A Phase II Study of Cabozantinib (XL184) for Plexiform Neurofibromas in Subjects With Neurofibromatosis Type 1 in Children and Adults
Phase: PHASE2
Conditions: NF1, Neurofibromatosis, Plexiform Neurofibromas
Sponsor: University of Alabama at Birmingham

 
 
 
 
 
 
Cover Page  
NF PROTOCOL 105 
A Phase II Study of Cabozantinib (XL184) for Plexiform Neurofibromas in 
Subjects with Neurofibromatosis Type 1 in Children and Adults 
NCT: 02101736 
 
Document Dated: May 1, 2019   
 
 
 
 
 
 
 
 
 
This page submitted: 2/3/2023  

NF Protocol #105  Version 2.1 
05/01/2019 
 
 
 
 
 
 
Neurofibromatosis (NF) Consortium 
 
NF PROTOCOL 105 
A Phase II Study of Cabozantinib (XL184) for Plexiform Neurofibromas 
in Subjects with Neurofibromatosis Type 1 in Children and Adults 
 
 
 
Sponsored by: 
 
Department of Defense 
USAMRMC 
And the 
Office of the Congressionally Directed Medical Research Programs (CDMRP)  
 
 
IND # 118308 
 
Protocol Chairs 
Michael Fisher, MD, Chair 
Jaishri Blakeley, MD, Co-Chair 
Amy Armstrong, MD, Co-Chair 
 
Medical Monitor 
Alyssa Reddy, MD

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Protocol Roster 
 
Study Chair 
Michael Fisher, MD 
Children’s Hospital of Philadelphia 
3501 Civic Center Boulevard 
Philadelphia, PA 19096 
Phone:  215-590-2800 
fisherm@email.chop.edu 
 
Study Co-Chairs 
Jaishri Blakely, MD 
Johns Hopkins University 
1550 Orleans Street Suite 1M16 
Baltimore, Maryland 21231 
Phone:  410-955-8837 
Fax:  410-614-9335 
Jblakel3@jhmi.edu 
 
Amy Armstrong, MD 
Riley Hospital for Children 
705 Riley Hospital Dr. 
RI 4340 
Indianapolis, IN  46202 
Phone:  317-948-8568 
Fax:  317-944-3107 
 amyearms@iu.edu 
 
Study Committee 
Kent Robertson, MD, PhD 
705 Riley Hospital Dr. 
RI 4340 
Indianapolis, IN  46220 
Phone:  417-944-8784 
krobert@iu.edu 
 
Brigitte Widemann, MD 
National Institutes of Health – NCI  
10 Center Drive  
Building 10-CRC: Room 1-5750 MSC 
Bethesda, MD  20892 
Phone: 240-760-6203 
Widemanb@mail.nih.gov 
 
Bruce Korf, MD, PhD 
University of Alabama at Birmingham 
1720 2nd Avenue South - 230 KAUL 
Birmingham, Alabama  35294-0024 
Phone:  205-934-9411 
Fax: 205-934-9488 
bkorf@uabmc.edu 
Medical Monitor 
Alyssa Reddy, MD 
University of California, San Francisco 
550 16th Street 
UC Box 0137 
San Francisco, CA 94758 
Phone: 415-353-2657 
Alyssa.Reddy@ucsf.edu 
 
Study Statistician 
Gary Cutter, PhD 
Department of Biostatistics 
University of Alabama at Birmingham 
1667 University Blvd - Ryals 410 
Birmingham AL  35243 
Phone:  205-975-5048 
Fax:  295-975-2531 
cutterg@uab.edu 
 
Study Statistician/NFCTC Co-PI (Data)  
Lloyd Edwards, PhD 
Department of Biostatistics 
U. of Alabama at Birmingham 
1665 Univ Blvd - Ryals 327D 
Birmingham AL  35243 
205-975-0687 Phone 
ljedward@uab.edu 
 
Clinical Nurse Manager 
Lynn Merritt, RN 
U. of Alabama at Birmingham 
1530 3rd Avenue South – Kaul 230 
Birmingham, AL  35294-0024 
Phone 205-934-5376 
jlynnrn@uab.edu 
 
Program Director 
Karen A. Cole-Plourde, BS 
University of Alabama at Birmingham 
1720 2nd Avenue South – 230 KAUL 
Birmingham, AL 35294-0025 
Phone:  205-934-5150 
Fax : 205-975-3543 
kcole@uab.edu 
 
 
 
 
 

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Central Biomarkers 
Cytokine analysis 
Khadijeh Bijangi-Vishehsaraei, MS, PhD 
Children’s Clinical Research     
Center/Translational Research and    
Integrated Biology, Indiana University 
705 Riley Hospital Drive, Room 2641 
Indianapolis, Indiana 46202 
Phone: 317-278-3050 
khbijang@iupui.edu 
   
Endothelial Progenitor Cells 
Karen Pollok, PhD 
Angio BioCore, Indiana University 
Contact: Emily Sims, Core Manager                   
980 W. Walnut St., R3-343 
Indianapolis, IN 46202 
Phone:  317-278-7232 
ecwillar@iupui.edu 
 
Central Imaging 
Eva Dombi, MD 
National Cancer Institute 
10 Center Drive 
Bldg 10-CRC, Rm 1-5750 
Bethesda, MD 20892 
Phone:  240-858-3852 
Fax:  301-402-1734 
dombie@mail.nih.gov 
 
Central Quality of Life 
Pam Wolters, PhD 
Pediatric Oncology Branch 
Bethesda, MD  20892-8200 
Phone:  301-496-0562 
Fax:  301-402-1734 
woltersp@mail.nih.gov 
 
 
 
 
 
 
Research Compliance Manager 
Juliette Southworth, BS, CCRP 
The University of Alabama at Birmingham – 
Kaul 230 
Birmingham, AL 35294-0024 
205-975-4075 Phone  
jsouthworth@uab.edu 
 
Department of Defense 
Kimberly Boelte Pope, PhD 
Science Officer (General Dynamics IT) 
Congressionally Directed Medical Research 
Programs 
1053 Patchel Street 
Frederick, MD 21702 
Phone:  301-619-4006 
Fax:  301-619-7796 
kimberly.b.pope2.ctr@mail.mil  
 
 
 

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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 
 
James Tonsgard, MD 
University of Chicago 
5841 South Maryland Avenue, MC 3055 
Chicago, IL  60637 
Phone:  773-702-6488 
tonsgard@midway.uchicago.edu 
Michael Fisher, MD 
Children’s Hospital of Philadelphia 
3501 Civic Center Boulevard 
Philadelphia, PA 19096 
Phone:  215-590-2800 
fisherm@email.chop.edu 
 
David Viskochil, MD, PhD 
University of Utah 
50 North Medical Drive – 2C412 SOM 
Salt Lake City, UT  84132 
Phone:  801-581-8943 
dave.viskochil@hsc.utah.edu 
Roger Packer, MD 
Children’s National Medical Center 
111 Michigan Avenue, NW 
Washington, DC  20010 
Phone:  202-884-2120 
rpacker@cnmc.org 
 
David Gutmann, MD, PhD 
Washington University School of Medicine 
660 South Euclid Avenue – Box 811 
St. Louis, MO  63110 
Phone: 314-362-7379  
gutmannd@neuro.wustl.edu 
Wade Clapp, MD 
Indiana University  
1044 West Walnut Street  
Cancer Center, Room 402A  
Indianapolis, IN  46202 
Phone: 317-278-9290 
dclapp@iu.edu 
Jeffrey Allen, MD 
New York Univ. Pediatrics 
160 E. 32nd Street – 2nd Floor 
Hassenfeld Children’s Center 
New York, NY 10016 
Phone: 212-263-9907 
Jeffrey.Allen@nyumc.org  
 
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 
Nicole Ullrich, MD, PhD 
Children’s Hospital Boston – Dept. of 
Neurology 
300 Longwood Avenue – Fegan 11 
Boston, MA  02115 
Phone: 617-355-2066 
Nicole.Ullrich@childrens.harvard.edu 
 
Elizabeth Schorry, MD  
Cincinnati Children’s Hospital Medical 
Center 
3333 Burnet Avenue - ML 4006 
Cincinnati, OH  45229 
Phone:  513-636-4760 
elizabeth.schorry@cchmc.org 
Brigitte Widemann, MD 
National Institutes of Health – NCI  
10 Center Drive; Building 10-CRC: Room 1-
5750 MSC 
Bethesda, MD  20892 
Phone: 301-496-7387 
widemanb@mail.nih.gov  

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Laura Klesse, MD, PhD 
Childrens Medical Center of Dallas 
University of Texas Southwestern Medical 
Center 
5323 Harry Hines Blvd. 
Dallas, Texas 75390-9063 
Phone:  214-456-3727 
Fax:  214-648-3122 
 
 
 
 
 
 
 
Affiliate sites  
Massachusetts General Hospital (Ullrich; Plotkin) 
Dana Farber Cancer Institute (Ullrich; Kieran) 
UCLA (Rosser; Silva) 
Johns Hopkins (Packer; Blakeley) 
Ohio State University (Schorry) 
Lurie Children's Hospital of Chicago (Tonsgard; Listernick and Goldman) 
 
 

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Roles and Responsibility of Study Personnel: 
 
Michael Fisher, MD:  Study PI, Protocol Chair.  Steering Committee Chair of NF Consortium 
Jaishri Blakeley, MD:  Protocol Co-Chair 
Amy Armstrong, MD:  Protocol Co-Chair 
 
Kent Robertson, MD:  Study Committee 
Brigitte Widemann, MD:  Study Committee  
Bruce Korf, MD, PhD:  NF Consortium PI, Study Committee, IND Holder 
Gary Cutter PhD: Study Statistician.  Biostatistician & Deputy Director of NF Operations Center 
Lloyd Edwards, PhD: Biostatistician & Co-PI NF Operations Center 
Alyssa Reddy, MD Medical Monitor 
Eva Dombi, MD: Volumetric MRI analysis of plexiform neurofibromas on protocol 
Pam Wolters, PhD: Quality of life and pain surveys 
Khadijeh Bijangi-Vishehsaraei, MS, PhD: Cytokine Biomarkers  
Karen Pollok, PhD: Endothelial Progenitor Cell Biomarkers 
Lynn Merritt, RN, : Clinical Coordinator – NF Operations Center 
Karen Cole-Plourde: Program Director – NF Operations Center 
Juliette Southworth, BS, CCRP: Research Compliance Manager – NF Operations Center 

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TABLE OF CONTENTS 
 
PAGE 
ABSTRACT/SCHEMA ............................................................................................................................................... 9 
EXPERIMENTAL DESIGN SCHEMA .................................................................................................................. 12 
1.0 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) ................................................................................ 14 
2.0 
BACKGROUND AND RATIONALE ........................................................................................................ 14 
2.1  
CABOZANTINIB TABLETS ........................................................................................................................... 22 
2.2  
CABOZANTINIB NONCLINICAL TOXICOLOGY .......................................................................................... 23 
2.3  
CLINICAL EXPERIENCE ............................................................................................................................. 24 
3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES .............................................................. 31 
3.1 
INFORMED CONSENT/ASSENT ................................................................................................................... 31 
3.2 
SCREENING PROCEDURES ......................................................................................................................... 32 
3.3 
STUDY ENROLLMENT ................................................................................................................................ 32 
4.0 
SUBJECT ELIGIBILITY ............................................................................................................................ 32 
4.1 
INCLUSION CRITERIA FOR ALL SUBJECTS: ............................................................................................... 32 
4.2  
EXCLUSION CRITERIA ............................................................................................................................... 35 
5.0 
REQUIRED DATA ...................................................................................................................................... 38 
5.1 
TESTS AND OBSERVATIONS ....................................................................................................................... 40 
5.2 
RECORDS TO BE KEPT................................................................................................................................ 40 
5.3 
ROLE OF DATA MANAGEMENT ................................................................................................................. 40 
6.0 
TREATMENT PROGRAM ........................................................................................................................ 41 
6.1 
TREATMENT OVERVIEW ........................................................................................................................... 41 
6.2   
RATIONALE FOR CABOZANTINIB DOSE SELECTION ................................................................................. 41 
6.3 
ADMINISTRATION, DOSE, SCHEDULE AND ROUTE ................................................................................... 42 
6.4  
CRITERIA FOR STARTING SUBSEQUENT CYCLES ...................................................................................... 44 
6.5  
DOSE ESCALATION SCHEMA ..................................................................................................................... 44 
6.6  
AGENT INFORMATION ............................................................................................................................... 45 
7.0  MODIFICATIONS FOR ADVERSE EVENTS .............................................................................................. 46 
7.1 
GENERAL GUIDELINES FOR TREATMENT DELAY, DOSE REDUCTION, OR STUDY DRUG ....................... 46 
DISCONTINUATION FOR TOXICITY ........................................................................................................................ 46 
7.2   
DEFINITION OF DOSE-LIMITING TOXICITY (DLT) .................................................................................. 46 
7.3   
DOSE MODIFICATIONS FOR ADVERSE EVENTS ........................................................................................ 47 
8.0   
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY ..................................................... 52 
9.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED .................................................... 54 
9.1 
REQUIRED CLINICAL, LABORATORY AND DISEASE EVALUATION .......................................................... 54 
9.2 
HISTORY AND PHYSICAL EXAMINATION AND VITAL SIGNS ...................................................................... 54 
9.3 
PHONE CALL.............................................................................................................................................. 54 
9.4 
LABORATORY TESTING ............................................................................................................................. 54 
9.5 
EKG ........................................................................................................................................................... 55 
9.6 
MRI FOR VOLUMETRIC ANALYSIS OF PLEXIFORM NEUROFIBROMA ....................................................... 55 
9.7 
QUALITY OF LIFE AND PAIN EVALUATIONS (REQUIRED) ........................................................................ 55 
9.8 
BIOMARKER STUDIES ................................................................................................................................ 58 
9.9 
BIOLOGICAL SPECIMENS FOR BANKING (APPENDIX XV) ........................................................................ 58 
10.0 
ADVERSE REPORTING REQUIREMENTS .......................................................................................... 59 
10.1 
DEFINITIONS .............................................................................................................................................. 59 

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10.2 
GRADING OF ADVERSE EVENTS USING COMMON TERMINOLOGY CRITERIA (CTCAE) ....................... 60 
10.3 
ATTRIBUTION: DEFINITIONS OF RELATIONSHIP TO STUDY MEDICATION ARE AS FOLLOWS: ................. 60 
10.4 
REPORTING PROCEDURES FOR ALL ADVERSE EVENTS ........................................................................... 61 
10.5 
EXPEDITED REPORTING GUIDELINES ...................................................................................................... 61 
10.6 
REPORTING OF PROTOCOL VIOLATIONS/DEVIATIONS AND UNANTICIPATED PROBLEMS ..................... 62 
11.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA ...... 63 
11.1 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY ........................................................................... 63 
11.2  
OFF STUDY CRITERIA ............................................................................................................................... 63 
12.0 
STATISTICAL AND ETHICAL CONSIDERATIONS ........................................................................... 64 
12.1 
SUBJECT ACCRUAL.................................................................................................................................... 64 
12.2 
STATISTICS AND FEASIBILITY ................................................................................................................... 64 
12.3 
STATISTICAL ANALYSIS PLAN .................................................................................................................. 66 
12.4 
DEFINITIONS OF EVALUABLE .................................................................................................................... 68 
13.0 
RESPONSE CRITERIA .............................................................................................................................. 68 
14.0 
HUMAN SUBJECTS PROTECTION & DATA SAFETY MONITORING PLAN .............................. 76 
15.0 
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS ........................................... 78 
16.0 
REFERENCES ............................................................................................................................................. 79 
APPENDIX I:  SCHEDULE OF EVALUATIONS ................................................................................................ 80 
APPENDIX II: PERFORMANCE STATUS SCALES/SCORES ......................................................................... 82 
APPENDIX III: PARTICIPANT DOSE DIARY ................................................................................................... 83 
APPENDIX IV:  PROTOCOL FOR REQUIRED PRE-STUDY AND ON-STUDY MRI STUDIES ............... 84 
APPENDIX V:  BIOMARKER STUDIES .............................................................................................................. 87 
APPENDIX VI:  PHARMACOKINETIC STUDIES ............................................................................................. 89 
APPENDIX VII:  CONSORTIUM QOL AND PAIN MEASURES ..................................................................... 97 
APPENDIX VIII: BLOOD PRESSURE NORMS ................................................................................................ 139 
APPENDIX IX: MRI ELIGIBILITY FORM ....................................................................................................... 142 
APPENDIX X: SUGGESTED PROPHYLAXIS AND TREATMENT FOR PALMAR-PLANTAR 
ERYTHODYSESTHESIA SYNDROME (PPE) ................................................................................................... 143 
APPENDIX XI: CABOZANTINIB DOSING NOMOGRAM ............................................................................. 144 
APPENDIX XII: PLEXIFORM NEUROFIBROMA SYMPTOM CHECKLIST ............................................ 146 
APPENDIX XIII: PN LOCATION AND ASSOCIATED MORBIDITIES ....................................................... 149 
APPENDIX XIV:  PLEXIFORM NEUROFIBROMA CLINICIAN MORBIDITY ASSESSMENT ............. 151 
APPENDIX XV:  BIOLOGICAL SPECIMEN FOR BANKING  – COLLECTION AND SHIPPING.......... 153 
 
 

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ABSTRACT/SCHEMA 
 
Background 
 
Neurofibromatosis type 1 (NF1) is one of the most common inherited disorders in the general 
population, affecting approximately 1 in 3500 people with an estimated 100,000 individuals 
afflicted in the United States alone.  NF1 is an autosomal dominant disorder caused by mutations in 
the NF1 tumor suppressor gene resulting in a deficiency in a protein called neurofibromin.  
Deficiency in neurofibromin allows activation of the Ras oncoprotein with resultant cutaneous and 
plexiform neurofibromas (a complex of Schwann cells, fibroblasts, endothelial cells, and mast 
cells), which may be disfiguring, painful and life threatening.  These tumors are refractory to most 
therapeutic approaches including chemotherapy, radiation, and surgery.  These tumors can result in 
significant morbidity if located near vital structures, including nerves, blood vessels, and the 
airway.  Thus, in this group of patients, the development of novel treatment interventions is needed. 
Receptor tyrosine kinase inhibitors are an emerging class of drugs in the treatment of malignancies.  
C-kit, in particular, is a tyrosine kinase that has been shown to be essential in the development of 
plexiform neurofibromas.  Preclinical investigation has elucidated the role of c-kit in the activation 
of mast cells, one of the components of plexiform neurofibromas and a limited number of clinical 
trials targeting c-kit are underway.  Targeting of multiple RTKs may increase efficacy either by 
synergy or blocking tumor escape pathways.  Subsequent screening of clinically relevant c-kit and 
multiple RTK inhibitors in an in vivo model of NF1 plexiform neurofibroma has identified 
cabozantinib (XL184) as an excellent candidate for clinical testing.  Cabozantinib is a small-
molecule RTK inhibitor that blocks phosphorylation of c-Met, RET, c-kit and VEGFR2 at 
nanomolar or subnanomolar concentrations.  C-MET and VEGFR2 are strong regulators of tumor 
angiogenesis.  Plexiform neurofibromas are highly vascular tumors and it is postulated that this 
may be a key mechanism in tumor development and growth.  In small animal NF1 models, 
cabozantinib shows strong biological activity and results in decreased tumor size, number and 
biologic activity.  Preliminary data shows that this molecule may be even more effective than 
agents currently undergoing clinical evaluation.  In preclinical trials, cabozantinib reduced mast 
cell concentration by greater than 50%.  Transgenic mice with plexiform neurofibromas treated 
with cabozantinib had a 70% reduction in tumor numbers as compared to vehicle controls and 50% 
reduction in tumor size for residual tumors.  Using FDG-PET, tumors in treated mice had 
significant reduction in metabolic activity.  Based on these striking results, we propose 
cabozantinib for human clinical trials for plexiform neurofibromas. 
 
 

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Primary Objectives 
 
1. Primary Aim:  To estimate the objective response rate (ORR) as defined by 20% volumetric 
MRI response of the target lesion to cabozantinib at 12 months in children and adults with 
NF1 plexiform neurofibromas by volumetric MRI imaging.  
2. Secondary Aims: 
1. To assess the tolerability and toxicity of cabozantinib in subjects with NF1. 
3. Exploratory Aims: 
1. To estimate the ORR of up to 2 non-target plexiform neurofibromas to cabozantinib by 
MRI. 
2. To assess quality of life and pain in subjects with NF1 and plexiform neurofibromas on 
cabozantinib  
3. To assess the  PedsQL NF1 QOL Module, a disease specific QOL scale, and the pain 
scales for use in this patient population 
4. To assess activity of cabozantinib on mast cell activity by FACS 
5. To describe changes by flow cytometry in peripheral blood monocyte counts, 
circulating endothelial cells, and plasma angiogenic factors during treatment with 
cabozantinib (see laboratory correlates section 13.0 C) 
6. To describe the baseline and change in circulating cytokine factors related to 
proliferating cells (see laboratory correlates section 13.0 C) 
7. To characterize the pharmacokinetic profile of cabozantinib in this population  
8. To determine whether patients who respond (≥20% objective radiographic response of 
target lesion by 12 cycles) to cabozantinib will maintain that response for 1 year off 
therapy 
9. To compare the volumetric assessment of plexiform neurofibroma response to therapy 
performed by two independent analysts using different volumetric analysis methods.  
 
 
 
Eligibility 
1.  Subject ≥ 3 years of age who meet clinical diagnostic criteria of neurofibromatosis type 
1 (NF1) or have known pathogenetic NF1 mutation AND 
2. Subjects must have plexiform neurofibroma(s) with a target lesion that has  evidence of 
progression by serial imaging OR known significant morbidity, such as (but not limited 
to) head and neck lesions that could compromise the airway or great vessels, brachial or 
lumbar plexus lesions that could cause nerve compression and loss of function, lesions 
that could result in major deformity (e.g., orbital lesions) or are significantly 
disfiguring, lesions of the extremity that cause limb hypertrophy or loss of function, and 
painful lesions.  Subjects with paraspinal plexiform neurofibromas will be eligible for 
this trial. Histologic confirmation of tumor is not necessary in the presence of consistent 
clinical and radiographic findings, but should be considered if malignant degeneration 
of a plexiform neurofibroma is clinically suspected. 
 
 
 
 

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Design 
• Cabozantinib will be administered orally daily on a continuous dosing schedule (28 days = 1 
treatment cycle).  
• Disease status will be evaluated using volumetric MRI analysis at regular intervals.  
• Pain reduction and quality of life outcomes will also be assessed. 
• Toxicity of chronic cabozantinib administration will be evaluated using physical and 
laboratory evaluations and adverse event reporting by patients. 

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EXPERIMENTAL DESIGN SCHEMA 
  
 
 
 
 
 
 
 
 
 
Un  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 3-12 (60 
mg) 
Cycle 1-2 (40 mg 
starting dose) 
De-
escalation 
of dose 
Dose 
escalation 
Response 
evaluation at 
4,8,12, (18, 24) 
months 
Study Entry 
See dosing schema for rules 
for de-escalation of dose 
secondary to toxicity 
Tumor response will be done by MRI volumetrics at 4, 8, and 12 months 
(prior to cycle 5, 9 and end of study). Subjects may remain on drug for 
up to 12 additional cycles and will have MRI done subsequently at 6 
months intervals.  Subjects who do not achieve at least 15% reduction in 
volume of the target tumor at the 8 month interval will be considered 
treatment failure and taken off study. 
Unacceptable Toxicity  
Off Study 
Unacceptable toxicity despite 
dose de-escalation or 
progressive disease 
Study Enrollment: Cohort A (age ≥16 years) 

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Study Enrollment: Cohort B (age 3-15 years) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 1-2 
(30 mg/m2) 
Response evaluation 
at 4,8,12, (18, 24) 
months 
Cycle 3-12 
(40 mg/m2) 
Dose 
reduction  
(23 mg/m2) 
Off Study 
Tumor response will be done by MRI volumetrics at 4, 8, and 12 months 
(prior to cycle 5, 9 and end of study). Subjects may remain on drug for 
up to 12 additional cycles and will have MRI done subsequently at 6 
months intervals.   Subjects in Cohort B who do not have a partial 
response (>20% reduction in tumor volume) by the end of 12 cycles will 
be taken off study. 
Unacceptable toxicity 
Unacceptable toxicity 
despite dose 
de-escalation or 
progressive disease 
Study Entry 

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1.0  
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
 
1.1 
Primary Aim:  To estimate the objective response rate (ORR) as defined by 20% volumetric 
MRI response of the target lesion to cabozantinib at 12 months in children and adults with 
NF1 plexiform neurofibromas by volumetric MRI imaging.  
 
1.2 
Secondary Aim: 
1.2.1 To assess the tolerability and toxicity of cabozantinib in subjects with NF1. 
 
1.3 
Exploratory Aims: 
1.3.1 To estimate the objective response rate of up to 2 non-target plexiform 
neurofibromas to cabozantinib by MRI. 
1.3.2 To assess quality of life and pain in subjects with NF1 and plexiform neurofibromas 
on cabozantinib  
1.3.3 To assess the PedsQL NF1 QOL Module, a disease specific QOL scale, and the pain 
scales for use in this patient population 
1.3.4 To assess activity of cabozantinib on mast cell activity by FACS 
1.3.5 To describe changes by flow cytometry in peripheral blood monocyte counts, 
circulating endothelial cells, and plasma angiogenic factors during treatment with 
cabozantinib. (see laboratory correlates section 13.0 C) 
1.3.6 To describe the baseline and change in circulating cytokine factors related to 
proliferating cells (see laboratory correlates section 13.0 C) 
1.3.7 To characterize the pharmacokinetic profile of cabozantinib in this population. 
1.3.8 To determine whether patients who respond (≥20% objective radiographic response 
of target lesion by 12 cycles) to cabozantinib will maintain that response for 1 year 
off therapy 
1.3.9 To compare the volumetric assessment of plexiform neurofibroma response to 
therapy performed by two independent analysts using different volumetric analysis 
methods. 
 
 
 
2.0 
BACKGROUND AND RATIONALE 
Introduction 
Cabozantinib (Exelixis) is a new chemical entity that inhibits multiple RTKs with growth-
promoting and angiogenic properties.  The primary targets of cabozantinib are MET, VEGFR2, 
RET, and c-KIT.  Cabozantinib is an orally bioavailable compound and marked tumor regression 
was observed in models tested.  In addition, clinical activity with the use of cabozantinib in a 
variety of tumor settings has been reported.  Receptor tyrosine kinases have been implicated in 
plexiform neurofibroma formation, particularly in the inflammatory response of mast cells, which 
appear essential in tumor progression.  Preclinical evaluation of cabozantinib has shown marked 
tumor regression in several tumor models, including Nf1 animal models of plexiform neurofibroma 
(see below).  In addition, cabozantinib has been tested in several Phase 1 and 2 clinical trials and 
has been FDA approved for medullary thyroid carcinoma and renal cell carcinoma.  Cabozantinib 
has been selected for further human clinical testing for NF1 plexiform neurofibromas because of its 

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activity in in vivo drug screens, including decrease in tumor size, number and metabolic activity by 
PET imaging.  This study will evaluate cabozantinib in a Phase 2 efficacy trial in children and 
adults with clinically significant NF1 plexiform neurofibromas.  To maximize safety and 
tolerability, there will intra-patient dose escalation starting at a predicted highly tolerable dose with 
a planned dose escalation to the target dose. 
 
Rationale for Development 
Neurofibromatosis type 1 (NF1), is a common human genetic disorder that affects approximately 
100,000 people in the United States alone.  Individuals afflicted with NF1 develop a wide range of 
malignant and non-malignant manifestations. Plexiform neurofibromas are benign tumors of the 
nerve sheath that occur in approximately 40% of patients with NF1.  They are a significant cause of 
morbidity in NF1 by causing pain, disfigurement or impairing function.  They are life threatening 
when they compress vital structures such as the airway or great vessels, or via transformation into 
malignant peripheral nerve sheath tumors.  Based on a series of novel observations made over the 
past decade, there is an increasing understanding of the requisite NF1 tumor microenvironment 
required for plexiform neurofibroma formation.  Nf1 heterozygous mast cell infiltration of pre-
neoplastic peripheral nerves in association with Nf1-deficient Schwann cells has been shown to be 
critical for tumor development.  Further, on the basis that c-kit receptor activation controls the 
release of mast cells from the bone marrow; mast cells are implicated as active participants in 
tumor formation. [1]  Based on these data, clinically available tyrosine kinase (including c-kit) 
inhibitors were tested in animal models of neurofibromas to evaluate efficacy on tumor as well as 
mast cell activation.  Of this group of compounds, Cabozantanib has emerged as a drug with 
significant impact on tumor volume, tumor apoptosis, and mast cell infiltration and as such has 
been selected for further clinical development. 
 
C-kit dependent microenvironment in Nf1-dependent tumors 
The notion of targeted therapy against the tyrosine kinase c-KIT for the specific treatment of Nf1-
dependent tumors stems from careful analysis of models which recapitulate both genetic, as well as 
the tumor microenvironment, in which these tumors develop.[1] 
 
a. In a series of experiments, Yang et al. showed that Nf1 loss of heterozygosity in the 
Schwann cell lineage is necessary but not sufficient to induce plexiform 
neurofibromas.[1]  In a murine model, animals with germline knockout allele of Nf1 and 
a floxed allele susceptible to recombination in the Schwann cell lineage (approximately 
10%) Krox20;Nf1flox/flox uniformly develop plexiform neurofibromas;  however, animals 
with wild type bone marrow (WT) with Krox20;Nf1flox/flox do not develop 
neurofibromas.  Animals with heterozygous Nf1 +/- bone marrow also do not develop the 
plexiform neurofibroma phenotype; however, animals with the Schwann cell lineage 
(Krox20;Nf1flox/flox) that are then subsequently transplanted with the bone marrow of 
animals with Nf1 +/- bone marrow now develop plexiform neurofibromas.  In a series of 
converse experiments, Yang was able to definitively show that this combination is not 
just necessary, but is required to form plexiform neurofibromas in mice. 
 
b. Analyses of the tumors from this model demonstrate the presence of the classic 
histological features of human plexiform neurofibromas including disruption of normal 
architecture; wavy Schwann cells and infiltrating cells with hyperchromatic nuclei, 

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excess collagen deposition, angiogenesis, classic ultrastructural abnormalities, and 
Schwann cell-specific markers.   
 
c. To further validate the model, mast cells were found to infiltrate the peripheral nerves 
preceding tumor appearance as evidenced by mast cell specific stains.  A small 
population of macrophages and rare B lymphocyte and T-lymphocyte populations were 
also observed.  Mice (Krox20;Nf1flox/flox) transplanted with wild type bone marrow 
showed no elevated mast cell infiltration. 
 
d. The c-Kit receptor tyrosine kinase (RTK) controls many aspects of mast cell 
development and function. [2]  In addition, c-kit activity governs migration, 
proliferation and survival of Nf1+/- bone marrow-derived mast cells.[3]  Using two 
different strains of mice with point mutations in the c-kit receptor resulting in a 
reduction in receptor tyrosine kinase activity, the concept of c-kit mediated tumor 
development was tested.  The two strains of c-kit mutated mice deficient in mast cell 
mobilization were intercrossed with Nf1+/- mice.  These mice then served as bone 
marrow donors to the Nf1 LOH Schwann cell lineage mice (Krox20;Nf1flox/flox).  These 
mice had significantly reduced morbidity and mortality due to progression of plexiform 
neurofibromas compared to mice that were transplanted without mutations in the c-kit 
receptor that were able to mobilize their mast cells demonstrating the importance of c-
kit signaling in plexiform development. 
 
e. Utilizing a cohort of 8-9-month-old Krox20; Nf1flox/- mice with FDG-PET positive 
tumors, imatinib mesylate, a potent inhibitor of c-kit, PDGFR, and c-abl, was 
administered orally at 200 mg/kg/day and compared to placebo control.  Animals 
treated with imatinib showed striking decrease in FDG-PET activity.  Also, histologic 
sections of plexiform neurofibromas that develop in the dorsal root ganglia were taken 
post-mortem showing a clear decrease in dorsal root ganglia plexiform volume in the 
imatinib mesylate treated group as compared to controls.  In the proximal surrounding 
nerves, mice treated with PBS placebo showed a distinct disruption of the normal nerve 
architecture and increase in cellularity compared to imatinib mesylate treated mice.   
 
Together these data makes a strong argument for the further clinical development of 
pharmacologic c-kit targeting for the treatment of Nf1 dependent plexiform neurofibromas. 
 
RTK inhibition of Nf1-dependent tumors by cabozantinib 
 
a. 
Activity of cabozantinib as inhibitor of multiple receptor tyrosine kinases 
(RTKs).   
Data from pharmacodynamic experiments show that, in vivo, cabozantinib inhibits 
several key RTKs that promote tumor cell proliferation and/or angiogenesis 
including c-Kit, MET, VEGFR2, and RET.  There is good correlation between 
increases in plasma drug concentrations and increased inhibition of receptor 
phosphorylation at the doses tested.  Results from dose-response experiments in 
mice indicated that the ED50 of targets is achieved at well-tolerated doses of 
cabozantinib at plasma exposure comparable to exposure observed in clinical trials.  
Cabozantinib produces prolonged inhibition of receptor phosphorylation; such as 

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sustained inhibition of MET and VEGFR2 for 10 hours after administration of a 
single dose of cabozantinib.  
 
b. 
Preclinical drug screen 
Compounds were selected for preclinical in vivo testing that were either undergoing 
clinical trials and/or commercially available.  All of the selected compounds were 
tyrosine kinase inhibitors.  These compounds were tested in 12 week in vivo studies 
in murine Nf1 plexiform neurofibroma models to screen for candidates for further 
clinical testing.  The two compounds shown here were cabozantinib (notated 
XL184) and XL647.  Cabozantinib (inhibitor of c-kit, met, RET and VEGFR2), met 
all established “success” guidelines for moving forward to human trials.  XL647 
(inhibits VEGFR2, EGFR, and Her-2) achieved some but not all success criteria and 
has not been selected to move forward. 
 
i. Criteria for success:  The criteria to move a drug forward included reduction in 
metabolic activity of a cohort by at least 30%, reduction of mast cell cellularity 
by at least 50%, and decrease in the absolute number of tumors by 25% 
 
ii. Drug toxicity:  All compounds selected are currently in clinical trials for other 
purposes and thus have had extensive preclinical safety and toxicity testing.  
None of the drugs tested were found to induce weight loss greater than 15%, nor 
did any drug cause mortality or other observable morbidity. 
 
c. 
Evaluation of Histologic criteria 
Figure 1A shows the results for biological effect of compounds on the reduction in 
mast cell cellularity of tumors as compared to tumors from mice that received 
placebo treatment.  The defined threshold for success is 50% (as noted by the red 
line).  XL184 (cabozantinib) reduced mast cell cellularity by greater than 50%. 
  
