, MA  02115 
Phone: 617-355-2066 
Nicole.Ullrich@childrens.harvard.edu 
 
Laura Klesse, MD, PhD 
The University of Texas Southwestern 
1935 Medical District Drive 
Dallas, TX 75235 
Phone: 214-456-2382 
Laura.Klesse@utsouthwestern.edu 
 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
6 
Affiliate Sites  
Massachusetts General Hospital (Ullrich; Plotkin) 
Dana Farber (Ullrich; Kieran) 
UCLA (Rosser; Nghiemphu) 
Johns Hopkins (Packer; Blakeley) 
Ann & Robert H. Lurie Children’s Hospital of Chicago (Waanders)   
Memorial Sloan Kettering Cancer Center (Karajannis; Piotrowski; Sait) 
Children's Hospital of Atlanta (Wolf) 
University of Minnesota (Moertel) 
 
Data and Safety Monitoring Board (DSMB) Members 
 
Wafik Zaky, MD, Chair  
Department of Pediatrics 
The University of Texas MD Anderson Cancer Center 
1515 Holcombe Blvd, Unit Number: 87 
Houston, TX 77030 
Phone: 713-745-1862 
Fax: 713-792-0608 
wzaky@mdanderson.org 
 
Teena Bhatla, MD, Member  
Director, Division of Pediatric Hematology-Oncology 
The Valerie Fund Children’s Center of Cancer and Blood Disorders 
Children’s Hospital of New Jersey at Beth Israel Medical Center 
201 Lyons Ave 
Newark, NJ 07112 
Phone: 973-926-7161 
Fax: 973-282-0395 
teena.bhatla@rwjbh.org 
 
Jennifer Clarke, MD, Member 
Department of Neurology 
UCSF Medical Center 
San Francisco, CA 
Phone: 415-353-2383 
Fax: 415-353-2167 
jennifer.clarke@ucsf.edu 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
7 
ABBREVIATIONS: 
 
ABI 
Auditory brainstem implant 
ABL 
Abelson murine leukemia viral oncogene homolog 1 
AE 
Adverse event 
ALK 
Anaplastic lymphoma kinase 
ALT 
Aspartate aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Alanine aminotransferase 
ALT 
Alanine transaminase/alanine transaminase 
ATP 
Adenosine triphosphate 
AUC 
Area under the curve 
BCR 
B-cell receptor 
BRAF 
v-Raf murine sarcoma viral oncogene homolog B 
BSR 
Biostatistics Shared Resource 
CBC 
Complete blood count 
CDMRP 
Congressionally Directed Medical Research Programs 
CI 
Confidence interval 
C-kit 
v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog 
CK 
Creatinine phosphokinase 
Cmax 
Maximum (peak) concentration 
C-met 
MET proto-oncogene, receptor tyrosine kinase 
CNS 
Central nervous system 
CR 
Complete response 
CRF 
Case report form 
CSF 
Cerebrospinal fluid 
CTCAE 
Common terminology criteria for adverse events 
CYP3A4 
Cytochrome P450, family 3, subfamily A, polypeptide 4 
DCC 
Data Coordinating Center 
DLCO 
Diffusing lung capacity for carbon monoxide 
DMSO 
Dimethyl sulfoxide 
DOD 
Department of Defense 
DPOAE 
Distortion product otoacoustic emissions 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
EGFR 
Epidermal growth factor receptor 
EML4 
Echinoderm microtubule-associated protein-like 4 
ENT 
Ear, nose and throat 
ErbB2 
Epidermal growth factor receptor 2 
EU 
European Union 
FDA 
Food and Drug Administration 
HER-2 
Human epidermal growth factor receptor 2 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
8 
HGFR 
Hepatocyte growth factor receptor 
HRPO 
Human Research Protection Official 
I.B. 
Investigator Brochure 
IAC 
Internal auditory canal 
IRB 
Institutional Review Board 
MLV 
Monitored live voice 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
NF2 
Neurofibromatosis type 2 
NFTI-QOL Neurofibromatosis 2 impact on quality of life 
NIH 
National Institutes of Health 
NOB 
Neuro-Oncology Branch (NCI) 
NOD/SCID Non-obese diabetic/severe combined immunodeficiency 
NPM 
Nucleophosmin 
NSCLC 
Non-small-cell lung carcinoma 
OAE 
Otoacoustic emissions 
PD 
Progressive disease 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PO 
Per os (by mouth) 
PR 
Partial response 
PS 
Performance score 
PTA 
Pure tone average 
QTc 
Corrected QT interval 
RON 
Receptor originated from Nantes 
ROS 
ROS proto-oncogene 1, receptor tyrosine kinase 
RT 
Radiation therapy 
SAE 
Serious adverse event 
SDS 
Speech discrimination score (interchangeable with WRS) 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SRT 
Speech reception threshold 
TRQ 
Tinnitus reaction questionnaire 
ULN 
Upper limit of normal 
VEGF 
Vascular endothelial growth factor 
VEGFR2 
Vascular endothelial growth factor receptor 2 
VS 
Vestibular schwannoma 
WBC 
While blood count 
WRS 
Word recognition score (interchangeable with SDS) 
 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
9 
PRECIS 
 
Background 
 
• Bilateral vestibular schwannomas (VS) are the hallmark of neurofibromatosis 2 (NF2).  As 
these tumors enlarge, they cause sensorineural hearing loss and, ultimately, complete hearing 
loss.   
• NF2-related vestibular schwannomas express Focal Adhesion Kinase 1 (FAK1)   
• Crizotinib, a small molecule kinase inhibitor, reduces NF2 schwannoma cell growth and 
tumor formation in preclinical schwannoma models via inhibition of FAK1 
 
Primary Objective 
 
• To estimate the best objective volumetric response rates to crizotinib in pediatric and adult 
NF2 patients with VS  
 
Eligibility 
 
• NF2 patients ≥6 years of age on day 1 of treatment 
• Subjects must have a target VS with the following qualities: 
o volumetrically measurable and ≥0.75 ml in size 
o volumetric evidence of progression over the past 18 months (defined as ≥20% 
annualized increase in volume) 
 
Design 
 
• Multi-Center, 2-stage, phase II open-label study  
• Planned treatment: crizotinib is taken continuously for up to 12 cycles (48 weeks) until 
disease progression or unacceptable toxicity, with re-treatment option of patients who 
complete 12 cycles of treatment without disease progression, but progress within the 
following 24 weeks after stopping treatment with crizotinib. 
• Response Evaluations: MRI brain (with 3D volumetrics, primary endpoint) and audiograms 
(if applicable, exploratory endpoint) at baseline and at the end of every 3rd cycle, i.e. every 
12 weeks. Volumetric measurements by central review will be used to determine eligibility 
and continuation on treatment. 
 
 
 
 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
10 
SCHEMA 
 
 
 
Patients who complete 12 cycles of treatment without disease progression, but within the 
following 24 weeks show disease progression (defined as ≥20% increase in target tumor 
volume compared to off-treatment volume), will be eligible for re-treatment on study, provided 
they still meet study eligibility criteria 
 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
11 
TABLE OF CONTENTS 
Primary Objective ....................................................................................................................................................... 9 
Eligibility ...................................................................................................................................................................... 9 
Design ........................................................................................................................................................................... 9 
SCHEMA .................................................................................................................................................................... 10 
1. 
OBJECTIVES .................................................................................................................................................. 14 
1.1 
Study Design .................................................................................................................................................. 14 
1.2 
Primary Objective ......................................................................................................................................... 14 
1.3 
Exploratory Objectives (including re-treatment phase) ................................................................................ 14 
2. 
BACKGROUND .............................................................................................................................................. 15 
2.1 
Neurofibromatosis 2 ...................................................................................................................................... 15 
2.2 
Study Agent(s) ............................................................................................................................................... 16 
2.3 
Rationale ....................................................................................................................................................... 19 
2.4 
Correlative Studies Background.................................................................................................................... 24 
3. 
PARTICIPANT SELECTION ........................................................................................................................ 24 
3.1 
Eligibility Criteria ......................................................................................................................................... 24 
3.2 
Exclusion Criteria ...................................................................................................................................... 26 
3.3 
Inclusion of Women, Minorities and Other Underrepresented Populations ................................................. 28 
4. 
SCREENING AND STUDY ENROLLMENT PROCEDURES .................................................................. 28 
4.1 
Informed Consent/Assent ............................................................................................................................... 28 
4.2 
Screening Procedures ................................................................................................................................. 28 
4.3 
Study Enrollment ......................................................................................................................................... 28 
4.4 
General Guidelines for all Participating Institutions ............................................................................. 28 
4.5 
Registration and Enrollment Process for All Participating Institutions .................................................... 29 
5. 
TREATMENT PLAN ...................................................................................................................................... 29 
5.1 
Safety Measures and Special Precautions: ................................................................................................ 30 
5.2 
Duration of Therapy ...................................................................................................................................... 31 
5.3 
Duration of Follow-Up .................................................................................................................................. 33 
5.4 
Criteria for Removal from Study ................................................................................................................... 33 
6. 
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS .................................... 33 
6.1 
Anticipated Toxicities .................................................................................................................................... 33 
6.2 
Toxicity Management and Dose Modifications/Delays ................................................................................. 33 
6.3 
Precautions and Management of Specific Toxicities: ................................................................................... 35 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
12 
7. 
DRUG FORMULATION AND ADMINISTRATION ................................................................................. 36 
7.1 
Crizotinib ....................................................................................................................................................... 36 
8. 
CORRELATIVE/SPECIAL STUDIES .......................................................................................................... 38 
8.1 
Pharmacokinetic Studies ............................................................................................................................... 38 
8.2 
Pharmacodynamic Studies ............................................................................................................................ 38 
8.3 
Laboratory correlative markers .................................................................................................................... 38 
9. 
SCHEDULE OF EVALUATIONS ................................................................................................................. 40 
10. 
MEASUREMENT OF EFFECT..................................................................................................................... 41 
10.1 Antitumor Effect– Solid Tumors .................................................................................................................... 41 
10.2 Antitumor Effect – Hematologic Tumors ....................................................................................................... 44 
10.3 Other Response Parameters: Hearing Response .......................................................................................... 44 
11. 
ADVERSE EVENT REPORTING REQUIREMENTS ............................................................................... 45 
11.1 Definitions ..................................................................................................................................................... 45 
11.2 Methods and Timing for Assessing and Recording Safety Variable .............................................................. 47 
11.3 Procedures for Eliciting, Recording, and Reporting Adverse Events ........................................................... 47 
11.4 SAE Expedited Reporting/Pfizer.................................................................................................................... 49 
11.5 Adverse Event Reporting to the US Army ...................................................................................................... 51 
11.6 Reporting Requirements ................................................................................................................................ 52 
11.7 Reporting to the Institutional Review Board (IRB) ....................................................................................... 52 
11.8 Reporting to the NIH Office of Biotechnology Activities (OBA) ................................................................... 52 
11.9 Reporting to the Institutional Biosafety Committee (IBC)............................................................................. 52 
11.10 Reporting to Hospital Risk Management....................................................................................................... 52 
12. 
DATA AND SAFETY MONITORING .......................................................................................................... 52 
12.1 Data Reporting .............................................................................................................................................. 53 
12.2 Safety Meetings ............................................................................................................................................. 53 
12.3 Monitoring ..................................................................................................................................................... 53 
12.4 Privacy .......................................................................................................................................................... 54 
12.5 Confidentiality ............................................................................................................................................... 54 
13. 
REGULATORY CONSIDERATIONS .......................................................................................................... 54 
13.1 Protocol Review and Amendments ................................................................................................................ 54 
13.2 Informed Consent .......................................................................................................................................... 54 
13.3 Ethics and Good Clinical Practice (GCP) .................................................................................................... 55 
13.4 Study Documentation .................................................................................................................................... 55 
13.5 Records Retention ......................................................................................................................................... 56 
13.6 Multi-center Guidelines ................................................................................................................................. 56 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
13 
13.7 Cooperative Research and Development Agreement (CRADA)/Clinical Trials Agreement (CTA) .............. 56 
14. 
STATISTICAL CONSIDERATIONS ............................................................................................................ 56 
14.1 Study Design/Endpoints ................................................................................................................................ 56 
14.2 Sample Size/Accrual Rate .............................................................................................................................. 57 
14.3 Stratification Factors .................................................................................................................................... 57 
14.4 Analysis of Exploratory Endpoints (including re-treatment phase) .............................................................. 57 
14.5 Reporting and Exclusions .............................................................................................................................. 58 
15. 
PUBLICATION PLAN .................................................................................................................................... 58 
16. 
REFERENCES ................................................................................................................................................. 60 
Appendix A: Schedule of Evaluations .................................................................................................................... 63 
Appendix B: Hearing Response Guidelines ............................................................................................................ 65 
Appendix C:  NFTI-QOL (Neurofibromatosis 2 impact on quality of life) ...................................................... 67 
Appendix D: Performance Status Criteria .............................................................................................................. 70 
Appendix E: Audiology Procedures ......................................................................................................................... 71 
Appendix F: MRI Protocols ...................................................................................................................................... 83 
Appendix G: Tinnitus Reaction Questionnaire (TRQ)  [Wilson et al., J Speech Hear Res 34, 1991] ................ 85 
Appendix H: Disintegration of Capsules for Patients Unable to Swallow Capsules ............................................ 87 
APPENDIX I: SUBJECT DIARY ON NF2 CRIZOTINIB PROTOCOL ............................................................ 90 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
14 
1. OBJECTIVES 
 
1.1 Study Design 
Subjects with Neurofibromatosis Type 2 (NF2) and progressive vestibular schwannoma 
(VS) will be treated with crizotinib administered orally. Crizotinib will be taken 
continuously until disease progression or unacceptable toxicity, in continuous treatment 
cycles of 28 days each, for a maximum of 12 cycles. Clinical response will be assessed 
by MRI (volumetrics, primary objective) and audiology at the end of every 3rd cycle. 
Subjects with volumetric tumor progression will be taken off protocol. Patients who 
complete 12 cycles of treatment without disease progression, but within the following 24 
weeks show subsequent disease progression (defined as >20% increase in target tumor 
volume compared to off-treatment volume), will be eligible for re-treatment on study for 
up to 48 additional weeks, provided they still meet study eligibility criteria.   
 
1.2 Primary Objective 
The primary objective of this study to estimate the best objective volumetric response 
rates (i.e. maximum tumor shrinkage) to crizotinib in NF2 patients with VS during up to 
12 cycles (48 weeks) of treatment.   
 
1.3 Exploratory Objectives (including re-treatment phase) 
Exploratory objectives are: 
 
(1) to describe the frequency of adverse events (possibly, probably, or definitely) related 
to crizotinib use in this patient population; 
 
(2) to determine the durability of volumetric 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); 
 
(3) to estimate hearing response rates (defined as an increase in word recognition score 
above the upper limit of the 95% critical difference from the baseline word recognition 
score, Appendix B) and 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 B); 
 
(4) to explore effects of treatment on quality of life using a validated questionnaire for 
NF2 patients (NFTI-QOL); 
 
(5) to explore association of volumetric or audiologic response with baseline and on-
treatment plasma levels of crizotinib targets and candidate biomarkers including FAK, 
MET, ROS and ALK; 
 
(6) to explore volumetric responses to crizotinib in NF2-associated non-VS tumors, such 
as meningiomas and ependymomas.  
 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
15 
(7) to learn about the durability of imaging and hearing responses after discontinuation of 
study drug. 
 
