A Phase 1/2 Study of Neoadjuvant Cabozantinib in Combination With Radiation Therapy for Sarcomas of the Extremities
Phase: PHASE1
Conditions: Sarcoma of the Extremity, Stage I Soft Tissue Sarcoma of the Trunk and Extremities, Stage IA Soft Tissue Sarcoma of the Trunk and Extremities, Stage IB Soft Tissue Sarcoma of the Trunk and Extremities, Stage II Soft Tissue Sarcoma of the Trunk and Extremities
Sponsor: University of Washington

 
 
Official Title 
A Phase 1/2 Study of Neoadjuvant Cabozantinib in 
Combination with Radiation Therapy for Sarcomas of the 
Extremities 
NCT Number 
NCT04220229 
Document Type 
Protocol and Statistical Analysis Plan 
Document Date 
8/4/2023 
 
 

Cabozantinib/Radiation 
Protocol: RG1003562 (CC10051)                                                
University of Washington 
Confidential and Proprietary 
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Final Protocol v4.0: 30DEC2022 
 
A Phase 1/2 Study of Neoadjuvant Cabozantinib in Combination with Radiation Therapy for 
Sarcomas of the Extremities 
Investigational Product 
 
Cabozantinib 
Protocol Number: 
 
RG1003562 (CC10051) 
Study Phase: 
 
1/2 
IND Number: 
 
146,712 
Sponsor-Investigator: 
 
Lee Cranmer, MD, PhD, FACP 
University of Washington  
825 Eastlake Avenue E., LG-350 
Seattle, WA, USA 98109 
Collaborator: 
 
Exelixis 
1851 Harbor Bay Parkway 
Almeda, CA 94502 
Statistics: 
 
Ted A. Gooley, PhD 
Fred Hutchinson Cancer Research Center (FHCRC) 
1100 Fairview Avenue N., M2-B230 
Seattle, WA, 98109 
Protocol Versions 
 
Date 
Original v1.0: 
 
September 21, 2019 
Version 2.0, Amendment 1 
 
December 3, 2019 
Version 3.0, Amendment 2 
 
December 19, 2019 
Version 4.0, Amendment 3 
 
December 30, 2022 
 
CONFIDENTIAL 
This protocol is provided to you as an Investigator, potential Investigator, or 
consultant for review by you, your staff, and ethics committee/institutional review 
board.  The information contained in this document is regarded as confidential and, 
except to the extent necessary to obtain informed consent, may not be disclosed to 
another party unless such disclosure is required by law or regulations.  Persons to 
whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them. 
 
IRO REC'D FEB 16 2023
FHCRC IRB Approval  
03/08/2023 
Document Released Date
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Cabozantinib/Radiation 
Protocol: RG1003562 (CC10051)                                                
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PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
 
 
 
 
Signature of Principal Investigator 
 
dd/mm/yyyy 
Lee Cranmer, MD, PhD, FACP 
Printed Name of Principal Investigator 
Institution Name:  University of Washington  
By my signature, I agree to personally supervise the conduct of this study at my study 
site and to ensure its conduct is in compliance with the protocol, informed consent, 
Institutional Review Board (IRB)/Ethics Committee (EC) procedures, instructions from 
Exelixis representatives, the Declaration of Helsinki, ICH Good Clinical Practices 
Guidelines, and local regulations governing the conduct of clinical studies. 
 
 
 
 
 
 
        
 
 
 
 
 
 
 
 
 
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Protocol: RG1003562 (CC10051)                                                
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PROTOCOL SYNOPSIS 
 
INVESTIGATIONAL 
PRODUCT 
Cabozantinib, an oral receptor tyrosine kinase inhibitor 
INDICATION 
Soft tissue sarcomas of the extremities, which are to be treated with 
radiation therapy 
TITLE 
A Phase I/II Study of Neoadjuvant Cabozantinib in Combination with 
Radiation Therapy for Sarcomas of the Extremities 
PROTOCOL 
NUMBER 
RG1003562 (CC10051) 
PHASE OF 
DEVELOPMENT 
1/2 
STUDY 
OBJECTIVES 
Primary Objective(s)  
• Phase I: To determine if administration of cabozantinib is safe 
and feasible in combination with neoadjuvant radiation therapy. 
• Phase II: To assess the proportion of subjects alive and free of 
both local and distant disease recurrence (and progression after 
incomplete resection) one year after treatment initiation.   
 