Apoptotic cells in the tumor were evaluated using TUNEL assays (Figure 1B).  
Each symbol shown indicates the mean number of apoptotic cells scored from 

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individual tumors.  XL184 (cabozantinib) treatment induced a consistent 2-fold 
increase in the apoptotic cells over the vehicle control group.  As a marker of 
proliferation, the tissue sections were stained with Ki-67, a tumor antigen that is 
found in growing dividing cells but is absent in the resting phase of cell growth.  
Both XL184 and XL647 resulted in a reduction in the number of proliferating cells 
that were scored per high power field (*P<0.01). 
 
 
d. 
Evaluation of metabolic activity   
 Small animal PET imaging studies was performed and examined changes in FDG 
uptake as a biomarker of response to experimental therapy in Krox20; Nf1flox/- mice.  
Imaging studies were performed prior to initiation of therapy and prior to sacrifice.  
All image data sets were transformed to standardized uptake value units (SUVs) and 
all voxel values above a threshold of SUV=1.0 within a 3-D volume of interest 
along the spine was integrated to form an FDG biomarker index.  The bar graph in 
Figure 2 demonstrates the observed results for a representative group of 
experimental drugs tested.  As expected, the placebo groups had an increase in the 
FDG uptake over the 12-week period. Consistent with the striking cellular changes 
observed from histologic specimens, following 12-weeks treatment, mice that 
received XL184 had a significant reduction in SUV uptake. 
 
 
Figure 1 A. 
 
Figure 1B 
 
 
Figure 1C. 
 
 
Figure 1. Histologic analysis. (A) Summary data showing the absolute number in mast cells in tumors of 
mice treated with XL184 and XL647 compared to placebo treated mice.  Red line indicates the designated 
more than 50% decrease in mast cell numbers. *P<0.01 for vehicle control group and both experimental 
groups. (B) Summary data of TUNEL positive cells observed in tumors of mice treated with XL184 and 
XL647. *P<0.01 for vehicle control group and XL184 group. (C) Ki67+ cells per high power field. *P<0.01 
compared to vehicle control groups. 

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Figure 2.  SUV integral.  The SUV integral is a measure of the elevated retention of FDG in a 3D volume of 
interest around the spinal cord.  The blue bar represents the pretreatment level, the red bar represent the 12 
weeks after the treatment.   
 
e. Tumor number was decreased following long-term treatment with XL 184 
(cabozantinib)  
To evaluate whether the histologic changes and the metabolic reduction in the XL184 
treated mice correlated with the tumor number changes, we measured tumor numbers and 
tumor size. As shown in Figure 3A, mice treated with XL184 had a 75% reduction in the 
average number of tumors as compared to that of vehicle controls (* p< 0.01). Of the 
residual tumors, XL184 treatment reduced the tumor size by greater than 50% compared to 
control group (*P<0.01) (Figure 3C).  Thus this compound meets both go/no go criteria 
established previously.  
 
 
f. Summary 
XL184 had a striking reduction in the number of tumors (>70%) and of the few 
residual tumors that were remaining, a 50% reduction in tumor size was observed.  
Thus this drug meets both established milestone 2 go/no go criteria and should be 
considered for a clinical trial. All correlative histologic and imaging data are 
completely consistent with this striking response.  
 
XL184 has been moved forward and is now in multiple phase 2 clinical trials and 
also in phase 3 clinical trials.  
Figure 3A. 
 
Figure 3B. 
 
Figure 3C. 
 
Figure 3. Measurement of the average tumor 
numbers following the long-term treatment with 
Xl184 or XL647.  (A) Mean number of tumors of 
Krox20; Nf1flox/- mice treated with vehicle vs. XL184. 
*p< 0.01 comparing vehicle to XL184. (B) Mean 
number of tumors of Krox20; Nf1flox/- mice treated 
with vehicle vs. XL647. *p< 0.01 comparing vehicle 
to XL647.  (C) Percent tumor size reduction. Mean 
percent residual tumor size as measured in area 
(mm2) is shown. *P<0.01. The red line indicates the 
50% threshold of tumor size. 

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Imaging and Measurement of Plexiform Neurofibromas 
 
 
 
Tumor response criteria that are used for cancers are based on one-dimensional (1-D) and 
two-dimensional (2-D) tumor measurements (Estey, Hoth et al. 1986; Therasse, Arbuck et al. 
2000). These methods have limited value in the assessment of treatment outcome for 
plexiform neurofibromas, which are frequently large, have a complex (non-spherical) shape, 
and have a slow, erratic growth pattern. In order to reproducibly quantify the size of these 
complex lesions and detect small changes in the size over time, we used MR imaging 
characteristics of plexiform neurofibromas to develop an automated method of lesion 
detection and volume measurement. Short T1-Inversion Recovery (STIR) MR images, on 
which plexiform neurofibromas are bright lesions compared with normal surrounding tissue, 
were used to develop a program for automated image analysis within MEDx (v3.41) software 
(Sensor Systems, Inc. Sterling, VA). Reproducibility and inter-observer variability of this 
automated method were determined by 2 observers who quantified volumes for plexiform 
neurofibromas of the orbit (n=2), face/neck (n=3), abdomen (n=1), and pelvis (n=3) on three 
different days (Solomon, Warren et al. 2004).  For each MR image (Figure 1A), the tumor is 
roughly outlined manually including a rim of low signal intensity normal tissue (Figure 1B). 
The program then performs a histogram analysis of signal intensity pixel by pixel and a 
threshold that distinguishes high signal intensity tumor from normal tissue is defined (Figure 
1C). Tumor contours are then determined using a gradient image, connected component 
analysis and automatic edge following operation (Figure 1D). There is an option for re-
analysis of MR images using an average or selected threshold. Tumor volume is calculated 
by summing the results from all images based on the resulting 2-D contours and slice 
thickness; and a report is generated. 
 
For comparison, the volume of each plexiform neurofibroma was also determined by each 
observer once by manually tracing the tumor borders on each MR image. The results of the 
application of the automated method and the correlation with the manual method are shown 
in the table below. 
 
Automated Volumetric MRI Analysis 
Observer 1 
Observer 2 
Figure 1: Axial MRI of pelvic plexiform neurofibroma. Steps of 
automated volumetric analysis A-D. 
A
B
D
C

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Mean tumor volume (ml)  
Median (range) 
291 
(80.9-1581) 
290 
(75.7-1603) 
Median Inter-day CV (%)  
(range) 
3.6 
(0.7-6.0) 
1.6 
(0.6-5.6) 
Difference in volume between observers (%) 
Median (range) 
6.4 (1.4 – 11.9) 
6.4 (1.4 – 11.9) 
Correlation automated vs. manual method, R 
0.999 
0.999 
 
This automated volumetric MRI analysis is applicable to most plexiform neurofibromas, has 
excellent intra- and inter-observer reproducibility and agrees with volumes determined by 
manual tumor tracing. This method was used in a phase II trial of the farnesyltransferase 
inhibitor tipifarnib, in the phase I and II trials of pirfenidone, in the phase I trial of peg-
interferon alfa-2b, and in the NF Consortium phase 2 trial of Sirolimus for children with NF1 
and plexiform neurofibromas to assess changes in tumor size. Imaging studies on these 
multicenter trials are sent to the NCI, POB, where volumetric MRI analysis is performed. 
Tumor progression on these trials is defined as an increase in plexiform neurofibroma volume 
by ≥ 20%.  
 
This volume increase corresponds to much smaller changes in 1-D, or 2-D measurements as 
outlined in the table below: 
 
Response Criteria 
RECIST 
Diameter, 
2r 
WHO 
Product, (2r)2 
Current NF1 trials 
Volume, 4/3Πr3 
Disease progression (Increase) 
20 
44 
73 
 
12 
25 
40 
6 
13 
20 
 
Shaded areas show current criteria used to define disease progression by RECIST, WHO, 
and the ongoing NF1 trials listed above. 
 
The use of this method of volumetric MRI analysis of PNs in 49 individuals with NF1 who 
were followed at the NIH for ≥ 18 months resulted in the following observations: 1) Time to 
disease progression is a realistic trial endpoint, provided progression is present at trial entry, 
in that progression can be documented within a clinically meaningful time period. The median 
time to progression on phase A (50% of individuals receive placebo, 50% receive drug) of 
the tipifarnib phase II trial is 18 months (range 3 to 36+ months). 2) Plexiform neurofibromas 
appear to grow more rapidly in younger compared to older children (see Figure below), and 
3) while the growth rate of PN is variable among patients, the growth rate within patient 
during the time of observation (median observation period 34 months, range 18-70 months) 
appeared to be constant (Dombi, Solomon et al. 2007). 4) Given the more rapid growth of PN 
in younger children, it appears critical that drug development for NF1 PN focuses on young 
patients.  
 

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Figure 2: Relationship between the slopes for percent change in plexiform neurofibroma (PN) volume and 
percent change in body weight per year (A). Values above the 45 degree line represent ratios of percent change 
in PN volume to percent change in body weight which are greater than 1. Closed symbols represent patients ≤ 
the median age (8.3 years) at study entry, and open symbols patients > 8.3 years.  Percent change in plexiform 
neurofibroma (PN) volume (B) and body weight (C) per year as a function of patient age at baseline. The shaded 
area indicates the 20% change in PN volume required for documentation of disease progression in ongoing 
clinical trials. The line in B represents an exponential fit to the data. 
 
 
2.1  
Cabozantinib tablets 
 
Exelixis internal number: XL184 
Chemical Name:  
Chemical Name: N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N’-(4-
fluorophenyl)cyclopropane-1,1-dicarboxamide, (2S)-hydroxybutanedioate 
 
Cabozantinib tablets are supplied as film coated tablets containing cabozantinib malate equivalent to 20 mg  
and contain microcrystalline cellulose, lactose anhydrous, hydoxypropyl cellulose, croscarmellose sodium, 
colloidal silicon dioxide, magnesium stearate and Opadry® yellow. All tablet strengths are prepared from a 
common blend and are distinguished by shape. The 20 mg tablets are round and the 60 mg tablets are oval. 
 

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Cabozantinib Tablet Components and Composition 
Ingredient  
Function 
% w/w 
Cabozantinib malate (25% drug load as cabozantinib) 
Active Ingredient 
31.7 
Microcrystalline Cellulose (Avicel PH-102) 
Filler 
38.9 
Lactose Anhydrous (60M) 
Filler 
19.4 
Hydroxypropyl Cellulose (EXF) 
Binder 
3.0 
Croscarmellose Sodium (Ac-Di-Sol) 
Disenegrant 
6.0 
Colloidal Silicon Dioxide, 
Glidant 
0.3 
Magnesium Stearate 
Lubricant 
0.75 
Opadry Yellow Film Coating which includes: 
- 
HPMC 2910/Hypromellose 6 cp  
- 
Titanium dioxide  
- 
Triacetin  
- 
Iron Oxide Yellow 
Film Coating 
4.00 
 
 
 
2.2  
Cabozantinib Nonclinical Toxicology 
 
Summary of Toxicology  
The nonclinical toxicity of cabozantinib was characterized in single- and repeat-dose toxicology 
studies in rats and dogs (see the current Investigator Brochure for summary tables); in vitro 
bacterial and mammalian genotoxicity bioassays; an in vivo clastogenic bioassay; reproductive and 
developmental toxicology studies, and cardiovascular, neurobehavioral, and respiratory safety 
pharmacology studies. The experimental designs, findings, and conclusions from these nonclinical 
toxicity studies are discussed in this section. 
 
Single-Dose Toxicology Studies  
Toxicity associated with single oral doses of cabozantinib was characterized in rats and dogs by 
dose-dependent changes in clinical signs, by clinical pathology changes reflective of toxicity to 
liver and hematopoietic tissues, and by histopathologic findings in multiple tissues.  
The NOAELs for the definitive single oral dose toxicity studies of cabozantinib in rats and dogs 
were considered to be < 100 mg/kg and 2000 mg/kg, respectively. The Cmax and AUC0-t values in 
rats dosed at 100 mg/kg are approximately 2-fold and 3-fold higher, respectively, than for dogs 
dosed at 2000 mg/kg; therefore, the higher systemic exposure to cabozantinib in rats correlates with 
the greater toxicity observed in this species at lower administered doses. 
 
Repeated-Dose Toxicology Studies  
Repeated oral administration of cabozantinib, for up to 6 months resulted in dose-dependent 
toxicity in both rats and dogs.  
 
The NOAELs for the subchronic toxicity studies in rats and dogs administered cabozantinib qd for 
14 consecutive days were considered to be 1 mg/kg/day and 10 mg/kg/day, respectively.  
Findings from chronic toxicity studies in rats and dogs following qd oral dosing of cabozantinib for 
180 days (26 weeks) are summarized in the current Investigator Brochure.  In rats, microscopic 
changes were present only in the kidneys of the 1-mg/kg/day dose group of both sexes, evidenced 

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by a slight, reversible increase in severity and/or incidence of chronic progressive nephropathy. 
Based on this, the NOAEL following chronic oral administration of cabozantinib for 180 days was 
considered to be 0.3 mg/kg/day. There was very little evidence of toxicity.  
 
In dogs, the only microscopic findings possibly related to cabozantinib administration (5 mg/kg qd 
× 180) were present in testes (hypospermatogenesis) and ovaries (corpora lutea absence). These 
microscopic findings may reflect a lack of sexual maturation in the young adult animals used in 
this study, rather than a test article-related change. Therefore, the NOAEL for cabozantinib in this 
study was considered to be 5 mg/kg/day. 
 
In a second 6-month toxicity study in dogs a higher cabozantinib dose (30 mg/kg) was tolerated for 
only 10 days due to body weight decreases of up to 11%. Following an 11-day drug holiday, dosing 
was reinitiated at a lower dose of 20 mg/kg for 122 and 172 days in males and females, 
respectively (“30/20 mg/kg/day”). The only cabozantinib -related macroscopic finding, which had 
no microscopic correlate, consisted of mild and/or moderate gray discoloration of the skin or head. 
Microscopic changes associated with cabozantinib administration were observed only in 
reproductive tissues (e.g., moderate to severe bilateral hypospermatogenesis in testes, and lack 
corpora lutea in ovaries), and were correlated with decreased testicular and ovarian weights. 
 
2.3  
Clinical Experience 
Clinical Summary 
As of 28 February 2018, 3017 subjects with cancer treated with cabozantinib in Exelisis sponsored 
single-agent studies has been performed. Clinical data are available from 18 studies of cabozantinib 
including four Phase 1 studies, one actively enrolling Phase 1b study, one Phase 1b/2 study, four 
Phase 2 studies, five Phase 3 study, one ongoing and enrolling Phase 4 study in MTC, one ongoing 
maintenance “roll-over” study, and one expanded access study. 
 
The most frequently observed adverse events (AEs) were diarrhea, fatigue, decreased appetite, 
nausea, Palmar-Plantar Erythrodysesthesia (PPE) syndrome, weight decreased, hypertension, 
vomiting, dysgeusia, and dysphonia.  Some of these events resulted in permanent study drug 
discontinuation, including fatigue, general physical health deterioration, decreased appetite, 
asthenia, , diarrhea, nausea, and vomiting.  The events to monitor of diarrhea, PPES, and 
hypertension include AEs that were reported in high frequency in previous cabozantinib studies 
and have been commonly observed with vascular endothelial growth factor – tyrosine kinase 
inhibitor (VEGFR-TKIs).  Less frequent effects but potentially life-threatening AEs that have been 
reported for subject receiving cabozantinib and other VEGF pathway inhibitors, are GI perforation, 
fistulas, abscesses, hemorrhage (grade 3), arterial thrombotic events, venous and mixed/unspecified 
thrombotic events, wound complications, osteonecrosis, proteinuria, and reversible posterior 
leukoencephalopathy syndrome (RPLS) which have been observed in clinical studies with 
cabozantinib.  There have been 44 subjects in pooled singe-agent studies with Grade 5 events 
assessed to be related to cabozantinib (note one subject had two Grade 5 AEs):  arterial thrombotic 
event (3 subjects), fistula (5subjects), GI perforation (5 subjects), Hemorrhage (23 subjects), 
venous and mixed/unspecified thrombotic events (7 subjects), and abscess (1 subject).   
 
Pediatric Experience 
The Children’s Oncology Group recently completed a Phase 1 trial of Cabozantinib in Children 
and Adolescents with refractory solid tumors. (Chuk et al. ASCO 2014).  In this study, 25 

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evaluable patients age 4-18 years (median 14) were enrolled.  In Part A (dose-finding) of the study 
(18 subjects), there was 1 DLT of grade 3 fatigue and headache at dose level 55 mg/m2/day.  In 
Part B (expansion cohort), there was 1 DLT of Grade 2 oral mucositis and Grade 2 palmar-plantar 
erythrodysesthesia at 40 mg/m2/day, and 2 DLTs of Grade 3 hypertension and proteinuria, and 
hypertension and reversible posterior leukoencephalopathy  syndrome, respectively, at 55 
mg/m2/day.  The toxicity profile in this study was concluded to be similar in adults and in children.   
 
 
 
 
However, in the steady-state pharmacokinetics analysis, cabozantinib exposure was highly variable 
and did not appear to be dose proportional.   
 
 
 
Based on comprehensive analysis of initial DLT data, DLT in later cycles as well as PK dosing, the 
recommended phase 2 dose of cabozantinib in children with solid tumors was determined to be 40 
mg/m2/day (equivalent to an adult dose of 72 mg/day).   
 
Adult NF1 Plexiform Neurofibroma Experience (NF105 Cohort A) 
In cohort A of this trial, of 21 subjects evaluable for toxicity, the most common adverse events (any 
grade) on study were gastrointestinal (all 21 subjects), asymptomatic hypothyroidism (n=16), 
fatigue (n=13), headaches (n=11), palmar-plantar erythrodysethesia (PPE, n=10), and leukopenia 
(n=9).  Eleven grade 3 adverse events occurred in 8 patients, including PPE (n=4), hypertension 

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(n=2), anorexia, vomiting, neutropenia, proteinuria, and skin infection. There were no grade 4 or 5 
AEs. 
 
Two patients discontinued cabozantinib due to dose limiting toxicity (DLT); both for PPE that did 
not resolve ≤ grade 1 within the protocol-mandated timeframe of 14 days to allow restarting of 
drug. There were a total of 10 dose reductions that occurred in seven subjects while on study for: 
PPE (n=7); skin infection (n=1); weight loss (n=2).  
 
Of the eight subjects with a partial response, only four reached that response by cycle 8, and the 
maximal tumor reduction did not occur until cycle 18 in 4 subjects and cycle 24 in 2 subjects.  
 
Because of the overall excellent safety profile of cabozantinib and the numerous late tumor 
responses, the requirement to stop study treatment in subjects who do not achieve at least a 15% 
reduction in tumor volume by 8 cycles will be eliminated in the pediatric cohort (Cohort B).  Of 
note, the initial rationale for this criteria was the hypotheses that the likelihood of achieving a 
partial response (20% reduction in tumor volume) by 12 months would be minimal if there was not 
a 15% reduction by 8 cycles.   
 
2.4 
Clinical Safety Profile 
 
Adverse Events 
As of 28 February 2018, AE data are available for 3017 subjects who have been dosed with 
cabozantinib.  
 
The most frequent AEs (≥ 5% incidence) reported at severity of Grade 3 and above include fatigue 
14.3%), hypertension (13.9%), diarrhea (10.7%), anemia (75%), PPES (9.4%), asthenia (7.0%), 
pulmonary embolism (5.3%), and decreased appetite (5.6%). 
 
The most frequently (≥ 20% incidence) observed AEs reported as related to cabozantinib, were 
diarrhea (52.9%), fatigue (50.1%), decreased appetite (43.0%), nausea (39.9%),  
PPES (37.0%), weight decreased (25.3%), vomiting (23.8%), dysgeusia (22.8%), hypertension 
(25.2%), and dysphonia (21.6%). 
 
 
Table 5-2: 
Summary of Adverse Events Experienced by ≥ 10% of Subjects Treated with 
Single-Agent Cabozantinib, N = 3017 
 
 
All AEs 
Related AEs 
Subjects 
with 
 
Subjects 
with 
 
MedDRA Preferred Term 
Subjects 
with AE 
n (%) 
≥ Grade 3 
AE 
n (%) 
Subjects 
with AE 
n (%) 
≥ Grade 3 
AE 
n (%) 
Number of subjects with at least one event 
3009 (99.7) 
2498 (82.8) 
2902 (96.2) 
1913 (63.4) 
Diarrhoea 
1817 (60.2) 
322 (10.7) 
1596 (52.9) 
293 (9.7) 
Fatigue 
1733 (57.4) 
432 (14.3) 
1513 (50.1) 
361 (12.0) 
Decreased appetite 
1573 (52.1) 
170 (5.6) 
1297 (43.0) 
132 (4.4) 
Nausea 
1478 (49.0) 
132 (4.4) 
1204 (39.9) 
98 (3.2) 

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Palmar-plantar erythrodysaesthesia syndrome 
1134 (37.6) 
284 (9.4) 
1117 (37.0) 
282 (9.3) 
Vomiting 
1015 (33.6) 
101 (3.3) 
719 (23.8) 
64 (2.1) 
Weight decreased 
988 (32.7) 
108 (3.6) 
764 (25.3) 
85 (2.8) 
Constipation 
900 (29.8) 
34 (1.1) 
388 (12.9) 
13 (0.4) 
Hypertension 
880 (29.2) 
418 (13.9) 
759 (25.2) 
365 (12.1) 
Dysgeusia 
723 (24.0) 
4 (0.1) 
688 (22.8) 
4 (0.1) 
Dysphonia 
718 (23.8) 
9 (0.3) 
604 (20.0) 
7 (0.2) 
Asthenia 
700 (23.2) 
210 (7.0) 
537 (17.8) 
153 (5.1) 
Aspartate aminotransferase increased 
596 (19.8) 
132 (4.4) 
483 (16.0) 
85 (2.8) 
Dyspnoea 
574 (19.0) 
95 (3.1) 
204 (6.8) 
24 (0.8) 
Abdominal pain 
568 (18.8) 
110 (3.6) 
282 (9.3) 
27 (0.9) 
Stomatitis 
558 (18.5) 
55 (1.8) 
526 (17.4) 
53 (1.8) 
Mucosal inflammation 
549 (18.2) 
56 (1.9) 
522 (17.3) 
54 (1.8) 
Anaemia 
544 (18.0) 
227 (7.5) 
236 (7.8) 
76 (2.5) 
Alanine aminotransferase increased 
511 (16.9) 
102 (3.4) 
432 (14.3) 
78 (2.6) 
Back pain 
510 (16.9) 
97 (3.2) 
59 (2.0) 
6 (0.2) 
Headache 
493 (16.3) 
31 (1.0) 
183 (6.1) 
3 (0.1) 
Pain in extremity 
477 (15.8) 
56 (1.9) 
200 (6.6) 
16 (0.5) 
Rash 
454 (15.0) 
17 (0.6) 
371 (12.3) 
15 (0.5) 
Cough 
443 (14.7) 
8 (0.3) 
97 (3.2) 
1 (< 0.1) 
Oedema peripheral 
416 (13.8) 
20 (0.7) 
114 (3.8) 
4 (0.1) 
Hypothyroidism 
413 (13.7) 
8 (0.3) 
343 (11.4) 
4 (0.1) 
Dizziness 
368 (12.2) 
14 (0.5) 
185 (6.1) 
3 (0.1) 
Dyspepsia 
363 (12.0) 
4 (0.1) 
264 (8.8) 
4 (0.1) 
Hypokalaemia 
361 (12.0) 
109 (3.6) 
161 (5.3) 
50 (1.7) 
Arthralgia 
345 (11.4) 
31 (1.0) 
88 (2.9) 
4 (0.1) 
Pyrexia 
329 (10.9) 
15 (0.5) 
59 (2.0) 
2 (0.1) 
Dry mouth 
319 (10.6) 
0 
261 (8.7) 
0 
Hypomagnesaemia 
313 (10.4) 
37 (1.2) 
205 (6.8) 
28 (0.9) 
Urinary tract infection 
309 (10.2) 
39 (1.3) 
31 (1.0) 
3 (0.1) 
Insomnia 
306 (10.1) 
1 (< 0.1) 
90 (3.0) 
0 
Dry skin 
304 (10.1) 
0 
255 (8.5) 
0 
Muscle spasms 
303 (10.0) 
2 (0.1) 
171 (5.7) 
1 (< 0.1) 
AE, adverse event; MedDRA, Medical Dictionary for Regulatory Activities. 
At each level of subject summarization, a subject is counted once if the subject reported one or more events. Adverse 
events were coded based on MedDRA version 17.0. 
Note: This table summarizes pooled data in the clinical database for single-agent cabozantinib studies (XL184-001, 
XL184-008, XL184-201, XL184-203, XL184-205, XL184-301 cabozantinib arm, XL184-306 cabozantinib arm, 
XL184-307 cabozantinib arm, XL184-308 cabozantinib arm, XL184-309 cabozantinib arm, and XL184-401). The 
denominator for percentages is the number of treated subjects. 
 
 
 
 
 

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Events to Monitor 
Adverse events of interest have been identified as categories of AEs that are known class effects 
of VEGF inhibitors, that may impact the risk/benefit of cabozantinib treatment, and that as a result 
of increased awareness should be diagnosed and appropriately clinically managed. 
 
The AEs of interest and their observed frequencies are discussed in this section and include 
data only from open-label studies with single-agent cabozantinib in the clinical database as of 
28 February 2018 (N = 3017). 
 
Events to Monitor (ETMs) in the Pooled Single-Agent Studies  
The definition a set of Events to Monitor (ETMs) in order to track events known to be associated 
with TKIs, VEGF pathway inhibition, and other events with potentially serious consequences. 
Each ETM comprises a set of AEs that are related to each other pathophysiologically. 
 
The ETMs of diarrhea, PPES, and hypertension include AEs that were reported in high 
frequency in previous cabozantinib studies and have been commonly observed with VEGFR-
TKIs. Less frequent but potentially life-threatening AEs that have been reported for subjects 
receiving cabozantinib and other VEGF pathway inhibitors are represented by the ETMs of GI 
perforations, fistulas, abscesses–all, intra-abdominal and pelvic abscesses, hemorrhages (≥ Grade 
3), arterial thrombotic events, venous and mixed/unspecified thrombotic events, wound 
complications, osteonecrosis, proteinuria, and RPLS. In the interest of routine surveillance, QT 
prolongation is also tracked. 
 
The AEs discussed in this section and summarized in Table 5-4 include data in the clinical 
database as of the AE cutoff dates for the Safety populations (ie, all subjects who received at 
least one dose of study treatment) from the pooled single-agent 
cabozantinib (N = 3017). 
  
 
Table 5-4 
Incidence of Events to Monitor 
 
ETMa 
Pooled Single-Agent Studiesb 
Cabozantinib (N = 3017) 
All 
n (%) 
Grade 3-4 
n (%) 
Grade 5 
n (%) 
Diarrhea 
1817 (60.2) 
322 (10.7) 
0 
PPES 
1134 (37.6) 
284 (9.4) 
0 
Hypertension 
911 (30.2) 
427 (14.2) 
0 
Venous and mixed/unspecified thrombotic events 
308 (10.2) 
216 (7.2) 
7 (0.2) 
Proteinuria 
212 (7.0) 
37 (1.2) 
0 
Hemorrhage (≥ Grade 3) 
147 (4.9)c 
124 (4.1) 
23 (0.8) 
Abscess–all 
135 (4.5) 
50 (1.7) 
1 (< 0.1) 
Intra-abdominal and pelvic abscess 
44 (1.5) 
28 (0.9) 
0 

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Arterial thrombotic events 
68 (2.3) 
42 (1.4) 
3 (0.1) 
Wound complications 
60 (2.0) 
19 (0.6) 
0 
Fistula 
48 (1.6) 
22 (0.7) 
5 (0.2) 
GI perforation 
42 (1.4) 
37 (1.2) 
5 (0.2) 
Osteonecrosisd 
39 (1.3) 
15 (0.5) 
0 
QT prolongatione 
31 (1.0) 
9 (0.3) 
0 
RPLS 
1 (< 0.1) 
1 (< 0.1) 
0 
ETM, event to monitor; GI, gastrointestinal; PPES, palmar-plantar erythrodysesthesia syndrome; RPLS, reversible 
posterior leukoencephalopathy syndrome. 
Note: A subject is counted once per ETM for the most severe event if reporting one or more event. 
a    The complete lists of reported MedDRA preferred terms for each ETM are defined in Appendix J. 
b    Subjects included in the single-agent pool are those who received cabozantinib on XL184-001, XL184-008, XL184-
201, XL184-203, XL184-205, XL184-301, XL184-307, XL184-306, XL184-308, XL184-309, and XL184-401. 
The data cutoff 
dates for the pooled single-agent studies are presented in Appendix F. The denominator for percentages is the number of 
treated subjects. 
c    By definition, the ETM of hemorrhage includes only events of ≥ Grade 3. The data presented are for events of ≥ Grade 3. 
d    The reported ETMs for osteonecrosis comprised osteonecrosis of the jaw (1.2%; 28 of 36 subjects had CRPC [from 
Studies XL184-203, -306, & -307]), osteonecrosis (0.1%), and osteoradionecrosis (< 0.1%). 
e    The reported ETMs of QT prolongation were electrocardiogram QT prolonged (1.0%) and electrocardiogram QT interval 
abnormal (< 0.1%). 
 
Discontinuation Due to Adverse Events 
As of 28 February 2018, 933 (30.9%) subjects in pooled single-agent studies of cabozantinib 
permanently discontinued cabozantinib  for the primary reason of AE or SAE. Adverse event 
data are available for all of these subjects. The most frequently reported AEs (≥1%) for subjects 
who discontinued for the primary reason of an AE or SAE were fatigue (3.8%), general physical 
health deterioration (2.7%), asthenia (1.9%), decreased appetite (1.9%), nausea (1.6%),diarrhea 
(1.0%), PPES (1.4%), and vomiting (1.0)% 
 
Deaths 
Through 28 February 2018, 275 of 743 subjects who received cabozantinib in ISTs conducted 
under separate US IND or ex-US equivalents held by the investigators; in these studies, reported 
in 551 SAEs in 310 cases. A total of 43 SAEs with fatal outcome were reported from ISTs through 
28 February 2018.  Twenty-five subjects died of progression of the underlying malignancy.  Of 
the 17 subjects with fatal SAEs not related to underlying malignancy, 12 died of events that were 
assessed as not related to underlying malignancy, 12 died of events that were assessed as not 
related to study treatment.  These comprised events of death (2 events), sudden death, sepsis, multi-
organ failure, intracranial tumor hemorrhage, and myelodysplastic syndrome.  One subject each 
died of fatal SAEs of hemorrhage and hypertensive heart disease that were considered possibly 
related to study treatment.   
 
Through 28 February 2018, 253 of 912 subjects in NCI-CTEP studies reported 1084 SAEs in 
456 cases.  A total of 75 subjects experienced SAEs with fatal outcome in NCI-CTEP studies.  
Forty-six subjects died due to progression of the underlying malignancy.  Of the 29 subjects with 
fatal SAEs not related to the underlying malignancy, 17 died of events assessed as not related to 

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study treatment.  Twelve subjects died of a fatal SAE that were considered possibly related to the 
study treatment: sepsis (2 subjects), death, sudden death, intracranial hemorrhage, cardiac arrest, 
acute kidney injury, jejunal perforation, embolism, colon fistula, respiratory failure, and 
pneumonitis (1 subject each).  
 
Volumetric Assessment of Plexiform Neurofibroma Size 
PNs are complex-shaped and slow-growing peripheral nerve sheath tumors that are challenging 
to measure by simple linear measurements. Automated volumetric MRI analysis can sensitively 
and reproducibly detect small changes in PN size and it has become the measurement method of 
choice to determine tumor response and time to disease progression in recent clinical trials.  
There are two volume segmentation methods optimized for PN measurement, MEDx developed 
at the National Cancer Institute (NCI) and 3DQI used by the Tumor Imaging Metrics Core at 
Massachusetts General Hospital (MGH). The NF Clinical Trials Consortium has utilized MEDx 
in all of its PN trials.  In a small, retrospective study volume measurements and volume changes 
over time were compared using these two different methods, and found good agreement. The 
goal is to prospectively evaluate a larger cohort of clinical trial participants to further define the 
level of agreement in volume measurements, disease status classifications, and objective 
response rates between MEDx and 3DQI. 
 
Overview of Proposed Study 
This phase II open label study will evaluate children and adults with neurofibromatosis type-1 
(NF1) and plexiform neurofibromas treated with cabozantinib (XL184).  This study will enroll 
subjects who either meet clinical diagnostic criteria or have an identified pathogenetic NF1 
mutation.  Subjects on study must have clinically significant plexiform neurofibroma defined as 
potentially life-threatening, impinging on vital structures or significantly impairing the quality of 
life from pain or other symptoms.  Patients must not have lesions suspicious for malignant 
tumors such as MPNSTs (malignant peripheral nerve sheath tumors) and suspicious tumors must 
be proven negative by histopathology prior to enrollment on study.  This study will be open to 
patients ≥3 years of age that meet eligibility criteria.  There will be two cohorts:  A. Cohort of 
subjects ≥ 16years of age, B. Subjects ≥3 years to 15 years of age with progressive plexiform 
neurofibroma.   
 
The study will be a Simon two-stage study design for cohort A.  It will be a single-arm open-
label study of cabozantinib and the primary endpoint is the ORR to cabozantinib at 1 year.  In the 
first stage, 9 evaluable subjects per cohort will be accrued.  If there is at least 1 response, accrual 
will continue to the second stage and an additional 8 evaluable subjects in that cohort will be 
enrolled.  To allow for 25% unevaluable subjects, a maximum of 24 subjects per cohort will be 
enrolled.  Radiographic response will be evaluated as the primary endpoint with 20% volumetric 
MRI response of the target lesion being the threshold criteria for tumor response.  A target lesion 
will be selected at time of enrollment and tumor evaluations will occur serially while on study. 
 