 
2. BACKGROUND 
 
2.1 Neurofibromatosis 2 
Neurofibromatosis type 2 (NF2) is an autosomal-dominant genetic disease with an 
incidence of approximately 1/40,000. The NF-2 gene is located on chromosome 22 and 
its gene product is named Merlin. Merlin’s function is not well understood, but it appears 
to act as a tumor suppressor. The majority of NF2 patients develop progressive hearing 
loss in adolescence or young adulthood due to unilateral or bilateral vestibular 
schwannomas (VS).1 Spinal tumors, including meningiomas, schwannomas and 
ependymomas, as well as intracranial tumors, mostly meningiomas, are also highly 
prevalent. NF2-related tumors, although mostly slow growing, cause considerable 
morbidity and mortality, particularly when first diagnosed at a young age. The available 
treatment options for these neoplasms, which often occur at multiple sites simultaneously, 
are non-curative and mostly limited to surgery and radiation therapy. As a result, all NF2 
patients suffer from major morbidity, mortality and significantly reduced life expectancy. 
Although classic chemotherapy is effective treatment for low-grade brain tumors, no such 
therapy has been validated for NF2 patients with multiple tumors for a variety of reasons. 
Most chemotherapeutic agents are mutagenic and there is reluctance to use them in 
patients with loss of tumor-suppressor function, such as NF2. Many chemotherapeutic 
drugs are neuro– and/or ototoxic, making them unsuitable for NF2 patients. Surgery 
remains the mainstay of therapy for VS, but carries major risks including complete 
deafness, facial palsy, stroke and CSF leak. Bevacizumab has emerged as a treatment 
option for NF2 patients, and may result in tumor shrinkage and/or hearing improvement 
in a subset of patients. In a recent prospective phase 2 study,2 fourteen adult and pediatric 
patients with NF2 and progressive hearing loss in the target ear were enrolled. The 
primary end point, confirmed hearing response (improvement maintained ≥3 months), 
occurred in five (36%) of 14 patients (95% CI, 13–65%; P <0.001). Eight patients (57%) 
had transient hearing improvement above the 95% CI for word recognition scores, and 
imaging response was seen in six (43%) of target VS. However, responses to bevacizumab 
are not sustained off treatment,3 and cumulative toxicities including hypertension and 
renal damage including proteinuria limit the long-term use of this therapy in responders. 
In addition, a subset of patients do not respond to therapy at all, or will progress after 
initial disease stabilization on bevacizumab. 
We have previously conducted prospective NF2 phase 2 clinical trials with molecular 
targeted agents, including lapatinib and everolimus.4,5 In the lapatinib study, four of 17 
evaluable patients experienced an objective volumetric response, defined as ≥15% 
decrease in VS volume (23.5%; 95% confidence interval [CI], 10%-47%), with median 
time to response of 4.5 months (range, 3-12). In responders, reduction in VS volumes 
ranged from -15.7% to -23.9%. Four of 13 patients evaluable for hearing met hearing 
criteria for response (30.8%; 95% CI, 13–58%), but only one patient experiences a 
sustained hearing response exceeding 9 months in duration. Median time to overall 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
16 
progression (i.e., volumetric progression or hearing loss) was 14 months. The estimated 
overall progression-free survival and volumetric progression-free survival at 12 months 
were 64.2% (95% CI, 36.9–82.1%) and 70.6% (95% CI, 43.1–86.6%), respectively. We 
concluded that lapatinib is well tolerated and has objective activity in a subset of NF2 
patients with progressive VS, although the hearing and volumetric responses appeared to 
be inferior compared to published results with bevacizumab.2,6,7 In our everolimus study, 
no objective imaging or hearing responses were observed in 9 evaluable patients with on 
stage 1 of the trial, and the study was closed according to predefined stopping rules.5 We 
concluded from this data that everolimus is ineffective for the treatment of progressive 
VS in NF2 patients, and a subsequent study suggested that everolimus may have modest 
activity in some patients by decreasing tumor growth velocity.8   
Taken together, additional effective medical treatment options for NF2 patients are 
urgently needed,9 including for those who do not respond or progress on bevacizumab, 
or are unable to tolerate bevacizumab due to toxicities.  
2.2 Study Agent(s) 
 
2.2.1 Crizotinib (NSC# 749005) 
Crizotinib (Xalkori®) is an ATP-competitive small-molecule oral inhibitor of the 
anaplastic lymphoma kinase (ALK), c-Met/hepatocyte growth factor receptor (HGFR), 
Recepteur d’Origine Nantais (RON), and ROS receptor tyrosine kinases and their 
oncogenic variants (e.g., c-Met/HGFR mutations and ALK or ROS1 fusion proteins). 
Crizotinib has been studied in a variety of in vitro and in vivo model systems to determine 
potency for inhibition of ALK, c-Met/HGFR, RON, or ROS1 RTK activity, kinase 
selectivity, antitumor efficacy, pharmacodynamics, pharmacokinetics, and mechanism of 
action (reviewed by Rodig, Shapiro and Ou10,11). Crizotinib demonstrated potent 
concentration-dependent inhibition of the kinase activity of ALK, c-Met/HGFR, RON, 
and ROS1 in biochemical assays and inhibited phosphorylation and kinase dependent 
function in cell-based assays. Crizotinib demonstrated potent and selective growth 
inhibitory activity and induced apoptosis in tumor cell lines exhibiting ALK fusion 
variants (EML4-ALK or NPM-ALK), ROS1 fusion variants, or exhibiting amplification 
of the ALK or c-Met/HGFR gene locus. In vivo, crizotinib demonstrated antitumor 
efficacy, including marked cytoreductive antitumor activity, in mice bearing tumor 
xenografts that expressed ALK fusion variants or activated c-Met/HGFR. The antitumor 
efficacy of crizotinib was dose-dependent and correlated to pharmacodynamic inhibition 
of phosphorylation of ALK fusion variants (EML4-ALK or NPM-ALK) or c-Met/HGFR 
in tumors in vivo. The collective rationale for investigation of crizotinib in clinical studies 
is built on genetic alteration of its molecular targets, its predicted ability to target multiple 
processes that are common to cancer progression, and preclinical efficacy data. Crizotinib 
received regular marketing approval in the United States (US) for the treatment of patients 
with metastatic NSCLC that is ALK-positive as detected by a Food and Drug 
Administration (FDA)-approved test. Crizotinib also received regular and conditional 
approvals in Switzerland and the European Union (EU), respectively, for the treatment of 
adults with previously treated ALK-positive advanced NSCLC. In early 2016, the FDA 
has approved a supplemental New Drug Application for crizotinib to treat patients with 
metastatic non-small cell lung cancer (NSCLC) whose tumors are ROS1 gene 
rearrangement positive.  

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
17 
The safety and activity of crizotinib has also been investigated in pediatric patients in a 
Children's Oncology Group phase 1 consortium study, which included patients with 
refractory solid tumors or anaplastic large-cell lymphoma (ALCL).12 Seventy-nine 
patients were enrolled in the study with a median age of 10.1 years (range 1.1-21.4). 
Crizotinib was well tolerated with a recommended phase 2 dose of 280 mg/m2 twice daily. 
Grade 4 adverse events in cycle 1 were neutropenia (two) and liver enzyme elevation 
(one). Grade 3 adverse events that occurred in more than one patient in cycle 1 were 
lymphopenia (two), and neutropenia (eight). The mean steady state peak concentration of 
crizotinib was 630 ng/mL and the time to reach this peak was 4 h (range 1-6). Objective 
tumor responses were documented in 14 of 79 patients (nine complete responses, five 
partial responses); and the anti-tumor activity was enriched in patients with known 
activating ALK aberrations (eight of nine with anaplastic large-cell lymphoma, one of 11 
with neuroblastoma, three of seven with inflammatory myofibroblastic tumor, and one of 
two with NSCLC). 
In a study of 121 patients under the age of 21, patients with ALCL and inflammatory 
myofibroblastic tumor (IMT) reported visual disorders in 65% and 50% of these patients. 
One pediatric patient with IMT did experience grade 3 myopic optic nerve disorder. The 
onset of visual disorders was approximately 1 week and the most common symptoms 
were blurred vision and visual impairment. Other symptoms included photopsia, biterous 
floaters, and photophobia.  
 
The pediatric recommended phase 2 dose of 280 mg/m2 twice daily is equivalent to nearly 
twice the standard recommended adult dose of 250 mg twice daily. In adult subjects, 
geometric mean AUC and Cmax continued to increase with doses above the standard dose 
of 250 mg BID. In the initial adult phase 1 studies, crizotinib was escalated to 300 mg 
orally twice daily, at which dose two patients experienced grade three fatigue. The dose 
of crizotinib was eventually reduced to 250 mg orally twice daily, found to be tolerable 
and was determined to be the recommended Phase II dose. In order to maximize long-
term tolerability of crizotinib in NF2 patients on this study, we will cap crizotinib at the 
standard adult dose on 250 mg twice daily for all patients, including children.     
 
Crizotinib (XALKORI®) Safety/Toxicity Summary 
Safety evaluation of XALKORI is based on more than 1,200 patients with ALK-positive 
metastatic NSCLC who received XALKORI as monotherapy at a starting oral dose of 250 
mg twice daily continuously. The most common adverse reactions (≥25%) of XALKORI 
are vision disorder, nausea, diarrhea, vomiting, constipation, edema, elevated 
transaminases, and fatigue. In the post-marketing experience, there is a report of increased 
blood creatine phosphokinase, but no frequency or adverse reaction was documented. 
 
ALK-positive metastatic NSCLC-Study 1: Patients in the XALKORI arm (n=172) 
received XALKORI 250 mg orally twice daily until documented disease progression, 
intolerance to therapy, or the investigator determined that the patient was no longer 
experiencing clinical benefit. A total of 171 patients in the chemotherapy arm received 
pemetrexed 500 mg/m2 (n=99) or docetaxel 75 mg/m2 (n=72) by intravenous infusion 
every three weeks until documented disease progression, intolerance to therapy, or the 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
18 
investigator determined that the patient was no longer experiencing clinical benefit. 
Patients in the chemotherapy arm received pemetrexed unless they had received 
pemetrexed as part of first-line or maintenance treatment. The median duration of study 
treatment was 7.1 months for patients who received XALKORI and 2.8 months for 
patients who received chemotherapy. Across the 347 patients who were randomized to 
study treatment (343 received at least one dose of study treatment), the median age was 
50 years; 84% of patients in the XALKORI arm and 87% of patients in the chemotherapy 
arm were younger than 65 years. A total of 57% of patients on XALKORI and 55% of 
chemotherapy patients were female. Forty-six percent (46%) of XALKORI-treated and 
45% of chemotherapy-treated patients were from Asia. Serious adverse reactions were 
reported in 64 patients (37.2%) treated with XALKORI and 40 patients (23.4%) in the 
chemotherapy arm. The most frequent serious adverse reactions reported in patients 
treated with XALKORI were pneumonia (4.1%), pulmonary embolism (3.5%), dyspnea 
(2.3%), and interstitial lung disease (ILD; 2.9%). Fatal adverse reactions in XALKORI-
treated patients in Study 1 occurred in 9 (5%) patients, consisting of: acute respiratory 
distress syndrome, arrhythmia, dyspnea, pneumonia, pneumonitis, pulmonary embolism, 
ILD, respiratory failure, and sepsis. Dose reductions due to adverse reactions were 
required in 16% of XALKORI-treated patients. The most frequent adverse reactions that 
led to dose reduction in the patients treated with XALKORI were alanine 
aminotransferase (ALT) elevation (7.6%) including some patients with concurrent 
aspartate aminotransferase (AST) elevation, QTc prolongation (2.9%), and neutropenia 
(2.3%). Discontinuation of therapy in XALKORI-treated patients for adverse reactions 
was 17.0%. The most frequent adverse reactions that led to discontinuation in XALKORI-
treated patients were ILD (1.7%), ALT and AST elevation (1.2%), dyspnea (1.2%), and 
pulmonary embolism (1.2%). Additional adverse reactions occurring at an overall 
incidence between 1% and 30% in patients treated with XALKORI included decreased 
appetite (27%), fatigue (27%), neuropathy (19%; dysesthesia, gait disturbance, 
hypoesthesia, muscular weakness, neuralgia, peripheral neuropathy, parasthesia, 
peripheral sensory neuropathy, polyneuropathy, burning sensation in skin), rash (9%), 
ILD (4%; acute respiratory distress syndrome, ILD, pneumonitis), renal cyst (4%), and 
hepatic failure (1%). 
ALK-positive metastatic NSCLC- Study 2: The safety analysis population in Study 2 
included 934 patients with ALK-positive metastatic NSCLC who received XALKORI in 
a clinical trial. The median duration of treatment was 23 weeks. Dosing interruptions and 
reductions due to treatment-related adverse events occurred in 23% and 12% of patients, 
respectively. The rate of treatment-related adverse events resulting in permanent 
discontinuation was 5%. The most common adverse reactions (≥25%) included vision 
disorder (55%), nausea (51%), vomiting (46%), diarrhea (46%), edema (39%), 
constipation (38%), and fatigue (26%). Description of selected adverse drug reactions. 
Vision disorders, most commonly visual impairment, photopsia, blurred vision, or 
vitreous floaters, occurred in 691 (56%) patients across clinical trials (n=1225). The 
majority (99%) of these patients had Grade 1 or 2 visual adverse reactions. Across clinical 
studies, one patient had a treatment-related grade 3 vision abnormality. Based on the 
Visual Symptom Assessment Questionnaire (VSAQ-ALK), patients treated with 
XALKORI in Study 1 reported a higher incidence of visual disturbances compared to 
patients treated with chemotherapy. The onset of vision disorders generally started within 
the first week of drug administration. The majority of patients on the XALKORI arm in 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
19 
Study 1 (> 50%) reported visual disturbances; these visual disturbances occurred at a 
frequency of 4-7 days each week, lasted up to 1 minute, and had mild or no impact (scores 
0 to 3 out of a maximum score of 10) on daily activities as captured in a patient 
questionnaire. Neuropathy, most commonly sensory in nature, occurred in 235 (19%) of 
1225 patients. Most events (95%) were Grade 1 or Grade 2 in severity. Renal Cysts Renal 
cysts occurred in 7 (4%) patients treated with XALKORI and 1 (1%) patient treated with 
chemotherapy in Study 1. The majority of renal cysts in XALKORI-treated patients were 
complex. Local cystic invasion beyond the kidney occurred, in some cases with imaging 
characteristics suggestive of abscess. 
Pediatric Safety/Toxicity Data 
The safety and activity of crizotinib has also been investigated in pediatric patients in a 
Children's Oncology Group phase 1 consortium study, which included patients with 
refractory solid tumors or anaplastic large-cell lymphoma.12 Seventy-nine patients were 
enrolled in the study with a median age of 10.1 years (range 1.1-21.4). Crizotinib was 
well tolerated with a recommended phase 2 dose of 280 mg/m2 twice daily. Grade 4 
adverse events in cycle 1 were neutropenia (two) and liver enzyme elevation (one). Grade 
3 adverse events that occurred in more than one patient in cycle 1 were lymphopenia 
(two), and neutropenia (eight). The mean steady state peak concentration of crizotinib was 
630 ng/mL and the time to reach this peak was 4 h (range 1-6). Objective tumor responses 
were documented in 14 of 79 patients (nine complete responses, five partial responses); 
and the anti-tumor activity was enriched in patients with known activating ALK 
aberrations (eight of nine with anaplastic large-cell lymphoma, one of 11 with 
neuroblastoma, three of seven with inflammatory myofibroblastic tumor, and one of two 
with NSCLC). 
The pediatric recommended phase 2 dose of 280 mg/m2 twice daily12 is equivalent to 
nearly twice the standard recommended adult dose of 250 mg twice daily. In adult 
subjects, geometric mean AUC and Cmax continued to increase with doses above the 
standard dose of 250 mg BID. In the initial adult phase 1 study,13 crizotinib was escalated 
to 300 mg orally twice daily, at which dose two patients experienced grade three fatigue. 
The dose of crizotinib was eventually reduced to 250 mg orally twice daily, found to be 
tolerable and was determined to be the recommended Phase II dose.  
Further information, including detailed toxicity data, is provided by Pfizer in the 
Crizotinib Investigator Brochure. 
 