Secondary Objective(s) 
• Rate of pathologic response. 
• Rate of surgical excision with negative margins. 
• Response rate (complete, partial, overall) of the combination 
therapy prior to surgery, as defined by RECIST 1.1 criteria. 
• Pattern of and time to local vs. distant recurrences. 
• Relapse-free and overall survival at various time points from 
study entry. 
• Safety and tolerability of combined treatment regimen, including 
the rate of discontinuation during the cabozantinib monotherapy 
component of the study. 
Exploratory Objective(s) 
• Comparison of pre- and post-treatment specimens to identify 
changes in activation of molecular pathways associated with 
MET genetic profiles associated with treatment response and 
with relapse-free survival.   
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• Evaluation of pre- and post-treatment specimens for mutational 
status of signaling pathways, including MAP-Kinase and AKT/m-
TOR pathways.   
• Explore changes in the immune microenvironment induced by 
this neoadjuvant treatment, in comparison to matched 
specimens obtained from the University of Washington 
pathology archives.  
• Radiomic studies to identify predictors of treatment response 
and relapse-free survival. 
 
STUDY 
ENDPOINTS 
Primary Endpoints 
• Phase I: Recommended Phase 2 dose (RP2D) of cabozantinib in 
combination with radiation 
• Phase II: Rate of relapse at 12 months after treatment initiation. 
Secondary endpoints 
• Rate of pathologic response. 
• Rate of surgical excision with negative margins. 
• Response rate (complete, partial, overall) of the combination 
therapy prior to surgery, as defined by RECIST 1.1 criteria. 
• Pattern of and time to local vs. distant recurrences. 
• Relapse-free and overall survival at various time points from 
study entry. 
• Safety and tolerability of combined treatment regimen. 
• Rate of treatment discontinuation prior to neoadjuvant radiation 
therapy. 
Exploratory endpoints 
• Comparison of pre- and post-treatment specimens to identify 
changes in activation of molecular pathways associated with 
MET genetic profiles associated with treatment response and 
with relapse-free survival.   
• Assessment of mutational status of signaling pathways, including 
MAP-Kinase and AKT/m-TOR pathways.   
• Assess changes in infiltration of immune cell subsets (CD4, CD8, 
myeloid) in the immune microenvironment induced by this 
neoadjuvant treatment, in comparison to matched specimens 
obtained from the University of Washington pathology archives.  
• 
Radiomic studies to identify predictors of treatment response 
and relapse-free survival, when comparing pre-treatment 
imaging with imaging prior to surgery (after completion of 
radiotherapy and concurrent cabozantinib). 
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SAMPLE SIZE 
ESTIMATE 
Phase I/Dose Escalation: Expected 6, but up to 12 subjects to identify the 
MTD. Subjects enrolled to Phase 1 who withdraw for reasons other than 
toxicity during the dose-limiting toxicity (DLT) period will be determined 
to be not evaluable and will be replaced. 
Phase II/Dose Expansion: 34 additional subjects 
For sample size determination, we assume the following:  
Null hypothesis: 1-yr RFS=75% 
Alternative hypothesis: 1-yr RFS=0.90 
Alpha=0.1 (one-sided) 
Beta=0.1 (power=90%) 
Total accrual=40 evaluable subjects. 
Anticipate accrual of 6 evaluable subjects from phase I component of 
study. 
34 subjects to accrue in phase II portion of study. 
Assuming 10% non-evaluable rate, 44 subjects would be accrued to the 
efficacy component of the study to yield 40 evaluable subjects. Subjects 
enrolled to Phase 2 who withdraw for toxicity during the initial lead-in 
cycle will be determined to be not evaluable and replaced. 
DURATION OF 
TREATMENT AND 
STUDY 
PARTICIPATION  
The study is expected to take approximately 36 months from first subject 
enrolled to last subject follow-up, including approximately 12 months of 
enrollment period, an estimated 5 months of treatment.  
 