In Cohort A, all subjects will start cabozantinib at 40 mg.  The published MTD for cabozantinib 
is 140 mg and the current recommended dose in Phase 3 clinical trials for subjects with 
medullary thyroid cancer is 100 mg.  Doses of 40 mg and 60 mg continue to show efficacy in on-
going phase 2 and phase 3 trials with reduced toxicity (personal communication John Frye, 
Exelixis).  Subjects who tolerate 40 mg for 2 cycles will escalate to 60 mg.  The rationale for this 

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is that the majority of subjects who develop toxicity do so after >2 weeks on drug as 
cabozantinib has a long half-life.  Subjects who experience dose-limiting toxicity (see Section 
7.0) at 40 mg will dose reduce to 20 mg when their toxicities resolve. Subjects without toxicity at 
40mg will increase to 60mg.  Subjects who experience toxicity at 60 mg will dose reduce to 40 
mg. This dosing schema is designed to maximize safety and tolerability in this new population of 
patients. 
 
In Cohort B, we will enroll a minimum of 17 evaluable subjects. To allow for up to 25% 
unevaluable subjects, a maximum of 24 subjects will be enrolled. Based on the preliminary 
response data (passed the threshold to move to stage 2) and minimal toxicity in Cohort A to date, 
a 2-stage design is not felt to be necessary for Cohort B. 
 
Subjects in Cohort B will start at 30 mg/m2/day dosing.  Dose will be escalated at cycle 3 if 
tolerated to 40 mg/m2.  Subjects who experience DLT at 40 mg/m2/day will dose reduce to 30 
mg/m2/day.  Subjects who experience DLT at 30 mg/m2/day will dose reduce to 23 mg/m2day.  
Actual dosing will be based on the dosing nomogram in Appendix XI. 
 
 
Subjects entered on the trial will be carefully monitored for the development of cabozantinib 
associated toxicities, and target modifications and interruptions will be performed as outlined in 
this protocol (see section 7.0). 
 
In all consenting subjects entered on this trial a complete pharmacokinetic profile of 
cabozantinib after administration will be evaluated.  In addition, cytokine and endothelial 
progenitor cell biomarkers will be drawn to assess treatment effect and to correlate with 
response. 
 
In addition, since plexiform neurofibromas may significantly impact the lives of patients with 
NF1, this study will evaluate the effects of the disease and treatment with cabozantinib on the 
quality of life (QOL) of these subjects by assessing health related QOL, pain intensity, and pain 
interference.     
 
 
3.0 
SCREENING AND STUDY ENROLLMENT PROCEDURES 
 
The NF Operations Center should be contacted to ensure availability of a treatment slot and PK 
slot. 
 
3.1 
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 patient or the patient’s parent(s) or guardian if the patient is a child.  When 
appropriate, pediatric patients will be included in all discussions. All patients and/or their 
parents or legally authorized representatives must sign a written informed consent.  Assent, 
when appropriate, will be obtained according to institutional guidelines. 
 

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• A study participant should sign the institution’s HIPAA Consent. 
• A study participant should sign the institution’s Release of Medical Information Waiver. 
 
3.2 
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 patient can be enrolled, the responsible institutional investigator must sign and date 
the completed eligibility checklist. The completed eligibility checklist should be faxed or 
scanned and emailed to the NF Operations Center to confirm eligibility prior to subject 
enrollment. 
 
3.3 
Study Enrollment 
Patients may be enrolled on the study once all eligibility requirements for the study have been 
met, and a treatment number for subject has been confirmed by the NF Consortium Operations 
Center. All patients who give informed consent for the protocol in order to undergo screening 
for eligibility will be registered but are not considered 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. 
 
4.0 
SUBJECT ELIGIBILITY 
 
All studies to determine eligibility must be performed within 2 weeks prior to enrollment. The 
baseline MRI study documenting disease status is required within 4 weeks prior to study entry. 
All clinical and laboratory data required for determining eligibility of a subject enrolled on this 
trial must be available in the subject's medical or research record which will serve as the source 
document for verification at the time of audit/monitoring.  
 
4.1 
Inclusion Criteria for all subjects: 
 
4.1.1 
All subjects must have an identified pathogenetic constitutional NF1 mutation OR the 
clinical diagnosis of NF1 using the NIH Consensus Conference criteria. In addition to a 
plexiform neurofibroma, one or more of the following diagnostic criteria for NF1 must be 
present: 
4.1.1.1 Six or more café-au-lait spots (≥0.5 cm in prepubertal subjects or ≥1.5 cm in post pubertal 
subjects) 
4.1.1.2 Freckling in the axilla or groin 
4.1.1.3 Optic glioma 
4.1.1.4 Two or more Lisch nodules 
4.1.1.5 A distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia or thinning of long 
bone cortex) 

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4.1.1.6 A first-degree relative with NF1 
 
4.1.2 
Subjects must have plexiform neurofibroma(s) that are progressive (see section 
4.1.2.1) OR are causing significant morbidity, such as (but not limited to) head and neck 
lesions that are compromising the airway or great vessels, brachial or lumbar plexus lesions 
that are causing nerve compression and loss of function, lesions causing major deformity 
(e.g., orbital lesions) or are significantly disfiguring (see section 4.1.2.2), lesions of the 
extremity that cause limb hypertrophy or loss of function, and painful lesions.  Patients 
with paraspinal plexiform neurofibromas will be eligible for this trial. Histologic 
confirmation of tumor is not necessary in the presence of consistent clinical and 
radiographic findings, but should be considered if malignant degeneration of a plexiform 
neurofibroma is clinically suspected.  
 
4.1.2.1  For subjects enrolled for tumor progression, progression is defined as:  
• Presence of new plexiform neurofibroma on MRI or CT (documented by 
comparison with prior MRI or CT), OR 
• A measurable increase in plexiform neurofibroma size (≥ 20% increase in the 
volume, or a ≥ 13% increase in the product of the two longest perpendicular 
diameters, or a ≥ 6% increase in the longest diameter) documented by comparison 
of two scans (MRI or CT) in the time period of approximately one year or less prior 
to evaluation for this study. 
 
4.1.2.2 For subjects enrolled for “major deformity” or a “significantly disfiguring” tumor, 
eligible tumors will be limited to tumors of the head & neck or those on other areas of the 
body that are unable to be concealed by standard garments.  In order to enroll a plexiform 
neurofibroma for these indications, the Study Chair or Co-Chair must be contacted to 
review patient eligibility prior to enrollment. 
 
4.1.3. 
Disease status:  
Measurable disease:  Subjects must have measurable plexiform neurofibroma(s) 
amenable to volumetric MRI analysis. For the purpose of this study, the target lesion 
must be seen on at least 3 consecutive MRI slices and the field of view must contain the 
entire tumor of interest.  Tumors must be at least 3 mL in volume (most PNs 3 cm in 
longest diameter will meet this criteria).  If the tumor is <3 cm in longest diameter, the 
patient may still be eligible.  Central review of the MRI of the target plexiform is 
required prior to enrollment to ensure that the tumor is measurable and amenable 
to volumetric analysis.  After consenting, please send the images on a CD along with the 
form in Appendix IX to Eva Dombi (see Appendix IX for address).  Central review will 
take 3-7 days (please plan accordingly). 
 
4.1.4. 
Age:   
Subjects must be 3 years of age at the time of study entry.  Subjects ≥16 years of age will 
be enrolled in Cohort A.  Subjects 3-15 years of age will be enrolled in Cohort B.   
 
4.1.5. 
Subjects unable to consent to study:   
Adults (>18 years of age) who are unable to provide informed consent will NOT be 

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enrolled on this study.  Written informed consent must be obtained from all patients (>18 
years of age) or their legal guardians (if the patient is <18 years of age).  
 
4.1.6. 
Performance Level:   
Subjects must have Karnofsky or Lansky ≥ 50% (Appendix II).  Note: Subjects who are 
unable to walk because of paralysis, but who are up in a wheelchair, will be considered 
ambulatory for the purpose of assessing the performance score. 
 
4.1.7. 
Prior Therapy 
Patients who underwent surgery for a progressive plexiform neurofibroma will be eligible 
to enter the study after the surgery, provided the plexiform neurofibroma was 
incompletely resected and is measurable. 
 
Patients are only eligible if complete resection of a plexiform neurofibroma with 
acceptable morbidity is not feasible, or if a patient with surgical option refuses surgery. 
 
Patients may have been previously treated for a plexiform neurofibroma but must have 
fully recovered from the acute toxic effects of all prior chemotherapy or radiotherapy 
prior to entering this study. 
 
a. Myelosuppressive chemotherapy:  Must not have received within 4 weeks of entry 
onto this study.  
b. Hematopoietic growth factors: At least 7 days since the completion of therapy with a 
growth factor that supports platelet, red or white cell number or function.   
c. Biologic (anti-neoplastic agent):  At least 14 days since the completion of therapy 
with a biologic agent.  For agents that have known adverse events occurring beyond 
14 days after administration (or 5 half-lives whichever is longer), this period must be 
extended beyond the time during which adverse events are known to occur.  These 
patients must be discussed with the Study Chair on a case-by-case basis. 
d. Investigational Drugs:  Subjects must not have received an investigational drug 
within 4 weeks. 
e. Steroids: Patients with endocrine deficiencies are allowed to receive physiologic or 
stress doses of steroids if necessary.   
f. 
XRT:  ≥ 6 months from involved field radiation to index plexiform neurofibroma(s); 
≥ 6 weeks must have elapsed if patient has received radiation to areas outside index 
plexiform neurofibroma(s). 
g. 
Surgery: At least 3 months since undergoing any major surgery.  At least 1 month 
since undergoing any minor surgery.  See section 4.2.1 for more details. 
 
4.1.8. 
Organ Function Requirements 
 
4.1.8.1.Adequate Bone Marrow Function Defined as: 
- 
Peripheral absolute neutrophil count (ANC) ≥ 1500/µL 
- 
Platelet count ≥ 100,000/µL (transfusion independent) 
- 
Hemoglobin ≥ 10.0 gm/dL (may receive RBC transfusions) 
 

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4.1.8.2.Adequate Renal Function Defined as: maximum serum creatinine 1.5 mg/dL 
 OR a creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73 m2 
 
Serum calcium, magnesium, and phosphorous with institutional normal limits 
(supplementation is permissible) 
 
4.1.8.3.Adequate Liver Function Defined As: 
- Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal 
(ULN) for age, and 
- SGPT (ALT) ≤ 5 x upper limit of normal (ULN) for age, and 
- Serum albumin ≥ 2 g/dL. 
 
4.1.8.4.  Blood pressure within upper limit of normal defined as: 
- A blood pressure (BP) ≤ 95th percentile for age, height, and gender and not 
receiving medication for treatment of hypertension. 
4.1.9. 
Major surgery:  Only patients who are not anticipated to need major surgery within 
the next 3 months of enrollment are eligible. 
 
4.2  
Exclusion Criteria 
 
4.2.1 Exclusion Criteria  
• Evidence of an active optic glioma or other low-grade glioma, requiring treatment with 
chemotherapy or radiation therapy.  Patients not requiring treatment are eligible for this 
protocol. 
• Patients with malignant glioma, malignant peripheral nerve sheath tumor, or other 
malignancy requiring treatment in the last 12 months. 
• Dental braces or prosthesis that interferes with volumetric analysis of the 
neurofibroma(s). 
• The subject is unable to swallow tablets 
• Women who are pregnant or breast-feeding.  
• Males or females of reproductive potential may not participate unless they have agreed 
to use an effective contraceptive method during the period they are receiving the study 
drug and for 3 months thereafter. Abstinence is an acceptable method of birth control. 
Women of childbearing potential will be given a pregnancy test within 7 days prior to 
administration of cabozantinib and must have a negative urine or serum pregnancy test. 
• The subject has received prior treatment with a small molecule kinase inhibitor or a 
hormonal therapy (including investigational kinase inhibitors or hormones) within 14 
days or 5 half-lives of the compound or active metabolites, whichever is longer, before 
the first dose of study treatment -OR- the subject has ever taken cabozantinib.  Note:  
Subjects with prostate cancer currently receiving LHRH or GnRH agonist may be 
maintained on these agents. 
• The subject has not recovered to baseline or CTCAE ≤ Grade 1 from toxicity due to all 
prior therapies except alopecia and other non-clinically significant AEs. 

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• The subject requires concomitant treatment, in therapeutic doses, with anticoagulants 
such as warfarin or warfarin-related agents, heparin, thrombin or Factor Xa inhibitors, 
or antiplatelet agents (e.g., clopidogrel). Low dose aspirin (≤ 81 mg/day), low-dose 
warfarin (≤ 1 mg/day), and prophylactic low molecular weight heparin (LMWH) are 
permitted. 
• The subject requires chronic concomitant treatment of strong CYP3A4 inducers (e.g., 
dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, 
phenobarbital, and St. John’s Wort).  The subject requires chronic concomitant 
treatment of strong CYP3A4 inhibitors (e.g., indinavir, nelfinavir, ritonavir, 
clarithromycin, itraconazole, ketoconazole, nefazodone, squinavir, telithromycin, 
aprepitant, erythromycin, fluconazole, grapefruit juice, verpamil, diltiazem, 
cimetidine, amiodarone, chloramphenicol, boceprevir, ciprofloxacin, delaviridine, 
diethyl-dithiocarbamate, fluvoxamine, gestodene, imatinib, mibefradil, mifepristone, 
norfloxacin, norfluoxetine, starfruit, telaprvir, voriconazole).  Because the lists of 
these agents are constantly changing, it is important to regularly consult a frequently 
updated list such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical 
reference texts such as the Physicians’ Desk Reference may also provide this 
information.  As part of the enrollment/informed consent procedures, the patient will 
be counseled on the risk of interactions with other agents, and what to do if new 
medications need to be prescribed or if the patient is considering a new over-the-
counter medicine or herbal product.   
• History of noncompliance to medical regimens 
• Patients unwilling to or unable to comply with the protocol, or who in the opinion of 
the investigator may not be able to comply with the safety monitoring requirements of 
the study 
• A known history of HIV seropositivity or known immunodeficiency. HIV testing will 
not be required as part of this trial, unless HIV is clinically suspected. 
• Impairment of gastrointestinal function or gastrointestinal disease that may 
significantly alter the absorption of cabozantinib (e.g. ulcerative disease, uncontrolled 
nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection). A 
nasogastric tube (NG tube) is allowed. 
• Patients who have an uncontrolled infection. 
• The subject has experienced any of the following: 
o clinically-significant gastrointestinal bleeding within 6 months before the first 
dose of study treatment 
o hemoptysis of ≥0.5 teaspoon (2.5 mL) of red blood within 3 months before the 
first dose of study treatment 
o any other signs indicative of pulmonary hemorrhage within 3 months before the 
first dose of study treatment 
o The subject has radiographic evidence of cavitating pulmonary lesion(s). Chest 
x-ray will not be required as part of this trial, unless cavitating pulmonary lesion 
is clinically suspected. 
• Other concurrent severe and/or uncontrolled medical disease which could compromise 
participation in the study (e.g. uncontrolled diabetes, uncontrolled hypertension, severe 

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infection, severe malnutrition, chronic liver or renal disease, active upper GI tract 
ulceration) 
• Cardiovascular disorders including: 
o Congestive heart failure (CHF): New York Heart Association (NYHA) Class 
III (moderate) or Class IV (severe) at the time of screening 
o Any history of congenital long QT syndrome 
o Baseline QTc interval >470 msec in women and >450 msec in men 
 Concomitant treatment with medications that prolong the QT 
interval and have a known risk of Torsades de Pointes is not 
contraindicated, but should be avoided if possible and will require more 
frequent EKG monitoring (see Section 6.3). 
• Any of the following within 6 months before the first  dose of study treatment: 
o unstable angina pectoris 
o clinically-significant cardiac arrhythmias 
o stroke (including TIA, or other ischemic event) 
o myocardial infarction 
o thromboembolic event requiring therapeutic anticoagulation (Note: subjects 
with a venous filter (e.g. vena cava filter) are not eligible for this study) 
• 
Any of the following within 28 days before the first dose of study treatment: 
o intra-abdominal tumor/metastases invading GI mucosa 
o active peptic ulcer disease, 
o inflammatory bowel disease (including ulcerative colitis and Crohn’s disease), 
diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis 
o malabsorption syndrome 
• 
Any of the following within 6 months before the first dose of study treatment: 
o abdominal fistula 
o gastrointestinal perforation 
o bowel obstruction or gastric outlet obstruction 
o intra-abdominal abscess. Note: Complete resolution of an intra-abdominal 
abscess must be confirmed prior to initiating treatment with cabozantinib even 
if the abscess occurred more than 6 months before the first dose of study 
treatment. 
• 
Other disorders associated with a high risk of fistula formation including PEG tube 
placement within 3 months before the first dose of study therapy  
• 
Other clinically significant disorders such as: 
o active infection requiring systemic treatment within 28 days before the first 
dose of study treatment 
o serious non-healing wound/ulcer/bone fracture within 28 days before the first 
dose of study treatment 
o history of organ transplant 
o concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 
days before the first dose of study treatment 
• History of major surgery as follows: 

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o Major surgery within 3 months of the first dose of cabozantinib if there were no 
wound healing complications or within 6 months of the first dose of 
cabozantinib if there were wound complications 
o Minor surgery  within 1 months of the first dose of cabozantinib if there were 
no wound healing complications or within 3 months of the first dose of 
cabozantinib if there were wound complications 
• In addition, complete wound healing from prior surgery must be confirmed at least 28 
days before the first dose of cabozantinib irrespective of the time from surgery 
 
 
5.0 
REQUIRED DATA 
 
IRB Approvals 
The PI from each participating institution will provide the NF Consortium Operations Center with 
a copy of the initial IRB protocol approval and the yearly IRB continuing reviews. The Study 
Coordinator will submit these to the USAMRMC ORP HRPO. Registration will be halted at a 
participating institution if a current continuing approval is not on file at the NF Consortium 
Operations Center.  
 
Each participating institution is required to maintain a current MPA or FWA in order to participate 
in government-sponsored Group research.  The files will be copied or made available for review 
by authorized persons as required for conduct of this trial. 
 
Amendments and Consents 
The PI from each participating institution will provide the NF Consortium Operations Center with 
a copy of IRB approval of all amendments to the protocol or consent. The NF Consortium 
Operations Center will provide these institutional reviews to the USAMRMC ORP HRPO.  As 
this trial receives funding by the US Army, substantive amendments to the research protocol and 
any amendments that could potentially increase risk to subjects must be submitted to the HRPO 
for approval prior to implementation and site distribution. The USAMRMC ORP HRPO defines 
a substantive amendment as a change in Principal Investigator, change or addition of an 
institution, elimination or alteration of the consent process, change to the study population that 
has regulatory implications (e.g. adding children, adding active duty population, etc.), significant 
change in study design (i.e. would prompt additional scientific review), or a change that could 
potentially increase risks to subjects.   
  
Data Collection and Toxicity Reporting 
The trial is being conducted by the NF Consortium.  Case report 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 NCI POB will receive MRI studies electronically or on CD and completed worksheets for 
volumetric analysis.  When sending the CD, the site must provide tracking # (FedEx or UPS) by 
email to Eva Dombi: dombie@mail.nih.gov. 
 
Upon analysis of these studies results will be transmitted to the NF Consortium Operations Center. 

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Biological specimens for banking will be handled and stored in the biorepository located in the 
Colket Translational Research Building at the Children’s Hospital of Philadelphia (CHOP), 
Philadelphia, PA.  The specimens will be under the management of the Center for Data Driven 
Discovery in Biomedicine (D3b) and the Biorepository Core (BioRC), according to their standard 
operating procedures (SOPs).  Samples will be stored at -80°C.  Biological specimens will be 
coded with a randomly generated study number prior to shipping to the biorepository in order to 
prevent identification of subjects and protect confidentiality.  The study number will not be 
derived from or related to information about the subject, and will not contain any elements of 
PHI.  The specimen number will be entered into the NF Consortium Operations Center eDES, 
thus providing a link between the specimen and the study data.  Specimens may be shared with 
outside investigators/laboratories, who may analyze (and store, if applicable) the samples. Shared 
specimens will be labeled only with a study number.  Requests for samples will be reviewed by 
the NF105 Study Chairs and the NFCTC Biology Committee.  If a subject withdraws consent to 
store samples after collection, existing samples in the biorepository will be destroyed; however, 
any samples already shared to an outside laboratory or other entity will not be destroyed and any 
data generated already from the samples will not be destroyed. 
 
Representatives from the FDA, NF Consortium Quality Assurance Committee, and the U.S. 
Army Medical Research and Material Command will have access to the data and research records.  
 
Alyssa Reddy, MD will serve as the medical monitor.  She will serve as a patient advocate and is 
independent of the clinical study team.  She will oversee the progress of the protocol, especially 
issues of individual subject/patient management and safety.  The medical monitor is required to 
review all unanticipated problems involving risks to subjects or others, including all serious and 
unexpected adverse events associated with the protocol as defined in Section 10.0.  The monitor 
provides an unbiased written report of the event.  
 
Handling of Research Samples 
This study is conducted at NF Consortium Sites and coordinated by the NF Consortium 
Operations Center.  Sample labeling, collection and initial processing will be conducted as 
outlined in the study Appendix V and VI. Blood samples obtained for biomarker analysis will be 
sent to Riley Hospital for Children (CCRC, Indiana School of Medicine) for analysis.  Blood 
samples for pharmacokinetic analysis will be sent to Alturas Analytics.  Samples will be stored 
in designated monitored freezers. The protocol specific subject ID number will identify 
samples.  Once analyzed for studies outlined in this protocol any remaining samples will be stored 
by Riley Hospital for Children until the study is complete, and the manuscript describing the study 
has been accepted for publication.  Any use of samples not outlined in this protocol will require 
prospective IRB review and approval.  The study will remain open and status reported to the IRB 
until all samples have been analyzed, reported or destroyed. Unintentional loss or destruction of 
any samples will be reported to the IRB as part of annual continuing reviews.  MRI studies of PN 
will be obtained as described in Appendix IV and be sent on CD to the NCI POB. MRI studies 
will be loaded on one of three Sun Workstations, which are password protected and allow access 
only to Drs Dombi, Widemann, or associate investigators on the trial. CDs will be stored in locked 
filing cabinets. 
 
Data and Center Audits 

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The trial will be audited by the NF Consortium Operations Center for compliance and safety. 
Independent monitors will visit participating sites and review case report forms and source 
documentation. Missing or spurious information and protocol deviations will be communicated 
in a report to the trial coordinating center.  Protocol deviations, which may result in compromise 
to safely administer study drug, or to determine study endpoints will be included in the annual 
protocol review to the USAMRMC ORP HRPO.   
 
All unexpected and serious adverse events will be forwarded to the Medical Monitor, the Study 
PI, the FDA, Exelixis, and the USAMRMC ORP HRPO by the NF Consortium Operations Center 
as defined in Section 8.0.  
 
Volumetric MRI analysis will be used to determine disease progression, and subjects will not be 
removed from study based on 1-D or 2-D MRI measurements or based on clinical measurement 
of superficial lesions.  
 
 
 
5.1 
Tests and Observations   
See Section 9.0 and Appendix I.  Unless otherwise noted, all tests to determine eligibility must be 
completed within 14 days of study entry. 
 
5.2 
Records to be kept 
Subject Registration and Case Report Forms 
 
Subjects will be registered with the NF Consortium Operations Center via the electronic data entry 
system (eDES). Electronic and paper Case Report Forms (CRFs) will be developed by the 
Consortium Operations Center and PI.  All data must be entered into the eDES.  Sites have the 
option of maintaining a printed copy of completed forms in the subject’s study binder that have 
been initialed and dated by the study team member entering the data into the paper case report 
form. 
 
Subjects must not be identified by name on any study documents that are sent off site to any 
agency.  The Subject Identification Number received upon data entry registration and placed on 
all case report forms and regulatory documents will identify subjects. 
 
All data entered on a paper CRF must be legibly recorded in indelible ink or typed.  A correction 
should be made by striking through the incorrect entry with a single line and entering the correct 
information adjacent to it.  The correction must be initialed and dated by the investigator or 
designated qualified individual.  Any requested information that is not obtained as specified in the 
protocol should have an explanation noted on the CRF as to why the required information was not 
obtained.  The electronic CRF provides audit trail showing when data is revised. 
 
5.3 
Role of Data Management 
 
5.3.1 Instructions concerning the recording of study data on CRFs will be provided by 
the NF Operations Center. 
5.3.2 It is the responsibility of the NF Operations Center to assure the quality of data for 

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their study.  This role extends from protocol development to generation of the final 
study database. 
 
 
6.0 
TREATMENT PROGRAM 
 
6.1 
Treatment Overview 
This is a Phase 2, single-arm, open-label study of cabozantinib in subjects with plexiform 
neurofibroma.  The primary endpoint is the ORR to cabozantinib after 12 cycles (~12 months). In 
cohort A, subjects who did not achieve at least 15% reduction in index tumor after 8 cycles (~8 
months) were considered treatment failures and taken off study.  For cohort B (pediatric cohort), 
because of the overall excellent safety profile of cabozantinib and the numerous late tumor 
responses in cohort A (adult cohort) (see protocol section 2.3), the requirement to stop study 
treatment in subjects who do not achieve at least a 15% reduction in tumor volume by 8 cycles 
will be eliminated.  Of note, subjects may begin cycle 9 and 13 while central review of tumor 
response is ongoing.  For cohort A, a Simon 2-stage design will be used.  In the first stage, 9 
evaluable subjects will be accrued.  If there is at least 1 response, accrual will continue to the 
second stage and an additional 8 evaluable subjects will be enrolled.  In Cohort B, we will enroll 
a minimum of 17 evaluable subjects. To allow for up to 25% unevaluable subjects, a maximum of 
24 subjects will be enrolled. Based on the preliminary response data (passed the threshold to move 
to stage 2) and minimal toxicity in Cohort A to date, a 2-stage design is not felt to be necessary for 
Cohort B.  For each cohort, if there are a total of 3 responses among the total of 17 evaluable 
subjects, cabozantinib will be considered of clinical interest in NF1 plexiform neurofibromas.   
 
6.2   
Rationale for Cabozantinib Dose selection  
 
Cohort A: The dosing for this study was developed based on review of existing efficacy and 
safety data from available cabozantinib therapeutic trials.  A cabozantinib starting dose of 100 
mg qDay has been studied in 171 CRPC (castration-resistant prostate cancer) subjects enrolled to 
the Phase 2 XL184-203 RDT.  Despite relatively high rates of dose reductions to the next lowest 
dose of 60 mg qDay within the first 12 weeks of therapy (51%), this starting dose resulted in 
high rates of pain relief, bone scan improvement, and overall disease control.  
In addition, preliminary data from a separate and ongoing dose-ranging study looking at lower 
doses of cabozantinib in CRPC coupled with results from a retrospective review of the Phase 2 
XL184-203 RDT indicate that lower doses below 100 mg qd are likely to retain efficacy while 
improving upon tolerability: 
Preliminary results from an ongoing dose-ranging study: To date, 9 subjects with 
metastatic CRPC enrolled to the first cohort (starting dose of 40 mg qd) are evaluable for 
bone scan response. All 9 subjects exhibit evidence of response on bone scan including 
two complete responses. Although most subjects did not have pain at baseline, one 
subject reported pain at baseline, which resolved by Week 6. No dose reductions or 
interruptions have been reported to date, although one subject discontinued study 
treatment for fatigue that was present at baseline and another subject discontinued 
because of a pathologic fracture. This provides preliminary evidence that lower doses are 
pharmacologically active in a patient population with advanced CRPC.  
 

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Retrospective review of Phase 2 XL184-203 RDT: While the overall rate of dose 
reduction from 100 mg to 60 mg was 51%, only 14% required an additional reduction in 
dose from 60 mg to the next lowest dose of 40 mg, which is consistent with an overall 
improvement in tolerability profile at the 60-mg dose level. The majority (69%) of 
subjects with pain at baseline who experienced early dose reduction (before Week 6) to 
60 mg went on to report pain improvement at Week 6. Moreover, 80% of these subjects 
remained progression-free and continued to report pain relief at the Week 12 time point. 
Thus the dose of 60 mg qd appears to offer improved tolerability while maintaining 
efficacy in a patient population with advanced CRPC and cancer-related pain at baseline.  
 
Further analysis of the timing of AEs that led to dose reductions or interruptions was 
conducted. The median time to first AE triggering a dose reduction or interruption at 100 
mg qd was 29 days, with very few subjects experiencing significant toxicity in the first 2 
weeks of study treatment. 
 
As such, for Cohort A, this study will take a conservative approach to maximize safety and 
tolerability in our subject population.  This study will adopt a starting cabozantinib dose of 40 
mg qDay.  Subjects will dose escalate after 2 cycles to 60 mg based on dose tolerability.  
Subjects who do not tolerate 40 mg will dose reduce to 20 mg (see section 7.0).  Doses will be 
capped at 60 mg.  The goal of this regimen is to improve the overall tolerability of cabozantinib 
while maintaining efficacy in this subject population.  The rationale for delaying dose escalation 
until cycle 3 is based on previous experience of AE with cabozantinib.  Because of the long half-
life of cabozantinib, the median AE on previous trials was 29 days further justifying a later dose 
escalation schema. 
Rationale for Dose selection for Cohort B: 
The recommended Phase 2 dose in pediatric solid tumors was established by the recently 
completed COG Phase 1 trial to be 40 mg/m2/day (see Section 2.3).  Based on this experience, 
this study will take a conservative approach to maximize safety and tolerability in our subject 
population.  This study will adopt a starting cabozantinib dose of 30 mg/m2/day.  Subjects will 
dose escalate after 2 cycles to 40 mg/m2/day based on dose tolerability.  Subjects who do not 
tolerate 30 mg/m2/day will dose reduce to 23 mg/m2/day (see section 7.0).  Doses will be capped 
at 60 mg/day max daily dose.  The goal of this regimen is to improve the overall tolerability of 
cabozantinib while maintaining efficacy in this subject population.  The rationale for delaying 
dose escalation until cycle 3 is based on previous experience of AE with cabozantinib.  Because 
of the long half-life of cabozantinib, the median AE on previous trials was 29 days further 
justifying a later dose escalation schema. 
 
Cabozantinib pharmacokinetics will be collected at steady state to compare drug kinetics and 
metabolism in this subject population compared to existing data from non-NF oncology subjects. 
(See Appendix I, VI) 
 
6.3 
Administration, Dose, Schedule and Route 
Treatment Program:  Subjects will receive cabozantinib orally once daily in continuous 
administration.  Cycles will be designated to last 28 days.  There will be no planned dose 

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interruptions except holds for toxicity.  The starting dose will be cabozantinib free base 40 mg 
daily with dose escalation after 2 cycles to 60 mg free base if no dose-limiting toxicity (see 
section 7.0) experienced in the previous cycle.  Cabozantinib will be held for subjects who 
experience dose-limiting toxicity until the toxicity grade has decreased to grade 1.  Cabozantinib 
will then be reduced by one dose level and not re-escalated in subsequent cycles.  Subjects who 
experience dose-limiting toxicity at the 20 mg dose level will be off study.  If 2 or more subjects 
experience dose-limiting toxicity at a particular dose level, study enrollment with be held while 
the DSMB reviews the toxicities.  Subjects already at that dose level who do not experience 
dose-limiting toxicity may continue.   
 
A cycle of therapy is considered to be 28 days, with the reporting period for each cycle being day 
1 to day 28.  In the absence of progressive disease or dose limiting toxicity (DLT), subjects may 
continue on therapy for a total of 12 total cycles.  Subjects who have a radiographic response 
(20% or greater reduction in tumor volume) on therapy at the end of 12 cycles can continue on 
therapy for up to an additional year.  The maximum duration for treatment under this study 
design is 24 cycles.  In cohort A, subjects who did not achieve at least 15% reduction in index 
tumor volume after 8 cycles (~8 months) were considered treatment failures and taken off study.  
For cohort B (pediatric cohort), because of the overall excellent safety profile of cabozantinib 
and the numerous late tumor responses in cohort A (adult cohort) (see protocol section 2.3), the 
requirement to stop study treatment in subjects who do not achieve at least a 15% reduction in 
tumor volume by 8 cycles will be eliminated.  Of note, subjects may begin cycle 9 and 13 while 
central review of tumor response is ongoing. 
 
Cabozantinib must be taken on an empty stomach.  Subjects must be instructed not to eat 
for at least 2 hours before and at least 1 hour after taking cabozantinib.  Subjects should be 
instructed to take their cabozantinib dose at approximately the same time every day.  If a subject 
misses a dose, the dose may be taken later only if it is within 12 hours of when the missed dose 
should have been taken.  The missed dose should not be made up if it is within 12 hours of the 
next scheduled dose.   
 
Cabozantinib tablets should be swallowed whole with at least 8 ounces of water.  The tablets 
should not be crushed. Grapefruit, grapefruit juice, Seville oranges and their products should be 
avoided by subjects taking cabozantinib. 
 
Cabozantinib should NOT be re-taken if vomiting occurs after taking a scheduled dose.  
Dosing may continue the next day as scheduled. 
 
Medications that prolong the QT interval and have a known risk of Torsades de Pointes should 
be avoided if possible, but are not explicitly excluded.  Such medications include: amiodarone, 
arsenic trioxide, astemizole, azithromycin, bepridil, chloroquine, chlorpromazine, cisapride, 
citalopram, clarithromycin, disopyramide, dofetilide, domperidone, droperidol, erythromycin, 
escitalopram, flecainide, halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, 
methadone, moxifloxacin, pentamidine, pimozide, probucol, procainamide, quinidine, 
sevoflurane, sotalol, sparfloxacin, terfenadine, thioridazine, vandetanib.  Because the lists of 
these agents are constantly changing, it is important to regularly consult a frequently updated list 

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such as www.azcert.org/medical-pros/drug-lists/list-01.cfm?sort=Generic_name.  If the subject 
starts such a medication, then EKG monitoring must be end of each cycle while on the 
medication. 
 
Medications that may prolong the QT interval and have a possible risk of Torsades de Pointes 
(see http://www.azcert.org/medical-pros/drug-lists/list-02.cfm?sort=Generic_name) should be 
avoided if possible, but are not explicitly excluded.  If the subject starts a medication with 
substantial evidence that the drug prolongs the QT interval, then EKG monitoring must be end of 
each cycle while on the medication. 
 
Subjects or their parents/guardians will keep a diary to document the intake of each dose of 
cabozantinib and potential side effects.  Subjects should be instructed to use the diary to record 
the date and time of each dose as well as observed side effects and supportive treatments used 
while on study. The subject may use the diary in Appendix III or a suitable alternative developed 
by the local institution.  The subject diary should be reviewed by the treating physician with the 
subject or subject’s family at each required clinical study evaluation.  In addition, leftover study 
medication should be collected at each on study evaluation, and drug should be accounted for at 
this time.  
 