2.3 Rationale 
Recent preclinical data from the Kissil lab (Scripps Research Institute, FL)14 provide a 
strong rationale for exploring crizotinib for the treatment of NF2 related tumors, including 
VS. 
Crizotinib inhibits schwannoma cell proliferation in vitro and tumor formation in vivo:  
Testing activity of different small molecule inhibitors in SC4 (mouse NF2-null Schwann 
cells) and HEI193 cells (NF2-null, derived from a schwannoma of an NF2 patient), 
identified the ALK/c-Met inhibitor crizotinib15,16 as a dose-dependent suppressor of cell 
proliferation. To assess if crizotinib inhibits tumor growth in vivo, an orthotopic model of 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
20 
NF2 was employed that recapitulates the tumor microenvironment of schwannomas, by 
injection of luciferase-tagged NF2-null schwannoma cells into a myelinated nerve.17-20 
Tumor progression was monitored every three days by bioluminescence imaging (BLI) 
and total flux counts were recorded for each animal. Ten days post injection, similar flux 
readings for all animals were validated and animals were enrolled randomly into control 
(vehicle only) or drug-treated cohorts and were treated (50mg/kg, PO, once daily) for a 
period of 24 days. Crizotinib treated mice had a significantly slower tumor growth rate 
than control animals (Figure 1A–B). After 24 days of treatment the animals were 
sacrificed and the tumors removed and weighed. Comparison of the cohorts demonstrates 
significantly lower average tumor weight in the crizotinib-treated group compared to 
control group (Figure 1C). Taken together, these data demonstrate that crizotinib has 
significant anti-proliferative activity against NF2-null Schwann cells in vitro and anti-
tumor activity in vivo. 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
21 
Figure 1: Crizotinib inhibits tumor growth in vivo.14 (A) Representative images from bioluminescence 
imaging (BLI) of mice carrying orthotopic tumors treated with crizotinib (50mg/kg) or vehicle control at day 
14 of treatment. NOD/ SCID mice were injected intraneurally with 5x104 SC4/pLuc-mCherry cells and were 
enrolled into treatment after 10 days. Mice were treated daily for 25 days and imaged every 3 days to follow 
tumor development. (B) Quantitative analysis of the flux reading from treated cohorts. A mixed-effects 
regression analysis indicated that the speed of tumor growth in treatment group is significantly slower than 
that in control group (p=0.003). (C) Distribution of tumor/body weight ratio in the cohorts treated with crizotinib 
or vehicle control. The results of t-test with equal variances show that the crizotinib-treated group has 
significant lower average tumor weight than that observed in control group (p<0.0001). For the in vivo 
experiments the N=9 in each cohort. 
   
Using pharmacological and genetic approaches, the Kissil lab demonstrated that the activity 
of crizotinib was mediated through focal adhesion kinase 1 (FAK1), a previously recognized 
target in NF2.21 SC4 and HEI193 cells were treated and FAK1 activation was assessed by 
immunoblot analysis using a phospho-specific antibody against FAK-Y397, which is 
phosphorylated in activated FAK1. Treatment with crizotinib resulted in decreased FAK-
Y397 phosphorylation, consistent with inhibition FAK1 (Figure 3A). To determine if FAK1 
is required for proliferation of SC4 or HEI193 cells, FAK1 expression was knocked down 
using shRNA or siRNA, respectively. Indeed, the knockdown of FAK1 significantly impaired 
cell proliferation. Subsequently, the effects of treating SC4 or HEI193 cells with small-
molecule FAK1 inhibitors were examined. Treatment of SC4 or HEI193 cells with defactinib 
(VS6303) or PND-1186 (VS-4718) significantly impaired cell proliferation in a dose-

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
22 
dependent manner. Additional experiments using gain of function approaches showed that 
crizotinib-resistant FAK1 mutants rescue proliferation of treated NF2-null schwann cells, 
and together with the loss of function data strongly implicate FAK1 inhibition as the main 
mechanism through which crizotinib mediates its effects in NF2-null schwannoma cells. 
In addition, other studies have shown that c-Met, may also represent a molecular target in 
schwannoma cells.22,23 
Expression of activated FAK in human VS tissue:  
To confirm activated target expression in human VS tissue from NF2 patients, fresh frozen 
tumor samples obtained from the NYU Brain Tumor Bank were subjected to Western blot 
analysis. Strong expression of phospho-FAK was observed in 6/6 (100%) of samples (Figure 
2, unpublished data). 
 
Figure 2: Expression of activated FAK in 
 
human VS tissue. Western blot analysis for total 
 
 
FAK and phospho-FAK(Tyr397) in VS frozen 
 
tissue lysates from NF2 patients. Tubulin was  
 
 
used as loading control. 
 
  
 
 
 
 
 
Blood-brain barrier considerations: 
Although crizotinib is considered not to cross the intact blood brain barrier, this is not 
expected to negatively impact on the therapeutic efficacy in NF2-related tumors. 
Meningiomas and VS are anatomically outside the blood brain barrier, and we have 
observed tumor tissue to plasma ratio of 4.3 ±1.9 (mean ±SD) in human VS tissue treated 
with the EGFR/ErbB2 receptor tyrosine kinase inhibitor lapatinib (Karajannis, et. al, 
Neuro-Oncology 14:i19, 2012 [abstract]). In addition, clinical activity of crizotinib has 
been reported in other contrast-enhancing intracranial tumors, such as brain metastases 
and even primary brain tumors.24-26 
Prior clinical studies and competing clinical trials: 
Over the past years, we and others have performed clinical studies, including prospective 
clinical trials, to investigate the potential of “molecular targeted” drugs to stop tumor 
growth and/or improve hearing in NF2 patients.9 The most effective therapy to date, 
bevacizumab, results in radiologic and hearing response rates of approximately 50%, 
respectively.27 In general, the treatment effect is only maintained with continued 
bevacizumab administration, which is time-limited due to cumulative toxicity, including 
hypertension and renal toxicity. Despite the success of bevacizumab for many NF2 
patients with vestibular schwannomas, alternative therapies remain urgently needed for 
NF2 patients with progressive tumor growth. This includes non-responders to 
bevacizumab, or patients who cannot tolerate continued administration due to acute or 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
23 
cumulative toxicity. In addition, bevacizumab is ineffective for NF2 patients with 
progressive meningiomas.28 Attractive drug candidates for these populations therefore 
would have a target profile and mechanism of action that is different from bevacizumab, 
and ideally have non-overlapping toxicities. Over the past several years, we have shown 
that we are able to successfully conduct and complete single-institution Phase 2 clinical 
trials in the NF2 population using molecular targeted agents, including lapatinib and 
everolimus, in a short time frame.4,5 The lapatinib trial showed only modest anti-tumor 
activity and the everolimus trial did not result in any objective responses, and there 
remains a need for novel therapies with better efficacy, ideally based on preclinical data. 
For this phase 2 clinical trial with crizotinib, we will follow a similar study design and 
endpoints, which are consistent with current consensus recommendations for NF2 clinical 
trials endpoints.29,30  
A Phase 2 clinical trial for NF2 patients with axitinib, a multi-kinase inhibitor with the 
VEGF receptor VEGFR2 as the dominant target (ClinicalTrials.gov identifier 
NCT02129647), is currently ongoing at Memorial Sloan Kettering Cancer Center and 
NYU Langone Medical Center. This study excludes NF2 patients who received prior 
bevacizumab. No other phase 2 clinical trials with molecular targeted therapy specifically 
for NF2 patients with progressive VS are currently open for accrual in North America 
based on ClinicalTrials.gov search. Defactinib, an investigational FAK inhibitor, is 
included in the NF2 mutant tumors stratum of the NCI-Molecular Analysis for Therapy 
Choice (NCI-MATCH) trial. This clinical trial will require biopsy and confirmation of 
NF2 mutation in tumor tissue. Although this trial is aimed at patients with advanced 
refractory solid tumors or lymphomas, some NF2 patients may be eligible for this study, 
which does not include NF2-specific eligibility criteria, endpoints and recommended 
assessments, such as volumetric analysis or hearing. The safety and toxicity of defactinib 
(VS-6063), which is not currently FDA approved, was investigated in a phase I study of 
in adult patients with advanced solid tumors,31 with the most frequent adverse events 
including nausea (37%), fatigue (33%), vomiting (28%), diarrhea (22%) and headache 
(22%). The safety of defactinib has not been studied in children. Of note, a ten-fold higher 
concentration of defactinib compared to crizotinib was required to inhibit growth in 
HEI193 cells.14  
In summary, the preclinical data from the Kissil lab identified crizotinib as a 
promising drug candidate for clinical study in NF2 patients with progressive VS.14 
The favorable toxicity profile and tolerability of crizotinib, including in children,12 
and compared to other multi-kinase inhibitors, is advantageous for potential long-
term administration in NF2. In addition, the non-overlapping molecular target and 
toxicity profiles of crizotinib, compared to bevacizumab, render crizotinib an attractive 
agent for NF2 patients, including non-responders to bevacizumab, or patients who 
develop dose-limiting toxicities on bevacizumab. Additional candidates for crizotinib 
include patients who have pre-existing contraindications to bevacizumab, such as 
difficult-to-control hypertension or prior CNS hemorrhage.  
Neurofibromatosis type 2 (NF2) is an autosomal-dominant genetic disease with an 
incidence of approximately 1/40,000. The NF-2 gene is located on chromosome 22 and 
its gene product is named Merlin. Merlin’s function is not well understood, but it appears 
to act as a tumor suppressor. The majority of NF2 patients develop progressive hearing 
loss in adolescence or young adulthood due to unilateral or bilateral vestibular 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
24 
schwannomas (VS). Other intracranial and spinal tumors, including meningiomas, 
schwannomas and ependymomas, are also highly prevalent. NF2-related tumors, although 
generally slow growing, cause considerable morbidity and mortality, particularly when 
first diagnosed at a young age. The available treatment options for these neoplasms, which 
often occur at multiple sites simultaneously, are non-curative and mostly limited to 
surgery and radiation therapy. As a result, all NF2 patients suffer from major morbidity, 
mortality and significantly reduced life expectancy.  
Recently published preclinical data from the Kissil lab shows that crizotinib inhibits NF2 
schwannoma cell proliferation and tumor formation in vivo, providing a strong rationale 
for exploring crizotinib for the treatment of NF2 related tumors, including VS. We 
hypothesize that crizotinib is effective in treating vestibular schwannomas in NF2 
patients, and propose to test this hypothesis in a prospective phase 2 clinical trial. 
Crizotinib is currently FDA approved for the treatment of patients with metastatic non-
small cell lung carcinoma that is anaplastic lymphoma kinase (ALK) positive. The 
favorable toxicity profile and tolerability of crizotinib compared to other multi-kinase 
inhibitors, including in children, is advantageous for potential long-term administration 
in NF2 patients. 
  
2.4 
Correlative Studies Background 
Prior studies, including in NF2 patients, have shown that circulating biomarkers can help 
predict tumor progression and response to molecular targeted therapies. For example, 
bevacizumab treatment was associated with decreased free vascular endothelial growth 
factor (not bound to bevacizumab) and increased placental growth factor in plasma. 
Hearing responses were inversely associated with baseline plasma hepatocyte growth 
factor (P = 0.019). Imaging responses were associated with high baseline tumor vessel 
permeability and elevated blood levels of vascular endothelial growth factor D and stromal 
cell-derived factor 1alpha (P = 0.037 and 0.025, respectively). 2 
There is no published data on molecular biomarkers for crizotinib in patients with NF2, 
and this study proposes to analyze baseline biomarkers with respect to outcomes (response) 
as well as the possible effect of crizotinib 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 criteria32 include presence of: 
• Bilateral vestibular schwannomas, OR 
• First-degree relative with NF2 and EITHER unilateral eighth nerve mass 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
25 
OR two of the following: neurofibroma, meningioma, glioma, schwannoma, 
juvenile posterior subcapsular lenticular opacity. 
 