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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ...................................................................................................................... 3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................................ 11 
1. 
INTRODUCTION .......................................................................................................... 15 
1.1. 
Soft Tissue Sarcoma ................................................................................................... 15 
1.1.1. 
Epidemiology ............................................................................................................. 15 
1.1.2. 
Standard Treatment .................................................................................................. 15 
1.1.3. 
Use of radiotherapy in adjuvant and neo-adjuvant therapy ..................................... 16 
1.1.4. 
Use of chemotherapy in adjuvant and neo-adjuvant therapy .................................. 17 
1.1.5. 
Use of chemoradiotherapy in adjuvant and neo-adjuvant therapy .......................... 19 
1.2. 
Cabozantinib Background .......................................................................................... 22 
1.3. 
Rationale for Combination of Cabozantinib with Radiation Therapy for High-
Risk Soft Tissue Sarcoma of the Extremities .............................................................. 23 
1.4. 
Rationale for Starting Dose Selection ........................................................................ 24 
2. 
STUDY OBJECTIVES AND ENDPOINTS ........................................................................ 25 
2.1. 
Objectives .................................................................................................................. 25 
2.1.1. 
Primary Objectives ..................................................................................................... 25 
2.1.2. 
Secondary Objective(s) .............................................................................................. 25 
2.1.3. 
Exploratory Objective(s) ............................................................................................ 25 
2.2. 
Endpoints ................................................................................................................... 25 
2.2.1. 
Primary Endpoints ..................................................................................................... 25 
2.2.2. 
Secondary endpoints ................................................................................................. 25 
2.2.3. 
Exploratory endpoints ............................................................................................... 26 
3. 
STUDY DESIGN ........................................................................................................... 27 
3.1. 
Dose-finding Phase 1 Portion of the Study: ............................................................... 27 
3.2. 
Dose Expansion Phase 2 Portion of the Study: .......................................................... 28 
3.3. 
Study Duration, End of Study, End of Treatment, End of Treatment Visit, 
Follow-up Period ........................................................................................................ 28 
4. 
STUDY POPULATION .................................................................................................. 30 
4.1. 
Number of Subjects ................................................................................................... 30 
4.2. 
Inclusion Criteria ........................................................................................................ 30 
4.3. 
Exclusion Criteria ....................................................................................................... 31 
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5. 
TABLE OF EVENTS ...................................................................................................... 34 
6. 
PROCEDURES ............................................................................................................. 37 
6.1. 
Screening Evaluations ................................................................................................ 37 
6.2. 
Treatment Period ....................................................................................................... 38 
6.2.1. 
Duration of Treatment ............................................................................................... 38 
6.2.2. 
Day 1 Assessment ...................................................................................................... 38 
6.2.3. 
Day 8 Assessment ...................................................................................................... 39 
6.2.4. 
Day 15 Assessment .................................................................................................... 39 
6.2.5. 
Disease Assessment ................................................................................................... 40 
6.3. 
End of Treatment Visit Assessment ........................................................................... 41 
6.4. 
Follow-up Period for Survival and Initiation of Anticancer Therapy ......................... 41 
6.4.1. 
30 Day Follow-Up Visit Therapy................................................................................. 41 
6.4.2. 
Long Term Follow-Up ................................................................................................. 42 
7. 
DESCRIPTION OF STUDY TREATMENTS ..................................................................... 43 
7.1. 
Cabozantinib .............................................................................................................. 43 
7.1.1. 
Cabozantinib Dosage, Administration, and Schedule ................................................ 43 
7.1.2. 
Cabozantinib Dose Modification and Stopping Rules ............................................... 43 
7.2. 
Radiation Therapy ...................................................................................................... 45 
7.2.1. 
Simulation .................................................................................................................. 45 
7.2.2. 
Planning ..................................................................................................................... 46 
7.2.3. 
Prescription Guidelines .............................................................................................. 46 
7.2.4. 
Treatment Delivery .................................................................................................... 47 
7.2.5. 
Treatment Interruption and Dose Modifications ...................................................... 47 