All subjects will receive MRI measurements after 4, 8, and 12 cycles.  Subjects who continue on 
drug beyond 12 cycles will undergo imaging after 18 and 24 cycles. 
  
6.4  
Criteria for starting subsequent cycles 
A cycle may be repeated every 28 days if the subject does not have evidence of progressive 
disease and has again met laboratory parameters as defined in the eligibility criteria, with the 
exception of ANC, which must be >1000 to start each cycle. 
 
 
6.5  
Dose escalation Schema 
 
Cohort A: The starting dose will be 40 mg with dose escalation after cycle 2 if no DLT (as 
defined in section 7.2) is experienced in the first 2 cycles.  Cabozantinib will be held for subjects 
who experience DLT until the toxicity grade has decreased to grade 1.  Cabozantinib will then be 
reduced by one dose level and not re-escalated in subsequent cycles.  Subjects who experience 
toxicity at dose level -1 will be off study. 
 
 
Dose Level 
 
Dose (mg/dose) 
            -1                                    
20 mg 
 1                
             
40 mg  
 2 
 
 
 
60 mg 
 
Cohort B:  The starting dose will be 30 mg/m2 with dose escalation after cycle 2 if no DLT (as 
defined in section 7.2) is experienced in the first 2 cycles.  Cabozantinib will be held for subjects 
who experience DLT until the toxicity grade has decreased to grade 1.  Cabozantinib will then be 
reduced by one dose level and not re-escalated in subsequent cycles.  Subjects who experience 
toxicity at dose level -1 will be off study. 

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Dose Level 
 
Dose (mg/m2/dose with max dose 60 mg/day) 
            -1                                    
23 mg/m2 
 1                
             
30 mg/m2 
 
 2 
 
 
 
40 mg/m2 
 
Actual dosing will be based on the dosing nomogram in Appendix XI. 
 
6.6  
Agent Information 
Composition, Formulation, and Storage 
At study sites, all study medication will be stored as described in the pharmacy manual and 
inventoried in accordance with applicable state and federal regulations. 
Investigational Treatment  
Chemical Name:  Chemical Name: N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N’-
(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, (2S)-
hydroxybutanedioate 
Cabozantinib Tablets and Storage 
Exelixis internal number: XL184 
Cabozantinib tablets are supplied as film coated tablets containing cabozantinib malate 
equivalent to 20 mg and 60 mg of cabozantinib and contain microcrystalline cellulose, lactose 
anhydrous, hydoxypropyl cellulose, croscarmellose sodium, colloidal silicon dioxide, 
magnesium stearate and Opadry® yellow. All tablet strengths are prepared from a common 
blend and are distinguished by shape. The 20 mg tablets are round and the 60 mg tablets are oval.  
The components of the tablets are listed in the table below. 
 
Table  
Cabozantinib Tablet Components and Composition 
Ingredient  
Function 
% w/w 
Cabozantinib malate (25% drug load as cabozantinib) 
Active Ingredient 
31.7 
Microcrystalline Cellulose (Avicel PH-102) 
Filler 
38.9 
Lactose Anhydrous (60M) 
Filler 
19.4 
Hydroxypropyl Cellulose (EXF) 
Binder 
3.0 
Croscarmellose Sodium (Ac-Di-Sol) 
Disenegrant 
6.0 
Colloidal Silicon Dioxide, 
Glidant 
0.3 
Magnesium Stearate 
Lubricant 
0.75 
Opadry Yellow Film Coating which includes: 
- 
HPMC 2910 / Hypromellose 6 cp  
- 
Titanium dioxide  
- 
Triacetin  
- 
Iron Oxide Yellow 
Film Coating 
4.00 
Cabozantinib should be stored at controlled room temperature (20◦C to 25◦C, 68◦F to 77◦F) 

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7.0  MODIFICATIONS FOR ADVERSE EVENTS 
 
7.1 
General Guidelines for Treatment Delay, Dose Reduction, or Study Drug 
Discontinuation for Toxicity 
Subjects will be monitored continuously for AEs throughout the study and for 30 days after the 
last dose of study treatment, and for any serious adverse event (SAE) assessed as related to study 
treatment or study procedures, even if the SAE occurs more than 30 days after the last dose of 
study treatment. 
 
Subjects will be instructed to notify their physician immediately of any and all AEs. Subjects 
experiencing one or more AEs due to the study treatment may require a dosing delay or reduction(s) 
in their dose in order to continue with study treatment.  
 
7.2   
Definition of Dose-Limiting Toxicity (DLT) 
Dose Limiting Toxicity Criteria 
 
Adverse events will be graded according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (CTCAE) (v4.0). Dose-limiting toxicity is defined as any of the 
following adverse events occurring during the DLT evaluation period that are at least possibly 
related to cabozantinib. 
 
DLT evaluation period is cycles 1 and 2 on initial dose, and cycles 3 and 4 for subjects who 
increase dose. 
 
For adverse events meeting the DLT definition at any time, dose limiting hematological and non-
hematological toxicities are handled differently. For hematologic toxicities, there must be recovery 
to meet eligibility or baseline parameters within 14 days of drug discontinuation. For general non-
hematologic toxicities, there must be recovery of the dose-limiting toxicity to (less than or equal) 
≤ Grade 1 or to meet eligibility or baseline parameters within 14 days of drug discontinuation.  
Dose modification parameters for specific non-hematologic toxicities including proteinuria, 
hypertension, deep vein thrombosis, liver toxicity, pancreatic toxicity and diarrhea are addressed 
in section 7.3.  If the required recovery for either hematologic or non-hematologic toxicity occurs 
within 14 days, then the subject may re-start Cabozantinib, but the dose will be reduced to the 
previous dose level.  If the subject is at 20 mg dose and does not meet the parameters for recovery 
by 14 days, then the subject will be off study. 
 
Dose limiting hematological and non-hematological toxicities are defined differently.  
Non-Hematological Dose Limiting Toxicity 
 
Any Grade 3 or Grade 4 non-hematological toxicity attributable to the 
investigational drug with the specific exclusion of: 
- Grade 3 nausea and vomiting of < 3 days duration 
- Grade 3 diarrhea ≤ 3 days duration 
- Grade 3 liver enzyme elevation, including ALT/AST/GGT/bilirubin, that 
return to levels that meet initial eligibility criteria or baseline within 7 
days of study drug interruption and that does not recur upon re-challenge 
with  Cabozantinib. Note: For the purposes of this study the ULN for 
ALT is defined as 45 U/L.  

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- Grade 3 fever < 5 days duration. 
- Grade 3 electrolyte abnormalities responsive to supplementation within 
one week. 
- Grade 3 asymptomatic amylase or lipase elevation that resolves to ≤ 
Grade 1 within 7 days of study drug interruption and that does not recur 
upon re-challenge with cabozantinib.   
- Grade 3 proteinuria, if confirmed by repeat P/C ratio obtained within 72 
hours of first measurement. 
 
• Dose-limiting hypertension 
a. Any Grade 4 hypertension 
b. A blood pressure >25 mmHg above the 95th percentile for age, height, and 
gender confirmed by repeated measurement is dose limiting. 
c. In subjects who begin antihypertensive therapy a blood pressure > 10 mmHg but 
≤ 25 mmHg above the 95th percentile for age, height, and gender for > 14 days 
is dose limiting. 
 
• Any Grade 2 non-hematological toxicity that persists for ≥ 7 days and 
is considered sufficiently medically significant or sufficiently 
intolerable by subjects that it requires treatment interruption. 
 
• Any toxicity requiring interruption of study drug for ≥ 7 days or which 
recurs upon drug challenge. 
 
• Note: Allergic reactions that necessitate discontinuation of study drug 
will not be considered a dose-limiting toxicity. 
 
Hematological dose limiting toxicity  
Hematological dose limiting toxicity is defined as: 
 
• Grade 3 febrile neutropenia of > 5 days duration 
• Grade 4 neutropenia 
• Grade 3 thrombocytopenia (platelets < 50,000) 
• Grade 3 anemia (Hb < 8) 
 
 
 
7.3   
Dose Modifications For Adverse events 
 
The Study Chair must be notified of any dosage modification or use of myeloid 
growth factor. 
 
Dose Modifications for Hematological Toxicity 
If a subject experiences dose-limiting Grade 4 neutropenia or grade 3 
thrombocytopenia, the treatment will be withheld. Counts should be 
checked every 3 - 4 days for thrombocytopenia and every other day for 

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neutropenia during this time. If the toxicity resolves to meet eligibility 
parameters within 14 days of drug discontinuation, the subject may resume 
treatment at the next lower dose level. Doses reduced for toxicity will not 
be re-escalated, even if there is minimal or no toxicity with the reduced 
dose.  
 
If dose-limiting toxicity does not resolve to meet eligibility or baseline parameters 
within 14 days of drug discontinuation, the subject must be removed from 
protocol therapy. 
 
If dose-limiting toxicity recurs in a subject who has resumed treatment at the 
reduced dose, the subject must be removed from protocol therapy. 
 
Dose Modifications for Non-Hematological Toxicity 
If a subject experiences non-hematological dose-limiting toxicity, the treatment 
will be withheld. If the toxicity resolves to (less than or equal to) ≤ grade 1 
or to meet eligibility or baseline parameters within 14 days of drug 
discontinuation, the subject may resume treatment at the next lower dose 
level. Doses reduced for toxicity will not be re-escalated, even if there is 
minimal or no toxicity with the reduced dose. 
 
If dose-limiting toxicity does not resolve to (less than or equal to) ≤ grade 1 or to 
meet eligibility or baseline parameters within 14 days of drug 
discontinuation, the subject must be removed from protocol therapy. 
 
If the same dose-limiting toxicity recurs in a subject who has resumed treatment 
at the reduced dose level, the subject must be removed from protocol 
therapy. 
 
Dose Modifications for Proteinuria 
• If urinalysis shows ≥ trace protein then obtain urine protein/creatinine 
(P/C) ratio.   
• If the urine P/C ratio is >1, consider confirming with a 24 hour protein 
assessment within 7 days.  
• If the urine P/C ratio ≤ 1.9 continue cabozantinib. If subject has Grade 
3 proteinuria (urine P/C ratio >1.9), a second measurement should be 
obtained within 72 hours. A second confirmation of Grade 3 proteinuria 
will be considered a DLT. 
• If the second measurement confirms Grade 3 proteinuria (urine P/C ratio 
>1.9), then interrupt cabozantinib treatment and re-assess weekly.   
• If cabozantinib is held for ≥ 14 days then remove from protocol therapy.  
If the urine P/C ratio decreases to ≤ 1.9 in < 14 days then resume 
cabozantinib at a lower dose.  
• Monitor the urine P/C ratio weekly for 2 consecutive weeks once 
protocol therapy resumes and obtain a 24-hour collection if ≥ 1 as above. 
• Cabozantinib should be discontinued in subjects who develop nephrotic 

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syndrome (proteinuria > 3.5 grams per day in combination with low 
blood protein levels, high cholesterol levels, high triglyceride levels, and 
edema). 
 
 
Dose Modifications for Hypertension 
• Baseline blood pressure (BP) is defined as the blood pressure obtained 
at the examination used for study enrollment. This baseline BP should be 
obtained as follows: 1) Obtain 3 serial blood pressures from the same 
extremity with the subject in the same position at rest with an 
appropriately sized cuff that are separated by at least 5 minutes. Avoid 
using the lower extremity if possible. 2) Average the systolic blood 
pressure from the 2nd and 3rd measurements. 3) Average the diastolic 
blood pressure from the 2nd and 3rd measurements. 4) The baseline BP is 
the average of the systolic over the average of the diastolic 
measurements. 
• Elevation in either the systolic or diastolic blood pressure should be 
considered when following the algorithm below. 
• The upper limit of normal (ULN) is defined as a BP equal to the 95th 
percentile for age, height, and gender. . 
• The NCI CTCAE will be utilized to determine the grade of hypertension 
for reporting purposes. 
• Elevated BP measurements should be repeated on the same day to 
confirm the elevation. If confirmed, subjects with elevated BP should 
have BP measurements performed at least twice weekly until BP is ≤ 
ULN. 
• The algorithm below will be used to manage cabozantinib - related 
hypertension. 
• Hypertension should be managed with appropriate anti-hypertensive 
agent(s) as clinically indicated. It is strongly recommended that 
nephrology or cardiology be consulted in the evaluation and management 
of hypertension. 
 

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Arm 1 of algorithm: 
• 
If blood pressure (BP) ≤ 95% for age, height, and gender, continue cabozantinib at the 
same dose. 
 
 
Arm 2 of algorithm: 
• 
If BP ≤ 10 mm Hg above the ULN for age, height, and gender, continue cabozantinib 
at the same dose and recheck the BP within 72 hours. 
o If the BP is ≤ ULN on recheck, continue cabozantinib at the same dose. 
o If the BP remains above the ULN on recheck, then start antihypertensive therapy 
(Section 8) and follow Arm 3 of the algorithm from the point that anti-hypertensive 
therapy is started. 
 
 
Arm 3 of algorithm: 
• 
If BP is 11 to 25 mm Hg above the 95% for age, height, and gender on ≥ 2 of 3 
measurements or > 35 mmHg above baseline on ≥ 2 of 3 measurements, start anti-
hypertensive therapy (see Section 8), continue cabozantinib at the same dose, and 
monitor BP at least twice weekly. 

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o If the BP returns to ≤ ULN within 14 days, continue cabozantinib at the same 
dose and continue anti-hypertensive therapy. 
o If the BP remains elevated ≤ 25 mm Hg above the 95% or > 35 mm Hg above 
baseline for more than 14 days after the institution of anti-hypertensive therapy, 
hold cabozantinib, monitor BP at least every 3 days, and follow Arm 4 of the 
algorithm from the point that cabozantinib is held. The antihypertensive therapy 
should be continued until the BP is less than the ULN. 
 
If the BP returns to ≤ ULN within 14 days, restart cabozantinib at a reduced 
dose (Section 6.5). 
 
If the BP remains > ULN for more than 14 days, subject is Off Protocol 
Therapy. 
o  If the BP increases to > 25 mm Hg above the ULN despite anti-hypertensive 
therapy, hold cabozantinib, but continue the anti-hypertensive agent(s). Monitor 
the BP as clinically indicated and follow Arm 4 of the algorithm from the point 
that cabozantinib is held. 
 
If the BP is ≤ ULN within 14 days, cabozantinib may be restarted at a reduced 
dose (Section 6.5). 
 
If the BP is > ULN for > 14 days, the subject is Off Protocol Therapy (Section 
11.1). 
 
Arm 4 of algorithm: 
• 
If BP is > 25 mm Hg above the 95% for age, height, and gender hold cabozantinib, 
monitor BP and administer anti-hypertensive therapy as clinically indicated. 
o If the BP returns to ≤ ULN within 14 days, cabozantinib may be restarted at a 
reduced dose (Section 6.5). 
o If the BP is > ULN for >14 days, the subject is Off Protocol Therapy. 
 
 
Arm 5 of algorithm: 
• 
If the participant develops Grade 4 hypertension, discontinue cabozantinib, monitor 
BP and administer anti-hypertensive therapy as clinically indicated. The subject is Off 
Protocol Therapy. 
 
 
 
Deep Venous Thrombosis  
If a subject develops a DVT while on cabozantinib, they will be taken Off Protocol 
Therapy. 
 
Dose Modifications for Liver Toxicity 
Cabozantinib should be held for grade 3 elevation of ALT, AST or bilirubin. Note: 
For the purposes of this trial the ULN for ALT is defined as 45 U/L. Cabozantinib 
may be re-administered at the same dose if levels of ALT, AST and bilirubin meet 
eligibility criteria or baseline within 7 days of drug discontinuation. Elevated 
laboratory parameters should be checked at least twice weekly until eligibility 
criteria are met.  
 
If lab values do not resolve to initial eligibility criteria or baseline within 7 days of 
interruption or if toxicity recurs with re-challenge, then this will be considered 
dose-limiting.  Cabozantinib will then be dose-reduced when eligibility criteria are 

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met. 
 
Dose Modifications for Pancreatic Toxicity 
Cabozantinib should be held if subject experiences Grade 3 asymptomatic amylase 
or lipase elevation. Elevated laboratory parameters should be checked at least twice 
weekly until ≤ Grade 1. 
 
If lab values do not resolve to ≤ 1 Grade within 7 days of interruption or if toxicity 
recurs with re-challenge, then this will be considered dose-limiting.  Cabozantinib 
will then be dose-reduced when eligibility criteria are met. 
 
Dose Modifications for Diarrhea 
• If dose-limiting Grade 3 (> 3 days) or Grade 4 therapy-associated diarrhea 
is experienced by a subject despite maximal use of anti-diarrheal 
medications, the dose of Cabozantinib should be held and reduced to the 
next lower dose level once the diarrhea has resolved. Doses reduced for 
toxicity will not be re-escalated, even if there is minimal or no toxicity with 
the reduced dose.  
• If dose-limiting Grade 3 (> 3 days) or Grade 4 diarrhea recurs despite 
maximal use of anti-diarrheals and dose reduction, the subject should come 
off protocol therapy. 
• Treatment of Diarrhea:  Each subject will be instructed to have Loperamide 
available and begin treatment at the first episode of poorly formed or loose 
stools or at the earliest onset of bowel movements more frequent than 
normally expected for the subject.  Subjects will also be instructed to contact 
their physician if any diarrhea occurs.  Take 4 mg (4 teaspoonfuls of the 1 
mg/5mL solution or 2 capsules/tablets) after the first loose bowel 
movement, followed by 2 mg (2 teaspoonfuls of the 1 mg/5mL oral solution 
or 1 capsule/tablet) every 2 hours.  During the night, the subject may take 4 
mg (4 teaspoonfuls of the 1 mg/5 mL oral solution or 2 capsules or tablets) 
every 4 hours.  Do not exceed 16 mg per day. 
 
8.0   
SUPPORTIVE CARE AND OTHER CONCOMITANT THERAPY 
 
Concurrent Anticancer Therapy 
Concurrent cancer therapy, including chemotherapy, radiation therapy, 
immunotherapy, or biologic therapy may NOT be administered to subjects 
receiving study drug. If these treatments are administered the subject will be 
removed from protocol therapy. 
 
Investigational Agents 
No other investigational agents may be given while the subject is on study. 
 
Supportive Care 
Appropriate antibiotics, blood products, anti-emetics, fluids, electrolytes and general 
supportive care are to be used as necessary. See Section 4.1 for drugs that should not 

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be used concomitantly due to potential interactions with cabozantinib. 
 
Diarrhea is a common side effect of cabozantinib. Loperamide should be used at the 
first sign of significant diarrhea.  
 
Palmar-plantar erythrodysesthesia syndrome (PPE; also known as hand-foot 
syndrome) is a common side effect of cabozantinib. Careful attention should be paid 
to skin exams and supportive care instituted early if any swelling or erythematous skin 
changes or symptoms of pain or burning/tingling are noted. Subjects should be 
instructed to apply moisturizing creams, avoid any trauma, harsh chemicals and limit 
hot water exposure. Topical steroid creams may be used and consider early 
dermatology referral (please see APPENDIX X for suggested prophylaxis and 
treatment for PPE).   
 
Growth Factors 
Growth factors that support platelet or white cell number or function can only be 
administered for culture proven bacteremia or invasive fungal infection. The Study 
Chair should be notified before growth factors are initiated. 
 
Concomitant Medications 
Medications that are strong inhibitors or inducers of CYP3A4 should be avoided  
 
The use of enzyme inducing anticonvulsants is not permitted.  
 
Medications that prolong the QT interval and have a known or possible risk of 
Torsades de Pointes should be avoided if possible, but are not explicitly excluded 
(see section 6/3) 
 
Surgery 
Subjects should not have elective surgical procedures while on therapy. For 
subjects who require emergent or urgent procedures (including dental surgery or 
invasive dental procedures), cabozantinib should be stopped at least 28 days prior 
to procedure, if feasible.  Therapy may not be restarted until adequate wound 
healing (at least 2 weeks after major procedures, 7 days after minor procedures such 
as port-a-catheters, and 3 days for external lines [e.g. Hickman or Broviac]. 
 
Concurrent Anti-Hypertensive Therapy 
The algorithm above will be used to grade and manage cabozantinib related 
hypertension. Should initiation of anti-hypertensive therapy be required, single 
agent therapy (commonly including the calcium channel blockers amlodipine or 
nifedipine, which are permissible without discussion with the study chair) should 
be started and the blood pressure should be monitored at least twice weekly until 
BP is within the 95th percentile for age, height, and gender. 
 
Management of Hypothyroidism 

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Subjects with Grade 2 hypothyroidism adequately managed with thyroid hormone 
replacement may continue on protocol therapy. Subjects with Grade 3 or greater 
hypothyroidism will be considered to have had a dose-limiting toxicity. These 
subjects should be managed according to guidelines for non-hematologic toxicity 
and should also be evaluated by an endocrinologist for further management. 
Subjects who enter the study on thyroid replacement should have their medication 
adjusted to maintain TSH in the normal range.  
 
 
9.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
 
Pre and on study evaluations are described in Appendix I. 
 
9.1 
Required Clinical, Laboratory and Disease Evaluation 
All entry/eligibility studies must be performed within 2 weeks prior to enrollment into the trial.  
The baseline MRI study documenting disease status is required within 4 weeks prior to study entry.  
Entry/eligibility studies (laboratory and MRI) may be counted as the baseline (pre-study) studies, 
as long as there has been no concerning change in clinical status prior to starting study drug (which 
must start within 14 days of enrollment). 
 
9.2 
History and physical examination and vital signs 
Physical examination will be performed prior to entry, at Day 15 +3 days, at the end of cycle 1 +1 
week, at cycle 2 Day 15 +1 week, at the end of cycle 2 +1 week, at cycle 3 Day 15 +1 week, at the 
end of cycle 3 +1 week, after cycles 4-12 +2weeks, and after cycles 14, 16, 18, 20, 22, 24 +2weeks.  
In addition, at the end of treatment +2 weeks if this is not encompassed in the times above. The 
exam must comprise a total body examination (general appearance, skin, neck, including thyroid, 
eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities and basic nervous 
system). Significant findings made after the start of study drug which meet the definition of an 
Adverse Event must be recorded.  
Vital sign assessment consists of height (first visit in Cohort A, and every visit in Cohort B), pulse, 
blood pressure, respiration rate, oxygen saturation by pulse oximeter, temperature and weight. 
Blood pressure, pulse and respiration rate should be measured on subjects after at least 3 minutes 
in the sitting position. 
 
 
9.3 
Phone Call 
Subjects will be called to assess drug compliance and toxicity at the end of cycles 13, 15, 17, 19, 
21, 23 +2weeks. 
 
9.4 
Laboratory Testing 
CBC with differential and platelets, comprehensive metabolic panel with Ca, Mg, Phos, lipase, 
and amylase must be performed within two weeks prior to entry on trial, at Day 15 +3 days, at the 
end of cycle 1 +1 week, at cycle 2 Day 15 +1 week, at the end of cycle 2 +1 week, at cycle 3 Day 
15 +1 week, at the end of cycle 3 +1 week, and after cycles 4-24 +2weeks.  In addition, at the end 
of treatment +2 weeks if this is not encompassed in the times above.   
 

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PT, PTT, INR must be performed within two weeks prior to entry on trial, at the end of cycles 1-
3 +1 week, and after cycles 4-24 +2weeks.  In addition, at the end of treatment +2 weeks if this is 
not encompassed in the times above. 
 
Urinalysis must be performed within two weeks prior to entry on trial, at the end of cycles 1-3 +1 
week, and after cycles 4-24 +2weeks.  In addition, at the end of treatment +2 weeks if this is not 
encompassed in the times above. 
 
Urine protein:creatinine ratio must be performed within two weeks prior to entry on trial, at the 
end of cycles 1-3 +1 week, and after cycles 4-24 +2weeks.  In addition, at the end of treatment +2 
weeks if this is not encompassed in the times above. 
 
Thyroid stimulating hormone must be performed within two weeks prior to entry on trial, at the 
end of cycle 1 +1 week, at the end of cycle 3 +1 week, after cycles 6, 9, 12, 16, 20, 24 +2 weeks.  
In addition, at the end of treatment +2 weeks if this is not encompassed in the times above. 
 
Urine or serum pregnancy test tests will be given to all females of childbearing age within 7 days 
prior to starting treatment medication.  In addition, tests will be administered at the end of cycles 
2 +1 week, and after cycles 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24 +2weeks.  In addition, at the end 
of treatment +2 weeks if this is not encompassed in the times above. 
 
9.5 
EKG 
12-lead EKG should be performed within two weeks prior to entry on trial, at the end of cycle 1 
+1 week, after cycle 2 +1 week, and after cycles 4, 6, 9, 12, 16, 20, 24 +2weeks.  In addition, at 
the end of treatment +2 weeks if this is not encompassed in the times above. 
 
9.6 
MRI for volumetric analysis of plexiform neurofibroma  
Evaluate the plexiform neurofibromas(s) by MRI within 4 weeks prior to cycle 1 and after cycles 
4 +2 weeks, 8 +2 weeks, 12 +2 weeks, 18 +2 weeks, and 24  +2 weeks while on study and at end 
of study +2 weeks.  To evaluate the durability of response, subjects who responded while on 
treatment, will be recommended but not required to have a follow-up MRI scan at approximately 
4 months and 12 months following completion of therapy.  If a subject starts another tumor-
directed therapy during the one year follow-up time, then they are off-study (and no further MRIs 
requested).  See Appendix IV for imaging protocol. 
 
9.7 
Quality of Life and Pain Evaluations (Required) 
This study will evaluate quality of life, pain intensity, and pain interference in patients during 
treatment with cabozantinib. The Pediatric Quality of Life Inventory (PedsQL) NF1 Module 
(Adult and Teen self-report forms) will be used to assess disease-specific QOL in subjects 16 
years and older (see table below).  The Pediatric Quality of Life Inventory (PedsQL) Generic 
Core Scales will be used to assess general health related QOL in children 3-15.     
 
Pain intensity in both cohorts will be assessed by self-report with the Numeric Rating Scale-11 
(NRS-11) and pain interference will be measured by the Brief Pain Inventory (BPI) Interference 
Scale in subjects > 16 and the Pain Interference Index in subjects 5-15 years.  The following 

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table summarizes the quality of life and pain questionnaires to be completed by age of the 
subjects.   
 
 
Quality of Life and Pain Questionnaires to be Completed by Age of Subject at Study Entry 
Subjects >16 years 
 
Questionnaire 
Age of Subject (years) 
at Study Entry 
 
16-20* 
21+* 
Disease Specific QOL 
Subject: PedsQL NF1 Module-Teen 
      or     Peds QL NF1 Module-
Adult 
 
X 
 
X 
Pain 
 
Age of Subject (years) 
 
16+** 
Subject: NRS-11 Pain Intensity 
X 
    and    BPI-Pain Interference 
X 
 
 
Background Information Forms to be Completed by the Subject 
 
 
 
 
*If subjects are 21 years old at study entry, they should be administered the Adult PedsQL NF1 Module. If subjects 
are 16 to 20 years old at study entry, they should be administered the Teen PedsQL NF1 Module.  However, if 
subjects turn 21 years old during the study, they should continue to be administered the Teen version of this scale 
that they started at study entry. 
**All subjects should complete the same self-report pain intensity and pain interference measures and background 
form.  
Patient Questionnaire 
Age of Patient (years) 
 
3 - 7 
8 - 15 
Pain Intensity 
 
 
Patient self-report: Numeric Rating Scale-11 
 
√ 
Pain Interference 
 
 
Patient self-report: Pain Interference Index 
 
√ 
Global Impression of Change  
 
 
Patient self-report:  Global Impression of Change 
Scale 
 
√ 
(follow-up evaluations only) 
General QOL 
 
 
Patient self-report: PedsQL Acute form 
 
 
√ 
8 - 12 
(Child) 
√ 
13 - 18 
(Teen) 
Questionnaire 
Age of Subject (years) 
 
16+** 
Background Information 
All subjects 
QOL Background Form 
X 

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Subjects 3 – 15 years 
 
 
Parent Questionnaires 
Age of Patient (years) 
 
3 - 7 
8 - 15 
Background Information 
 
 
Parent report:  Pediatric Background Form 
√ 
√ 
Pain Interference 
 
 
Parent proxy report: Pain Interference Index 
 
√ 
(5 - 7) 
√ 
Global Impression of Change  
 
 
 
Parent report:  Global Impression of Change Scale 
 
√ 
(5 - 7; follow-
ups evals only) 
√ 
(follow-up evaluations only) 
General QOL 
 
 
Parent proxy report: PedsQL Acute form 
√ 
2 - 4 
(Toddler) 
√ 
5 - 7  
(Young Child) 
√ 
8 - 12 
(Child) 
√ 
13 - 18 
(Teen) 
 
 
Clinician Questionnaire 
Age of Patient (years) 
 
3 - 7 
8 - 15 
Global Impression of Change 
 
 
Clinician observer report: Global Impression of 
Change Scale 
√ 
(follow-up evaluations only) 
√ 
(follow-up evaluations only) 
√ Administer items with a check mark under the correct age range of the patient 
 
 
To allow for more meaningful analysis of the QOL data, the subject (for those >16 years) and the 
parent/primary caregiver (for pediatric subjects 3 – 15 years) also will complete a background 
information form at study entry and each QOL assessment.  This form will collect general 
information such as their level of education, work/school status, psychiatric diagnoses, and pain 
medications, as well as the visibility of NF1 tumors and severity of NF1 symptoms. 
 
These forms should be completed pre-treatment, after cycle 4 +2 weeks, 8 +2 weeks, 12 +2 
weeks, 18 +2 weeks, and 24 +2 weeks.  In addition, at the end of treatment +2 weeks if this is not 
encompassed in the times above.  When administering these forms, review the instructions with 
the subjects and check to make sure they answered all the items.  If subjects have difficulty 
reading, it is permissible to read the items to them, but the subjects should answer the items 
themselves.  Completed forms should be sent (fax or mail copies) to the NF Consortium 
Operations Center within 2 weeks of completion.  For any questions regarding the QOL/pain 
assessment please contact: Pam Wolters at woltersp@mail.nih.gov.  See Appendix VII for a 
description of the QOL and pain measures and forms. 

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The QOL documents will be reviewed centrally by Dr. Pam Wolters.  If any responses are noted 
that suggest serious emotional distress, the PI at the subject’s site will be notified.  The site PI 
will be responsible for acknowledging to Dr. Wolters receipt of these concerns and for initiating 
appropriate action as deemed clinically necessary. 
 
9.8 
Biomarker studies 
1.  Plasma biomarker (cytokine) assays will be performed using multiplex simultaneous 
quantification of thirty soluble cytokines and growth factors including: VEGF, TGF-β, PDGF-
AB/BB, MCP-1, MIP1α, MIP1β, TNFα, GM-CSF, EGF, IL-13, IL-1rα, IL-10, IL-4, IL6, FGF-2, 
and RANTES. The multiplex assay will be performed according to the manufacturer’s protocol 
(Millipore Milliplex, Billerica, MA) and analyzed on a Luminex 200 cytometer with StarStation 
software (Luminex Corp, Austin, TX). Plasma samples for each subject and each treatment time 
point will be stored at -80C and thawed once for simultaneous assay.  Samples will be collected 
within two weeks prior to cycle 1, at Day 15 +3 days, at the end of cycles 2 +1 week, and at the 
end of cycles 4 +1 week. 
 
Rationale:  It has been well recognized that cytokines mediate and regulate immunity and 
inflammation, which are an important component of the biological milieu associated with cancer 
progression.  Cytokines have been used as biomarkers in research for prognosis and have been 
associated with symptoms and adverse outcomes in multiple conditions, including cancer.  We 
have previously shown that multiple cytokines/growth factors are altered in subjects with 
plexiform neurofibromas as well as in tumor murine model of NF1.  Our unpublished data 
suggest that the cytokine levels are associated with tumor progression and responsiveness to 
Gleevec therapy.  The examination of cytokine patterns has been limited by traditional laboratory 
methods.  Multiplex now permits the characterization of a broader array of cytokines in a single 
specimen.  Because cytokines operate in integrated networks, a more complete understanding 
will be gained as multiple cytokines can be examined for patterns of response that may be 
associated with response to the treatment and the prognosis of NF1. 
 
Please see Appendix V for details regarding obtaining sample and shipment. 
 
2.  Polychromatic Flow Cytometry (PFC) & Identification of Circulating Progenitor Cells 
(CPCs):  PFC for the identification of CPCs will be performed at three time points.  Whole blood 
will be drawn in EDTA tubes and sent for processing to the Indiana University Simon Cancer 
Center’s Angiogenesis, Endothelial and Pro-Angiogenic Cell Core (AEPCC) Facility, which is 
directed by Dr. Karen Pollok.  Using the PFC protocol developed by Dr. Case (Estes et al., 
Current Protocols in Cytometry), the phenotypic detection and enumeration of CPCs will be 
performed, and the ratio of pro-angiogenic (i.e. CD133+) vs. non-angiogenic CPCs will be 
calculated on all samples.  Data obtained will then be correlated with tumor response.  Samples 
will be collected within two weeks prior to cycle 1, at Day 15 +3 days, at the end of cycles 2 +1 
week, and at the end of cycles 4 +1 week and sent immediately to the AEPCC Facility. 
 
9.9 
Biological Specimens for banking (Appendix XV) 
Blood Samples will be drawn at baseline (pre-treatment), after course 4 (+2 weeks), after course 
12 (+2 weeks), and at the end of treatment (+2 weeks) if this is not encompassed in the times 

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above.   In addition, blood samples should be drawn around the time of tumor biopsy if tumor 
tissue is being submitted. 
 
The following will be collected at each time point: 
• Streck tube (for plasma):  ~ 2 mL.  
• EDTA tube (for DNA):  ~ 5 mL.   
• PAXGene tube (for RNA) ~ 2.5 mL. 
 
Tubes should be inverted at least 10 times after being drawn. 
 
The samples will only be obtained if the total blood volume does not exceed 5 mL/kg.  If not 
enough blood can be drawn for all tubes, the priority order for obtaining the specimens is:   
1) Streck tube, 2) EDTA tube, 3) PAXGene tube. 
 
Label the specimens with the specimen labels provided with the specimen kit. 
 