 
The Manchester criteria33 include 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 progressive and measurable disease, defined as at least 
one VS with the following qualities: 
•  ≥ 0.75 ml (on volumetric analysis) that can be accurately measured by 
contrast-enhanced cranial MRI scan with fine cuts through the internal 
auditory canal (1 mm slices, no skip) 
• MRI evidence of progression over the past 18 months (defined as ≥20% 
annualized increase in volume) 
Note: pre-baseline MRI to be submitted together with baseline MRI for 
central volumetric review and confirmation of eligibility. 
3.1.3 Age ≥ 6 years on day 1 of treatment.   
3.1.4 Life expectancy of greater than 1 year. 
3.1.5 Lansky/Karnofsky performance status ≥ 60 (see Appendix D). 
3.1.6 Organ and marrow function as defined below: 
• Absolute neutrophil count ≥ 1,500/ μl 
• Platelets ≥ 100,000/ μl 
• Total bilirubin within ≤ 1.5 X institutional upper limit of normal 
• 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:     

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
26 
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 Fully recovered from acute toxic effects of any prior chemotherapy, 
biological modifiers or radiotherapy 
3.1.8 Any neurologic deficits must be stable for ≥1 week 
3.1.9 Patient or parent/legal guardian must be able to provide signed informed 
consent and assent (as applicable for minors) 
 
 
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 previously received crizotinib 
3.2.2 Patients currently receiving medical anticancer therapies or who have 
received medical anticancer therapies within 4 weeks of the start of study 
drug (including chemotherapy and molecular targeted agents), as these may 
interfere with the study drug 
3.2.3 Monoclonal antibody treatment and/or agents with prolonged half-lives: At 
least three half-lives must have elapsed from the last dose prior to enrollment 
3.2.4 Radiation therapy to a study target tumor within 1 year prior to enrollment, 
or any radiation therapy within 4 weeks prior to enrollment, as these may 
interfere with our ability to assess response to study drug 
3.2.5 Prior treatment with any investigational drug within the preceding 4 weeks, 
as they may interfere with the study drug 
3.2.6 Unstable or rapidly progressive disease, including patients who require 
glucocorticoids for symptomatic control of brain or spinal tumors, as this 
would represent a high risk for inability to comply with the study 
requirements  

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
27 
3.2.7 Use of drugs or foods that are known potent CYP3A4 inhibitors, including 
but not limited to ketoconazole, itraconazole, miconazole, clarithromycin, 
erythromycin, ritonavir, indinavir, nelfinavir, saquinavir, amprenavir, 
delavirdine, nefazodone, diltiazem, verapamil, and grapefruit juice, as this 
would interfere with study drug metabolism 
3.2.8 Use of drugs that are known potent CYP3A4 inducers, including but not 
limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, 
tipranavir, ritonavir, and St. John’s wort, as this would interfere with study 
drug metabolism 
3.2.9 Use of drugs that are CYP3A4 substrates with narrow therapeutic indices, 
including but not limited to pimozide, aripiprazole, triazolam, 
dihydroergotamine, ergotamine, astemizole, cisapride, terfenadine and 
halofantrine, as this would interfere with study drug metabolism 
3.2.10 Ongoing cardiac dysrhythmias of CTCAE grade ≥2, uncontrolled atrial 
fibrillation of any grade or prolonged QTc interval (>480 msec), as patients 
with these conditions would be expected to have an increased risk for cardiac 
toxicity related to study drug   
3.2.11 Patients who have any severe and/or uncontrolled medical conditions or 
other conditions that could affect their participation in the study such as: 
• symptomatic congestive heart failure of New York heart Association 
Class III or IV  
• unstable angina pectoris, symptomatic congestive heart failure, 
myocardial infarction within 6 months of start of study drug, serious 
uncontrolled cardiac arrhythmia or any other clinically significant 
cardiac disease 
• severely impaired lung function as defined as spirometry and DLCO 
that is 50% of the normal predicted value and/or O2 saturation that is 
90% or less at rest on room air 
• active (acute or chronic) or uncontrolled severe infections 
• liver disease, such as cirrhosis or severe hepatic impairment (Child-
Pugh class C). 
3.2.12 Impairment of gastrointestinal function or gastrointestinal disease that may 
significantly alter the absorption of crizotinib (e.g., ulcerative disease, 
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small 
bowel resection) 
3.2.13 Female patients who are pregnant or breast feeding, or adults of reproductive 
potential who are not using effective birth control methods. Adequate 
contraception must be used throughout the trial and for 90 days after the last 
dose of study drug, as the effects of crizotinib on an unborn fetus are not 
known. Females of childbearing potential must have a negative serum 
pregnancy test within 7 days prior to administration of crizotinib. 
3.2.14 Male patients whose sexual partner(s) are women of child bearing potential, 
who are not willing to use adequate contraception during the study and for 
90 days after the last dose of study drug. 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
28 
3.2.15 History of significant noncompliance to medical regimens that would 
jeopardize compliance with study therapy 
3.2.16 Patients unwilling to or unable to comply with the study protocol  
 
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. SCREENING AND STUDY ENROLLMENT PROCEDURES 
   
The NF Operations Center should be contacted to ensure availability of a treatment slot. 
4.1 
Informed Consent/Assent 
The investigational nature and objectives of the trial, the procedures and treatments 
involved and their attendant risks and discomforts, and potential alternative therapies will 
be carefully explained to the subject or the subject’s parent(s) or guardian if the subject is 
a child, and a signed informed consent and assent will be obtained according to 
institutional and federal guidelines. In addition, study participants should sign the 
institution’s HIPAA Consent if not already included in the study consent document.  
4.2 
Screening Procedures 
Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial 
must only be done after obtaining written informed consent. Documentation of the informed 
consent for screening will be maintained in the subject’s research chart. Studies or 
procedures that were performed for clinical indications (not exclusively to determine 
eligibility) may be used for baseline values even if the studies were done before informed 
consent was obtained. 
Before the subject can be enrolled, the responsible institutional investigator must sign and 
date the completed eligibility checklist. The completed eligibility checklist and de-
identified supporting clinical documentation should be scanned and emailed for review and 
signed off by the Study PI and/or Study Co-PI and the NF Operations Center to confirm 
eligibility prior to subject enrollment. 
4.3 Study Enrollment 
Subjects may be enrolled on the study once all eligibility requirements for the study have 
been met and a treatment number for subject treatment has been confirmed by the NF 
Consortium Operations Center as well as either the study chair or study co-chair. Subjects 
who give informed consent for the protocol in order to undergo screening for eligibility 
are not considered enrolled and should not be enrolled until the screening is completed 
and they are determined to meet all eligibility criteria. Treatment must start within 14 
days of enrollment. Subjects must not receive any protocol therapy prior to 
enrollment. Baseline evaluations should be repeated if time between first screening 
and start of protocol therapy exceeds 28 days. 
4.4 General Guidelines for all Participating Institutions 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
29 
The required forms for subject registration can be found on the UAB online entry 
system. 
Following registration, participants should complete screening procedures and verify 
all eligibility criteria prior to enrollment into the study. Participants should begin 
protocol treatment within 14 days of enrollment. Issues that would cause treatment 
delays should be discussed with the Principal Investigator. If a participant does not 
receive protocol therapy following registration and enrollment, the participant’s protocol 
status must be changed. The 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 and the UAB NFCTC Operations Center (section 7.1.7). A participating site 
may order the agent only after all initial IRB approvals have been obtained (site, UAB 
and DOD).  
 
4.5 
Registration and Enrollment Process for All Participating Institutions 
To register a participant, the following forms should be entered and locked in the 
electronic data collection system (eDCS) by the study coordinator or designee:  
• Registration and Demographics Form 
• IRB Consent Form 
• MRI Transmittal Form 
 
To complete enrollment, the following forms should be entered and locked in eDCS: 
• MRI Acknowledgement (to be entered by Central Imaging at DFCI) 
• Inclusion and Exclusion Forms must be completed and locked prior to enrollment 
in eDES. However, the Exclusion Form cannot be locked until approval to enroll is 
received from the study chairs performing the eligibility review.  
 
NOTE: Registration with NF Consortium’s web-based data entry system can be 
conducted anytime, but the DCCsupport can only be provided during the business 
hours of 8am – 5pm EST Monday through Friday.  
 
5. TREATMENT PLAN  
Crizotinib will be taken continuously until disease progression or unacceptable toxicity, in 
continuous treatment cycles of 28 days each, for a maximum of 12 cycles of initial therapy. 
Clinical response will be assessed by MRI (volumetrics, primary objective) and audiology at 
the end of every 3rd cycle. Subjects with volumetric tumor progression will be taken off 
protocol. Patients who complete 12 cycles of treatment without disease progression, but 
within the following 24 weeks show subsequent disease progression (defined as >20% 
increase in target tumor volume compared to end of cycle tumor volume), will be eligible for 
re-treatment on study for up to 12 cycles/48 additional weeks, provided they still meet study 
eligibility criteria (See Section 5.2).   
The study drug crizotinib will be administered orally. The investigator will instruct the 
patient/family to take/administer the study drug exactly as specified in the protocol, and the 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
30 
subjects will receive detailed instructions for drug administration along with a drug diary (see 
Appendix I).  
All subjects will be provided with drug diaries and asked to record each dose of crizotinib. 
Drug diaries will be collected by the investigator after each cycle.  
Crizotinib should be administered orally once or twice daily, depending on prescribed dose 
level. For twice daily administration, crizotinib should be taken approximately 12 hours apart, 
preferably in the morning and evening, at approximately the same time every day with or 
without food. If the patient vomits or misses a dose, an additional dose should not be taken. 
The next prescribed dose should be taken at the usual time. 
Crizotinib will be provided by Pfizer, Inc., and is available as 200 mg and 250 mg hard gelatin 
capsules. Patients are advised to take crizotinib with or without food and whole. Crizotinib 
will be taken continuously until disease progression or unacceptable toxicity, in continuous 
treatment cycles of 28 days each (maximum of 12 cycles): 
Patients who are unable to swallow capsules may take crizotinib as described in Appendix H: 
Disintegration of Capsules for Patients Unable to Swallow Capsules. 
Starting dose for adults (≥18 years of age): standard adult dose of 250 mg PO twice daily 
(dose level D). 
Starting dose for children (<18 years of age): based on body surface area (BSA) according 
to the dose level table below (equivalent to 280 mg/m2/dose twice daily), with a maximum 
dose of 250 mg PO twice daily (dose level D):  
 
Dose Level 
BSA [m2] 
Total Daily Dose 
Dose 
A 
<0.45 
200 mg 
200 mg PO once daily 
B 
0.45-0.70 
250 mg 
250 mg PO once daily 
C 
0.71-0.88 
400 mg 
200 mg PO twice daily 
  D* 
  ≥0.89 
500 mg 
250 mg PO twice daily 
*adult starting dose level (standard adult dose) 
 
 
5.1 
Safety Measures and Special Precautions: 
Prior to each treatment cycle, the patient should be carefully assessed for toxicities.  
Decisions for retreatment or dose modification/interruption should follow the dose 
modification guidelines in Section 6.2. 
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. 
 
5.1.1 CYP3A4/5 inhibitors/inducers  
As crizotinib is an inhibitor of CYP3A4, patients chronically receiving medications 
known to be metabolized by CYP3A4 and with narrow therapeutic indices including 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
31 
pimozide, aripiprazole, triazolam, dihydroergotamine, ergotamine, astemizole, 
cisapride, terfenadine and halofantrine are not eligible. The topical use of these 
medications (if applicable) is allowed.  
CYP3A4 Inhibitors: Patients chronically receiving drugs that are known potent 
CYP3A4 inhibitors within 7 days prior to study enrollment, including but not limited 
to ketoconazole, itraconazole, miconazole, clarithromycin, erythromycin, ritonavir, 
indinavir, nelfinavir, saquinavir, amprenavir, delavirdine, nefazodone, diltiazem, 
verapamil, and grapefruit juice are not eligible. The topical use of these medications 
(if applicable), e.g. 2% ketoconazole cream, is allowed. 
CYP3A4 Inducers: Patients chronically receiving drugs that are known potent 
CYP3A4 inducers within 12 days prior to study enrollment, including but not 
limited to carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, tipranavir, 
ritonavir, and St. John’s wort are not eligible. The topical use of these medications 
(if applicable) is allowed. 
This list should not be considered all inclusive: please refer to other resources, such 
as http://medicine.iupui.edu/clinpharm/ddis/main-table, for additional information. 
Steroids: If clinically indicated, short (≤14 days) courses of steroids, such as 
prednisone or dexamethasone, are allowed for patients with vestibular 
schwannomas and sudden-onset, transient hearing loss on protocol therapy. All such 
treatments must be documented in the clinical chart and study records. 
5.1.2.  
Suicidal Risk 
Question 24 of the Tinnitus Reaction Questionnaire (TRQ; See Appendix G) elicits 
possible suicidal ideation. A clinician should review this questionnaire immediately 
after it is completed and assess for any possible suicidal risk if the answer score is 
>2. Any concerns of suicidality should be immediately addressed with the 
responsible institutional investigator. 
 
5.2 
Duration of Therapy 
Treatment will be administered in continuous treatment cycles of 28 days duration. 
Temporary treatment interruptions as per protocol, e.g. for toxicity, will not alter the 
length of cycles or timing of required observations. Initial treatment may continue for up 
to 12 cycles/48 weeks, or until one of the following criteria applies (whichever occurs 
first): 
• Primary target tumor enlarges by ≥20% (as defined in Section 10.1.4.1). 
Additional tumors may be monitored for growth or response, but any 
progression in those tumors will not trigger discontinuation of therapy. 
Audiologic responses will be determined, but will not be used as primary response 
criteria. 
• New or worsening existing medical condition that prevents further protocol-
specific administration of treatment 
• Unacceptable adverse event(s), including, but not limited to: 
o Any Grade 4 non-hematological toxicity 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
32 
o Grade 4 febrile neutropenia 
o Grade 3 or 4 left ventricular systolic dysfunction 
o Grade 3 or 4 penumonitis 
o Grade 4 prolonged QTc interval 
o Any hematological or non-hematological toxicity requiring treatment 
interruption for ≥3 weeks 
o Pregnancy during the study period (for female participants) 
o All Grade 4 events thought to be related to crizotinib by the investigator 
(NOTE: Patients who have an ongoing crizotinib-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) 
• 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. 
Re-treatment option: Patients who complete 12 cycles of treatment without disease 
progression, but within the following 24 weeks show subsequent disease progression 
(defined as >20% increase in target tumor volume compared to off-treatment volume), 
will be eligible for re-treatment on study for up to 12 additional cycles/48 additional 
weeks, provided they still meet study eligibility criteria.   
 
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 (e.g., 
investigator or sponsor concern) should continue the schedule of study observations at the 
discretion of the principal investigator. 
NOTE: Hearing represents an exploratory endpoint, and therefore Progressive 
Hearing Loss (PHL) as defined in Section 10.3 in a target or non-target ear, does not 
require discontinuation of study therapy. 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).  
 
 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
33 
5.3 
Duration of Follow-Up  
Patients discontinued from the treatment phase of the study for any reason will be 
evaluated approximately 30 days (30–35 days) after the last dose of study drug taken.  
Follow-up of adverse event is required until the event or its sequelae resolve or stabilize 
at a level acceptable to the investigator and sponsor. To learn about the durability of 
imaging and hearing responses, the study team may contact the local study investigator 
and request results from MRIs, audiograms and clinical assessments obtained during a 
period of up to 18 months after discontinuation of study drug. 
  
5.4 
Criteria for Removal from Study  
Participants will be removed from study when any of the criteria listed in Section 5.2 
applies. The reason for study removal and the date the participant was removed must be 
documented in the data entry system. Alternative care options will be discussed with the 
participant. 
 
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.   
Dose delays and modifications will be made using the recommendations outlined in Sections 
6.2 and 6.3. Toxicity assessments will be done using the CTEP Version 5.0 of the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) which is identified and located 
on the CTEP website at https://evs.nci.nih.gov/ftp1/CTCAE/About.html. 
If possible, symptoms should be managed symptomatically. In the case of toxicity, 
appropriate medical treatment should be used (including anti-emetics, anti-diarrheals, etc.). 
 