Blood specimens must be shipped (unprocessed) same day at ambient temperature to the 
biorepository by overnight delivery using shipping container provided by the biorepository (see 
Appendix XV). 
 
Tumor Tissue (optional) will be collected from subjects undergoing a clinically indicated 
procedure and who consent: 
• Fresh frozen tissue:  1-2 pea sized aliquots (~ 0.3 cm3, equivalent to 0.8 cm in diameter) 
of excess (left over) tumor tissue.  Place each aliquot in a separate cryovial and label the 
specimen with subject’s study number. Snap freeze the aliquots in liquid nitrogen 
(preferred) or dry ice and then store in a freezer at -80°C or below until they can be sent to 
the biorepository. 
• 1 H&E stained slide cut from each submitted piece to confirm tumor is present.  
• If fresh frozen tissue is unavailable, please submit processed DNA (at least 3 micrograms) 
and RNA (at least 400 nanograms with optimal RIN > 7) if available.  
 
Fresh frozen tissue or DNA/RNA must be shipped on dry ice via overnight delivery using 
shipping materials provided by the biorepository (see Appendix XV). H&E slide should be 
shipped at ambient temperature. 
 
 
10.0 
ADVERSE REPORTING REQUIREMENTS 
 
10.1 Definitions 
 
• Adverse Events: An adverse event is any new, undesirable medical occurrence or change 
(worsening) of an existing condition in a subject that occurs during treatment, whether or not 
considered to be product related. Therefore, adverse events are treatment emergent signs or 
symptoms. Elective hospitalizations for pretreatment conditions (e.g., elective cosmetic 
procedures) are not adverse events. Non-clinically significant abnormal laboratory values 
should not be reported as adverse events; however, any clinical consequences of the 

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abnormality should be reported as adverse events.  All adverse events must be noted on the 
case report forms and submitted to the operations center within 2 weeks of completion of every 
treatment cycle. 
 
For all adverse events, the investigator must pursue and obtain information adequate both to 
determine the outcome of the adverse event and to assess whether it meets the criteria for 
classification as a serious adverse event requiring immediate notification (within 24 hours) to 
the site PI and clinical coordinator, as well as the NF Operations Center.  Follow-up of the 
adverse event, even after the date of therapy discontinuation, is required if the adverse event 
or its sequelae persist. Follow-up is required until the event or its sequelae resolve or stabilize 
at a level acceptable to the investigator and sponsor. 
 
• Serious Adverse Events: A serious adverse event is defined by regulatory agencies as one that 
suggests a significant hazard or side effect, regardless of the investigator’s or sponsor’s opinion 
on the relationship to investigational product. 
 
This includes, but may not be limited to, any event that (at any dose): 
is FATAL 
is LIFE THREATENING (places the subject at immediate risk of death); 
requires HOSPITALIZATION or prolongation of existing hospitalization; 
is a persistent or significant DISABILITY/INCAPACITY; or 
is a CONGENITAL ANOMALY/BIRTH DEFECT 
 
Important medical events that may not be immediately life threatening or result in death or 
hospitalization, but may jeopardize the subject or require intervention to prevent one of the 
outcomes listed above, or result in urgent investigation, may be considered serious. Examples 
include allergic bronchospasm, convulsions, and blood dyscrasias.  
 
10.2 
Grading of Adverse Events using Common Terminology Criteria (CTCAE) 
 
Adverse events (toxicities) will be graded according to the National Cancer Institute CTCAE 
version 4.0 for reporting of adverse events.  A copy of the current version of the CTCAE 
version 4.0 can be downloaded from the CTEP home page: 
http://ctep.cancer.gov/reporting/ctc.html  
 
 
10.3 
Attribution: Definitions of relationship to study medication are as follows: 
 
• UNRELATED: bears no relation to timing of medication, similar to symptoms or signs expected 
in the disease process, does not recur on rechallenge. 
• UNLIKELY: does not have temporal relationship to intervention, could readily have been 
produced by the subject’s clinical state, environmental, or other interventions, does not 
reappear or worsen with reintroduction of intervention. 
• POSSIBLY: bears relation to timing of medication, similar to symptoms or signs expected in the 

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disease process, does not recur on rechallenge. 
• PROBABLY: bears clear relation to timing of medication, distinct from symptoms or signs 
expected in the disease process, does not recur on rechallenge. 
• DEFINITELY: bears clear relation to timing of medication, distinct from symptoms or signs 
expected in the disease process, occurs on rechallenge. 
 
The expected adverse events related to administration of cabozantinib are listed in Section 7.3.  
All other adverse events not attributed to cabozantinib will be considered unexpected. Adverse 
events attributable to cabozantinib will be reported if the adverse events are at an intensity that 
is more severe than previously documented or considered significant by the investigator. 
 
 
10.4 
Reporting Procedures for All Adverse Events 
 
All observed or volunteered adverse events, regardless of suspected causal relationship to study drug, will 
be recorded as Adverse Events in the case report forms and submitted to the Operations Center within 2 
weeks of completion of each treatment cycle. Events involving adverse drug reactions, illnesses with 
onset during the study, or exacerbation of pre-existing illnesses should be recorded. Objective test 
findings (e.g. abnormal laboratory test results) should also be recorded.  
 
It will be left to the investigator’s clinical judgment whether or not an adverse event is of sufficient 
severity to require that the subject should be removed from treatment. A subject may also 
voluntarily withdraw from treatment due to what he or she perceives as an intolerable adverse 
event. If either of these occurs, the subject will be given appropriate care under medical supervision 
until symptoms cease or until the condition becomes stable. 
 
The severity of toxicities will be graded in accordance with the Common Terminology Criteria for 
Adverse Event (CTCAE) version 4.0 (http://ctep.cancer.gov/reporting/ctc.html ). 
 
The relationship of adverse events to the study medications will be assessed by means of the question: “Is 
there a reasonable possibility that the event may have been caused by the study medication?” Please answer 
Yes or No.  
 
 
10.5 
Expedited Reporting Guidelines 
 
The following adverse events require expedited reporting: 
• All adverse events that are both serious and unexpected 
• Adverse events that might influence the benefit-risk assessment of administration of 
cabozantinib as outlined in the protocol 
• All grade 5 adverse events 
• Any adverse event that might require a target reduction 
• A serious adverse event that occurs within 30 days of the last dose of the investigational agent 
• Pregnancy 

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If a subject or a subject’s partner becomes pregnant while receiving investigational 
therapy or within 30 days after the last dose of study drug, a report should be 
completed and expeditiously submitted 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 cabozantinib should be reported as an SAE. 
• Expedited AE reporting timelines defined: 
“24 hours; 3 business days” – The investigator must initially report the AE within 24 hours 
(or immediately if the event is fatal or life-threatening) of learning of the event to the Study 
Chair (fisherm@email.chop.edu) and NF Operations Center followed by a complete written 
report within 3 business days of the initial 24-hour report. 
 
Adverse events requiring expedited reporting will be reported and documented on Form FDA 
3500A MedWatch Form http://www.fda.gov/medwatch/getforms.htm) and forwarded to: 
 
NF Consortium Operations Center 
Clinical Nurse Manager:  Lynn Merritt, RN                                  205-934-5376 
Program Director:  Karen Cole – Plourde, BS                               205-934-5140 
Research Compliance Manager:  Juliette Southworth, BS             205-975-4075 
Direct Email:  nfcop@uab.edu  
 
 
The clinical research manager from the NF Consortium Operations Center will forward all 
related adverse events that are both serious and unexpected to the FDA on Form FDA 3500A 
MedWatch Form http://www.fda.gov/medwatch/getforms.htm to: 
  
MedWatch 
Fax: 1-800-FDA-0178 
 
The final MedWatch Form or CIOMS-1 form must be submitted by the study site to Exelixis 
within one to two business days of submission to the FDA or applicable regulatory agency 
(including confirmation of date that the report was submitted) to allow Exelixis time to cross-
report to Exelixis’ IND. E-mail: drugsafety@exelixis.com ; Fax 650-837-7392. 
 
10.6 
Reporting of Protocol Violations/Deviations and Unanticipated Problems 
 
Site reporting to NF Operations Center 
Sites will report unanticipated problems and/or protocol deviations that impact subject safety or 
the scientific integrity of the study to the Operations Center promptly to nfcop@uab.edu.  Other 
protocol violations and deviations should be reported to the NF Operations Center annually.   
 
NF Operations Center reporting requirements 
The Operations Center will report unanticipated problems that impact subject safety or the 
scientific integrity of the study to the USAMRMC ORP HRPO promptly.  Unanticipated problems 

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will also be reported to the protocol team, Medical Monitor, and DSMB. 
 
All unanticipated problems involving risk to subjects or others must be promptly reported by the 
NF 
Operations 
Center 
via 
phone 
(301-619-2165), 
email 
(usarmy.detrick.medcom-
usamrmc.other.hrpo@mail.mil), or facsimile (301-619-7803) to the HRPO.  A complete written 
report will follow the initial notification.  In addition to the methods above, the complete report 
can be sent to the US Army Medical Research and Materiel Command, ATTN: MCMR-RP, 810 
Schreider Street, Fort Detrick, Maryland 21702-5000.   
 
Suspensions, clinical holds (voluntary or involuntary), or terminations of this research by the IRB, 
the institution, the Sponsor, or regulatory agencies will be promptly reported to the USAMRMC 
ORP HRPO. 
 
Other protocol violations and deviations that do not impact subject safety or affect scientific 
integrity of the study will be provided annually to the Sponsor. 
 
 
 
 
11.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA  
 
11.1 
Criteria for Removal from Protocol Therapy 
a.   Progressive disease 
b.  < 15% reduction in index tumor volume after 8 cycles. (Of note, subjects may begin cycle 9 while 
central review of tumor response is ongoing) (Cohort A only) 
c.   < 20% reduction in index tumor volume after 12 cycles. (Of note, subjects may begin cycle 13 
while central review of tumor response is ongoing)  
d.  Completion of cycle 24 
e.  Cabozantinib-related toxicity requiring removal (see Section 7) 
f.  Refusal of further protocol therapy by subject/parent/guardian 
g.  Other cancer develops 
h.  Non-compliance that in the opinion of the investigator does not allow for on-going participation. 
i.  Physician determines it is not in the subject’s best interest. 
j.  Participant is prescribed a non-allowed concomitant medicine during study. 
k. Subject must have surgery on a target PN. 
l.  Subject becomes pregnant 
• If a subject becomes pregnant while receiving investigational therapy or within 30 days 
after the last dose of study drug, the subject should be followed until the outcome of the 
pregnancy. 
 
Subjects who are off protocol therapy are to be followed until they meet the criteria for OFF Study 
(see below). 
 
11.2  Off Study Criteria 
For subjects who did not have a response (<20% shrinkage of target tumor) or have tumor 
progression (≥ 20%) at any time: 

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a) Thirty days after the last dose of cabozantinib (but note that subjects with ongoing toxicity 
should be followed until the toxicity resolves or 30 days, whichever is longer) 
 
For subjects who had a response (≥20% target tumor shrinkage by 12 cycles) and never experience 
tumor progression: 
b) Completion of their one year follow-up MRI scan 
 
For all subjects (supercedes “a” or “b”): 
c)  Death 
d)  Lost to follow-up 
e)  Withdrawal of consent for any further data submission. 
f)  Initiation of subsequent other medical treatment directed towards the plexiform neurofibroma 
g)  Initiation of medical treatment (e.g. chemotherapy, biologic therapy, radiation therapy) 
directed towards other NF1-related tumor, such as an optic pathway glioma.  
h) Outcome of Pregnancy (for subjects who become pregnant while receiving investigational 
therapy or within 30 days after the last dose of study drug). 
 
 
12.0 
STATISTICAL AND ETHICAL CONSIDERATIONS   
 
12.1 
Subject Accrual 
Subjects of both genders, from all racial and ethnic groups are eligible for this trial if they meet 
the criteria outlined in Section 4.0. 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. Most plexiform neurofibroma 
grow out of proportion to somatic growth for a period of time during childhood, but may reach a 
plateau by the end of puberty.  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 patient 
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. 
 
 
12.2 Statistics and Feasibility 
 
Sample Size 
Cohort A:  Minimum: 9 evaluable subjects  Maximum: 19 evaluable subjects Target: 17 evaluable 
subjects. To allow for 25% unevaluable subjects, a maximum of up to 24 subjects will be enrolled. 
We anticipate enrollment to be completed in 24 months with primary outcome measure defined in 
30 
months. 
 
The sample size for this trial is based on three primary factors:  safety based on risk versus benefit; 
efficacy of 25% response rate and power of 80% to achieve feasibility if this rate were true.   In 
order to balance these factors, we propose a two stage Simon Optimal Design (ref Controlled 
Clinical Trials 10:1-10 1989) for cohort A.  Two stage designs are designed to provide an overall 

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Type I error that is based on the probability of stopping at the end of Stage 1 plus the conditional 
probability of rejecting the drug given one passed Stage 1 to get to Stage 2.  Thus, the overall Type 
I error was set at 5% and power at 80%.   We assume a null hypothesis success rate of 5% versus 
a treatment with a 25% response rate.   
 
Stage 1 for cohort A will consist of 9 subjects to provide evidence of effectiveness and safety.   If 
at least 1 of the 9 subjects achieves a radiographic response (≥20% reduction in tumor volume) the 
study will be allowed to recruit the total sample size of 17 evaluable subjects.  The Stage I 
boundary is the same 0 of 9.  The second stage of the design requires only 3 or more of the 17 
subjects to have a positive response. If the null hypothesis is true, there is a 63% chance of 
terminating after Stage 1.  If the probability of success is actually 0.25, there is a 92% chance that 
1 or more subjects will exhibit a 20% reduction in tumor volume at Stage 1.  Thus, it is expected 
that the trial will continue with continuous recruitment if the 25% success rate is correct.   
 
For safety reasons, in cohort A, subjects who did not achieve at least a 15% reduction in tumor 
volume were not be continued beyond 8 cycles, as the likelihood of achieving a response (20% 
reduction in tumor volume) by 12 months is minimal. These subjects will be discontinued from 
the trial and counted in an "Intent to Treat" analysis as evaluable and as failures.  If there are no 
subjects with a response (20% or more reduction in tumor volume) by the end of 8 cycles, but one 
or more with a 15% or more tumor volume reduction, recruitment will be suspended until the 
decision on futility (0 of 9 with at least 20% or more reduction in tumor volume after 12 cycles) 
or successful continuation can be definitively recommended.   That is, if there are a number of 
subjects with 15% up to but not achieving a 20% reduction in tumor volume, the study will follow 
those subjects up to their post cycle 12 visit to determine if the recruitment can be restarted.  If 
none of these 9 achieves a 20% tumor volume reduction by 1 year, the study will be terminated. 
 
Cohort B:  Enroll up to 24 evaluable subjects. Target: minimum of 17 evaluable subjects. To allow 
for up to 25% unevaluable subjects, a maximum of 24 subjects will be enrolled. We anticipate 
enrollment to be completed within 12 months with the primary outcome measure defined in 24 
months. 
 
The sample size for this trial is based on the safety and feasibility data needed:  thus, safety based 
on risk versus benefit.  For feasibility, we expect at least efficacy of a 25% response rate.   We are 
only interested if cabozantinib is positive and thus, assume a 1 sided test using a Type I error of 
5%.  We assume a null hypothesis success rate of 5% versus a treatment with a 25% response rate.  
If all 20 patients are evaluable there is 80% power to detect differences between 25% and 5% with 
80% power.   The power in this strata is 64% when the minimal sample size is realized.  Based on 
the preliminary response data (passed the threshold to move to stage 2) and minimal toxicity in 
Cohort A to date, a 2-stage design is not felt to be necessary for Cohort B. 
 
For cohort B (pediatric cohort), because of the overall excellent safety profile of cabozantinib and 
the numerous late tumor responses in cohort A (adult cohort) (see protocol section 2.3), the 
requirement to stop study treatment in subjects who do not achieve at least a 15% reduction in 
tumor volume by 8 cycles will be eliminated.   
 
 

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12.3 
Statistical Analysis Plan 
The basic statistical analysis plan for this proof of concept study will describe the subject 
population by baseline characteristics:  clinical, PK/PD, Quality of Life and pain scores at 
baseline.  Following complete accrual, study logistics will be summarized as per a Consort 
Diagram with reasons for withdrawal or unable to complete the study tabulated for each cohort 
separately.  Appropriate data analysis sets will be defined. The full-analysis set will include data 
from all subjects who receive ≥1 dose of therapy on this study; a safety analysis set will 
comprise data from subjects in the full-analysis set with any treatment doses. Other data sets 
(responding, evaluable, and pharmacodynamic/pharmacokinetic data sets) will be defined and 
will include data from subjects who have the necessary baseline and on-study measurements to 
provide interpretable results for specific parameters of interest. 
 
Descriptive summaries will be prepared to show sample size, mean, standard deviation, 95% 
confidence intervals (CIs) on the mean, median, minimum, and maximum for continuous 
variables and counts, percentages, and 95% CIs on the percentage for categorical variables. This 
will be done for each cohort separately.   For endpoints relating to tumor control, subject well-
being, and biomarkers, analyses will be done based on the full-analysis, responding, evaluable, 
or pharmacodynamic data sets, as appropriate. Time-to-event analyses will be performed with 
reference to the date of first treatment on this study.  Analyses will focus on evaluation of 
outcomes within each treatment arm and will be largely descriptive in nature as per the sample 
size justification section within cohort.  Changes in tumor volumes, etc. will be summarized by 
medians, ranges, and the corresponding 95% CI.  Continuous and categorical variables will also 
be summarized as appropriate.   
 
If both cohorts achieve the maximum number of participants, a pooled, but stratified analysis 
will be conducted to assess the estimates of success.  Relationship of outcomes will be compared 
between cohort A and cohort B using stratified regression analyses and/or Cochran-mantel-
Haenszel tests. 
 
Based on the safety analysis set, information regarding study treatment administration, drug 
dosing and cycle compliance, safety variables, will be described and summarized. Using data 
from the pharmacokinetic analysis set plasma concentrations will also be described and 
summarized.  Peak, Trough, Area under the curve and mean serum levels will be compared to 
tumor responsiveness.  Safety will be assessed via tabulations of AEs and SAEs as well as Diary 
recordings following treatment dose/cycle of therapy. 
 
All analyses for outcome results will be based on evaluable subjects, as defined in section 12.4. 
 
At the end of the trial, we will report poor performance if the treatment is rejected at Stage 1, not 
meeting the criteria of at least 1 success in 9 cases.  If there is no success at Stage II, we will 
report a failure to reject the null hypothesis using the conditional probability of the added 
subjects. If the null hypothesis is rejected, the probability of the estimated success rate will be 
reported and 95% confidence intervals as well as the distribution of changes in tumor size. 
 
An early stopping rule will be invoked for both cohorts to potentially prevent accrual of subjects 
onto the study in the event that cabozantinib is associated with a higher than acceptable rate 

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of dose-limiting toxicity (DLT) requiring removal from study (set at 10% or higher) during the 
first 2 cycles. Toxicity will be continuously monitored.  As per the 2nd table below, if at any time 
>2 of the first 10 subjects or 4 or more of the first 15 total subjects are removed for DLT, then 
accrual will be stopped until the DSMB reviews safety and efficacy data for the study and 
recommends termination or despite the DLT (because of the benefit:risk assessment or other 
reasoning) recommends reopening recruitment.  Boundaries for DSMB for consideration of 
terminating each cohort (both cohort A and B) would be the same. 
 
Table 1:  Stopping Boundaries requiring DSMB to consider terminating trial  
Number of subjects Trial will be stopped if the number of subjects with severe 
toxicity is greater than or equal to the number below 
10 
3   
(equivalent to a p-value of 0.07 that the rate of severe 
toxicity is 10% or less) 
15 
4 
(equivalent to a p-value of 0.055 that the rate of severe 
toxicity is 10% or less) 
 
 
Using these rules and the binomial distribution, the chance of putting the trial on hold and 
potentially stopping early within the first 10 subjects: 
True probability of toxicity 
Chance of stopping early 
.10 
7% 
.20 
32% 
.25 
47% 
.30 
62% 
.35 
74% 
.40 
83% 
 
 
For the comparison of volumetric measures, 60 consecutive patients enrolled on 
Neurofibromatosis Clinical Trials Consortium PN studies will be included (including NF108). 
Two groups of independent volume measurements (NCI-MEDx and MGH-3DQI) will be 

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performed of the target lesions on up to 5 MRIs per subject (pre-study, baseline, pre-cycle 5, pre-
cycle 9, pre-cycle 13). Interval change will be calculated to classify disease status as follows: 
progressive disease (PD) if volume increase is > 20%, partial response (PR) if volume decrease 
is > 20%, and stable disease (SD) if change is < 20% between time points.  Of note, the results of 
the MEDx analysis at the NCI will be utilized in analyzing and making decisions on the clinical 
trial, as has been done on all previous Neurofibromatosis Clinical Trials Consortium PN trials.  
The results of the 3DQI analysis of each scan performed at the MGH will not be released to sites 
or the study team while the study is ongoing.  Wilcoxon signed rank test will be used to 
statistically compare the numerical difference between PN volumes at each time-point, and the 
numerical difference between the percent changes in PN volumes over time. The Jonckheere-
Terpstra trend test will be used to establish the degree of significance of the association in 
disease status classifications. After establishing the overall degree of agreement, the McNemar 
test for paired categorical data (for two categories) or an exact marginal homogeneity test (for 3 
ordered categories) will be used to demonstrate the degree of balance in the discordant results. 
For the fraction of concordant disease status classifications and the overall response rate 95% 
confidence intervals will be calculated. 
 
12.4 
Definitions of Evaluable 
 
12.4.1  
Evaluable for Toxicity - 
Subjects who receive at least 1 dose of the study drug and are removed from treatment for 
toxicity are evaluable.  Any subject who completed one full cycle of therapy is evaluable 
for toxicity. 
 
12.4.2 
Evaluable for Response – Subjects who have completed at least two cycles of 
therapy and have had their first follow-up MRI evaluation. Subjects who did not respond 
and are later found to have a target tumor other than a plexiform neurofibroma (e.g. 
malignant peripheral nerve sheath tumor) are not evaluable for response.  
 
 
13.0 
RESPONSE CRITERIA  
 
Tumor Assessment 
Tumor response should be assessed by MRI at study entry and at after 4, 8, and 12 cycles.  
Subjects with at least a 20% reduction in tumor volume may continue on study and will be 
assessed by MRI after 18 and 24 cycles. Subjects with PD should have their treatment 
discontinued, and they should enter the post-treatment phase of the study. The same method for 
tumor assessment should be employed at every assessment.  
 
A.  Tumor Response Criteria for Plexiform Neurofibromas:  Tumor response is primary 
study variable and is the primary aim of this trial.  Tumor response will be evaluated by 
volumetric MRI STIR imaging.  Subjects who complete at least 2 cycles of therapy will 
be evaluable for disease response.  Serial measurements of lesions are to be done with 
MRI.  The same method of assessment is to be used to characterize each identified and 
reported lesion at baseline and during follow-up.   

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B. Methodology to Determine Tumor Measurement:   
 
Volumetric MRI Method: 
Tumor response criteria that are used for cancers are based on one-dimensional (1-D) and two-
dimensional (2-D) tumor measurements. These methods have limited value in the assessment of 
treatment outcome for plexiform neurofibromas, which are frequently large, have a complex 
(non-spherical) shape, and have a slow growth pattern.  
 
In order to reproducibly quantify the size of these complex lesions and detect small changes in 
the size over time, we used MR imaging characteristics of plexiform neurofibromas to develop 
an automated method of lesion detection and volume measurement. Axial and coronal short T1-
inversion recovery (STIR) MR images are obtained to encompass the entire PN using a slice 
thickness of 5-10 mm with no skips between slices. PN volume is determined using a method 
developed on the MEDx software platform. This method is based on 1) contrast, defined by 
intensity in the tumor (high signal intensity) compared with the surrounding tissue (low signal 
intensity), 2) intensity gradient, defining the outside border (margin) of the lesion, and 3) size of 
the lesion. PN are substantial in size, and small isolated areas of high signal intensity can be 
ignored, because their contribution to the PN volume is insignificant. The steps of volumetric 
analysis are outlined in Figure 9.  
Figure 9: Steps of automated volumetric MRI analysis of plexiform neurofibromas (PN): A) 
Original axial short T1 inversion recovery MRI of a neck PN. The PN appears bright vs. normal 
surrounding tissue. During the analysis a region of interest including the tumor and some low 
signal intensity surrounding tissue is manually outlined on each MRI slice. B) The program 
derives a histogram of pixel signal intensity and identifies a threshold that separates PN from 
surrounding tissue and C) The program automatically defines the tumor contour. 
 
This automated method is sensitive (detects volume changes as small as 10%) and reproducible 
(coefficient of variation 0.6-5.6%), and yields similar results to manual tumor tracings 
(R=0.999). 
 
This automated volumetric MRI analysis is applicable to most plexiform neurofibromas, and was 
used in a phase II trial of the farnesyltransferase inhibitor tipifarnib, in the phase I and II trials of 
pirfenidone, in the phase I trial of peg-interferon alfa-2b, and in the NF Consortium phase 2 trial 
of Sirolimus for children with NF1 and plexiform neurofibromas to assess changes in tumor size. 
Imaging studies on these multicenter trials are sent to the NCI, POB, where volumetric MRI 
analysis is performed. Tumor progression on these trials is defined as an increase in plexiform 
neurofibroma volume by ≥ 20%. This volume increase corresponds too much smaller changes in 
1-D, or 2-D measurements as outlined in the Table below: 

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Table 4-2: 
Equivalent percent change in diameter (RECIST), product of perpendicular diameters (WHO), 
and volume for spherical lesions (e.g., increasing the diameter of a sphere by 6% results in a 20% 
increase in the volume). Bold typeface highlight the definition of progression according to the 
standard RECIST and WHO criteria, and the definition for progression by volumetric 
measurements used on several currently ongoing clinical trials for NF1-related plexiform 
neurofibromas.   
 
Percent Change in Tumor Size 
RECIST 
Diameter (1D) 
WHO  
Product (2D) 
Ongoing NF1 Studies  
Volume (3D) 
6% 
13% 
20% 
12% 
25% 
40% 
20% 
44% 
73% 
 
C.  Overall Response Assessment:   
Response Criteria for target lesions:  For the purposes of this study, only the primary or 
target lesion will be assessed for response.  Subjects will have volumetric MRI of target 
lesion done at 4 months, 8 months, and 12 months.  Subjects who show objective 
response at 12 months can continue at the discretion of the investigator for up to 24 total 
cycles.  For cohort A, subjects who did not show at least a 15% reduction in index tumor 
volume at 8 months were considered treatment failures and taken off study.  For cohort B 
(pediatric cohort), because of the overall excellent safety profile of cabozantinib and the 
numerous late tumor responses in cohort A (adult cohort) (see protocol section 2.3), the 
requirement to stop study treatment in subjects who do not achieve at least a 15% 
reduction in tumor volume by 8 cycles will be eliminated. 
 
If subject has lesions outside of target lesion, up to two non-target lesions may be 
selected and imaged at the same recommended intervals and submitted for analysis.    
 
Partial Response (PR): ≥20% decrease in the volume of target lesion taking as reference 
the initial baseline measurements. 
 
Stable Disease (SD):  Neither sufficient decrease in the volume of target lesion to qualify 
for PR (taking as reference the initial baseline measurements), nor sufficient increase in 
target lesion to qualify for PD, (taking as reference the smallest disease measurement 
since the treatment started). 
 
Progressive Disease (PD): 20% or more increase in the volume of ANY target or non-
target lesion, taking as reference the smallest product observed since the start of 
treatment. 
 
 

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Correlative Response Variables 
1.  Serum bioactivity and cytokine measurements:   
We have reported that mast cells, a cellular component in neurofibromas, play important role in the 
pathogenesis of neurofibromas and other skin malignancies in both human and murine systems 
(Coussens,1999; Galli SJ,1993; Hirota, 1993; Ryan, 1994; Galli,1993; Kerdel, 1987). Mast cells produce 
and release multiple mediators into the tumor microenvironment. These factors include histamine, 
serotonin, proteoglycans, and leukotrienes subsequent to activation of the c-kit receptor (Galli, 1993; Serve, 
1995).  Furthermore, mast cells release multiple growth factors such as vascular endothelial growth factor 
(VEGF) (Boesiger, 1998), an angiogenic factor, chemotactic factor for Schwann cells (Sondell, 1999), 
PDGF-B which promotes fibroblast proliferation and collagen synthesis.  We have shown that kit-ligand is 
a key growth factor that is pivotal in all aspects of cellular functions of mast cells, such as proliferation, de 
novo synthesis of cytokines, degranulation, and migration to emerging tumors (Yang, 2003). Most 
importantly, targeting ckit pathway significantly reduced tumor size in a murine model of NF1 and a single 
case of NF1 patient with a plexiform neurofibroma. In the present study, we propose to evaluate cytokine 
levels in serum of NF1 subjects. The cytokine panel includes ~30 cytokines/chemokines/growth 
factors that have been reported altered in neurofibromas and other cancer types by us and others. 
Plasma biomarker assays will be performed using multiplex simultaneous quantification of about 
thirty soluble cytokines and growth factors including: VEGF, TGF-β, PDGF-AB/BB, MCP-1, 
MIP1α, MIP1β, TNFα, GM-CSF, EGF, IL-13, IL-1rα, IL-10, IL-4, IL6, FGF-2, and RANTES. 
The multiplex assay will be performed according to the manufacturer’s protocol (Millipore 
Milliplex, Billerica, MA) and analyzed on a Luminex 200 cytometer with StarStation software 
(Luminex Corp, Austin, TX). Plasma samples of each subject at each treatment time point will be 
stored at -80C and thawed once for simultaneous assay. 
 
 
 
2.  Polychromatic Flow Cytometry & Identification of Circulating Progenitor Cells  
 
Endothelial progenitor cells (EPCs) and circulating progenitor cells (CPCs) are bone 
marrow-derived cells (BMDCs), which serve as important biomarkers of disease and for 
measuring the impact of anti-angiogenic treatments of cancer.  Using conventional flow 
cytometry, Duda et al., recently standardized a method for enumerating specific EPC 
populations in blood that serve as biomarkers for vascular disease risk and response to anti-
angiogenic therapies in human cancers [15]. Flow cytometry is a rapidly 
developing/expanding field, and recent improvements in technologies and various flow 
cytometry strategies have now been employed to measure circulating EPC and CPC 
concentrations in human peripheral blood. Utilizing a novel polychromatic flow cytometry 
(PFC) strategy to further characterize and purify CPCs, our group has shown that CPCs are 
phenotypically and functionally distinct from that of the well-studied EPCs [16].  This PFC 
technique is highly reproducible, allowing for use in longitudinal studies and eliminates 
any ambiguous data interpretation.  In addition, the PFC protocol is cost and time effective, 
and can be completed in 2-2.5 hours utilizing existing commercially available technology. 
 

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In fact, subtle differences in phenotype separating the CPC population into pro-angiogenic 
and non-angiogenic populations turn out to be quite important, and is primarily based on 
the expression of the cell surface marker, CD133.  By identifying the CD133+ sub-
population of the CPCs, which represent pro-angiogenic CPCs, the ratio of pro-CPCs 
versus non-CPCs are quite different in various disease states  (Estes et al., Cytometry A, 
77A(9):115-121, 2011).  In normal patients, the ratio is 1.2-2.  Cancer patients have a ratio 
>2.5, which has been shown to decrease to within the normal range following treatment 
with the anti-angiogenic compound Sutent.  Furthermore, in patients with peripheral artery 
disease (PAD), the ratio is <1 (Estes et al., Cytometry A, 77A(9):115-121, 2011).  
Therefore, the ratio of pro-CPCs vs. non-CPCs may be utilized as a reliable marker for 
certain diseases, disease status and to monitor response to therapy/treatment.   
 
 
 
 
 
 
For 
example, 
treatment 
of 
metastatic 
breast 
cancer 
patients 
with 
Sunitinib 
resulted 
in 
decreased 
numbers of pro-
angiogenic CPCs 
as compared to untreated patients.  Interestingly, when the treatment regime was coupled 
with Taxol, an increase in the non-angiogenic CPC fraction was observed. Therefore, it is 
extremely important to perform optimal PFC acquisition and analysis of these 2 
phenotypically and functionally distinct cell sub-populations in order to obtain 
reproducible, reliable and accurate results. 
 
 
 
 
Untreated 
Sunitinib 
Taxol 

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Furthermore, in a recent study by 
Pradhan et al., looking at CPCs in 
pediatric patients with various solid 
tumors as compared to age matched 
healthy 
controls, 
it 
was 
demonstrated that patients with 
cancer had a higher ratio of pro-
CPCs versus non-CPCs. The median 
ratio of the pro-CPCs versus non-
CPCs was 2.12 (0.34-5.95) at 
baseline for the patients, while the 
healthy controls had a median ration 
of 1.23 (0.24-1.54). Following 
treatment, the median ratio for the 
patients dropped to 1.59 (0.21-8.75) (Pradhan et al., Cytometry Part B: Clinical Cytometry, 
80B(5):335-338, 2011). This was the first time that the two subsets had been reported in 
any human malignancy. 
 
Additionally, injection of the purified pro-angiogenic CPC fraction was shown to enhance 
tumor growth in a murine xenograft model.  In summary, NOD/SCID mice harboring pre-
established melanoma xenografts (~100mm3) were intravenously injected with purified 
human pro-CPCs, phosphate buffered saline (PBS), non-CPCs (Figure 4, Expt I) or CD34+ 
cells (Figure 4, Expt II).  Intravenous injection of pro-CPCs in mice harboring melanoma 
xenografts resulted in a statistically significant increase in tumor growth overtime when 
compared to controls (i.e. PBS, CD34+ cells or non-CPCs) (Figure 4). In addition, at the 
completion of the study, excised tumors were weighed to further document changes in 
tumor growth. Tumors from mice injected with the pro-CPCs were significantly larger than 
tumors from the mice that received vehicle control (PBS) or CD34+ cells (Figure 5) (Estes 
et al., Cytometry A, 77A(9):115-121, 2011). Histological analysis of tumors for the 
presence of human CPCs is in progress. In all future experiments, we will use CD34+ cells 
as the negative control population. While we realize that pro-CPCs are certainly present in 
the CD34+ cell population, our data suggest that the level of the pro-CPCs is not high 
enough in the bulk CD34+ population to promote tumor progression unless the pro-CPCs 
are first purified from the CD34+ population. 
 