6.1 
Anticipated Toxicities 
Toxicities with a possible association to crizotinib treatment are listed in Section 2.2.1. 
6.2 
Toxicity Management and Dose Modifications/Delays 
Any toxicities associated or possibly associated with crizotinib treatment should be 
managed according to standard medical practice. There is no available antidote for 
crizotinib.  
For patients who are unable to tolerate the protocol-specified dosing schedule, dose 
adjustments are permitted in order to keep the patient on study drug. If administration of 
crizotinib must be interrupted because of unacceptable toxicity, drug dosing will be 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
34 
interrupted or modified according to rules described below. For patients who experience 
unacceptable toxicity at dose level A (Section 5.0), crizotinib will be discontinued 
permanently. 
Toxicity will be assessed using the NIH-NCI Common Terminology Criteria for Adverse 
Events, version 5.0.  
Recommendations for action based on type of toxicity are shown in the following table:  

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
35 
Toxicity 
Actions 
Non-hematological toxicity (with the exception of those 
listed in Section 6.3 Precautions and management of 
specific toxicities) 
 
Grade 1–2  
 
If the toxicity is tolerable to the patient, maintain the 
same dose. If the toxicity is intolerable to patient, 
interrupt crizotinib until recovery to grade ≤1. Then 
reintroduce crizotinib at same dose. 
If event returns to grade 1-2 and is intolerable to the 
patient, then interrupt crizotinib until recovery to 
grade ≤1. Then reintroduce crizotinib at the lower dose 
level. 
Grade 3 
 
Interrupt crizotinib until recovery to grade ≤1 or 
baseline. Then reintroduce crizotinib at a lower dose 
level.  
Grade 4 
Discontinue crizotinib. 
Hematological toxicity 
 
Grade 2 Thrombocytopenia (platelets <75, 
≥50x109/L)  
Interrupt crizotinib until recovery to grade ≤1 (>75 
x109/L). Then reintroduce crizotinib at initial dose. 
If thrombocytopenia again returns to grade 2,  
interrupt crizotinib until recovery to grade ≤1. Then 
reintroduce crizotinib at the lower dose level.  
Grade 3 Thrombocytopenia (platelets <50, ≥25 
x109/L) 
 
Interrupt crizotinib until recovery to grade ≤1 
(platelets ≥75 x109/L).  Then resume crizotinib at one 
dose level lower.  If grade 3 thrombocytopenia recurs, 
discontinue crizotinib. 
Grade 4 Thrombocytopenia (platelets <25 x109/L) 
Discontinue crizotinib. 
Grade 3 Neutropenia (neutrophils <1, ≥0.5 x109/L) 
Interrupt crizotinib until recovery to grade ≤1 
(neutrophils ≥1.5 x 109/L). Then resume crizotinib at 
the initial dose.  If ANC again returns to Grade 3, hold 
crizotinib until the ANC ≥1.5 x 109/L.  Then resume 
crizotinib dosing at the lower dose level.  Discontinue 
patient from study therapy for a third episode of grade 
3 neutropenia. 
Grade 4 Neutropenia (neutrophils <0.5 x109/L) 
Interrupt crizotinib until recovery to grade ≤1 
(neutrophils ≥1.5 x 109/L). Then resume crizotinib at 
the lower dose level. If grade 3 or grade 4 neutropenia 
occurs despite this dose reduction, discontinue 
crizotinib. 
Grade 3 febrile neutropenia (not life-threatening) 
Interrupt crizotinib until resolution of fever and 
neutropenia to grade ≤1. Hold further crizotinib until 
the ANC ≥1,500/mm3 and fever has resolved. Then 
resume crizotinib at the lower dose level. If febrile 
neutropenia recurs, discontinue crizotinib. 
Grade 4 febrile neutropenia (life-threatening) 
Discontinue crizotinib. 
Any hematological or non-hematological toxicity 
requiring interruption for ≥3 weeks 
Discontinue crizotinib 
For additional precautions and management of specific toxicities see Section 6.3. 
 
6.3 
Precautions and Management of Specific Toxicities: 
Pneumonitis (in absence of infection other pulmonary disease)  
Grade 1: Continue at the same dose level.  

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
36 
Grade 2: If suspected, strongly consider administration of 100 mg of oral or intravenous 
prednisolone in single daily or two divided doses. The suggested dose for patients who 
develop pulmonary toxicity is methylprednisolone 1 mg/kg IV every 12 hours for a 
minimum of seven days. 
Upon occurrence of pneumonitis, study therapy should be held, and the Study Chair and 
Research Manager should be notified within 48 hours. 
Grades 3–4: If suspected, strongly consider administration of 100 mg of oral or 
intravenous prednisolone in single daily or two divided doses. The suggested dose for 
patients who develop pulmonary toxicity is methylprednisolone 1 mg/kg IV every 12 
hours for a minimum of seven days. Discontinue crizotinib and do not retreat.  
Prolonged QTc interval (as confirmed by a cardiologist) 
Grade 1: Continue at the same dose level.  
Grade 2: Continue at the same dose level. Assess electrolytes (particularly Ca++, K+, 
Mg+) and concomitant medications. Correct any electrolyte abnormalities. 
Grade 3: Withhold current dose until recovery to Grade ≤1. Assess and correct 
electrolytes (particularly Ca++, K+, Mg+) and concomitant medications. Upon recovery 
to Grade ≤1, resume treatment by reducing the dose by 1 dose level if no other cause for 
QTc prolongation is found, otherwise resume at the same dose. 
Grade 4: Discontinue treatment and do not retreat. 
Vision disorder/loss of vision 
Monitor patients for vision changes while on crizotinib, and withhold crizotinib in 
patients who develop Grade 2 vision disorder until recovery to less than or equal to Grade 
1, then resume crizotinib after dose reduction by 1 dose level. Ophthalmologic 
examination, including visual acuity and slit lamp examination, should be performed at 
screening, end of cycle 1, 3, 6, 9, 12, and at the time a visual event is reported, and again 
if vision disorder persists or worsens in severity. Permanently discontinue crizotinib in 
patients who develop Grade 3 vision disorder or vision loss. 
Increased Creatine phosphokinase level 
Grade 1: Continue at the same dose level.  
Grade 2: Continue at the same dose level. Assess for any symptoms of muscle pain, 
muscle cramping, electrolytes (particularly Ca++, K+, Mg+) and concomitant medications. 
Correct any electrolyte abnormalities. 
Grade 3: Withhold current dose until recovery to Grade ≤1. Assess and correct 
electrolytes (particularly Ca++, K+, Mg+) and concomitant medications. Upon recovery 
to Grade ≤1, resume treatment by reducing the dose by 1 dose level if no other cause for 
increased creatine phosphokinase is found, otherwise resume at the same dose. 
Grade 4: Discontinue treatment and do not retreat. 
 
7. DRUG FORMULATION AND ADMINISTRATION  
 
7.1 
Crizotinib 
 
7.1.1 Description 
Other Names. PF-02341066, XALKORI® 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
37 
Chemical Name. R)-3-[1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-5-[1-(piperidin-4-
yl)-1Hpyrazol-4-yl]pyridin-2-amine 
Molecular Weight. 450.34 Daltons 
Mode of Action. Crizotinib is an orally bioavailable, ATP-competitive, small-
molecule multi-kinase inhibitor including c-met, ALK and FAK 
Physical Description. White to pale yellow powder 
Route of Administration. Oral 
For further details and molecule characterization, see the crizotinib Investigator 
Brochure. 
7.1.2 Form 
Crizotinib is supplied as 250 and 200 mg hard gelatin capsules. The drug product 
consists of crizotinib and compendial excipients in a hard gelatin capsule. The 
capsules are packaged in high-density polyethylene (HDPE). 
7.1.3 Storage and Stability 
Crizotinib is stored according to the labeled conditions. 
7.1.4 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. 
7.1.5 Availability 
Distribution:  Crizotinib will be supplied free of charge by Pfizer, Inc. and will be 
distributed to investigators by a designated central pharmacy (UAB Pharmacy).  
7.1.6 Administration 
The study drug crizotinib will be self-administered or administered by a parent/legal 
guardian. The investigator will instruct the patient to take the study drug exactly as 
specified in the protocol. For patients who are prescribed crizotinib twice daily, it 
should be administered approximately 12 hours apart, preferably in the morning and 
evening, at approximately the same time every day with or without food. If the 
patient vomits or misses a dose, an additional dose should not be taken. The next 
prescribed dose should be taken at the usual time. Patients who are unable to 
swallow capsules may take crizotinib as described in Appendix H: Disintegration of 
Capsules for Patients Unable to Swallow Capsules. 
7.1.7 Ordering 
Crizotinib will be provided by Pfizer, Inc. and shipped to The UAB Investigational 
Drug Service (IDS), which is designated as the Central Pharmacy. The UAB IDS is 
responsible for the transfer and transportation of shipment of crizotinib to study 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
38 
sites. Transport of crizotinib to study sites must be pre-approved by the sponsor and 
IRB before any study drug will be transported. Crizotinib will be transported in 
accordance with specific storage requirements. 
 
When study drug is needed at a study site, an electronic ordering system is utilized 
for planned transport of study drug, with date and time specifications included in 
the request. To initiate an order, the UAB IDS ordering form will be sent to 
nfcop@uab.edu. Once received, NFCTC will approve the order and forward to UAB 
IDS. UAB IDS will arrange the transportation to the requesting site. Crizotinib will 
be shipped out 3-7 business days after the UAB IDS ordering form is received. Once 
the study site receives the shipped product, the form must be completed and sent 
back to nfcop@uab.edu. 
7.1.8 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.  
 
Drug accountability records should be submitted to nfcop@uab.edu. 
7.1.9 Destruction and Return 
At the end of the study, unused supplies of crizotinib 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 Candidate Biomarkers 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
39 
There is no published data on molecular biomarkers for crizotinib in patients with 
NF2, and this study proposes to analyze baseline biomarkers with respect to 
outcomes (response) as well as the possible effect of crizotinib on biomarker levels 
over time. 
We will collect blood samples from the patients before and during the course of 
treatment (see study table). Analysis of plasma levels of total and phosphorylated 
MET, FAK, ROS and ALK, which represent known molecular targets of 
crizotinib, as well as HGF, will be performed using ELISA assays. The level of 
these candidate biomarkers during treatment with crizotinib will be compared to 
the baseline level. Samples will not be collected during the retreatment therapy. 
8.3.2 Collection of specimen(s) 
Sample Collection Time Points 
Blood samples will be obtained for protein analysis of candidate biomarkers for 
crizotinib therapy when clinical labs are drawn at the following time points: 
• Prior to initiating therapy (cycle 1) 
• End of cycles 1, 3 and 12  
 
Blood collection (needed for each time point sample) 
o Collect 8 ml of blood in a polypropylene 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. 
o Heparin MUST NOT be used as an anticoagulant as it may interfere 
with downstream methodology. 
8.3.3 Handling of specimens 
Centrifuge tubes collected at 700 G for 20 minutes at 4C° (without brakes) 
within 30 minutes of collection. 
Prepare two labels each printed with Study-No., patient ID, 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.:  NF110 
Investigator:   
Patient-ID:  
Sample Type:  Plasma  
Date of sampling: (mm/dd/yy) 
Time of Sampling:  (hh:mm) (24-hr format) 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
40 
 
• 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 Kissil 
Laboratory on DRY ICE in a Styrofoam box. 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 Kissil Laboratory at the address provided below. 
8.3.4 Shipping and analysis of specimen(s) 
Multiple specimens may be batched together for shipping. 
Specimens should be shipped Monday to Wednesday only by overnight 
FedEx to the following address: 
 
H. Lee Moffitt Cancer Center 
University of South Florida 
Attn: Kissil Lab, SRB 22234 
3011 W Holly Drive 
Tampa, FL 33612 
Phone: 813-745-0019 
Scott.Troutman@moffitt.org 
 
On the day of shipment, the study coordinator will notify the Kissil 
Laboratory via email: Scott.Troutman@moffitt.org to expect the upcoming 
shipment and include the estimated date of arrival and FedEX tracking 
number.  
All analysis will be performed within the Kissil Laboratory.  
8.3.5 Future use of specimen(s) 
Leftover 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 Kissil Laboratory.  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 Kissil Laboratory to have the sample destroyed. 
 
9.  SCHEDULE OF EVALUATIONS 
Baseline evaluations are to be conducted within 28 days prior to start of protocol therapy.  

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
41 
The baseline (prestudy) visit includes drug dispensing, and repeat baseline evaluations if 
time between first screening and dispensing exceeds 28 days. Otherwise, baseline 
evaluations need not be repeated, unless there is a significant change in the patient’s 
clinical condition. 
Each cycle is 28 days. Interruptions of study drug (e.g., due to toxicity) do not affect the 
length of cycles. All evaluations should be obtained at the end of a cycle, or within 7 days 
prior to starting a new cycle. 
The schedule of evaluations, including all required observations, is shown in Appendix A. 
 
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 Dombi and colleagues29 for neurofibromatosis-associated lesions.  
10.1.1 Definitions 
Evaluable for toxicity: All patients will be evaluable for toxicity from the time of 
their first treatment with crizotinib. 
Evaluable for objective response: Only those patients who have received at least 
one cycle (4 weeks) 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 (1 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) 
that led to enrollment in the protocol. In cases where subjects have bilateral 
progressive tumors that fulfill eligibility criteria, the target lesion should be the 
larger of the two tumors on imaging. Target lesions should be identified at baseline 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
42 
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 VS 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 4 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 post-
contrast Gradient Echo 3D imaging with fine cuts (1 mm slices, no skip) 
preferably through the entire brain, and at the minimum including the entire 
target tumor (see Appendix F). 
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 Volumetric measurements by central review 
(Appendix F) will be used to determine eligibility and continuation on 
treatment. Hearing will be measured in standardized fashion as described in 
Appendix E.  Hearing response (Section 10.3) will be defined by the change 
in word recognition scores, taking as reference the baseline word recognition 
score (Appendix B and Section 10.3). 
Radiographic Response (RR): At least a 20% decrease in the volume of the 
target lesion, 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 lowest 
tumor volume during treatment volume. 
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 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
43 
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 
lowest tumor volume during treatment 
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 date that the 
word recognition score decreases beneath the upper limit of the 95% critical 
difference of the baseline word recognition score. 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
44 
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 tumor progression and 
freedom from progressive hearing loss  
The proportion of patients alive and free from progressive tumor growth after 3, 6, 
12, and 12 cycles from the start of treatment will be determined. The proportion of 
patients alive and free from progressive hearing loss after 3, 6, 9, and 12 cycles will 
be determined.   
10.1.7 Response Review 
Central review of audiologic and radiologic data will be performed at MSKCC and 
MGH. Audiograms collected during the study period will be sent to the Operations 
Center and to the team at MSKCC for analysis. A study member (under the guidance 
of lead study audiologist Kerri O’Connor, AuD, CCC-A) will extract data for review 
by the Principal Investigator and lead audiologist.  
MRI images from enrolled subjects will be transmitted by the Partners Secure File 
Transfer (sFTP) to the Dana-Farber/Harvard Cancer Center Tumor Imaging Metric 
Core (TIMC) for central analysis of tumor volume. The procedures for clinical sites 
to upload MRI scans are provided in Appendix F. 
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 then sent to the 
Principal Investigator at each study site within 2 business days of receiving the files. 
A secondary review of volumetric image analyses (identified by participant code) 
done by TIMC may be performed at MSKCC through the TIMC website. If 
necessary, re-review of volumetric measurements by TIMC may be requested.   
 