This evidence is compelling, and supports the role of pro-angiogenic CPCs in tumor 
progression, as well as the potential utility of the CPC ratio as a powerful biomarker in 
various disease states, including cancer.  We will examine the role of CPCs as a biomarker 
in NF1 plexiform subjects treated with cabozantinib. 
 
 
Figure 5. Comparison of Tumor Weights. At the end of the
study, the mice were euthanized and the tumors from each
cohort of mice were harvested and weighed. Tumor weights
are from Expt II. *p<0.001, CPCs vs CD34 or PBS control. N=4
mice/cohort.
0
0.2
0.4
0.6
0.8
1
1.2
CPC
CD34
PBS
weight (g)
*

NF Protocol #105  Version 2.1 
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PFC and CPCs:  PFC for the identification of CPCs will be performed at four time points 
as per protocol.  Whole blood will be drawn in EDTA tubes and sent immediately for 
processing to the Indiana University Angio BioCore, which is directed by Dr. Karen 
Pollok.   As samples are received, using the PFC protocol developed by Dr. Jamie Case 
(Estes et al., Current Protocols in Cytometry, 52(9):9.33.1-9.33.11, 2010), the phenotypic 
detection and enumeration of CPCs will be performed, and the ratio of pro-angiogenic (i.e. 
CD133+) vs. non-angiogenic CPCs will be calculated on all samples.  Data obtained will 
then be correlated with tumor response. 
 
3.  Pharmacokinetics 
Plasma samples will be collected for the purpose of determining XL184 concentrations 
for pharmacokinetic analysis of XL184 and/or metabolite concentrations. 
 
For Cohort A: Blood samples will be obtained at the following time points: Cycle 1 Day 
1 (pre, 4 hours after the first dose), Cycle 1 Day 15 (pre, and 4 hours after dose), Cycle 1 
Day 28 (pre and 4 hours after dose) for subjects remaining on study, and if possible any 
time a subject experiences a DLT.  
 
For Cohort B: Blood samples will be obtained at the following time points: Cycle 1 Day 
1 (pre first dose), Cycle 2 Day 1 (pre-dose), Cycle 3 Day 1 (pre-dose) and Cycle 4 day 1 
(pre-dose) 
 
Blood samples (3 ml) will be collected in 3-mL K2-EDTA Vacutainer tubes (lavender 
top) tubes for pharmacokinetic evaluation. Record the exact time that the sample is drawn 
along with the exact time that the drug is administered. 
 
Tubes should be chilled on wet ice or in a refrigerator prior to collection. Immediately 
after blood collection, blood tubes should be inverted several times and then kept on wet 
0
2
4
6
8
10
12
9
13
16
20
27
31
fold increase
Days post-injection
CPC
CD34
PBS
Expt II:-
0.5x105 CPCs/mouse
0
5
10
15
20
25
30
3
7
10
17
22
27
fold increase
Days post-injection
CPC
nonCPC
PBS
Expt I:-
1x105 CPCs/mouse
*
*
*
*
*
*
*
Figure 4. Intravenous Injection of CPCs Results in Significant Increases in Melanoma Xenograft Growth. NOD/SCID mice
bearing human melanoma xenografts were intravenously injected with CPCs, control cells (Expt I=nonCPCs; Expt II= CD34+
cells) or PBS. Tumor growth was monitored over time by caliper measurement. * p<0.001, CPCs vs. control cells or PBS. N=3-
4 mice/cohort.

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ice until centrifuged. Within 30 minutes of blood collection, samples should be separated 
by centrifugation for 10 minutes (1000 - 1200 g) at approximately 4°C. The resultant 
plasma should be withdrawn in approximately equal volumes into two (2) appropriately 
labeled polypropylene tubes for PK assay and stored (within 1 hour of the blood sampling 
time) at -70°C or lower until shipment. The analyst should attempt to transfer the 
maximum amount of plasma without disturbing the barrier between the red blood cells 
(bottom layer) and the plasma (top layer). One tube is the primary sample; the other tube 
is the back-up sample. Samples should be shipped to the following address: 
Alturas Analytics, Inc. 
Attn: Jennifer Zimmer, PhD 
Senior Scientist Executive Laboratory Manager 
1324 Alturas Dr. 
Moscow, ID 83843 
Phone: (208) 883-3400 
Fax: (208) 882-9246 
Email: jzimmer@alturasanalytics.com 
Refer to Appendix VI for additional sample processing and shipping instructions. 
PK data will be analyzed and summarized by Exelixis Inc.  
 
 

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14.0 
HUMAN SUBJECTS PROTECTION & DATA SAFETY MONITORING PLAN 
 
Rationale for Subject Selection 
Neurofibromatosis type 1 is a genetic disorder and the incidence of the disease in the 
various racial and ethnic groups may vary. This may impact on our ability to recruit 
sufficient numbers of patients within each group to this trial.  Subject accrual in regards to 
gender, and racial and ethnic groups is described in Section 4.0.  None of these groups are 
excluded from participation in the trial.  Females who are pregnant or breast feeding will 
not be eligible for entry onto the trial because of the potential risks that cabozantinib could 
pose to the fetus or newborn.  This trial is designed to determine the activity of cabozantinib 
in adolescents and adults with NF1 and inoperable PN.  Individuals will be enrolled only 
at sites that participate in the NF consortium. Subjects may also be referred from outside 
centers but treatment will be directed at an NF consortium site. 
  
Evaluation of benefits and risks/discomforts  
The potential benefit from participation in this trial is the stabilization or reduction in the 
size of the PN, relief of symptoms caused by the PN, and prolongation of life. The primary 
risk to the subjects from participation in this trial is due to cabozantinib toxicities (Section 
7.3), which have been reversible when they occur.  Subjects enrolled on this trial will be 
carefully monitored for the development of toxicities, and guidelines for target 
modifications, discontinuation of drug, and a toxicity stopping rule are in place. Blood 
samples will be obtained on this trial for pharmacokinetic, pharmacodynamic, and 
pharmacogenetic studies; these are mandatory.  Samples will be identified by a code 
number that can be traced to the subject only by contacting the trial coordinating center.  
However, as the blood samples are linked to the subject’s name, a small risk persists that 
unauthorized persons could gain access to information. Some testing may eventually reveal 
information that could result in discrimination with health or life insurance or employment.  
We believe that these risks are minimal since it is already known that subjects enrolled on 
the study have neurofibromatosis. All research results will be kept confidential. Results 
from the pharmacodynamic and pharmacogenetic studies will be considered preliminary 
and will require further analysis for verification. Therefore, results will not be 
communicated with the research subjects. Subjects also have the right to withdraw the 
blood specimens obtained for research purposes at any time.  
 
Risks to subjects from banking biological specimens include the risks of the blood draws 
for research purposes. Tumor specimens will be taken only from leftover specimens that 
were obtained for clinical purposes. The amount of blood to be obtained is minimal 
(approximately 10 ml) and no more than 5 mL/kg will be taken from any subject in a single 
day.  Risks associated with blood draw are pain, bleeding or bruising at the spot where the 
needle is inserted, and rarely fainting or infection. Every attempt to draw the research blood 
samples in conjunction with other clinical blood draws will be made so that the risk of 
infection is not increased. Blood draws will be performed by trained personnel who are 
experienced in working with children and familiar with the challenges of drawing blood 
from this population.  The risk of biological specimen banking is minimized by coding the 
specimens prior to shipping to the biorepository in order to prevent identification of 
subjects and protect confidentiality.  In addition, the study subject ID number linked to the 
specimen will be maintained separately at the NF Consortium Operations Center at UAB.   

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Depending on the age of the subject MRI studies may require sedation or anesthesia, which 
is associated with additional risks. Separate informed consent will be obtained from 
research subjects for sedation or anesthesia for MRI scans. 
 
Risk/benefit analysis 
The primary objective of this phase II trial is to define the objective response rate of PN 
treated with cabozantinib, and thus subjects entered on the trial will be treated with 
therapeutic intent and response to the therapy will be closely monitored. Therefore, this 
protocol involves greater than minimal risk, but presents the potential for direct benefit to 
individual subjects. The potential benefit of this treatment with cabozantinib is that it may 
stop or slow down the growth of PN, or shrink PN. In addition cabozantinib may lessen the 
symptoms, such as pain, that are caused by the tumor. The MRI data in this study will be 
analyzed by a special approach called “volumetric MRI,” in addition to being read in a 
standard manner by a radiologist. The volumetric MRI approach will provide more precise 
measurement of the size of PN, and therefore will give more complete and objective 
information on which to base any possible future treatment decisions.  Volumetric MRI is 
currently not available on a routine clinical basis. 
 
Consent and assent process and documentation 
The investigational nature and objectives of this trial, the procedures and treatments 
involved and their attendant risks and discomforts and benefits, and potential alternative 
therapies will be carefully explained to the patient and the patient’s parents or guardian if 
he/she is a child, and a signed informed consent document will be obtained. Consent will 
be obtained by the site PI or an associate investigator on the trial according to state and 
institutional guidelines.  When appropriate, pediatric patients will be included in all 
discussions and assent documented.  All patients and/or their parents or legally authorized 
representatives must sign a written informed consent.  Assent, when appropriate, will be 
obtained according to institutional guidelines. 
This is a multi-institutional trial, and the NF Operations Center will require evidence of 
local IRB approval and of USAMRMC ORP HRPO approval of the protocol prior to 
allowing for accrual of subjects at that institution. This trial will be conducted in 
compliance with the protocol, Good Clinical Practice (GCP) and the applicable regulatory 
requirements.  
 
Medical Monitor and Data Safety Monitoring Plan 
The trial PI and clinical coordinator will review the study progress regularly. Subjects 
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 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.  
 
Alyssa Reddy, MD will be the medical monitor for this study. She is a qualified physician 
and is not associated with this particular protocol.  She will work closely with the Principal 
Investigator to monitor the participants’ treatment while on this study. 

NF Protocol #105  Version 2.1 
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For research determined to be greater than minimal risk, DODI 3216.02 requires that the IRB 
approve, by name, an independent /medical monitor with expertise consonant with the 
nature of risk(s) identified within the research protocol.  The IRB must approve a written 
summary of the monitors’ duties, authorities, and responsibilities.  
  
The medical monitor’s duties should be based on specific risks or concerns about the research. The 
medical monitor may perform oversight functions and report their observations and findings to the 
IRB or a designated official.  The medical monitor may be identified from within or outside the 
PI’s institution. 
  
Medical monitor functions may include: 
• 
observing recruitment and enrollment procedures and the consent process for individuals, 
groups or units,  
• 
overseeing study interventions and interactions,  
• 
reviewing monitoring plans and UPIRTSO reports;  
• 
overseeing data matching, data collection, and analysis 
  
There may be more than one medical monitor (e.g., if different skills or experiences are necessary). 
The monitor may be an ombudsman or a member of the data safety monitoring board. 
At a minimum, the medical monitor: 
• 
may discuss the research protocol with the investigators, interview human subjects, and 
consult with others outside of the study about the research;  
• 
shall have authority to stop a research protocol in progress, remove individual human 
subjects from a research protocol, and take whatever steps are necessary to protect the 
safety and well-being of human subjects until the IRB can assess the monitor’s report; 
• 
shall have the responsibility to promptly report their observations and findings to the IRB 
or other designated official and the HRPO.  
 
In addition, on this study, the medical monitor is specifically required to review all unanticipated 
problems involving risk to subjects or others, serious adverse events and all subject deaths 
associated with the protocol and provide an unbiased written report of the event.  At a minimum, 
the medical monitor should comment on the outcomes of the event or problem, and in the case of 
a serious adverse event or death, comment on the relationship to participation in the study.  The 
medical monitor should also indicate whether he/she concurs with the details of the report provided 
by the study investigator.   
 
15.0 
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS 
The Principal Investigator (Protocol Chair) holds the primary responsibility for 
publication of the study results; provided that the PI will provide any such publication to 
Exelixis, Inc. for review at least sixty (60) days prior to submission and also comply with 
any provisions regarding publication as are agreed to between the Neurofibromatosis 
Clinical Trials Consortium and Exelixis, Inc. in the Clinical Trial Agreement related to 
this study. The results will be made public within 24 months of the end of data collection. 
However, 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 

NF Protocol #105  Version 2.1 
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79 
 
Committee of Medical Journal Editors. In any event, a full report of the outcomes should 
be made public no later than three (3) years after the end of data collection. Authorship 
for abstracts and manuscripts resulting from this study will be determined according to 
guidelines established by the International Committee of Medical Journal Editors. 
 
16.0 
REFERENCES 
 
1. 
Yang, F.C., et al., Nf1-dependent tumors require a microenvironment containing Nf1+/-- and c-
kit-dependent bone marrow. Cell, 2008. 135(3): p. 437-48. 
2. 
Galli, S.J., M. Tsai, and B.K. Wershil, The c-kit receptor, stem cell factor, and mast cells. What 
each is teaching us about the others. Am J Pathol, 1993. 142(4): p. 965-74. 
3. 
Ingram, D.A., et al., Genetic and biochemical evidence that haploinsufficiency of the Nf1 tumor 
suppressor gene modulates melanocyte and mast cell fates in vivo. J Exp Med, 2000. 191(1): p. 
181-8. 
4. 
Kumar, R., et al., Myelosuppression and kinase selectivity of multikinase angiogenesis inhibitors. 
Br J Cancer, 2009. 101(10): p. 1717-23. 
5. 
Abrams, T.J., et al., SU11248 inhibits KIT and platelet-derived growth factor receptor beta in 
preclinical models of human small cell lung cancer. Mol Cancer Ther, 2003. 2(5): p. 471-8. 
6. 
Yang, F.C., et al., Nf1-dependent tumors require a microenvironment containing Nf1+/-- and c-
kit-dependent bone marrow. Cell, 2008. 135(3): p. 437-48. 
7. 
Staser, K., F.C. Yang, and D.W. Clapp, Mast cells and the neurofibroma microenvironment. Blood, 
2010. 116(2): p. 157-64. 
8. 
Kurzrock, R., et al., Activity of XL184 (Cabozantinib), an Oral Tyrosine Kinase Inhibitor, in 
Patients With Medullary Thyroid Cancer. J Clin Oncol, 2011. 
 
 
 
 
 

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APPENDIX I:  SCHEDULE OF EVALUATIONS 
STUDIES TO BE OBTAINED 
Pre-
Study1 
Cycle 1 
Cycle 2, 3 
Cycle 4-12 
 
Cycle 13-24 
Completion 
of Rx 
History 
X 
End 
Day 15, End 
(each cycle) 
End 
(each cycle) 
Post cycle 14, 16, 
18, 20, 22, 24 
X 
Physical exam with vital signs 
and pulse ox 
X 
Day 15, 
End 
Day 15, End 
(each cycle) 
End 
(each cycle) 
Post cycle 14, 16, 
18, 20, 22, 24 
X 
Height, weight, BSA2 
X 
End 
Day 15, End 
(each cycle) 
End 
(each cycle) 
Post cycle 14, 16, 
18, 20, 22, 24 
X 
Blood pressure 
X 
Day 15, 
End 
Day 15, End 
(each cycle) 
End 
(each cycle) 
Post cycle 14, 16, 
18, 20, 22, 24 
X 
Performance Status 
X 
End 
Day 15, End 
(each cycle) 
End 
(each cycle) 
Post cycle 14, 16, 
18, 20, 22, 24 
X 
Subject Diary 
X 
End 
End 
(each cycle) 
End 
(each cycle) 
Post cycle 14, 16, 
18, 20, 22, 24 
X 
Phone Call (to assess drug 
compliance and toxicity) 
 
 
 
 
Post cycle 13, 15, 
17, 19, 21, 23 
 
CBC, differential, platelets 
X 
Day 15, 
End 
Day 15, End 
End 
(each cycle) 
End 
(each cycle) 
X 
CMP3 with Ca, Mg, Phos, lipase, 
amylase 
X 
Day 15, 
End 
Day 15, End 
End 
(each cycle) 
End 
(each cycle) 
X 
PT, PTT, INR 
X 
End 
End 
(each cycle) 
End 
(each cycle) 
End 
(each cycle) 
X 
Urinalysis 
X 
End 
End 
(each cycle) 
End 
(each cycle) 
End 
(each cycle) 
X 
Urine protein/creatinine 
X 
End 
End 
(each cycle) 
End 
(each cycle) 
End 
(each cycle) 
X 
Pregnancy test4 
X5 
 
End cycle 2  
Post cycle 4, 6, 
8, 10, 12 
Post cycle 14, 16, 
18, 20, 22, 24 
X 
Thyroid stimulating hormone 
X 
End 
End cycle 3 
Post cycle 6, 9, 
12 
Post cycle 16, 20, 24 
X 
12- lead EKG6 
X 
End 
End cycle 2 
Post cycle 4, 6, 
9, 12 
Post cycle 16, 20, 24 
X 
MRI of target tumor 
X 
 
 
Post cycle 4, 8, 
12 
Post cycle 18, 24 
X7 
QOL  
X 
 
 
Post cycle 4, 8, 
12 
Post cycle 18, 24 
X 
Plexiform Neurofibroma 
Symptom Checklist 
X 
 
 
Post cycle 4, 8, 
12 
Post cycle 18, 24 
X 
Plexiform Neurofibroma 
Location & Associated 
Morbidities Form 
X 
 
 
 
 
 
Plexiform Neurofibroma 
Clinician Morbidity Checklist 
X 
 
 
Post cycle 4, 8, 
12 
Post cycle 18, 24 
X 
Peripheral blood for cytokine 
assays 
X 
Day 15 
End cycle 2 
Post cycle 4 
 
 
CPC biological markers – flow 
X 
Day 15 
End cycle 2 
Post cycle 4 
 
 
Pharmacokinetics8 
X 
Cohort 
A:Day 
15, End  
Cohort 
B: Day 1, 
Day 28 
Cohort B: 
Cycle 3 Day 
1 
Cohort B: Cycle 
4 Day 1 
 
 
Blood and Tissue collection9 
X 
 
 
Post cycle 4, 12 
 
X 

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1. All studies to determine eligibility must be performed within 2 weeks prior to enrollment unless otherwise 
indicated (See section 9.0).  Consent must be obtained prior to enrollment but does not expire at 2 weeks. 
2. Height only required at baseline in Cohort A.  Obtain at each study visit for Cohort B. 
3. CMP should include: sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, glucose, albumin, 
total protein, SGOT (AST), SGPT (ALT), total bilirubin, alkaline phosphatase 
4. For females of childbearing age 
5. Within 7 days prior to starting treatment 
6. If the subject starts a medication with substantial evidence that the drug prolongs the QT interval, then EKG 
monitoring must be end of each cycle while on the medication (see section 6.3) 
7. For subjects with tumor response, MRI is recommended at 4 months and 12 months off therapy (except if they 
start other tumor-directed therapy). 
8. PK  for cohort A will be done Day 1, 15, 28: predose and 4 hours postdose. PK for Cohort B will be done  Cycle 1 
Day 1, Cycle 2 day 1, Cycle 3 day 1 and Cycle 4 Day 1 
9. Blood samples should be drawn at the indicated time points as well as around the time of tumor biopsy if tumor 
tissue is being submitted (if the patient undergoes a clinically indicated tissue collection procedure). The following 
will be collected at each time point: Streck tube (for plasma):  ~ 2 mL; EDTA tube (for DNA):  ~ 5 mL; PAXGene 
tube (for RNA) ~ 2.5 mL. 

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APPENDIX II: PERFORMANCE STATUS SCALES/SCORES 
 
 
PERFORMANCE STATUS CRITERIA 
Karnofsky and Lansky performance scores are intended to be multiples of 10 
Karnofsky 
Lansky 
Score 
Description 
Score 
Description 
100 
Normal, no complaints, no evidence 
of disease 
100 
Fully active, normal. 
90 
Able to carry on normal activity, 
minor signs or symptoms of disease. 
90 
Minor restrictions in physically strenuous 
activity. 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
80 
Active, but tires more quickly 
70 
Cares for self, unable to carry on 
normal activity or do active work. 
70 
Both greater restriction of and less time 
spent in play activity. 
60 
Required occasional assistance, but is 
able to care for most of his/her needs. 
60 
Up and around, but minimal active play; 
keeps busy with quieter activities. 
50 
Requires considerable assistance and 
frequent medical care. 
50 
Gets dressed, but lies around much of the 
day; no active play, able to participate in 
all quiet play and activities. 
40 
Disabled, requires special care and 
assistance. 
40 
Mostly in bed; participates in quiet 
activities. 
30 
Severely 
disabled, 
hospitalization 
indicated.  Death not imminent. 
30 
In bed; needs assistance even for quiet 
play. 
20 
Very sick, hospitalization indicated.  
Death not imminent. 
20 
Often sleeping; play entirely limited to 
very passive activities. 
10 
Moribund, fatal processes progressing 
rapidly. 
10 
No play; does not get out of bed. 
 
 

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APPENDIX III: PARTICIPANT DOSE DIARY 
Reviewed by treating physician:   
 Date:         /         /                  
 
Parent/Participant Signature: 
  
Date:         /         /                  
 
† Rate nausea mild if you are able to eat and drink a reasonable amount, moderate if you can eat and drink but the amount is substantially decreased, or severe if you are unable to eat and drink. Note: Cabozantinib should 
be taken daily at same time if possible.  Cabozantinib should be taken on an empty stomach (fasting is required 2 hours before and 1 hour after each cabozantinib dose).  Do NOT re-take if vomiting occurs after taking a 
scheduled dose. 
 
 
PID 1: ______   PID 2: _______ 
Cycle Number:  
Cycle Start Date: 
 
 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Dose Taken 
place X in box 
 1 = Taken 
 2 = Missed 
 1 = Taken 
 2 = Missed 
 1 = Taken 
 2 = Missed  
 1 = Taken 
 2 = Missed 
 1 = Taken 
 2 = Missed 
 1 = Taken 
 2 = Missed 
 1 = Taken 
 2 = Missed 
Dose  
(taken once per day) 
          mg 
          mg 
          mg 
          mg 
          mg 
          mg 
          mg 
Date Dose Taken 
 
 
 /  
 /  ______ 
 
  
 /  
 /  ______ 
 
  
 /  
 /  ______ 
 
  
 /  
 /  _______ 
 
  
 /  
 / ________ 
 
  
 /  
 / ________ 
 
      
 /  
 /  ______ 
 
Time Dose Taken 
 
 
 :  
 
AM 
PM 
 
 
 :  
 
AM 
PM 
 
 
 :  
 
AM 
PM 
 
 
 :  
 
AM 
PM  
 
 
 :  
 
AM 
PM  
 
 
 :  
 
AM 
PM  
 
 
 :  
 
AM 
PM  
SIDE EFFECTS 
Nausea † 
see scale below and 
place X in box 
 0 = None 
 1 = Mild 
 2 = Moderate 
 3 = Severe 
 0 = None 
 1 = Mild 
 2 = Moderate 
 3 = Severe 
 0 = None 
 1 = Mild 
 2 = Moderate 
 3 = Severe 
 0 = None 
 1 = Mild 
 2 = Moderate 
 3 = Severe 
 0 = None 
 1 = Mild 
 2 = Moderate 
 3 = Severe 
 0 = None 
 1 = Mild 
 2 = Moderate 
 3 = Severe 
 0 = None 
 1 = Mild 
 2 = Moderate 
 3 = Severe 
Vomiting 
# of times in 24 hr 
Diarrhea 
# of times in 24 hr 
Rash 
Specify Location    
Other: write in               
OTHER MEDICATIONS 
 Medication  Name 
Dose 
Frequency 
Start Date 
Stop Date 
Reason for Use of Medication 
 
  
 /  
 /   
 
  
 /  
 /   
 
 
 
 /  
 /   
 
 
 /  
 /   
 
 
  
 /  
 /   
 
  
 /  
 /   
 

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APPENDIX IV:  PROTOCOL FOR REQUIRED PRE-STUDY AND ON-STUDY 
MRI STUDIES 
Prior to starting treatment on this study a target plexiform neurofibroma must be identified.  
In addition, up to two non-target plexiform neurofibromas may be identified as well.  
The goal will be to use 3-D MRI only to follow the target and non-target plexiform 
neurofibroma(s) (a maximum of three lesions), which will be defined as index lesion(s).  
Pre-study imaging evaluation: 
1. Identify and select the index plexiform neurofibroma(s) (a maximum of three lesions) 
for 3-D MRI evaluation based on prior imaging studies. Should there be more than 3 
progressing plexiform neurofibromas; the three most clinically relevant plexiform 
neurofibromas should be followed by 3-D MRI analysis. 
2. Perform 3-D MRI sequences on the selected index lesions as outlined in the MRI 
acquisition protocols below.  
 
On study imaging evaluation: 
 
Unless clinically indicated otherwise obtain MRI of the index lesions only as outlined in 
the MRI acquisition protocol below at baseline and then after cycle 4, 8, 12, 18, 24 and end 
of study. 
 
MRI protocols: 
 
Images intended for volumetric analysis need to be performed without gaps between slices. 
Every attempt should be made to image the entire PN. The target tumor should be 
positioned close to the center of the imaging field and the outer edge of the tumor should 
be within the field of view. Peripheral nerve sheath tumors can be well visualized without 
the use of contrast agents on short TI inversion recovery (STIR) sequences because they 
have high signal intensity relative to normal tissues. The imaging protocol in the table 
below should be used for the imaging of the target and non target PN.  
 
If necessary, participating institutions may modify the MRI sequences to optimize 
differentiation of tumor and surrounding tissue.  Modifications should be noted, such that 
the same imaging protocol, and, if possible, the same MRI scanner, can be used for all 
subsequent MRI studies.  
All MRI studies requested per protocol will be submitted to the NCI POB within 1 week 
of acquisition for volume analysis.  
 
 
 
 
 
 
 

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Volumetric sequence for PN** 
Axial STIR 
Recommended 
Range 
Head-Neck or 
Small## Trunk-
Extremity PN 
Large## Trunk-
Extremity PN 
Echo Train Length 
5 - 15 
7 
15 
TR 
3000 - 6000 
6000 
4000 
TE 
30 - 50 
34 
30 
TI 
150-180 
150 
150 
Slice Thickness 
3 - 10 mm 
3 mm 
10 mm 
Skip 
0 
0 
0 
Matrix 
256x256 -  
512x512 
256x256 
320 x256 - 
512x512 
FOV 
18 - 50 cm 
22 cm 
45 cm 
Phase FOV 
0.8 
0.8 
0.8 
NEX 
2 - 4 
3 
2 
Frequency Direction 
A→P 
A→P 
A→P 
**Spinal/paraspinal PN should be imaged with the appropriate protocol based on tumor size. 
Tumors that include the neck and trunk, for which the majority of the tumor is in the trunk, should 
be imaged with the Large Trunk-Extremity PN protocol. 
##Tumors < 5 cm in longest diameter would be considered small.  Tumors > 10 cm longest diameter 
would be considered large.  Tumors between 5-10 cm in longest diameter should be imaged with 
the appropriate protocol based on best FOV coverage.   
Please contact Dr. Dombi if there are questions regarding the appropriate coverage or imaging 
protocol. 

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Data Analysis:  
• All MRI data will be analyzed at the Pediatric Oncology Branch of the NCI.  The MRI 
data from each scan will be processed to assess the volume of the index plexiform 
neurofibroma(s). The tumor will be traced on subsequent contiguous MR slices, the 
numbers summed and then multiplied by the slice thickness to obtain a numerical 
volume measurement.  The tumor will be identified by high signal on the STIR images 
not corresponding to known normal anatomic structures and corresponding with the 
cycle of known nerves. Each subject’s volumetric measurement obtained from the 
initial MRI will serve as the baseline against which to assess incremental changes in 
volume that occur during the subsequent intervals.  Volumetric measurements and 1-
D, and 2-D data analysis will be done by 3 physicians trained in 1-D, 2-D, and 3-D 
MRI data analysis at the Pediatric Oncology Branch, NCI at an Image Review 
Workstation using MEDx software (Sensor Systems Inc.). Volumetric measurements 
will be used to determine disease progression as outlined in Section 13.0. Drs. Dombi 
and Widemann will inform Participating Investigators, the Principal Investigator, and 
the NF Consortium Operations Center about the results of the MRI study by written 
report. 
 
Image and Data Acquisition: 
• In order to perform quantitative analysis the Pediatric Oncology Branch must receive 
the imaging data from the investigator sites. All MRI studies requested per protocol 
will be submitted to the NCI POB within 1 week of acquisition for volume analysis. 
The Pediatric Oncology Branch will check all materials received for completeness and 
will notify the site if data, images, or information are missing or incomplete.  Dr. Dombi 
will confirm for each patient in screening that the MRI imaging is adequate and that 
the target PN is measurable and amenable to volumetric MRI analysis.   
• Address for shipment of imaging studies: 
Eva Dombi, MDNCI, POB 
10 Center Drive, Building 10, room 1-5750 
Bethesda, MD 20892-1101 
Phone: 301-451-7023 
E-mail: dombie@mail.nih.gov  

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APPENDIX V:  BIOMARKER STUDIES 
 
Biomarker Submission 
A.  Cytokines 
Peripheral blood (6mL) will be collected via venous puncture into an 8 mL EDTA 
purple top tube (or divide between two 6 mL EDTA tubes).  Spin at 2200 rpm 
(1200-1300g) for 15 minutes (break and acceleration ‘on’) at 4°C.  Collect plasma 
and distribute/aliquot 1-1.5 mL into each 2mL cryovial (1-5 cyrovials). Fix a 
printed label on each tube with: site, patient ID number, sample time point, date, a 
# and amount/vial. Store samples at -80⁰C until being shipped as a batch on dry 
ice.     
Ship by FedEx Monday to Thursday on dry ice to: 
CCRC, Indiana University School of Medicine 
705 Riley Hospital Dr. 
RI 2641 
Indianapolis, IN 46202 
Attn: Khadijeh (Sholeh) Bijangi-Vishehsaraei, MS, PhD 
 
B. Endothelial Progenitor Cell (Contacts: Emily Sims, ecwillar@iu.edu and Matt 
Repass, mjrepass@iu.edu) 
Once a subject has been identified and a baseline visit has been scheduled email: 
nfstudy@iu.edu to have CPT and balance CPT tubes sent to your site.  CPT tubes 
have a 6 month shelf life.  Store CPT tubes in an upright position out of direct 
sunlight and heat. 
 
16 mL of peripheral blood (PB) will be collected via venous puncture into three 
6mL EDTA purple top tube.  For local processing, the PB sample will then be 
brought to the Angio BioCore at Indiana University with processing beginning 
within one hour of collection.  
 
For off-site samples, 16 mL of PB will first be collected via venous puncture into three 
6mL EDTA purple top tubes.  The PB will then be transferred into two 8mL CPT tubes, 
gently invert eight times to mix blood with anticoagulant. The sample must be processed 
within 2 hours of blood collection . Centrifuge for 30 minutes at 1500-1800g at room 
temperature.  The centrifugation will separate the mononuclear cell (MNC) fraction and 
the plasma above the ficoll plug with the red blood cells passing through and going 
beneath the plug. Following centrifugation, the plasma/MNCs will then be poured into 
two clean/new 6mL EDTA tubes and shipped overnight (at room temperature) to the 
Angio BioCore.  The MNCs are stable for 24 hours post collection after centrifugation 
and, therefore, must be shipped same day. All tubes should be labeled with site, patient 
ID number, sample time point, and date. 
 
Please only ship samples by Federal Express priority overnight Monday through 
Thursday.  Please inform the Angio BioCore of your incoming shipment 

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(ecwillar@iupui.edu, mjrepass@iupui.edu). 
 
Ship by FedEx to: 
Emily Sims & Matt Repass 
 
Angio BioCore Lab  
980 West Walnut Street, R3 Room C343 
Indianapolis, IN, 46202 
317-278-7232 
 
 

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APPENDIX VI:  PHARMACOKINETIC STUDIES 
Pharmacokinetic Worksheet  
 
Subject Consortium ID number: _____________ 
BSA (m2): 
 
Cabozantinib (mg)  
 
mg given :  
 
Cohort A (≥16 years of age) 
Each study site will need: 
1.  Centrifuge with horizontal rotor capable of producing 1200 x g (set to 4oC). 
2.  Non-defrosting freezer (-70°C or below) 
 
Once sites have approval for enrollment and have possible candidate(s), contact Linh 
Nguyen, linguyen@exelixis.com  & Clinical_Supplies@exelixis.com to request PK 
laboratory kits.  Request should include completed PK request form. Provide correct 
contact person and shipping address for shipments and allow 5 days for shipment.  
Clinical sites will receive a Pharmacokinetic (PK) kit for each subject from Exelixis.  
Since PK kits are subject specific, do not interchange materials between the kits.  Each 
kit contains several extra tubes and labels in addition to those required for the scheduled 
collections.  
 
For Cohort A there will be a total of 6 samples drawn.  Blood samples (3mL will be drawn 
for pharmacokinetic profile during cabozantinib (XL184) therapy at the following 
timepoints:  
• Cycle 1, Day 1 (C1D1):  Pre-cabozantinib dose (collected within 15 minutes prior 
to cabozantinib dosing) and 4 hours post cabozantinib dose 
• Cycle 1, Day 15 (C1D15): Pre-cabozantinib dose (collected within 15 minutes 
prior to cabozantinib dosing), and 4 hours post cabozantinib dose  
• Cycle 1, Day 28 (C1D28): Pre-cabozantinib dose (collected within 15 minutes 
prior to cabozantinib dosing), and 4 hours post cabozantinib dose  
 
 
Procedure for Cohort A:   
Samples will be drawn as 3 mL whole blood into K2EDTA (lavender top) tubes 
 
1. Prior to obtaining blood from subjects at each timepoint, gather the following 
supplies together from the Study XL184-IST-014 PK Kit and your site supplies:   
• Obtain three barcoded plasma labels for PK sample. Confirm that the sample 
type, the date and collection time pre-printed on each label correspond with 
the sample type, date and time you will be collecting 
• One 3 mL K2-EDTA Vacutainer tube for each PK sample timepoint 
• Two Polypropylene tubes for PK plasma aliquot   
• Transfer pipettes 
• Dry ice (if –20 or -70°C freezer is not available) 
2. Write the subject number, and site number (as applicable) in the spaces provided on 
the label.  Record the last four digits from the barcode on the label onto the subject’s 

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chart and PK shipping logs in the comment column. See Figure below for an example of 
the barcoded labels 
3. Apply the barcoded labels to each of the three tubes for PK samples (1 for whole 
blood and 2 for plasma aliquots). 
4. Secure each label with a strip of transparent cellophane tape. 
 