10.2 Antitumor Effect – Hematologic Tumors 
N/A 
10.3 Other Response Parameters: Hearing Response 
 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
45 
Hearing Response (HR): Improvement in word recognition score above the 95% 
critical difference, taking as reference the baseline word recognition score (Appendix 
B).  
 
Stable Hearing (SH): Persistence of word recognition score within the 95% critical 
difference, taking as reference the baseline word recognition score (Appendix B). 
 
Progressive Hearing Loss (PHL): Decline in word recognition score below the 95% 
critical difference, taking as reference the baseline word recognition score (Appendix 
B). 
 
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 crizotinib, 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. 
 
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 
investigator’s 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 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
46 
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 the Operations Center ANY serious treatment 
emergent adverse event as soon as possible. The Operations Center will report ANY 
serious treatment emergent adverse event to Pfizer Drug Safety, FDA, UAB IRB 
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.'  
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 (I.B). 
11.1.4.2 Unexpected adverse event 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
47 
For the purposes of this study, unexpected adverse events are those not 
listed in the Package Insert or current Investigator Brochure or not 
identified. This includes adverse events for which the specificity or 
severity is not consistent with the description in the package insert or I.B. 
For example, under this definition, hepatic necrosis would be unexpected 
if the package insert 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), the 
Sponsor, and Pfizer, Inc. in accordance with 21 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 the 
time of first dose of study drug. The reporting period for both AEs and SAEs 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 crizotinib (see following guidance), and actions taken. 
To ensure consistency of AE and SAE causality assessments, investigators should 
apply the following general guideline: 
Yes: There is a plausible temporal relationship between the onset of the AE and 
administration of crizotinib; 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 crizotinib; and/or the AE abates or resolves upon 
discontinuation of the crizotinib or dose reduction and, if applicable, reappears upon 
re-challenge. 
No: Evidence exists that the AE has an etiology other than the crizotinib (e.g., 
preexisting medical condition, underlying disease, intercurrent illness, or 
concomitant medication); and/or the AE has no plausible temporal relationship to 
crizotinib 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 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
48 
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 5.0 of the NCI Common Terminology Criteria for 
Adverse Events (CTCAE v. 5.0) will be utilized for AE reporting. The CTEP 
Version 5.0 of the CTCAE is identified and located on the CTEP website at 
https://evs.nci.nih.gov/ftp1/CTCAE/About.html. 
All appropriate treatment areas should have access to a copy of the CTEP Version 
5.0 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 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 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
49 
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 28 days after the last dose of study drug, a report should 
be completed and expeditiously submitted to the Pfizer, 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 crizotinib 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 crizotinib 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. 
11.3.2.7 Reconciliation/Pfizer 
The Sponsor agrees to conduct reconciliation for the product. Pfizer 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. 
 
11.4 SAE Expedited Reporting/Pfizer 
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 using the SAE reporting form in eDCS, and MedWatch Form 3500a. This 
includes events meeting the criteria outlined in Section 11.1.3, as well as the following: 
• Grade 3 (severe) events that are unexpected and at least possibly 
related/associated with the intervention. 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
50 
• 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.  
 
All SAEs should be entered on the SAE CRF in the eDCS and recorded on a 
MedWatch 3500a Form and sent to NF Consortium Operations Center (Attn: 
Research Nurse Manager; nfcop@uab.edu) and Dr. Matthias Karajannis 
(karajanm@mskcc.org) within 24 hours. 
  
The NF Consortium is also responsible for notifying the UAB IRB, DSMB and 
appropriate Regulatory agencies, including any Pfizer-related reporting 
requirements.   
 
MedWatch 3500a Reporting Guidelines: 
For Investigator-Sponsored Studies, some additional reporting requirements for 
the FDA apply in accordance with the guidance set forth in 21 CFR 314.80. 
 
The report should include the following information within the Event 
Description (Section B.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 
 
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 faxed to: 
 
MedWatch 
Fax: 1-800-FDA-0178 
 
MedWatch 3500A (Mandatory Reporting) form is available at: 
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM0
48334.pdf 
  
 
 
Additional Pfizer Expedited Reporting Guidelines  

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
51 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
subject receives first crizotinib dose and until at least 30 days after the last administration 
of crizotinib must be reported to Pfizer. 
 
Even though there may not be an associated SAE, exposure to the Pfizer Product during 
pregnancy and exposure to the Pfizer Product during lactation are reportable. 
 
SAEs that occur after completion of the reporting time period as defined above are 
reportable to Pfizer if the Investigator suspects a causal relationship between the Pfizer 
product and the SAE. 
 
Information about all SAEs will be collected and recorded on the MedWatch Form 3500a. 
All applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to 
each specific study treatment on the MedWatch Form 3500a and email to NF Operations 
Center (nfcop@uab.edu) immediately for a death or life-threatening event, and within 24 
hours for all other reportable SAEs. 
 
The NF Operations Center will forward any SAE report within 24 hours (or immediately 
if the event is fatal or life-threatening) of learning of the event to Pfizer followed by a 
complete written report within 24 hours of the initial 24-hour report. 
 
The original copy of the MedWatch Form must be kept with the case report form 
documentation at the site. 
 
When new, updated, or corrected information about a previously reported SAE is 
obtained, a follow-up report should be submitted on a new MedWatch Form that includes 
the data that are new or revised from the previous report. Follow-up information should 
never be added to a previously submitted report form. Ensure that any new events included 
on a follow-up report are marked as serious and a causality assessment is provided for 
each of them. The follow-up information should describe whether the event has resolved 
or continues, if and how it was treated, and whether the patient continued or withdrew 
from study participation.   
 
Pfizer US Clinical Trial Department Fax: 1-866-997-8322 
11.5 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 11.1.3 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 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
52 
working days of the initial contact to ATTN: MCMR-RCQ, 504 Scott Street, Fort Detrick, 
Maryland 21702-5012 or email.  
11.6 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.  
11.6.1 Non-Serious Adverse Event Reporting  
Non-serious adverse events will be reported to the NF Consortium via the  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 Pfizer by the NF 
Consortium. 
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: Juliette Southworth 
Phone: (205) 975-4075 
Email: jsouthworth@uab.edu 
 
All SAE reports will be reported to Study PI by the Operations Center via emails from the 
data entry system.  
 
11.8 Reporting to the NIH Office of Biotechnology Activities (OBA) 
N/A  
11.9 Reporting to the Institutional Biosafety Committee (IBC) 
N/A 
11.10 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. 
12. DATA AND SAFETY MONITORING 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
53 
12.1 Data Reporting 
12.1.1 Method  
The NF Consortium Data Coordinating Center at CHOP will collect, manage, 
and monitor data for this study.  
12.1.2 Data Collection  
The trial is being conducted by the NF Consortium. Case reports forms 
developed by the NF Consortium Operations Center will be used for submitting 
clinical data to the Operations Center. Data must be submitted to the Operations 
Center within two weeks of completing each required evaluation while the 
subject is on study. 
The NF Consortium DCC is responsible for compiling and providing the data to 
the Principal Investigator for review. 
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 research monitor has been selected for this study (Diana Osorio, MD, MPH, see roster 
at beginning of protocol). The research 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 research 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 research 
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 research 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 research monitor to be possibly or definitely related to participation and 
reports of events resulting in death should be promptly forwarded to the USAMRMC 
ORP OHRO. 
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 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
54 
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. 
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 UAB IRB and the DOD 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. 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
55 
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: 
• 
E6 Good Clinical Practice: Consolidated Guidance 
www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM129515.pdf  
• 
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  
 
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, but it is not mandated. 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
56 
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 
Operations Center, and Participating Institutions are presented in the Multi-Center Data 
and Safety Monitoring Plan. 
• The Protocol Chair and NF Consortium Operations 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.  
• Drug Distribution Center - UAB Research Pharmacy 
According to 21 CFR 312.6, UAB IDS will label the packaging of the 
investigational drug with the following statement: "Caution: New Drug - 
Limited by Federal law to investigational use". 
UAB IDS will maintain records showing the receipt, shipment, and other 
pertinent information of the investigational drug including:  
- Name of the investigator to whom the drug is shipped 
- Date, quantity, and batch number of each shipment 
- Return, destruction, or other appropriate disposition of unused study drug 
To request study drug, the UAB Ordering Form will be used and all correspondence 
regarding ordering be sent to nfcop@uab.edu. 
13.7 Cooperative Research and Development Agreement (CRADA)/Clinical Trials 
Agreement (CTA)  
N/A 
 
14. STATISTICAL CONSIDERATIONS  
 
14.1 Study Design/Endpoints 
To evaluate efficacy, imaging response is treated as a binary variable whereby patients 
who achieve a volumetric response in the target tumor at any point within 12 months from 
beginning of therapy are considered responders and all other patients are nonresponders. 
A 2-stage Simon design will be used.34 Crizotinib will be considered not of sufficient 
interest for further evaluation if the true response rate in evaluable subjects (as defined 
below) is 5% (p0) or less and considered active if the true response rate is 25% or greater 
(p1). With alpha (Type I error, probability of rejecting crizotinib with a true response rate 
5% under H0) set at 0.05 and beta (Type II error, probability of failing to reject a treatment 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
57 
with true response rate 25% under Ha) set at 0.2, the required sample size is 9 patients for 
stage 1 and an additional 8 patients for stage 2. If there are no responses after the first 
stage is completed, crizotinib will be deemed ineffective and the trial terminated. 
Recruitment will be halted after the 9th evaluable patient is enrolled (stage 1) until at least 
one response is observed during the first 12 cycles. Crizotinib will be considered effective 
and of interest for further study if after successful completion of both stages, the 
cumulative number of responses is ≥3. Using this 2-stage design, the probability of early 
termination is 0.63 if the true response rate to crizotinib is 5% or lower.  
Stage 
Cumulative number of patients 
with volumetric responses 
Decision 
Stage 1: 
enter 9 patients 
0 
Terminate the trial: 
agent ineffective 
1 or more 
Inconclusive result: 
continue trial 
(proceed to Stage 2) 
Stage 2: 
enter 8 additional 
patients 
2 or less 
Terminate the trial: 
agent ineffective 
3 or more 
Continue the trial to 
obtain full sample size: 
agent effective 
 
14.2 Sample Size/Accrual Rate 
Subjects of both genders, from all racial and ethnic groups are eligible for this trial if they 
meet the criteria outlined in Section 3.1. To date, there is no information that suggests 
differences in drug metabolism or disease response among racial or ethnic groups or 
between the genders, indicating that results of the trial will be applicable to all groups. 
Efforts will be made to extend the accrual to a representative population, but in a phase II 
study with limited accrual, a balance must be struck between subject safety considerations 
and limitations on the number of individuals exposed to potentially toxic or ineffective 
treatments on the one hand, and the need to explore gender, racial, and ethnic aspects of 
clinical research on the other. If differences in outcome that correlate to gender, age, 
racial, or ethnic identity are noted, accrual may be expanded or additional studies may be 
performed to investigate those differences more fully. 
A maximum of 19 eligible subjects will be accrued into the trial, allowing for up to 10% 
of non-evaluable patients. We believe this 10% rate is reasonable given our prior 
experience with NF2 phase 2 clinical trials. 
The expected accrual rate will be 2 subjects/month.   
14.3 Stratification Factors 
None 
14.4 Analysis of Exploratory Endpoints (including re-treatment phase) 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
58 
• Frequency of adverse events (possibly, probably, or definitely) related to crizotinib 
use in this patient population will be summarized.  
• Audiologic responses will be summarized over time using descriptive statistics and 
graphical displays. Similarly, quality of life will be summarized over time in these 
patients. Additional descriptive analyses will be carried out for adults versus children.  
• The association between audiometric and volumetric responses will be summarized 
over time with graphical displays and the association between best binary responses 
will be summarized using contingency tables over time, using Chi-square as a 
measure of association.  
• In the analysis of the TRQ and NFTI-QOL questionnaire data, compliance with 
questionnaire administration (defined as the proportion of questionnaires actually 
received out of the expected number) will be calculated, and questionnaires will be 
scored as recommended in the instructions for the instruments.35,36 
 
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 crizotinib. 
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. 
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. Sub-analyses 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 sub-analyses 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 12 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 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
59 
Editors. A full report of the outcomes should be made public no later than 1 year after the 
end of data collection.  
 