(Note: it is important that the following steps are completed in sequence immediately 
within 30 minutes after collection of blood samples, unless otherwise noted): 
5. Collect 3 mL of blood into a pre-labeled K2-EDTA Vacutainer tube (the tube with 
the Lavender Top)  
6. Record the exact time (24-hour clock) that each sample was collected (be sure to use 
the same clock for recording both sampling and dosing times). 
7. Invert the collection tube gently at least 5 times. (If separation of the plasma fraction 
cannot be immediately performed at this time, store the samples on ice, or refrigerate 
the sample, and re-mix the samples by gentle inversion prior to proceeding to step 8). 
8. Separate the plasma fraction by centrifugation (1000-1200 × g for 10 minutes) using 
standard laboratory methods, materials, and equipment. A refrigerated centrifuge is 
preferred, and if available, should be set to 4ºC. 
9. Aliquot the plasma (equal volume) into each of two pre-labeled 5-mL polypropylene 
tubes (primary and backup aliquots), being careful not to transfer blood cells.  
10. Verify that each tube is tightly capped. 
11. Store the plasma aliquots immediately in a non-defrosting freezer at -70°C (-20°C 
freezer can be used if -70°C freezer is not available). Samples must be stored on dry 
ice if a freezer is not immediately available. 
12. For each subject, plasma samples should be shipped on dry ice to Alturas. 
 
 
 

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Figure: Example of the barcoded label for Plasma PK Samples 
 
 
 
 
lllllllllllllllllllllllllllllllllll 
Subject #: _______ 
Coll Date: Y 
Coll Time: Z 
Site #: _________ 
Matrix: Plasma 
Subject No. 
 
Site No 
Record on CRF and PK 
Shipping Log 
Handwrite the following onto the label: 
 41092000XXXX 
 41092000XXXX 

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Cohort B (3-15 years of age) 
Sites will use their own supplies to collect PK samples and apply a pre-printed label. The 
following supplies will be needed per timepoints: 
1. Vacutainer Lavender Top Plastic, K2 EDTA, 3 mL tube 
2. Transfer tube cryovial, 1.5 mL 
3. Transfer pipettes 
4. Labels 
5. Dry ice 
6. Centrifuge with horizontal rotor capable of producing 1200 x g (set to 4oC). 
7.  Non-defrosting freezer (-70°C or below) 
 
For Cohort B there will be a total of 4 samples drawn.  Blood samples (3ml will be drawn 
for pharmacokinetic profile during cabozantinib (XL184) therapy at the following 
timepoints: 
• Cycle 1, Day 1 (C1D1): Pre-cabozantinib dose (collected within15 minutes prior to 
cabozantinib dosing)  
• Cycle 2, Day 1 (C2D1) ±2 days: Pre-cabozantinib dose (collected within 15 minutes 
prior to Cabozantinib dosing),  
• Cycle 3 Day 1 (C3D1) ±2 days: Pre-cabozantinib dose (collected within15 minutes 
prior to cabozantinib dosing) 
• Cycle 4 Day 1 (C4D1) ±2 days: Pre-cabozantinib dose (collected within15 minutes 
prior to cabozantinib dosing) 
 
Procedure for Cohort B:   
Samples will be drawn as 3 mL whole blood into K2EDTA (lavender top) tubes 
 
1. 
Prior to obtaining blood from subjects at each timepoint, gather the following supplies:   
• One 3 mL K2-EDTA Vacutainer tube for each PK sample timepoint 
• Transfer tube cryovial, 1.5 mL  
• Transfer pipettes 
• Labels 
• Dry ice (if –20 or -70°C freezer is not available) 
2. 
Write the subject number, site number (as applicable) and Visit (C1D1, C2D1, C3D1 
or C4D1) on the labels. 
3. 
Apply the labels to each of the three tubes for PK samples (1 for whole blood and 2 
for plasma aliquots). 
4. 
Secure each label with a strip of transparent cellophane tape. 
 
(Note: it is important that the following steps are completed in sequence immediately 
within 30 minutes after collection of blood samples, unless otherwise noted): 
 
5. 
Collect 3 mL of blood into a pre-labeled K2-EDTA Vacutainer tube (the tube with the 
Lavender Top)  
6. 
Record the exact time (24-hour clock) that each sample was collected (be sure to use 
the same clock for recording both sampling and dosing times). 
7. 
Invert the collection tube gently at least 5 times. (If separation of the plasma fraction 

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cannot be immediately performed at this time, store the samples on ice, or refrigerate 
the sample, and re-mix the samples by gentle inversion prior to proceeding to step 8). 
8. 
Separate the plasma fraction by centrifugation (1000-1200 × g for 10 minutes) using 
standard laboratory methods, materials, and equipment. A refrigerated centrifuge is 
preferred, and if available, should be set to 4ºC. 
9. 
Aliquot the plasma (equal volume) into each of two pre-labeled 5-mL cryovial tubes 
(primary and backup aliquots), being careful not to transfer blood cells.  
10. Verify that each tube is tightly capped. 
11. Store the plasma aliquots immediately in a non-defrosting freezer at -70°C (-20°C 
freezer can be used if -70°C freezer is not available). Samples must be stored on dry 
ice if a freezer is not immediately available. 
12. For each subject, plasma samples should be shipped on dry ice to Alturas. 
 
Packaging Instructions:  
1. The first aliquot of PK samples should be shipped to Alturas Inc. after each 
subject completed the C1D28 (for Cohort A) and C4D1 (for Cohort B).  
2. The second aliquot of PK samples should be maintained at the sites as backup 
samples and be shipped along with the next available shipment.  
3. Please pack all the samples for each subject in each sealable bag 
4. Prior to shipment, verify that each tube is tightly sealed. 
5. Place the tubes into a sealable plastic bag (one subject per bag) surrounded by 
absorbent material.  
6. Complete the PK sample Shipping Log (noted below) based on the information on 
the site form recorded by the site staff. For each subject, place a copy of the 
shipping log into its own plastic bag, seal, and then add it to the bag containing 
that patient’s samples. Retain a copy of each shipping log for your records. Seal 
the bag. 
7. Place the plastic bags into a suitable Styrofoam shipping container 
(e.g., ThermoSafe) and fill with enough dry ice for 2 days in transit 
(e.g., 14 pounds). 
8. Write the FedEx tracking number on each shipping log sheet and fax the log sheet 
to the attention of Dr. Zimmer at Alturas at (208) 882-9246. 
9. Complete the Federal Express air bill and place it on the outside of the shipping 
container. 
 
After each shipment, please notify Linh Nguyen, PhD (linguyen@exelixis.com), Jennifer 
Zimmer, PhD (jzimmer@alturasanalytics.com) at Alturas Ajalytics, and the NF 
Consortium Operations Center representative, Lynn Merritt, RN (nfcop@uab.edu). 
 
Shipping Instructions:  Samples will be shipped on dry ice Monday thru Thursday by 
Federal Express. 
 
Ship samples to: 
Alturas Analytics, Inc. 
Attn: Jennifer Zimmer, PhD 
Executive Laboratory Manager 

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1324 Alturas Dr. 
Moscow, ID 83843 
Phone: (208) 883-3400 
Fax: (208) 882-9246 
Email: jzimmer@alturasanalytics.com 
 
 
** NOTE:  Samples should be stored in -70°C freezer until the C1D28 (for Cohort A) and 
C4D1 (for Cohort B),and shipped as a batch per subject. 
 
 

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Cohort A: Protocol XL184-IST-014 PK Plasma Samples Shipping Log Relative to 
Dosing Time 
Site Number: 
Site Name:  
Subject ID: 
 
 
Comments : 
(Please note any 
discrepancies) 
 
Visit 
PK Sample Shipped 
Not 
Done 
Date 
Collected      
(dd mmm 
yyyy) 
Time 
(24-h 
clock) 
Nominal 
Time 
Relative to 
Dosing Hour 
Plasma Sample 
Prima
ry 
Back
up 
 
Cycle 1, Day 
1 (C1D1) 
0 (pre-dose) 
  
  
  
 
_____:__
___ 
 
4 hours post-
dose 
  
  
  
 
_____:__
___ 
 
Cycle 1, Day 
15 
(C1D15) 
0 (pre-dose) 
  
  
  
 
_____:__
___ 
 
4 hours post-
dose 
  
  
  
 
_____:__
___ 
 
Cycle 1, Day 
28 
(C1D28) 
0 (pre-dose) 
 
4 hours post-
dose 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
_____:__
___ 
 
_____:__
___ 
 
 
 
 
Shipping Prepared by: ______________________ Date Shipped: __________________ 
 
 
Courier Used: ____________________________ 
Tracking No. __________________ 
 
Fax to the attention of Dr. Jennifer Zimmer at Alturas at Fax: (208) 882-9246.  
 
 
 

N F  Pr ot oc ol # 1 0 5   V ersi o n 2. 1 
0 5 / 0 1 / 2 0 1 9   
9 6 
 
C o h ort B: Pr ot o c ol X L 1 8 4- I S T- 0 1 4 P K Pl as m a S a m ples S hi p pi n g L o g Rel ati ve t o 
D osi n g Ti me 
 
Site N u m ber:  
Site N a me:  
S u bject I D: 
 
 
C o m me nts  : 
( Pl e ase n ote 
a n y 
discre p a ncies)  
 
Visit  
P K S a m ple S hi p pe d  
N ot 
D o ne  
D ate 
C ollecte d                      
( d d m m m 
y y y y) 
Ti me  
( 2 4-h 
cl oc k) 
N o mi n al 
Ti me 
Rel ati ve t o 
D osi n g 
H o ur  
Pl as m a S a m ple  
Pri m a
r y 
B ac k u
p 
 
C ycle 1, Da y 1 
( C 1 D 1) 
0 ( pre -d os e)  
 
 
 
 
_ _ _ _ _:
_ _ _ _ _  
 
C ycle 2 , Da y 1  
( C2 D 1)  
0 ( pre -d os e)  
 
 
 
 
_ _ _ _ _:
_ _ _ _ _  
 
C ycle 3 , Da y 1 
( C3 D 1)  
0 ( pre -d os e)  
 
 
 
 
_ _ _ _ _:
_ _ _ _ _  
 
C ycle 4 , Da y 1 
( C4 D 1)  
0 ( pre -d os e)  
 
 
 
 
_ _ _ _ _:
_ _ _ _ _  
 
 
 
 
S hi p pi n g Pre par e d b y: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Date S hi p pe d: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
 
 
C o urier Use d: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Trac k i n g N o. _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
F a x t o t he att e nti o n of Dr. Je n nif er Zi m mer at Alt ur as at F a x: ( 2 0 8) 8 8 2- 9 2 4 6.  
 

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APPENDIX VII:  CONSORTIUM QOL AND PAIN MEASURES 
 
Below is a description of the QOL and pain measures to be administered in this protocol 
organized by the domain that the questionnaire assesses.   
 
SUBJECTS > 16 YEARS: 
 
NF1 Disease Specific QOL Measure 
The Adult PedsQL™ NF1 Module is a 74-item a self-report instrument to assesses NF1 
disease-specific quality of life (QOL) in adults, ages 21 years and older. It is comprised of 
16 scales: 1) Physical functioning (8 items), 2) Emotional functioning (5 items), 3) Social 
functioning (3 items), 4) Cognitive functioning (5 items), 5) Communication (3 items), 6) 
Worry (7 items), 7) Perceived physical appearance (3 items), 8) Pain and Hurt (3 items), 
9) Paresthesias (2 items), 10) Skin irritation (5 items), 11) Sensation (4 items), 12) 
Movement and Balance (4 items), 13) Fatigue (3 items), 14) Daily activities (12 items), 
15) Treatment anxiety (4 items) and 16) Sexual functioning (3 items) (Nutakki et al., 
submitted; N. Swigonski, personal communication, September 26, 2012).   
 
The Teen PedsQL™ NF1 Module is a 75-item self-report for adolescents and young adults, 
ages 14 to 20 years of age, which includes 16 scales: 1) Physical functioning (8 items), 2) 
Emotional functioning (5 items), 3) Social functioning (3 items), 4) Cognitive functioning 
(7 items), 5) Communication (3 items), 6) Worry (6 items), 7) Perceived physical 
appearance (3 items), 8) Pain & Hurt (3 items), 9) Paresthesias (2 items), 10) Skin irritation 
(5 items), 11) Sensation (4 items), 12) Movement & Balance (4 items), 13) Fatigue (3 
items), 14) Daily activities (12 items), 15) Treatment anxiety (4 items) and 16) School 
Activities (3 items). 
 
The PedsQL™ NF1 Module format, instructions, and Likert response scale are similar to 
the PedsQL™ 4.0 Generic Core Scales and other PedsQL™ Disease-Specific Modules. 
The instructions ask how much of a problem each item has been during the past one month.  
A 5-point response scale is used for all items in the three versions of the instrument (0= 
never a problem, 1= almost never a problem, 2= sometimes a problem, 3= often a problem, 
4= almost always a problem). Items are reverse scored and linearly transformed to a scale 
of 0-100 similar to PedsQL™ 4.0 Generic Core Scales (0= 100, 1= 75, 2= 50, 3=25, 4=0).  
Higher scores indicate better HRQOL and fewer symptoms or problems.  The total scale 
score is computed as the sum of all items on the PedsQL™ NF1 Module divided by the 
number of items answered (this accounts for missing data).  Subscale scores are computed 
as the sum of the items divided by the number of items that were answered in that scale.  If 
more than 50% of the items in the scale are missing, the scale score is not computed. 
 
Feasibility, measured by the percentage of missing responses, was 4.8 % for all scales on 
the adult version of the PedsQL™ NF1 Module.  Internal consistency reliability for the 
Total Scale score (alpha =0.97) and Scale reliabilities ranging from 0.72 to 0.96 were 
acceptable for group comparisons. The PedsQL™ NF1 module distinguished between NF1 
adults with excellent to very good, good, and fair to poor health status.  Thus, preliminary 
data demonstrates the initial feasibility, reliability and validity of the PedsQL™ NF1 

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module in adult subjects (Nutakki et al., personal communication).  The preliminary data 
in a small sample of adolescents also looks promising with good feasibility (percentage of 
missing responses was 8.9%) and a total scale reliability of 0.96 (N. Swigonski, personal 
communication, October 10, 2012).   
 
Pain Measures 
 
1. Pain Intensity 
The Numerical Rating Scale-11 (NRS-11) is a self-report segmented 11-point numeric 
scale that assesses pain intensity22.  It consists of a horizontal line with 0 representing “no 
pain” at the right end of the line and 10 representing “worst pain you can imagine” at the 
left end.  Subjects are asked to circle the one number from 0 to 10 that best describes their 
“most important tumor pain” and 2) their “overall tumor pain” at its worst during the past 
week.  It takes less than 1 minute to complete.  The NRS-11 is recommended as a core 
outcome measure of pain intensity for clinical trials21.   
 
2. Pain Interference 
The Brief Pain Inventory (BPI)—Pain Interference Scale is a 7-item self-report 
questionnaire that measures the extent to which pain interferes with daily functioning20.  
Subjects are asked to indicate how much pain interfered with various activities (general 
activity, mood, walking, normal work, relations with other people, sleep, and enjoyment of 
life) in the past week, with scores ranging from 0 (does not interfere) to 10 (completely 
interferes).  A total score is obtained by taking the mean of the scores for all 7 items; thus, 
the total pain interference score can range from 0 to 7. This scale takes less than 2 minutes 
to complete.  These items are recommended to assess pain interference in clinical trials21.  
 
Background Information 
To allow for more meaningful analysis of the QOL data, the participant (for subjects > 16 
years) will complete a background information form at study entry and each subsequent 
QOL evaluation.  This form will collect general information such as the subject’s level of 
education, work status, psychiatric diagnoses, and pain medications, as well as the 
perceived visibility of NF1 tumors and severity of NF1 symptoms.   
 
Administration Guidelines 
These QOL and pain measures should be completed pre-treatment, after cycle 4 +2 weeks, 
8 +2 weeks, 12 +2 weeks, 18 +2 weeks, and 24 +2 weeks.  When administering these forms, 
review the instructions with the subjects and check to make sure they answered all the 
items.  If subjects have difficulty reading, it is permissible to read the items to them, but 
the subjects should answer the items themselves.  Completed forms should be sent (fax or 
mail copies) to the NF Consortium Operations Center within 2 weeks of completion.  For 
any questions regarding the QOL/pain assessment please contact: Pam Wolters at 
woltersp@mail.nih.gov. 
 
If subjects are 21 years old at study entry, they should be administered the Adult PedsQL 
NF1 Module.  If subjects are 16 to 20 years old at study entry, they should be administered 
the Teen PedsQL NF1 Module. However, if subjects turn 21 years old during the study, 

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they should continue to be administered the Teen version of this scale that they started at 
study entry. 
All subjects should complete the same self-report pain intensity and pain interference 
measures and background form.  
 
Please see section 9 for a table listing the self-report QOL and pain measures to be 
completed by the subject. 
 
 
 
 

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NF1 QOL BACKGROUND INFORMATION SHEET 
 
 
 
 
 
 

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PAIN QUESTIONNAIRE 
 
 
 

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QOL INSTRUMENT (TEEN REPORT): 16 to 20 years old 
 
 
QOL INSTRUMENT (TEEN REPORT) 
For teens and young adults (16 to 20 years old) with NF-1 
 
 
 
                                                    DIRECTIONS 
Teens with neurofibromas sometimes have special problems. Please tell us how much of a problem each 
one has been for you during the past ONE month by choosing the appropriate options: 
 
0 if it is never a problem              
1 if it is almost never a problem 
2 if it is sometimes a problem 
3 if it is often a problem 
4 if it is almost always a problem 
 
 
There are no right or wrong answers. 
If you do not understand a question, take your best guess. 
Thank you for your help! 
                                                                                                                                                    
                                                                                                                                                    
 
 

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QOL INSTRUMENT (TEEN REPORT): 16 to 20 years old 
 
Participant’s Study ID:  
 
 
 
Course Number: 
 
 
 
Protocol: 
 
 
 
 
 
Visit Date: 
 
 
 
 
 
 
Please select which of the following describes you the best:  
o I am a teen or young adult  (14 to 20 years old) with Neurofibromatosis Type 1 (NF-1) 
o Other, please specify _______________________________ 
 
How old are you? (in years)  ________________ 
 
Do you have plexiform neurofibromas?  
o Yes  
o No 
o Don’t know 
If yes, on a scale of 0 to 10 (where 0 is plexiform neurofibromas have no impact to 10 where 
plexiform neurofibromas have a huge impact), please rate the impact of your plexiform 
neurofibromas on your day-to-day life. ___________ 
 
In general, how would you rate your health? 
o Excellent  
o Very Good 
o Good 
o Fair 
o Poor 
 
 
How many times did you visit the doctor for your NF-1 in the past ONE year?  ____________ 
On average, how many different medications do you take for your NF-1 in a day? _________ 
 
 
 
 
 
 
 
 
 

NF Protocol #105  Version 2.1 
05/01/2019  
104 
QOL INSTRUMENT (TEEN REPORT): 16 to 20 years old 
 
Participant’s Study ID:  
 
 
 
Course Number: 
 
 
 
Protocol: 
 
 
 
 
 
Visit Date: 
 
 
 
 
 
 
In the past ONE month, how much of a problem has this been for you... 
PHYSICAL FUNCTIONING (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Having headaches 
0 
1 
2 
3 
4 
2.  Feeling physically weak 
0 
1 
2 
3 
4 
3.  Walking more than one block 
0 
1 
2 
3 
4 
4.  Climbing stairs 
0 
1 
2 
3 
4 
5.  Running 
0 
1 
2 
3 
4 
6.  Doing a sports activity or exercise 
0 
1 
2 
3 
4 
7.  Lifting something heavy 
0 
1 
2 
3 
4 
8.  Doing chores around the house 
0 
1 
2 
3 
4 
 
EMOTIONAL FUNCTIONING (problems with...) Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Feeling anxious 
0 
1 
2 
3 
4 
2.  Feeling sad 
0 
1 
2 
3 
4 
3.  Feeling angry 
0 
1 
2 
3 
4 
4.  Feeling frustrated 
0 
1 
2 
3 
4 
5.  Feeling helpless or hopeless 
0 
1 
2 
3 
4 
 
SOCIAL FUNCTIONING (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Feeling isolated from others 
     0 
      1 
     2 
    3 
     4 
2.  Getting support from others 
     0 
      1 
     2 
    3 
     4 
3.  Having enough energy for social activities 
     0 
      1 
     2 
    3 
     4 
 
COGNITIVE FUNCTIONING (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Keeping attention on things 
     0 
      1 
     2 
    3 
     4 
2.  Remembering what people tell you 
     0 
      1 
     2 
    3 
     4 
3.  Remembering what you just heard or read 
     0 
      1 
     2 
    3 
     4 
4.  Thinking quickly 
     0 
      1 
     2 
    3 
     4 
5.  Solving math problems 
     0 
      1 
     2 
    3 
     4 
6.  Writing school papers or reports 
     0 
      1 
     2 
    3 
     4 
7.  Remembering what you were just thinking 
     0 
      1 
     2 
    3 
     4 
 
 
 
 

NF Protocol #105  Version 2.1 
05/01/2019  
105 
QOL INSTRUMENT (TEEN REPORT): 16 to 20 years old 
 
Participant’s Study ID:  
 
 
 
Course Number: 
 
 
 
Protocol: 
 
 
 
 
 
Visit Date: 
 
 
 
 
 
 
COMMUNICATION (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Telling the doctors and nurses how you feel 
0 
1 
2 
3 
4 
2.  Asking the doctors and nurses questions 
0 
1 
2 
3 
4 
3.  Talking with others about your disorder 
0 
1 
2 
3 
4 
 
WORRY (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Worrying about neurofibromas 
0 
1 
2 
3 
4 
2.  Worrying about side effects from medical 
treatments 
0 
1 
2 
3 
4 
3.  Worrying about whether or not medical treatments 
are working 
0 
1 
2 
3 
4 
4.  Worrying that neurofibromas will grow bigger or 
reoccur 
0 
1 
2 
3 
4 
5.  Worrying about my future or the risk of having 
children  with Neurofibromatosis Type 1 
0 
1 
2 
3 
4 
6.  Worrying about the risk of other health related 
issues associated with Neurofibromatosis Type 1 
0 
1 
2 
3 
4 
 
PERCEIVED PHYSICAL APPEARANCE 
 (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Feeling that I am not good looking 
0 
1 
2 
3 
4 
2.  Not wanting other people to see my neurofibromas 
0 
1 
2 
3 
4 
3.  Being embarrassed about others seeing my body 
0 
1 
2 
3 
4 
 
PAIN AND HURT (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Aching or hurting 
0 
1 
2 
3 
4 
2.  Aching or hurting a lot 
0 
1 
2 
3 
4 
3.  Not sleeping because of pain 
0 
1 
2 
3 
4 
 
PARESTHESIAS (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  A burning sensation in some part of my body 
0 
1 
2 
3 
4 
2.  A tingling sensation in some part of my body 
0 
1 
2 
3 
4 
 
 
 
 
 

NF Protocol #105  Version 2.1 
05/01/2019  
106 
QOL INSTRUMENT (TEEN REPORT): 16 to 20 years old 
 
Participant’s Study ID:  
 
 
 
Course Number: 
 
 
 
Protocol: 
 
 
 
 
 
Visit Date: 
 
 
 
 
 
SKIN IRRITATION (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Itching  
0 
1 
2 
3 
4 
2.  Itching a lot 
0 
1 
2 
3 
4 
3.  Getting a skin rash when exposed to sun 
0 
1 
2 
3 
4 
4.  Tolerating temperature changes 
0 
1 
2 
3 
4 
5.  Rough skin 
0 
1 
2 
3 
4 
 
SENSATION (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Vision in one or both eyes 
0 
1 
2 
3 
4 
2.  Seeing well enough with glasses or contact  lenses  
0 
1 
2 
3 
4 
3.  Hearing in one or both ears 
0 
1 
2 
3 
4 
4. Speech 
0 
1 
2 
3 
4 
 
MOVEMENT AND BALANCE (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Bending my body 
0 
1 
2 
3 
4 
2.  Moving one or both legs 
0 
1 
2 
3 
4 
3.  Using or moving one or both arms 
0 
1 
2 
3 
4 
4.  Keeping balance when sitting/standing 
0 
1 
2 
3 
4 
 
SCHOOL ACTVITIES (problems with...) 
Never 
Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Writing or drawing with a pen or pencil 
0 
1 
2 
3 
4 
2.  Carrying school books 
0 
1 
2 
3 
4 
3.  Using a mouse or keyboard on the computer 
0 
1 
2 
3 
4 
 
DAILY ACTVITIES (problems with...) 
Never 
Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Putting on shoes 
0 
1 
2 
3 
4 
2.  Buttoning my shirt 
0 
1 
2 
3 
4 
3.  Combing my hair 
0 
1 
2 
3 
4 
4.  Getting into the bathroom to use the toilet 
0 
1 
2 
3 
4 
5.  Undressing to use the toilet 
0 
1 
2 
3 
4 
6.  Getting in and out of bathtub or shower 
0 
1 
2 
3 
4 
7.  Brushing my teeth 
0 
1 
2 
3 
4 
8.  Eating with a fork and knife 
0 
1 
2 
3 
4 
9.  Using a phone 
0 
1 
2 
3 
4 
10. Shopping 
0 
1 
2 
3 
4 
11. Managing money 
0 
1 
2 
3 
4 
12. Driving 
0 
1 
2 
3 
4 

NF Protocol #105  Version 2.1 
05/01/2019  
107 
QOL INSTRUMENT (TEEN REPORT): 16 to 20 years old 
 
Participant’s Study ID:  
 
 
 
Course Number: 
 
 
 
Protocol: 
 
 
 
 
 
Visit Date: 
 
 
 
 
 
 
FATIGUE (problems with...) 
Never 
Almost  
Never 
Some- 
times 
Often 
Almost 
Always 
1.  Feeling tired 
0 
1 
2 
3 
4 
2.  Resting a lot 
0 
1 
2 
3 
4 
3.  Having enough energy to do things that I like to do 
0 
1 
2 
3 
4 
 
TREATMENT ANXIETY(problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Getting scared about going to the doctor 
0 
1 
2 
3 
4 
2.  Getting scared about going to the hospital 
0 
1 
2 
3 
4 
3.  Being responsible for my medicines or  therapy 
0 
1 
2 
3 
4 
4.  Managing my Neurofibromatosis Type 1 
0 
1 
2 
3 
4 
 
Please write any comments that you have about how NF-1 affects your health and well-being. 
Please write any comments about the survey and whether or not it captures how NF-1 affects 
people’s health and well-being.

NF Protocol #105  Version 2.1 
05/01/2019  
108 
QOL INSTRUMENT (ADULT REPORT): > 21 years old 
 
QOL INSTRUMENT (ADULT SURVEY) 
For adults (> 21 years old) with NF-1 
 
 
                                                    DIRECTIONS 
This survey is for ADULTS with NF 1.  Neurofibromatosis type 1 sometimes causes special problems. 
Please tell us how much of a problem each one has been for you during the past ONE month by circling: 
 
0 if it is never a problem 
1 if it is almost never a problem 
2 if it is sometimes a problem 
3 if it is often a problem 
4 if it is almost always a problem 
 
There are no right or wrong answers. 
If you do not know an answer, take your best guess. 
Thank you for your help! 
                                                                                                                                                    
  
 
 
 
 

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109 
QOL INSTRUMENT (ADULT REPORT): > 21 years old 
 
Participant’s Study ID:  
 
 
 
Course Number: 
 
 
 
Protocol: 
 
 
 
 
 
Visit Date: 
 
 
 
 
 
 
Please select which of the following describes you the best (you can choose more than one):  
o I am an adult with Neurofibromatosis Type 1 (NF-1)  
o I am a professional who treats people with NF-1 
o I am a friend or family member of a person with NF-1 
o Other, please specify ___________________ 
 
How old are you? (in years)  ________________ 
 
Do you have plexiform neurofibromas?  
o Yes  
o No 
o Don’t know 
If yes, on a scale of 0 to 10 (where 0 is plexiform neurofibromas have no impact to 10 where plexiform 
neurofibromas have a huge impact), please rate the impact of your plexiform neurofibromas on your 
day-to-day life. ___________ 
 
In general, how would you rate your health? 
o Excellent 
o Very good 
o Good 
o Fair 
o Poor 
 
How many times did you visit the doctor for your NF-1 in the past ONE year? _____________ 
 
On average, how many different medications do you take for your NF-1 in a day? _________ 
 
 
 

NF Protocol #105  Version 2.1 
05/01/2019  
110 
QOL INSTRUMENT (ADULT REPORT): > 21 years old 
 
Participant’s Study ID:  
 
 
 
Course Number: 
 
 
 
Protocol: 
 
 
 
 
 
Visit Date: 
 
 
 
 
 
 
In the past ONE month, how much of a problem has this been for you... 
PHYSICAL FUNCTIONING (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Feeling physically weak 
0 
1 
2 
3 
4 
2.  Walking more than one block 
0 
1 
2 
3 
4 
3.  Climbing stairs 
0 
1 
2 
3 
4 
4.  Running 
0 
1 
2 
3 
4 
5.  Doing a sports activity or exercise 
0 
1 
2 
3 
4 
6.  Lifting something heavy 
0 
1 
2 
3 
4 
7.  Doing chores around the house 
0 
1 
2 
3 
4 
 
EMOTIONAL FUNCTIONING (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Feeling anxious 
     0 
      1 
     2 
    3 
     4 
2.  Feeling sad 
     0 
      1 
     2 
    3 
     4 
3.  Feeling angry 
     0 
      1 
     2 
    3 
     4 
4.  Feeling frustrated 
     0 
      1 
     2 
    3 
     4 
5.  Feeling helpless or hopeless 
     0 
      1 
     2 
    3 
     4 
 
SOCIAL FUNCTIONING (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Getting support from others 
     0 
      1 
     2 
    3 
     4 
2.  Having enough energy for social activities 
     0 
      1 
     2 
    3 
     4 
 
COGNITIVE FUNCTIONING (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Keeping attention on things 
     0 
      1 
     2 
    3 
     4 
2.  Remembering what people tell you 
     0 
      1 
     2 
    3 
     4 
3.  Remembering what you just heard/read 
     0 
      1 
     2 
    3 
     4 
4.  Thinking quickly 
     0 
      1 
     2 
    3 
     4 
5.  Remembering what you were just thinking 
     0 
      1 
     2 
    3 
     4 
 
COMMUNICATION (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Telling the doctors and nurses how you feel 
0 
1 
2 
3 
4 
2.  Asking the doctors and nurses questions 
0 
1 
2 
3 
4 
3.  Talking with others about your disorder 
0 
1 
2 
3 
4 
Participant’s Study ID:  
 
 
 
Course Number: 
 
 
 

NF Protocol #105  Version 2.1 
05/01/2019  
111 
QOL INSTRUMENT (ADULT REPORT): > 21 years old 
 
Protocol: 
 
 
 
 
 
Visit Date: 
 
 
 
 
 
 
WORRY (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Worrying about my neurofibromas 
0 
1 
2 
3 
4 
2.  Worrying about side effects from medical treatments 
0 
1 
2 
3 
4 
3.  Worrying about whether or not medical treatments are 
working 
0 
1 
2 
3 
4 
4.  Worrying that neurofibromas will grow bigger or reoccur 
0 
1 
2 
3 
4 
5.  Worrying about my future or the risk of having children  
with Neurofibromatosis Type 1 
0 
1 
2 
3 
4 
6.  Worrying about the risk of other health related issues 
associated with Neurofibromatosis Type 1 
0 
1 
2 
3 
4 
 
PERCEIVED PHYSICAL APPEARANCE 
                               (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Feeling that I am not good looking 
0 
1 
2 
3 
4 
2.  Not wanting other people to see my neurofibromas 
0 
1 
2 
3 
4 
3.  Being embarrassed about others seeing my body 
0 
1 
2 
3 
4 
 
PAIN AND HURT (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Aching or hurting 
0 
1 
2 
3 
4 
2.  Aching or hurting a lot 
0 
1 
2 
3 
4 
3.  Not sleeping because of pain 
0 
1 
2 
3 
4 
 
PARESTHESIAS (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  A burning sensation in some part of my body 
0 
1 
2 
3 
4 
2.  A tingling sensation in some part of my body 
0 
1 
2 
3 
4 
 
SKIN IRRITATION (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Itching  
0 
1 
2 
3 
4 
2.  Itching a lot 
0 
1 
2 
3 
4 
3.  Getting a skin rash when exposed to sun 
0 
1 
2 
3 
4 
4.  Tolerating temperature changes 
0 
1 
2 
3 
4 
5.  Rough skin 
0 
1 
2 
3 
4 
 
 
 

NF Protocol #105  Version 2.1 
05/01/2019  
112 
QOL INSTRUMENT (ADULT REPORT): > 21 years old 
 
 
Participant’s Study ID:  
 
 
 
Course Number: 
 
 
 
Protocol: 
 
 
 
 
 
Visit Date: 
 
 
 
 
 
 
SENSATION (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Vision in one or both eyes 
0 
1 
2 
3 
4 
2.  Seeing well enough with glasses or contact  lenses  
0 
1 
2 
3 
4 
3.  Hearing in one or both ears 
0 
1 
2 
3 
4 
4. Speech 
0 
1 
2 
3 
4 
 
MOVEMENT AND BALANCE (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Bending my body 
0 
1 
2 
3 
4 
2.  Moving one or both legs 
0 
1 
2 
3 
4 
3.  Using or moving one or both arms 
0 
1 
2 
3 
4 
4.  Keeping balance when sitting or standing 
0 
1 
2 
3 
4 
 
DAILY ACTVITIES (problems with...) 
Never 
Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Putting on shoes 
0 
1 
2 
3 
4 
2.  Buttoning my shirt 
0 
1 
2 
3 
4 
3.  Combing my hair 
0 
1 
2 
3 
4 
4.  Getting into the bathroom to use the toilet 
0 
1 
2 
3 
4 
5.  Undressing to use the toilet 
0 
1 
2 
3 
4 
6.  Getting in and out of bathtub or shower 
0 
1 
2 
3 
4 
7.  Brushing my teeth 
0 
1 
2 
3 
4 
8.  Eating with a fork and knife 
0 
1 
2 
3 
4 
9.  Using a phone 
0 
1 
2 
3 
4 
10. Shopping 
0 
1 
2 
3 
4 
11. Managing money 
0 
1 
2 
3 
4 
12. Driving 
0 
1 
2 
3 
4 
 
FATIGUE (problems with...) 
Never Almost  
Never 
Some- 
times 
Often Almost 
Always 
1.  Feeling tired 
0 
1 
2 
3 
4 
2.  Resting a lot 
0 
1 
2 
3 
4 
3.  Having enough energy to do things that I like to do 
0 
1 
2 
3 
4 
 
TREATMENT ANXIETY(problems with...) 
Never 
Almost  
Never 
Some- 
times 
Often 
Almost 
Always 
1.  Getting scared about going to the doctor 
0 
1 
2 
3 
4 

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113 
QOL INSTRUMENT (ADULT REPORT): > 21 years old 
 
2.  Getting scared about going to the hospital 
0 
1 
2 
3 
4 
3.  Being responsible for my medicines or  therapy 
0 
1 
2 
3 
4 
Participant’s Study ID:  
 
 
 
Course Number: 
 
 
 
Protocol: 
 
 
 
 
 
Visit Date: 
 
 
 
 
 
 
SEXUAL 
FUNCTIONING 
(problems 
with...) 
Never 
Almost  
Never 
Some- 
times 
Often 
Almost 
Always 
Not 
Applicable 
1.  Fatigue or lack of energy affecting your 
satisfaction with your sex life 
0 
1 
2 
3 
4 
        5 
2.  Pain affecting your satisfaction with your 
sex life 
0 
1 
2 
3 
4 
5 
3.  Ability to have children with a fertile 
partner 
0 
1 
2 
3 
4 
5 
 
 
Please write any comments that you have about how NF-1 affects your health and well-being. Please write 
any comments about the survey and whether or not it captures how NF-1 affects people’s health and well-
being. 
 