 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
60 
16. REFERENCES  
 
1. Evans DG, Huson SM, Donnai D, et al: A clinical study of type 2 neurofibromatosis. Q J Med 
84:603-18, 1992 
2. Blakeley JO, Ye X, Duda DG, et al: Efficacy and Biomarker Study of Bevacizumab for Hearing 
Loss Resulting From Neurofibromatosis Type 2-Associated Vestibular Schwannomas. J Clin 
Oncol 34:1669-75, 2016 
3. Mautner VF, Nguyen R, Knecht R, et al: Radiographic regression of vestibular schwannomas 
induced by bevacizumab treatment: sustain under continuous drug application and rebound 
after drug discontinuation. Ann Oncol 21:2294-5, 2010 
4. Karajannis MA, Legault G, Hagiwara M, et al: Phase II trial of lapatinib in adult and pediatric 
patients with neurofibromatosis type 2 and progressive vestibular schwannomas. Neuro Oncol 
14:1163-70, 2012 
5. Karajannis MA, Legault G, Hagiwara M, et al: Phase II study of everolimus in children and 
adults with neurofibromatosis type 2 and progressive vestibular schwannomas. Neuro Oncol 
16:292-7, 2014 
6. Plotkin SR, Stemmer-Rachamimov AO, Barker FG, 2nd, et al: Hearing improvement after 
bevacizumab in patients with neurofibromatosis type 2. N Engl J Med 361:358-67, 2009 
7. Plotkin SR, Singh MA, O'Donnell CC, et al: Audiologic and radiographic response of NF2-
related vestibular schwannoma to erlotinib therapy. Nat Clin Pract Oncol 5:487-91, 2008 
8. Goutagny S, Raymond E, Esposito-Farese M, et al: Phase II study of mTORC1 inhibition by 
everolimus in neurofibromatosis type 2 patients with growing vestibular schwannomas. J 
Neurooncol 122:313-20, 2015 
9. Karajannis MA, Ferner RE: Neurofibromatosis-related tumors: emerging biology and therapies. 
Curr Opin Pediatr 27:26-33, 2015 
10. Rodig SJ, Shapiro GI: Crizotinib, a small-molecule dual inhibitor of the c-Met and ALK 
receptor tyrosine kinases. Curr Opin Investig Drugs 11:1477-90, 2010 
11. Ou SH: Crizotinib: a novel and first-in-class multitargeted tyrosine kinase inhibitor for the 
treatment of anaplastic lymphoma kinase rearranged non-small cell lung cancer and beyond. 
Drug Des Devel Ther 5:471-85, 2011 
12. Mosse YP, Lim MS, Voss SD, et al: Safety and activity of crizotinib for paediatric patients with 
refractory solid tumours or anaplastic large-cell lymphoma: a Children's Oncology Group phase 
1 consortium study. Lancet Oncol 14:472-80, 2013 
13. Camidge DR, Bang YJ, Kwak EL, et al: Activity and safety of crizotinib in patients with ALK-
positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol 
13:1011-9, 2012 
14. Troutman S, Moleirinho S, Kota S, et al: Crizotinib inhibits NF2-associated schwannoma 
through inhibition of focal adhesion kinase 1. Oncotarget, 2016 
15. Liu X, Wang Q, Yang G, et al: A novel kinase inhibitor, INCB28060, blocks c-MET-dependent 
signaling, neoplastic activities, and cross-talk with EGFR and HER-3. Clin Cancer Res 
17:7127-38, 2011 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
61 
16. Cui JJ, Tran-Dube M, Shen H, et al: Structure based drug design of crizotinib (PF-02341066), 
a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase 
and anaplastic lymphoma kinase (ALK). J Med Chem 54:6342-63, 2011 
17. Saydam O, Ozdener GB, Senol O, et al: A novel imaging-compatible sciatic nerve schwannoma 
model. J Neurosci Methods 195:75-7, 2011 
18. Wong HK, Lahdenranta J, Kamoun WS, et al: Anti-vascular endothelial growth factor therapies 
as a novel therapeutic approach to treating neurofibromatosis-related tumors. Cancer Res 
70:3483-93, 2010 
19. Licciulli S, Maksimoska J, Zhou C, et al: FRAX597, a small molecule inhibitor of the p21-
activated kinases, inhibits tumorigenesis of neurofibromatosis type 2 (NF2)-associated 
Schwannomas. J Biol Chem 288:29105-14, 2013 
20. Yi C, Troutman S, Fera D, et al: A tight junction-associated Merlin-angiomotin complex 
mediates Merlin's regulation of mitogenic signaling and tumor suppressive functions. Cancer 
Cell 19:527-40, 2011 
21. Poulikakos PI, Xiao GH, Gallagher R, et al: Re-expression of the tumor suppressor NF2/merlin 
inhibits invasiveness in mesothelioma cells and negatively regulates FAK. Oncogene 25:5960-
8, 2006 
22. Fuse MA, Plati SK, Burns SS, et al: Combination Therapy with c-Met and Src Inhibitors 
Induces Caspase-Dependent Apoptosis of Merlin-Deficient Schwann Cells and Suppresses 
Growth of Schwannoma Cells. Mol Cancer Ther 16:2387-2398, 2017 
23. Dilwali S, Roberts D, Stankovic KM: Interplay between VEGF-A and cMET signaling in 
human vestibular schwannomas and schwann cells. Cancer Biol Ther 16:170-5, 2015 
24. Kaneda H, Okamoto I, Nakagawa K: Rapid response of brain metastasis to crizotinib in a 
patient with ALK rearrangement-positive non-small-cell lung cancer. J Thorac Oncol 8:e32-3, 
2013 
25. Kinoshita Y, Koga Y, Sakamoto A, et al: Long-lasting response to crizotinib in brain metastases 
due to EML4-ALK-rearranged non-small-cell lung cancer. BMJ Case Rep 2013, 2013 
26. Chi AS, Batchelor TT, Kwak EL, et al: Rapid radiographic and clinical improvement after 
treatment of a MET-amplified recurrent glioblastoma with a mesenchymal-epithelial transition 
inhibitor. J Clin Oncol 30:e30-3, 2012 
27. Plotkin SR, Merker VL, Halpin C, et al: Bevacizumab for progressive vestibular schwannoma 
in neurofibromatosis type 2: a retrospective review of 31 patients. Otol Neurotol 33:1046-52, 
2012 
28. Nunes FP, Merker VL, Jennings D, et al: Bevacizumab treatment for meningiomas in NF2: a 
retrospective analysis of 15 patients. PLoS One 8:e59941, 2013 
29. Dombi E, Ardern-Holmes SL, Babovic-Vuksanovic D, et al: Recommendations for imaging 
tumor response in neurofibromatosis clinical trials. Neurology 81:S33-40, 2013 
30. Plotkin SR, Ardern-Holmes SL, Barker FG, 2nd, et al: Hearing and facial function outcomes 
for neurofibromatosis 2 clinical trials. Neurology 81:S25-32, 2013 

Crizotinib Protocol Version : 1.7  
Version Date : 9/15/2023 
 
62 
31. Jones SF, Siu LL, Bendell JC, et al: A phase I study of VS-6063, a second-generation focal 
adhesion kinase inhibitor, in patients with advanced solid tumors. Invest New Drugs 33:1100-
7, 2015 
32. Mulvihill JJ, Parry DM, Sherman JL, et al: NIH conference. Neurofibromatosis 1 
(Recklinghausen disease) and neurofibromatosis 2 (bilateral acoustic neurofibromatosis). An 
update. Ann Intern Med 113:39-52, 1990 
33. Baser ME, Friedman JM, Wallace AJ, et al: Evaluation of clinical diagnostic criteria for 
neurofibromatosis 2. Neurology 59:1759-65, 2002 
34. Simon R: Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10:1-10, 
1989 
35. Wilson PH, Henry J, Bowen M, et al: Tinnitus reaction questionnaire: psychometric properties 
of a measure of distress associated with tinnitus. J Speech Hear Res 34:197-201, 1991 
36. Hornigold RE, Golding JF, Leschziner G, et al: The NFTI-QOL: A Disease-Specific Quality of 
Life Questionnaire for Neurofibromatosis 2. J Neurol Surg B Skull Base 73:104-11, 2012 
37. Thornton AR, Raffin MJ: Speech-discrimination scores modeled as a binomial variable. Journal 
of speech and hearing research 21:507-18, 1978 
 
 

 
Crizotinib Protocol Version : 1.7 
  
 
 
 
Version Date :  9/15/2023 
 
63 
Appendix A: Schedule of Evaluations 
 
Each cycle is 28 days, with no extension for drug interruptions. All required evaluations should be obtained within days 21-28 of a cycle. Assessments at the end of cycle 12 
may be obtained within 1 week after completion of cycle 12.  
† Includes drug dispensing, and repeat baseline evaluations if time between first screening and dispensing exceeds 4 weeks. Otherwise, baseline evaluations need not be repeated, 
unless there is a significant change in the patient’s clinical condition. 
# *Includes glucose, calcium, albumin, total protein, sodium, potassium, bicarbonate, chloride, blood urea nitrogen, creatinine, alkaline phosphatase, alanine amino transferase, aspartate 
amino transferase, bilirubin     **Required for women of childbearing potential within 7 days of starting crizotinib.     ***Not required for patients with no measurable hearing.     
****Question 24 of the Tinnitus Reaction Questionnaire (TRQ; See Appendix G) elicits possible suicidal ideation. A clinician should review this questionnaire immediately after 
it is completed and assess for any possible suicidal risk if the answer score is >2. Any concerns of suicidality should be immediately addressed with the responsible institutional 
investigator. 
 
STUDIES TO BE OBTAINED  
Baseline 
Cycle 1  
Subsequent cycles  
Off-Treatment Follow-Up 
(30–35 days post treatment) 
Informed Consent 
X 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
Ophthalmologic examination 
X 
 
End of cycle 1, 3, 6, 9, 12 
 
Oxygen Saturation (SaO2) 
X 
 
 
 
History  
X 
Prior to start †  
End of cycle 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12  
X 
Physical Exam  
X 
Prior to start †  
End of cycle 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 
X 
Vital Signs  
X 
Prior to start †  
End of cycle 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 
X 
Performance Status  
X 
Prior to start †  
End of cycle 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 
X 
CBC, diff, comprehensive 
metabolic panel*, Mg, Phos, CK 
X 
Prior to start † 
End of cycle 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 
X 
Biomarker blood sample 
X 
 
End of cycle 1, 3, 12 
 
Serum Pregnancy test ** 
X 
Prior to start **   
End of cycle 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 
X 
Subject Diary Review  
 
 
End of cycle 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 
 
ECG (QTc) 
X 
Prior to start † 
End of cycle 3, 6, 9, 12 
 
MRI Brain with volumetric 
analysis 
X 
Prior to start † 
End of cycle 3, 6, 9, 12 
 
Audiogram *** 
X 
Prior to start † 
End of cycle 3, 6, 9, 12 
 
NFTI-QOL 
(subjects age ≥16 years only) 
X 
Prior to start † 
End of cycle 6, 12 
 
TRQ Tinnitus Assessment 
(subjects age ≥18 years only****) 
X 
Prior to start † 
End of cycle 6, 12 
 

 
Crizotinib Protocol Version : 1.7 
  
 
 
 
Version Date :  9/15/2023 
 
64 
 
Retreatment Option- Schedule of Evaluations 
 
STUDIES TO BE OBTAINED  
Baseline 
Cycle 13 
Subsequent cycles  
Off-Treatment Follow-Up 
(30–35 days post treatment) 
Informed Consent 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
Ophthalmologic examination 
X 
 
End of cycle 13, 15,18, 21, 24 
 
Oxygen Saturation (SaO2) 
X 
 
 
 
History  
X 
Prior to start †  
End of cycle 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24  
X 
Physical Exam  
X 
Prior to start †  
End of cycle 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24  
X 
Vital Signs  
X 
Prior to start †  
End of cycle 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24  
X 
Performance Status  
X 
Prior to start †  
End of cycle 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24  
X 
CBC, diff, comprehensive 
metabolic panel*, Mg, Phos, CK 
X 
Prior to start † 
End of cycle 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24  
X 
Serum Pregnancy test ** 
X 
Prior to start ***   End of cycle 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24  
X 
Subject Diary Review  
 
 
End of cycle 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24  
 
ECG (QTc) 
X 
Prior to start † 
End of cycle 15, 18, 21, 24 
 
MRI Brain with volumetric 
analysis 
X 
Prior to start † 
End of cycle 15, 18, 21, 24 
 
Audiogram *** 
X 
Prior to start † 
End of cycle 15, 18, 21, 24 
 
NFTI-QOL 
(subjects age ≥16 years only) 
X 
Prior to start † 
End of cycle 18, 24 
 
TRQ Tinnitus Assessment 
(subjects age ≥18 years only)**** 
X 
Prior to start † 
End of cycle 18, 24 
 
Each cycle is 28 days, with no extension for drug interruptions. All required evaluations should be obtained within days 21-28 of a cycle. Assessments at the end of cycle 24 
may be obtained within 1 week after completion of cycle 24.  
† Includes drug dispensing, and repeat baseline evaluations if time between first screening and dispensing exceeds 4 weeks. Otherwise, baseline evaluations need not be repeated, 
unless there is a significant change in the patient’s clinical condition. 
*Includes glucose, calcium, albumin, total protein, sodium, potassium, bicarbonate, chloride, blood urea nitrogen, creatinine, alkaline phosphatase, alanine amino transferase, aspartate 
amino transferase, bilirubin.     **Required for women of childbearing potential within 7 days of starting crizotinib.     ***Not required for patients with no measurable hearing.     
****Question 24 of the Tinnitus Reaction Questionnaire (TRQ; See Appendix G) elicits possible suicidal ideation. A clinician should review this questionnaire immediately after 
it is completed and assess for any possible suicidal risk if the answer score is >2. Any concerns of suicidality should be immediately addressed with the responsible institutional 
investigator. 
 

Crizotinib Protocol Version : 1.7 
Version Date 9/15/2023 
 
65 
Appendix B: 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 and 
Raffin.37  
 
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 

Crizotinib Protocol Version : 1.7 
Version Date 9/15/2023 
 
66 
70 
52–86 
≥ 88 
≤ 50 
72 
54–86 
≥ 88 
≤ 52 
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 
 
 
 
 

Crizotinib Protocol Version : 1.7 
Version Date 9/15/2023 
 
67 
Appendix C:  NFTI-QOL (Neurofibromatosis 2 impact on quality of life) 
 
To be administered to patients ≥16 years only 
 
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 
 

Crizotinib Protocol Version : 1.7 
Version Date 9/15/2023 
 
68 
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 
 
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 
 
 
 

Crizotinib Protocol Version : 1.7 
Version Date 9/15/2023 
 
69 
Guy’s NFTI-QOL 
 
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 
 
 
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. 

Crizotinib Protocol Version : 1.7 
Version Date 9/15/2023 
 
70 
Appendix D: Performance Status Criteria 
 
Karnofsky Scale 
(recipient age ≥ 16 years) 
Lansky Scale 
(recipient age <16 years) 
Able to carry on normal activity; no special 
care is needed 
Able to carry on normal activity; no special 
care is needed 
100 Normal, no complaints, no evidence of 
disease 
100 Fully active 
90 Able to carry on normal activity 
90 Minor restriction in physically strenuous play 
80 Normal activity with effort 
80 Restricted in strenuous play, tires more easily, 
otherwise active 
Unable to work, able to live at home, cares for 
most personal needs, a varying amount of 
assistance is needed 
Mild to moderate restriction 
70 Cares for self, unable to carry on normal 
activity or to do active work 
70 Both greater restrictions of, and less time spent 
in active play 
60 Requires occasional assistance but is able to 
care for most needs 
60 Ambulatory up to 50% of time, limited active 
play with assistance/supervision 
50 Requires considerable assistance and frequent 
medical care 
50 Considerable assistance required for any active 
play, fully able to engage in quiet play 
Unable to care for self, requires equivalent of 
institutional or hospital care, disease may be 
progressing rapidly 
Moderate to severe restriction 
40 Disabled, requires special care and assistance 
40 Able to initiate quite activities 
30 Severely disabled, hospitalization indicated, 
although death not imminent 
30 Needs considerable assistance for quiet activity 
20 Very sick, hospitalization necessary 
20 Limited to very passive activity initiated by 
others (e.g., TV) 
10 Moribund, fatal process progressing rapidly 
10 Completely disabled, not even passive play 
 
 
 

Crizotinib Protocol Version : 1.7 
Version Date 9/15/2023 
 
71 
Appendix E: 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. The local Lead 
Audiologist will also act as a stable contact on behalf of their center. Finally, the Senior Study 
Audiologist (MSKCC) 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 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 

Crizotinib Protocol Version : 1.7 
Version Date 9/15/2023 
 
72 
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. 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. 
The Lead Audiologist at each site will ensure that threshold tests are performed in the standard 
manner. This includes the Hughson-Westlake bracketing procedure. A 200 ms. ON versus 

Crizotinib Protocol Version : 1.7 
Version Date 9/15/2023 
 
73 
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. 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. 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. 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. 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.  
  

Crizotinib Protocol Version : 1.7 
Version Date 9/15/2023 
 
74 
4.4 Word Recognition  
Speech intelligibility will be evaluated for each ear using standard word recognition 
of monosyllables. All tests will use recorded lists (CID-W22, Ira Hirsh recording, 
Q/MASS v 2) supplied by the Senior Study Audiologist, including standardized score 
sheets. 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, 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 Index 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.  
 
on the asymptote of the curve. 13 Using software developed for this purpose, Table 1 
was created for setting “High” speech levels: 

Crizotinib Protocol Version : 1.7 
Version Date 9/15/2023 
 
75 
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. 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. 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. 
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.  
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 

Crizotinib Protocol Version : 1.7 
Version Date 9/15/2023 
 
76 
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. 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 zero (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 
phones and insert phones. Standard speech-shaped noise is assumed in this calculation and 
will be the masker used at the study centers. 
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 

Crizotinib Protocol Version : 1.7 
Version Date 9/15/2023 
 
77 
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. Stenger’s test 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. 