 
 
 

NF Protocol #105  Version 2.1 
05/01/2019  
114 
 
SUBJECTS 3 - 15 YEARS: 
 
I. QOL and Pain Measures for Subjects 3 – 15 years 
 
In participants with plexiform neurofibromas (PN) in all locations, this study will assess general health-
related qualify of life (QOL) and pain (pain intensity and pain interference) using patient-reported outcomes 
(PROs) as well as global impression of change as described below. 
 
Description of QOL and Pain Measures 
 
General Health-Related Quality of Life 
Pediatric Quality of Life Inventory (PedsQL; Varni, 2001):  The PedsQL 4.0 Generic Core Scales (Acute 
Form assessing the past 7 days) are multidimensional child self-report and parent proxy report scales to 
assess health-related quality of life (QOL) in children, adolescents, and young adults ages 2 – 25 years.  It 
is a brief standardized pediatric QOL scale with good reliability and validity, which includes both generic 
and disease specific modules.  It consists of a 23-item core measure of global QOL that has four subscales:  
physical functioning, emotional functioning, social functioning, and school functioning.  The domain of 
physical functioning will be used as a specific secondary outcome measure for this study, especially the 
parent proxy for younger children as it assesses children under 6 years of age.  
There are different forms for parents of patient’s ages 2 – 18 years (toddler: 2 – 4; young child: 5 – 7; child: 
8 – 12; adolescent:  13 – 18) and parallel self-report forms for patient’s ages 5 – 25 years (young child: 5 – 
7; child: 8 – 12; adolescent: 13 – 18; young adult:  18 – 25).  It takes approximately 5 - 10 minutes to 
complete.  For this study, children from 8 to 15 years of age will complete self-report measures of the 
PedsQL, and parents or legal guardians of children from 3 to 15 years of age will complete the parent proxy 
report measures of the PedsQL.   
 
Pain Intensity 
The Numerical Rating Scale-11 (NRS-11) is a self-report segmented 11-point numeric scale that assesses 
pain severity (Hawker et al., 2011).  It consists of a horizontal line with 0 representing “no pain” at the right 
end of the line and 10 representing “worst pain you can imagine” at the left end.  Patients are asked to circle 
the one number from 0 to 10 that best describes their worst pain over the past week for the following: 1) 
most important tumor pain chosen by the participant, 2) target tumor pain and 2) other pain.  It takes less 
than 5 minute to complete.  The NRS-11 is recommended as a core outcome self-report measure of pain 
intensity for clinical trials (Dworkin et al., 2005) in children with NF1 (Wolters, et al., 2013).  Children, 
ages 8 to 15 years, will complete self-report measures of the NRS-11 for this study.   
 
Pain Interference 
The Pain Interference Index (PII) is a 6-item measure that assesses the degree to which pain has interfered 
with daily activities in the past week. This measure was developed in Sweden and validated in Swedish 
with a group of children and adolescents with longstanding idiopathic pain (Wicksell, Melin, Lekander, & 
Olsson, 2009). The author (R. Wicksell) translated the measure into English, and members of the 
Neurobehavioral Group (S. Peron and P. Wolters) worked with the Swedish group to modify the wording 
to make it more readable and to shorten the time frame to one week, and we adapted it to create a parallel 
parent version. Dr. Wicksell and the Swedish research group are supportive of our efforts to validate the 
self-report and parent versions of the PII in NF1. Results of our validation studies in children with NF1 and 
their parents indicate that the internal consistency and construct validity of the PII are good.  These data 
support the use of the PII to assess pain interference in youth with NF1 and PNs (Martin et al., submitted).  

NF Protocol #105  Version 2.1 
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115 
 
For this study, children from 8 to 15 years of age will complete self-report PII, and parents or the legal 
guardian of children from 5 to 15 years of age will complete the parent proxy report PII.   
 
Global Impression of Change 
The patient Global Impression of Change (GIC) Scale evaluates the clinical significance of changes in pain 
intensity or other PN morbidities. We will administer an adapted version of the self-report GIC Scale at the 
follow-up PRO evaluations only (it should not be given pre-study because it assesses change from 
baseline).  A parallel parent proxy report form also was developed.  On the adapted GIC, patients (and their 
parents separately) will give their overall impression of change in level of the child’s 1) tumor pain, 2) other 
pain, and 3) PN morbidity from before initiation of the study drug to the current evaluation point. This 
global measure of change will be administered to children >8 years and for parents of children > 5 years of 
age at each PRO assessment.  The GIC Scale has been used in several research studies on chronic pain in 
adults and more recently children (Arnold et al., 2011; Mohammad et al., 2014). It has been recommended 
by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) for 
clinical trials involving chronic pain (Dworkin et al., 2005; McGrath et al., 2008).  
 
Global Impression of Change (in PN morbidities) 
We also adapted the GIC for clinicians to rate change in PN morbidities for each participant from before 
the initiation of cabozantinib to the current evaluation point based on their history and physical examination.  
This global measure of change will be completed for participants of all ages by a clinician (familiar with 
the participant).   
 
Pediatric Background Information 
The Pediatric QOL Background Form should be completed by the parents/primary caregivers of all patients 
ages from 3-15 years at each evaluation to document information about demographics, use of pain 
medication, and NF1 disease severity.  These data will be used to better interpret the PRO data.   
 
Administration of QOL and Pain Measures 
• Participants will complete the PRO measures at baseline (prior to starting treatment) and then after cycle 
4 +2 weeks, 8 +2 weeks, 12 +2 weeks, 18 +2 weeks, and 24 +2 weeks, except for the Global Impression of 
Change scale that will only be administered at the follow-up evaluations because it assesses change from 
baseline.   
 
Self-report 
• Children, 8 to 15 years of age, will complete the self-report measures of the PedsQL, NRS-11, and PII at 
baseline and all follow-up evaluations.  The GIC scale will be done only at the follow-up evaluations after 
the other measures have been completed.   
 
Parent Proxy Report 
• Parents (or the legal guardian) of children, 3 to 15 years of age, will complete the parent proxy measures 
of the PedsQL and a background form.   
 
• Parents (or the legal guardian) of children, 5 to 15 years of age, also will complete the parent proxy 
measures of the PII.  At the follow-up evaluations only, they will be administered the GIC scale, which is 
to be completed after the other measures have been done.   
 
 
 

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Clinician Report 
• Clinicians will complete the Global Impression of Change of the morbidities at the follow-up evaluations 
only for pediatric participants of all ages (3-15 years).   
 
References: 
Arnold LM, Zlateva G, Sadosky A, Emir B, Whalen E. Correlations between fibromyalgia symptom and 
function domains and patient global impression of change: a pooled analysis of three randomized, placebo-
controlled trials of pregabalin. Pain Med. Feb 2011;12(2):260-267. 
Dworkin, RH, Turk, DC, Farrar, JT et al., (2005).  Core outcome measures for chronic pain clinical trials: 
IMMPACT recommendations.  Pain, 113, 9 – 19.   
Hawker, G.A., Mian, S., Kendzerska, T., & French, M.  (2011).  Measures of Adult Pain.  Arthritis Care & 
Research, 63 (S11), S240-S252. 
Martin, S., Nelson Schmitt, S., Wolters, P., Abel, B., Toledo-Tamula, M., Baldwin, A., Wicksell, R.K., 
Merchant, M., and Widemann, B.  Development and Validation of the English Pain Interference Index and 
Pain Interference Index – Parent Report.  Manuscript submitted. 
McGrath PJ, Walco GA, Turk DC, et al. Core outcome domains and measures for pediatric acute and 
chronic/recurrent pain clinical trials: PedIMMPACT recommendations. J Pain. Sep 2008;9(9):771-783. 
Mohammad S, Di Lorenzo C, Youssef NN, et al. Assessment of abdominal pain through global outcomes 
and recent FDA recommendations in children: are we ready for change? J Pediatr Gastroenterol Nutr. Jan 
2014;58(1):46-50. 
Varni JW, Seid M, Kurtin PS.  (2001).  PedsQL 4.0: Reliability and validity of the pediatric quality of life 
inventory version 4.0 generic core scales in healthy and patient populations. Med Care, 39, 800–812. 
Varni JW, Burwinkle TM, Seid M. (2005). The PedsQL as a pediatric patient-reported outcome: Reliability 
and validity of the PedsQL measurement model in 25,000 children. Expert Rev Pharmacoecon Outcomes 
Res, 5:705–719. 
Wicksell RK, Melin L, Lekander M, Olsson GL. (2009).  Evaluating the effectiveness of exposure and 
acceptance strategies to improve functioning and quality of life in longstanding pediatric pain - A 
randomized controlled trial. Pain, 141:248-257. 
Wolters, P.L., Martin, S., Merker, V.L., Gardner, K.L., Hingtgen, C.M., Tonsgard, J.H., Schorry, E.K., 
Baldwin, A. for the REiNS International Collaboration. (2013).  Patient-reported outcomes in 
neurofibromatosis and schwannomatosis clinical trials.  Neurology, 81, (Suppl 1), S6-S14.  
 
 
 
 
 

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APPENDIX VIII: BLOOD PRESSURE NORMS 
 
 
 
 
Blood pressure (BP) levels for MALES 
 
Systolic Blood Pressure, mm Hg
Diastolic Blood Pressure, mm Hg
Age 
BP 
Percentile of Height 
Percentile of Height 
(years) Percentile 5th 10th 25th 50th 75th 90th 95th 5th 10th 25th 50th 75th 90th 95th 
16 
95th 
129 130 
132 134 
135 
137 137 82 
83 
83 
84 
85 
86 
87 
≥17 
95th 
131 132 
134 136 
138 
139 140 84 
85 
86 
87 
87 
88 
89 
 
 
Blood pressure (BP) levels for FEMALES 
 
Systolic Blood Pressure, mm Hg
Diastolic Blood Pressure, mm Hg
Age 
BP 
Percentile of Height 
Percentile of Height 
(years) Percentile 5th 10th 25th 50th 75th 90th 95th 5th 10th 25th 50th 75th 90th 95th 
16 
95th 
125 126 
127 
128 
130 
131 
132 
82 
82 
83 
84 
85 
85 
86 
≥17 
95th 
125 126 
127 
129 
130 
131 
132 
82 
83 
83 
84 
85 
85 
86 
 
 
 

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Blood pressure (BP) levels for BOYS 
 
Systolic Blood Pressure, mm Hg 
Diastolic Blood Pressure, mm Hg 
Age 
BP 
Percentile of Height 
Percentile of Height 
(years) 
Percentile 
5th 
10th 
25th 
50th 
75th 
90th 95th 5th 
10th 25th 50th 75th 90th 95th 
1 
95th 
98 
99 
101 
103 
104 
106 
106 
54 
54 
55 
56 
57 
58 
58 
2 
95th 
101 
102 
104 
106 
108 
109 
110 
59 
59 
60 
61 
62 
63 
63 
3 
95th 
104 
105 
107 
109 
110 
112 
113 
63 
63 
64 
65 
66 
67 
67 
4 
95th 
106 
107 
109 
111 
112 
114 
115 
66 
67 
68 
69 
70 
71 
71 
5 
95th 
108 
109 
110 
112 
114 
115 
116 
69 
70 
71 
72 
73 
74 
74 
6 
95th 
109 
110 
112 
114 
115 
117 
117 
72 
72 
73 
74 
75 
76 
76 
7 
95th 
110 
111 
113 
115 
117 
118 
119 
74 
74 
75 
76 
77 
78 
78 
8 
95th 
111 
112 
114 
116 
118 
119 
120 
75 
76 
77 
78 
79 
79 
80 
9 
95th 
113 
114 
116 
118 
119 
121 
121 
76 
77 
78 
79 
80 
81 
81 
10 
95th 
115 
116 
117 
119 
121 
122 
123 
77 
78 
79 
80 
81 
81 
82 
11 
95th 
117 
118 
119 
121 
123 
124 
125 
78 
78 
79 
80 
81 
82 
82 
12 
95th 
119 
120 
122 
123 
125 
127 
127 
78 
79 
80 
81 
82 
82 
83 
13 
95th 
121 
122 
124 
126 
128 
129 
130 
79 
79 
80 
81 
82 
83 
83 
14 
95th 
124 
125 
127 
128 
130 
132 
132 
80 
80 
81 
82 
83 
84 
84 
15 
95th 
126 
127 
129 
131 
133 
134 
135 
81 
81 
82 
83 
84 
85 
85 
16 
95th 
129 
130 
132 
134 
135 
137 
137 
82 
83 
83 
84 
85 
86 
87 
≥17 
95th 
131 
132 
134 
136 
138 
139 
140 
84 
85 
86 
87 
87 
88 
89 
Instructions for using this BP Chart: 
1. Measure the patient’s blood pressure using an appropriate size cuff. 
2. Select appropriate chart for a female or male patient. 
3. Using the “age” row and “height” column determine if the BP is within the ULN. 
 
 
This table was taken from “The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents” 
PEDIATRICS Vol. 114 No. 2 August 2004, pp. 555-576. 
 
 
 
 
 

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Blood pressure (BP) levels for GIRLS 
 
Systolic Blood Pressure, mm Hg 
Diastolic Blood Pressure, mm Hg 
 
 
Age 
BP 
Percentile of Height 
Percentile of Height 
(years) 
Percentile 
5th 10th 25th 50th 75th 90th 95th 
5th 
10t
25th 50th 
75th 
90th 
95th 
1 
95th 
100 101 
102 
104 
105 
106 
107 
56 
57 
57 
58 
59 
59 
60 
2 
95th 
102 103 
104 
105 
107 
108 
109 
61 
62 
62 
63 
64 
65 
65 
3 
95th 
104 104 
105 
107 
108 
109 
110 
65 
66 
66 
67 
68 
68 
69 
4 
95th 
105 106 
107 
108 
110 
111 
112 
68 
68 
69 
70 
71 
71 
72 
5 
95th 
107 107 
108 
110 
111 
112 
113 
70 
71 
71 
72 
73 
73 
74 
6 
95th 
108 109 
110 
111 
113 
114 
115 
72 
72 
73 
74 
74 
75 
76 
7 
95th 
110 111 
112 
113 
115 
116 
116 
73 
74 
74 
75 
76 
76 
77 
8 
95th 
112 112 
114 
115 
116 
118 
118 
75 
75 
75 
76 
77 
78 
78 
9 
95th 
114 114 
115 
117 
118 
119 
120 
76 
76 
76 
77 
78 
79 
79 
10 
95th 
116 116 
117 
119 
120 
121 
122 
77 
77 
77 
78 
79 
80 
80 
11 
95th 
118 118 
119 
121 
122 
123 
124 
78 
78 
78 
79 
80 
81 
81 
12 
95th 
119 120 
121 
123 
124 
125 
126 
79 
79 
79 
80 
81 
82 
82 
13 
95th 
121 122 
123 
124 
126 
127 
128 
80 
80 
80 
81 
82 
83 
83 
14 
95th 
123 123 
125 
126 
127 
129 
129 
81 
81 
81 
82 
83 
84 
84 
15 
95th 
124 125 
126 
127 
129 
130 
131 
82 
82 
82 
83 
84 
85 
85 
16 
95th 
125 126 
127 
128 
130 
131 
132 
82 
82 
83 
84 
85 
85 
86 
≥17 
95th 
125 126 
127 
129 
130 
131 
132 
82 
83 
83 
84 
85 
85 
86 
Instructions for using this BP Chart: 
1. 
Measure the patient’s blood pressure using an appropriate size cuff. 
2. 
Select appropriate chart for a female or male patient. 
3. 
Using the “age” row and “height” column determine if the BP is within the ULN. 
 
This table was taken from “The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood 
Pressure in Children and Adolescents” PEDIATRICS Vol. 114 No. 2 August 2004, pp. 555-576. 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX IX: MRI ELIGIBILITY FORM  
 
This form must accompany all MRI studies sent to the NCI POB for review of target plexiform 
neurofibroma eligibility (i.e. whether it is measurable and amenable to volumetric analysis).  Please mail 
the MRI on a CD along with this form to: 
 
 
Eva Dombi, MD 
 
NCI, POB 
 
10 Center Drive  
Building 10 CRC, Room 1-5750 
 
Bethesda, MD 20892 
 
Phone: 301-451-7023 
 
E-mail: dombie@mail.nih.gov  
 
 
 
PID#1: ________ 
 
 
Date of MRI:  ___________ 
 
 
 
Location of target plexiform: 
_______________________________________________ 
 
 
 
From: 
Name of Investigator:  _______________________________________________ 
 
Study Center:   
_______________________________________________ 
 
Phone #: 
 
_______________________________________________ 
 
Email Address:   
_______________________________________________ 
 
 
 
 
 
 
_____________________________________________________________________________________ 
From Eva Dombi, MD:  
 
The target PN is measurable and amenable to volumetric analysis:  
 
 
Yes:_____________ 
No: ____________ 
 
Comments: _______________________________________________ 
 

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APPENDIX X: SUGGESTED PROPHYLAXIS AND TREATMENT FOR PALMAR-
PLANTAR ERYTHODYSESTHESIA SYNDROME (PPE) 
 
These guidelines were developed by the company (Exelixis) based on their experience treating over 1000 
patients. These guidelines are helpful in prevention and treatment. 
 
Prophylaxis:  
Ammonium lactate 12% cream BID to palms of hands and soles of feet. 
 
Treatment: (to begin as soon as mild symptoms begin) 
1. Urea 20% cream twice daily and 
2. Clobetasol 0.05% cream once to twice daily 
 
 
 
 
Management of Treatment-Emergent Hand-Foot Syndrome (PPES) 
CTCAE v.4.0 Grade  
Action To Be Taken  
Grade 1 
Study treatment may be continued at the current dose if PPES is clinically 
insignificant and tolerable. Otherwise, study treatment should be reduced to the 
next lower dose level.a Start urea 20% cream twice daily AND clobetasol 0.05% 
cream once daily. Reassess at least weekly; if PPES worsens at any time or does 
not improve after 2 weeks, proceed to the intervention guidelines for Grade 2. 
Grade 2  
Study treatment may be continued if PPES is tolerated. Study treatment should be 
dose reduced or interrupted if PPES is intolerable. Continue urea 20% cream 
twice daily AND clobetasol 0.05% cream once daily and add analgesics 
(eg, NSAIDs/gamma-aminobutyric acid agonists) for pain control if needed. 
Reassess at least weekly; if PPES worsens or affects self-care, proceed to the 
intervention guidelines for Grade 3. 
Grade 3 
Interrupt study treatment until severity decreases to Grade 1 or 0. Continue 
treatment of skin reaction with clobetasol 0.05% cream twice daily AND 
analgesics. Resume study drug at a reduced dose if PPES recovers to Grade ≤ 1. 
Discontinue subject from study treatment if PPES does not improve within 
6 weeks. 
CTCAE, Common Terminology Criteria for Adverse Events; NSAID, non-steroidal anti-inflammatory drug; PPES, palmar 
plantar erythrodysesthesia syndrome. 
a Permitted dose levels are defined by individual protocols. 

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APPENDIX XI: CABOZANTINIB DOSING NOMOGRAM 
 
 
23 mg/m2, 
Level -1 
30 mg/m2, 
Level 1 
40 mg/m2, 
Level 2 
Dose/Schedule 
Weekly Dose 
0.34 – 0.43 
 
 
20 mg M, W, F 
60 mg 
0.44 – 0.55 
0.35 – 0.42 
 
20 mg M, W, F, Sun 
80 mg 
0.56 – 0.68 
0.43 – 0.52 
0.33 – 0.39 
20 mg M, W, H, Sat, Sun 
100 mg 
0.69 – 0.79 
0.53 – 0.60 
0.40 – 0.45 
20 mg M, T, W, F, Sat, Sun 
120 mg 
0.80 - 0.96 
0.61 – 0.73 
0.46 – 0.55 
20 mg Daily 
140 mg 
0.97 – 1.11 
0.74 – 0.85 
0.56 – 0.64 
40 mg M, W, F, Sun 
160 mg 
1.12 – 1.36 
0.86 – 1.04 
0.65 – 0.78 
40 mg M, W, H, Sat, Sun 
200 mg 
≥ 1.37 
1.05 – 1.21 
0.79 – 0.90 
40 mg M, T, W, F, Sat, Sun 
240 mg 
 
≥ 1.20 
0.91 – 1.09 
40 mg Daily 
280 mg 
 
 
1.10 – 1.17 
60 mg M, W, H, Sat, Sun 
300 mg 
 
 
1.18 – 1.36 
60 mg M, T, W, F, Sat, Sun 
360 mg 
 
 
≥ 1.37 
60 mg Daily 
420 mg 
 
 
 
 
 

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Yes dose 
limiting 
toxicity
23mg/m2
30 mg/m2
Cycle 1-2
Off study
Yes dose 
limiting 
toxicity
No dose 
limiting 
toxicity
No dose 
limiting 
toxicity
40 mg/m2
Cycle 3 +
No dose 
change
No Dose 
limiting 
toxicity
Yes dose 
limiting 
toxicity
30 mg/m2
No dose 
change
No Dose 
limiting 
toxicity
No dose 
change
Dosing Flow Chart Cohort B (3 – 15 years)

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APPENDIX XII: PLEXIFORM NEUROFIBROMA SYMPTOM CHECKLIST  
To be completed by Patient if able, otherwise completed by the Parent/Guardian. To be completed by the 
same individual at each timepoint. 
 
Testing should be performed pre-treatment, and then post cycles 4, 8, 12, 18, 24. 
 
Select one:  
Pre-treatment  ☐  
Post  cycle 4  ☐  
Post cycle 8  ☐   
Post cycle 12  ☐ 
 
 
Post cycle 18  ☐       
Post cycle 24  ☐  
Other (Please specify): _________________________ 
 
For each item below, please check one box (unless otherwise indicated) to describe how much each of these 
has been a problem for you in the past two weeks: 
 
1) Fatigue/feeling tired 
  
 Not at all   A little 
 Some 
 Pretty much     A lot 
 
  
2) Sleep problems 
  
 Not at all   A little 
 Some 
 Pretty much     A lot 
3) Less appetite  
    (eating less) 
 
 Not at all   A little 
 Some 
 Pretty much     A lot 
4) More appetite  
    (eating more)  
 Not at all   A little 
 Some 
 Pretty much     A lot 
 
5) Headaches 
  
 Not at all   A little 
 Some 
 Pretty much     A lot 
 
  
6) Vision changes 
  
 Not at all   A little 
 Some 
 Pretty much     A lot 
7) Decreased hearing 
  
 Not at all   A little 
 Some 
 Pretty much     A lot 
8) Mouth Sores 
 
 Not at all   A little 
 Some 
 Pretty much     A lot 
9) Trouble swallowing 
     
 Not at all   A little 
 Some 
 Pretty much     A lot 
10) Choking 
  
 Not at all   A little 
 Some 
 Pretty much     A lot 
11) Snoring 
 
 Not at all   A little 
 Some 
 Pretty much     A lot 
12)Frequent awakenings 
at night 
 Not at all   A little 
 Some 
 Pretty much     A lot 
 
 
 
13) Cough 
  
 Not at all  
 A little 
 Some 
 Pretty much       A lot 

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14) Wheezing 
  
 Not at all  
 A little 
 Some 
 Pretty much       A lot 
15) Difficulty breathing  
 Not at all  
 A little 
 Some 
 Pretty much       A lot 
 
16) Chest pain 
  
 Not at all  
 A little 
 Some 
 Pretty much       A lot 
 
  
17) Palpitations/fluttering 
  
 Not at all  
 A little 
 Some 
 Pretty much       A lot 
18) Shortness of breath  
with activity 
  
 Not at all  
 A little 
 Some 
 Pretty much       A lot 
19) Shortness of breath at 
rest 
 
 Not at all  
 A little 
 Some 
 Pretty much       A lot 
20) Swelling in hands/feet     
 Not at all  
 A little 
 Some 
 Pretty much       A lot 
 
21) Abdominal pain 
  
 Not at all   A little 
 Some 
 Pretty much     A lot 
 
  
22) Heartburn 
  
 Not at all   A little 
 Some 
 Pretty much     A lot 
23) Nausea 
  
 Not at all   A little 
 Some 
 Pretty much     A lot 
24) Vomiting 
 
 Not at all   A little 
 Some 
 Pretty much     A lot 
25) Diarrhea 
     
 Not at all   A little 
 Some 
 Pretty much     A lot 
26) Constipation 
  
 Not at all   A little 
 Some 
 Pretty much     A lot 
27) Stool incontinence 
 Not at all   A little 
 Some 
 Pretty much     A lot 
 
28) Pain with urination 
  
 Not at all   A little  Some 
 Pretty much     A lot 
 
  
29) 
Increased 
urinary 
frequency/urgency 
  
 Not at all   A little  Some 
 Pretty much     A lot 
30)Difficulty beginning  
urination 
  
 Not at all   A little  Some 
 Pretty much     A lot 
31)Urinary incontinence 
 Not at all   A little  Some 
 Pretty much     A lot 
 
32) Weakness 
 
 Not at all  
 A little 
 Some 
 Pretty much       A lot 

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If yes, where?   
 
  
33) Muscle pain 
 
If yes, where? 
 Not at all  
 A little 
 Some 
 Pretty much       A lot 
 
34) Dizziness 
  
 Not at all  
 A little 
 Some 
 Pretty much       A lot 
 
  
35) Numbness 
 
 Not at all  
 A little 
 Some 
 Pretty much       A lot 
36) Tingling     
 Not at all  
 A little 
 Some 
 Pretty much       A lot 
 
 
 
COMPLETED BY:  
 
 
 
 
 
DATE 
 
 

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APPENDIX XIII: PN LOCATION AND ASSOCIATED MORBIDITIES 
INSTRUCTIONS:  
 
To be completed by the Site PI prior to starting treatment 
- 
Assess PN location(s) by clinical exam and imaging studies (target PN and up to 2 non target PN; fill out a separate form for each PN)  
- 
List morbidities present using numbers below (see list) 
- 
If no morbidity present, list potential morbidities based on PN site(s) 
 
PN Location 
 
PN Associated Morbidities 
 
R 
L 
B/L 
Pain 
(Y/N) 
Present PN Morbidities (using numbers listed below)/ 
Comments 
Potential Morbidities 
Orbit 
 
 
 
 
 
 
Face 
 
 
 
 
 
 
Ear canal 
 
 
 
 
 
 
Tongue 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anterior neck/upper airway 
 
 
 
 
 
 
Posterior neck  
(cervical paraspinal) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mediastinum 
 
 
 
 
 
 
Intra-thoracic 
 
 
 
 
 
 
Thoracic/paraspinal/chest wall 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver 
 
 
 
 
 
 
Abdominal  
 
 
 
 
 
 
Mesentery 
 
 
 
 
 
 
Posterior abdomen/pelvis 
(Lumbo-sacral plexus) 
 
 
 
 
 
 
Perineum/peri-rectal/bladder 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Upper arm 
(Brachial plexus) 
 
 
 
 
 
 
Forearm 
 
 
 
 
 
 
Hand 
 
 
 
 
 
 
 
 
 
 
 
 
 
Thigh/upper leg 
 
 
 
 
 
 
Lower leg 
 
 
 
 
 
 
Foot 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other (please specify):  
 
 
 
 
 
 
 
 
Morbidities:  
1- Vision loss 
2- Facial motor dysfunction 
3- Auditory loss 
4- Difficulty swallowing 
5- Abnormal speech 
6- Airway obstruction 
7- Respiratory compromise 
8- Bladder dysfunction 
9- Bowel dysfunction 
10- Motor weakness 
11- Decreased range of motion 
12- Sensory deficit  
13- PN related Disfigurement/ appearance 
 
14- Other (please describe): 
 
 
 
***Instruction to site PI:  Please place asterisk next to target lesion morbidity.   
 
 
 
 
 

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APPENDIX XIV:  PLEXIFORM NEUROFIBROMA CLINICIAN MORBIDITY ASSESSMENT 
 
Instructions 
• To be completed by the treating physician. 
• At baseline, please identify morbidities.   
• Please fill out a separate form for each PN identified in Appendix XIII) 
• At follow-up, for each morbidity identified at baseline, please document whether the noted morbidity is: 
o worse 
o stable 
o improved but still present 
o resolved 
• Please include comments (ex. previously was using 2 pain medications and now using one; previously on Bipap setting of 8, 
now on Bipap setting of 4).  If available, please provide any objective applicable testing results related to morbidities (in the 
comments box). 
 
Please document the Baseline Morbidities. 
 
Baseline Morbidity 1: 
 
Baseline Morbidity 2: 
 
Baseline Morbidity 3: 
 
Baseline Morbidity 4:   
 
 
 
COMPLETED BY: ___________________________________ DATE: __________________________

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Follow-up assessments should be performed post cycles 4, 8, 12, 18, 24.  
 
Select one:  
Post  cycle 4  ☐  
Post cycle 8  ☐   
Post cycle 12  ☐ 
 
 
Post cycle 18  ☐       
Post cycle 24  ☐  
Other (Please specify): _________________________ 
 
Evaluation Date:     
 
For each baseline morbidity, please document whether the morbidity is:  
1) worse; 2) stable; 3) improved but still present; or 4) resolved 
 
 
Select One 
Comments 
Baseline 
Morbidity 
#1 
- Worse 
- Stable 
- Improved but still present 
- Resolved 
 
Baseline 
Morbidity 
#2 
- Worse 
- Stable 
- Improved but still present 
- Resolved 
 
Baseline 
Morbidity 
#3 
- Worse 
- Stable 
- Improved but still present 
- Resolved 
 
Baseline 
Morbidity 
#4 
- Worse 
- Stable 
- Improved but still present 
- Resolved 
 
 
COMPLETED BY: ___________________________________ DATE: __________________________ 

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APPENDIX XV:  BIOLOGICAL SPECIMEN FOR BANKING  – COLLECTION AND 
SHIPPING 
 
1) Blood  
Prior to the day of blood draw, the site will have arranged for a sample collection kit supplied by the 
biorepository to be shipped to the site.  The Center for Data Driven Discovery in Biomedicine (D3b) at 
CHOP will be providing kits and labels. The kit will contain tubes and bar-coded labels (which include a 
specimen number) for blood collection.  It will also contain shipping materials and instructions for sending 
collected blood samples to the biorepository, as well as a pre-paid shipping label. 
 
Samples 
• 
Streck tube (for plasma):  ~ 2 mL.   
• 
EDTA tube (for DNA):  ~ 5 mL.   
• 
PAXGene tube (for RNA) ~ 2.5 mL. 
 
Tubes should be inverted at least 10 times after being drawn. 
 
The samples will only be obtained if the total blood volume does not exceed 5 mL/kg.  If not enough blood 
can be drawn for all tubes, the priority order for obtaining the specimens is: 1) Streck tube, 2) EDTA tube, 
3) PAXGene tube. 
 
Label the specimens with the specimen labels provided with the specimen kit. 
 
Blood samples must be shipped (unprocessed) same day at ambient temperature to the biorepository by 
overnight delivery using shipping container provided by the biorepository.  Samples must be shipped 
Monday through Thursday. 
 
Enter the specimen numbers into the NF Consortium Operations Center eDES. 
 
For questions about shipping, kits, tubes, etc., and to confirm the shipping address prior to sending samples, 
please contact:  Elizabeth Appert (apperte@email.chop.edu) and BioRc (biorc@email.chop.edu). 
 
2) Tumor Tissue 
Prior to the day of surgery, the site will have arranged for a tissue sample collection kit supplied by the 
biorepository to be shipped to the site.  The Center for Data Driven Discovery in Biomedicine (D3b) at 
CHOP will be providing kits and labels. The kit will contain bar-coded cryovials (which include a specimen 
number) for tissue collection.  It will also contain shipping materials and instructions for sending collected 
tissue samples to the biorepository, as well as a pre-paid shipping label. 
 
Samples 
• 
Fresh frozen tissue:  1-2 pea sized aliquots (~ 0.3 cm3, equivalent to 0.8 cm in diameter) of excess 
(left over) tumor tissue.  Place each aliquot in a separate cryovial and label the specimen with 
subject’s study number. Snap freeze the aliquots in liquid nitrogen (preferred) or dry ice and then 
store in a freezer at -80°C or below until they can be sent to the biorepository. 
• 
1 H&E stained slide cut from each submitted piece to confirm tumor is present.  
• 
If fresh frozen tissue is unavailable, please submit processed DNA (at least 3 micrograms) and 
RNA (at least 400 nanograms with optimal RIN > 7) if available.  
 
Label the specimen manifest with the subject’s study number. 
Fresh frozen tissue or DNA/RNA must be shipped on dry ice via overnight delivery using shipping 

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materials provided by the biorepository. The H&E slide should be shipped at ambient temperature.  Samples 
must be shipped Monday through Thursday. 
 
Enter the specimen numbers into the NF Consortium Operations Center eDES. 
 
For questions about shipping, kits, tubes, etc., and to confirm the shipping address prior to sending 
samples, please contact:  Elizabeth Appert (apperte@email.chop.edu) and BioRc 
(biorc@email.chop.edu).