Crizotinib Protocol Version : 1.7 
Version Date 9/15/2023 
 
78 
 

Crizotinib Protocol Version : 1.7 
Version Date 9/15/2023 
 
79 
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 Study 
Audiologist (Kerri O’Connor, 
oconnok7@mskcc.org) when they are 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.  

Crizotinib Protocol Version : 1.7 
Version Date 9/15/2023 
 
80 
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. 
7.2 
Audiometer 
Audiometers that meet the American National Standard Specifications for Audiometers 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 

Crizotinib Protocol Version : 1.7 
Version Date 9/15/2023 
 
81 
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 Audiometers 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. 
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 Study Audiologist (Kerri O’Connor) 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 

Crizotinib Protocol Version : 1.7 
Version Date 9/15/2023 
 
82 
(Senior Study Audiologist) will keep copies of each of the study audiograms and records of 
the transfer process.  
 
 
 

Crizotinib Protocol Version : 1.7 
Version Date 9/15/2023 
 
83 
Appendix F: MRI Protocols 
 
Image Acquisition 
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 
7) Post-contrast Gradient Echo 3D imaging with fine cuts (1 mm slices, no skip) 
preferably through the entire brain, and at the minimum including the entire target 
tumor. 
 
NOTE:  The post-contrast Gradient Echo 3D imaging with fine cuts (1 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). Suitable post-contrast Gradient Echo 3D imaging 
sequences include BRAVO (GE), MPRAGE (Siemens), 3D-T1 TFE (Philips), 3D GEIR (Hitachi) 
and 3D Fast FE (Toshiba).  
 
All images used for volumetric analysis will be reviewed by the PI or co-PI to verify the 
following:  
• Prior to patient enrollment, the PI or co-PI will review volumetric assessments to confirm that 
1) baseline volumetrics were performed on post-contrast Gradient Echo 3D imaging with fine 
cuts (1 mm slices, no skip), 2) target tumors were volumetrically measurable and ≥0.75 ml in 
size, and 3) protocol defined criteria were met for progression (i.e., volumetric evidence of 
progression over the past 18 months, defined as ≥20% annualized increase in volume) 
• For imaging response assessment on study, the PI or co-PI will review volumetric assessments 
to verify whether 1) volumetrics were performed on post-contrast Gradient Echo 3D imaging 
with fine cuts (1 mm slices, no skip), 2) protocol defined criteria were met for imaging response 
or progression (defined as ≥20% decrease or increase in volume compared to lowest tumor 
volume during treatment, respectively) 
 
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 procedures 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 

Crizotinib Protocol Version : 1.7 
Version Date 9/15/2023 
 
84 
of Dr. Gordon Harris for central analysis of tumor volume. (see section 10.1.7). Sites that are unable 
to de-identify scans without removing scan date and scanner information may upload images 
without removal of PHI if institution allows.  Once uploaded, TIMC will de-identify scans prior to 
archiving in their system. TIMC will then inform PI or co-PI to confirm proper sequences by email. 
 
 
 
Non-Partners Access  
1. Email TIMC Help Desk and provide two email addresses for account registration (a 
primary and a backup, if necessary) 
2. TIMC will send an invite via the Partners Healthcare Secure File Sharing service 
3. Click the link in the email to accept the invitation and register your account 
*Please note: Invitations expire after 7 days 
a. Check Spam and Junk folders for invite if not received in Inbox  
4. Create a password 
5. Click Register 
Partners Access 
1. Go to  https://transfer.partners.org/courier/web/1000@/wmLogin.html 
2. Click I don’t have an account yet  
3. Enter E-mail address and click Register 
Send Files 
1. Create a folder on your desktop 
2. Copy DICOM data from CD into the desktop folder 
a. Remove any image viewers as this will interfere with data upload to the local 
analysis software 
3. Right click folder > Send To > Compressed (zipped) folder 
4. Log in to the system: https://transfer.partners.org/courier/web/1000@/wmLogin.html 
5. Select Send File tab 
6. Enter tumormetrics@partners.org  into the To field 
7. Select Choose File > browse for the zipped file on your desktop  
8. Add any notes pertaining to the scan or assessment (optional)  
9. Select notification preferences from the Additional Options field (optional) 
10. Click Send 
11. Click OK after receiving confirmation that the files have been sent 
Please contact the TIMC Help Desk at tumormetrics@partners.org for any questions. 
 

Crizotinib Protocol Version : 1.7 
Version Date 9/15/2023 
 
85 
Appendix G: Tinnitus Reaction Questionnaire (TRQ)  [Wilson et al., J Speech Hear Res 34, 1991] 
To be administered to patients ≥18 years only 
SUBJECT IDENTIFIER :   ______________________________ 
 
*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 
 
Number Item 
Scores* 
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 

Crizotinib Protocol Version : 1.7 
Version Date 9/15/2023 
 
86 
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 
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 
 
 

Crizotinib Protocol Version : 1.7 
Version Date 9/15/2023 
 
87 
Appendix H: Disintegration of Capsules for Patients Unable to Swallow Capsules 
 
PRESCRIBING INFORMATION 
Crizotinib (Xalkori) capsules are intended for twice daily administration and are not a delayed-, extended-, 
or sustained-release formulation. It is supplied commercially as a hard shell gelatin capsule with a pink 
opaque cap and body (250 mg strength) and a pink opaque cap and white opaque body (200 mg strength).1 
The solubility of crizotinib in aqueous media decreases over the range pH 1.6 to pH 8.2 from > 10 mg/mL 
to < 0.1 mg/mL. The log of the distribution coefficient (octanol/water) at pH 7.4 is 1.65. Capsules should 
be swallowed whole and patients should not crush, dissolve or open capsules.1 
 
LITERATURE SEARCH 
As of September 16, 2016, a search of the published medical literature failed to identify any data regarding 
the disintegration of capsules for ease oral administration. However, we are aware of unpublished data 
that discusses this topic. This information is presented below. 
 
BACKGROUND 
Xalkori is an immediate-release formulated capsule (not a delayed-, extended-, or sustained-release 
formulation).2 A proportion of the patient population may not be able to swallow capsules. Specific 
pharmacokinetic and stability studies have not formally evaluated the method of capsule disintegration in 
water as described in this letter; however, the 1001 and PROFILE 1005 studies allowed capsules to be 
disintegrated in water and administered orally as necessary.3 The instructions that follow below may be 
applied to commercial crizotinib supply.4 
 
CLINICAL DATA 
Unpublished Data 
Preparation of Liquid Suspension Formulation Using Clinical Study Supply 
Administration of crizotinib (clinical study supply) using a liquid suspension formulation was made 
possible within the clinical trials for patients unable to swallow whole capsules. The instructions provided 
below applied to the administration of clinical supply crizotinib; however, the instructions that follow 
below may be applied to commercial crizotinib supply. Oral suspension dosing is accomplished via the 
disintegration of a capsule in 2 tablespoonfuls of boiling water, followed by the addition of 
1 tablespoon of room temperature or cold water in a 6-8 ounce drinking glass. Dosing of the suspension 
is followed by three 1 tablespoonful water rinses of the glass.3 
Once the suspension preparation process was begun, all steps were conducted in the order as outlined below. 
Suspensions should be prepared at the time of dosing and may NOT be stored. The suspension is dosed 
immediately after preparation. All preparation was performed in a clean working space. 
Inspection of glass and spoons prior to each dose preparation was performed to ensure that the supplies 
are clean, dry and particulate-free.3 
No specific safety precautions were described; however, during preparation, handlers were instructed not 
to breathe in crizotinib dust and to avoid crizotinib contact with skin, eye, and clothing. The preparation 
area and supplies were cleaned immediately after completion of the dosing process. Local disposal and 
drug accountability practices were utilized. The patient and/or caregiver should go through practice 
preparation of the instructions to gain familiarity with this procedure.3 
 
 
 
Supplies Used 
Pfizer cannot make specific recommendations regarding the types of supplies used. The following was 
used in the clinical study program.3 
 

Crizotinib Protocol Version : 1.7 
Version Date 9/15/2023 
 
88 
• Crizotinib capsule(s) 
• 6-8 ounce drinking glass 
• Tap water or bottled water 
• Stirring spoon 
• Tablespoon (1 TBSP=15 mL) measuring spoon 
• Mint candies (optional and used for masking any unpleasant taste) 
 
Instructions 
 Preparation and Administration of Oral Liquid Suspension Formulation as Used in Clinical Studies3 
Step 1 
One cup of boiling water (tap or bottled water) was prepared. 
Step 2 
1 TBSP of the above boiling water was measured and poured into the drinking glass. 
Step 3 
The prescribed crizotinib dosage was added to the drinking glass. Note: The capsule was not 
opened. 
Step 4 
Using the spoon, the solution in Step 3 was stirred continuously for at least 2 minutes. 
Step 5 
A mint candy was administered to the patient (optional) allowing it to dissolve in mouth to aid in 
masking undesirable taste. 
Step 6 
Another 1 TBSP of boiling water was measured and poured into the drinking glass containing the 
crizotinib dosage. 
Step 7 
This solution was stirred with a spoon continuously for another 2 minutes. 
Step 8 
An additional 1 TBSP of room temperature or cold water was poured into the solution, rinsing the 
stirring spoon in the process such that any solids on the spoon were removed and rinsed into the 
glass. 
Step 9 
Any undissolved candy in the mouth of the patient was removed. 
Step 10 
Immediately before dosing, the drinking glass’s contents were swirled vigorously for 10 seconds. 
Step 11 
The suspension was administered to the patient. 
Step 12 
In the same drinking glass, 1 TBSP of room temperature water was added, rinsing the inside walls 
of the glass in the process. The contents were swirled vigorously for 10 seconds. This was 
administered to the patient for drinking. 
Step 13 
Repeat Step 12 two more times. 
Step 14 
One mint candy was administered to the patient (optional). 
Note: Specific pharmacokinetic studies have not been performed to evaluate the method of capsule disintegration for 
ease of oral administration as described in this letter using the clinical supply crizotinib formulation. Therefore, Pfizer 
Inc cannot guarantee that the use of this method will result in comparable safety or efficacy outcomes to that observed 
with oral administration of the intact commercially available crizotinib capsule formulation. 
 
In-Use Shelf-Life and Storage Requirements 
The crizotinib suspension is dosed immediately after preparation. A stability study conducted showed no 
chemical degradation during dose delivery using the above instructions. A shelf life of 2 hours has been 
validated. No extended stability or temperature excursion data for this formulation is available.3 
 
REFERENCES 
1. 
Xalkori® (crizotinib) capsules. Package Insert. Pfizer. 
2. 
Data on file (57). Pfizer. 
3. 
Data on file (11). Pfizer. 
4. 
Data on file (14). Pfizer. 

Crizotinib Protocol Version : 1.7 
Version Date 9/15/2023 
 
89 
Instructions for Patients 
Preparation and Administration of Oral Liquid Suspension of Crizotinib (Xalkori) 
• Crizotinib capsule(s) 
• 6-8 ounce drinking glass 
• Tap water or bottled water 
• Stirring spoon 
• Tablespoon (1 TBSP=15 mL) measuring spoon 
• Mint candies (optional and used for masking any unpleasant taste) 
Instructions 
Step 1 
Prepare one cup of boiling water (tap or bottled water). 
Step 2 
Pour 1 TBSP of the above boiling water into the drinking glass. 
Step 3 
Add prescribed crizotinib dose to the drinking glass. Note: do not open 
capsule. 
Step 4 
Using the spoon, stir the solution prepared in Step 3 for at least 2 minutes. 
Step 5 
Optional: dissolve mint candy in patient’s mouth to aid in mask undesirable taste. 
Step 6 
Pour another 1 TBSP of boiling water into the drinking glass containing the 
crizotinib dose. 
Step 7 
Stir solution with a spoon continuously for another 2 minutes. 
Step 8 
Pour and additional 1 TBSP of room temperature or cold water into the 
solution, rinsing the stirring spoon in the process such that any solids on the 
spoon are removed and rinsed into the glass. 
Step 9 
Remove any undissolved mint candy from patient’s mouth. 
Step 10 
Swirl drinking glass’s contents vigorously for 10 seconds. 
Step 11 
Immediately administer suspension to the patient. 
Step 12 
In the same drinking glass, add 1 TBSP of room temperature water, rinsing the 
inside walls of the glass in the process. Swirl the contents vigorously for 10 
seconds, and administer to the patient for drinking. 
Step 13 
Repeat Step 12 two more times. 
Step 14 
Optional: Administer one mint candy to the patient. 
 
 

Crizotinib Protocol Version : 1.7 
Version Date 9/15/2023 
 
90 
APPENDIX I: SUBJECT DIARY ON NF2 CRIZOTINIB PROTOCOL 
 
Patient Name: _______________________     Cycle #: _____     Start Date: ___/____/_______ 
 
 Dose Level 
 (Circle one) 
BSA [m2] 
Dose 
A 
<0.45 
200 mg once daily 
B 
0.45-0.70 
250 mg once daily 
C 
0.71-0.88 
200 mg twice daily 
D 
  ≥0.89 
250 mg twice daily 
 
Instructions: 
1) Every day, record each dose of crizotinib taken 
2) Crizotinib should be taken once or twice daily, with or without food, depending on 
prescribed dose level. For twice daily administration, crizotinib should be taken 
approximately 12 hours apart, preferably in the morning and evening. 
3) If missing a dose (e.g., due to vomiting), do not take another dose. Resume dosing 
with the next scheduled dose. 
 
 
Date 
 
AM Dose 
taken 
(check) 
PM Dose 
taken 
(check) 
Comments 
Day 1 
 
 
 
 
Day 2 
 
 
 
 
Day 3 
 
 
 
 
Day 4 
 
 
 
 
Day 5 
 
 
 
 
Day 6 
 
 
 
 
Day 7 
 
 
 
 
Day 8 
 
 
 
 
Day 9 
 
 
 
 
Day 10 
 
 
 
 
Day 11 
 
 
 
 
Day 12 
 
 
 
 
Day 13 
 
 
 
 
Day 14 
 
 
 
 

Crizotinib Protocol Version : 1.7 
Version Date 9/15/2023 
 
91 
Day 15 
 
 
 
 
Day 16 
 
 
 
 
Day 17 
 
 
 
 
Day 18 
 
 
 
 
Day 19 
 
 
 
 
Day 20 
 
 
 
 
Day 21 
 
 
 
 
Day 22 
 
 
 
 
Day 23 
 
 
 
 
Day 24 
 
 
 
 
Day 25 
 
 
 
 
Day 26 
 
 
 
 
Day 27 
 
 
 
 
Day 28