7.2.6. 
Quality Assurance ...................................................................................................... 47 
8. 
STUDY DRUG MANAGEMENT .................................................................................... 49 
8.1. 
Description of Study Drugs ........................................................................................ 49 
8.1.1. 
Cabozantinib Packaging, Labeling, and Storage ........................................................ 49 
8.1.2. 
Study Treatment Accountability ................................................................................ 49 
9. 
SAFETY ....................................................................................................................... 51 
9.1. 
Adverse Events and Laboratory Abnormalities ......................................................... 51 
9.1.1. 
Adverse Events (AEs) ................................................................................................. 51 
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9.1.2. 
Serious Adverse Events (SAEs) ................................................................................... 51 
9.1.3. 
Relationships to Study Treatment ............................................................................. 52 
9.1.4. 
Serious Adverse Event Reporting .............................................................................. 52 
9.1.5. 
Regulatory Reporting ................................................................................................. 53 
9.2. 
Other Safety Considerations ...................................................................................... 54 
9.2.1. 
Laboratory Data ......................................................................................................... 54 
9.2.2. 
Pregnancy/Lactation Exposure .................................................................................. 54 
9.2.3. 
Follow-Up of Adverse Events ..................................................................................... 54 
10. 
MANAGEMENT OF TOXICITY AND COMPLICATIONS ................................................. 55 
10.1. 
Guidelines for Management of Potential Adverse Events ........................................ 55 
10.2. 
Cabozantinib Related Toxicity ................................................................................... 55 
10.2.1. 
Dose-Limiting Toxicity ................................................................................................ 55 
10.2.2. 
Adverse Event Management Algorithms ................................................................... 57 
10.2.3. 
Cabozantinib Dose Reinstitution and Reescalation ................................................... 70 
10.2.4. 
Dose re-escalation is not permitted. Overdose ......................................................... 70 
10.3. 
Radiation Therapy Related Toxicity ........................................................................... 70 
11. 
CONCOMITANT MEDICATIONS AND PROCEDURES ................................................... 71 
11.1. 
Permitted Medications and Procedures .................................................................... 71 
11.2. 
Prohibited Medications and Procedures ................................................................... 72 
11.3. 
Potential Drug Interactions with Cabozantinib ......................................................... 73 
12. 
STATISTICAL CONSIDERATIONS ................................................................................. 75 
12.1. 
Safety Analysis ........................................................................................................... 75 
12.2. 
Efficacy Analysis ......................................................................................................... 75 
12.3. 
Exploratory Analysis................................................................................................... 75 
12.4. 
Sample Size Considerations ....................................................................................... 75 
12.5. 
Primary Analysis ......................................................................................................... 76 
13. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY ............................... 77 
13.1. 
Discontinuation from Investigational Product or Study ............................................ 77 
13.2. 
Sponsor-Investigator Decision to Withdraw or Terminate Subject’s 
Participation Prior to Study Completion .................................................................... 77 
14. 
REGULATORY OBLIGATIONS ...................................................................................... 79 
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14.1. 
Informed Consent ...................................................................................................... 79 
14.2. 
Institutional Review Board/Independent Ethics Committee .................................... 79 
14.3. 
Subject Confidentiality ............................................................................................... 80 
14.4. 
Protocol Amendments ............................................................................................... 80 
14.5. 
Termination of the Study ........................................................................................... 80 
15. 
DATA HANDLING AND RECORDKEEPING ................................................................... 81 
15.1. 
Data Quality Assurance .............................................................................................. 81 
15.2. 
Data/Documents ........................................................................................................ 81 
15.3. 
Data Management ..................................................................................................... 81 
15.4. 
Investigator Responsibilities for Data Collection ....................................................... 81 
15.5. 
Sample Storage and Destruction ............................................................................... 81 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE......................................................... 83 
16.1. 
Study Monitoring ....................................................................................................... 83 
16.2. 
Audits and Inspections ............................................................................................... 83 
17. 
STUDY DOCUMENTATION AND RECORD-KEEPING ................................................... 84 
17.1. 
Investigator’s Files and Retention of Documents ...................................................... 84 
17.2. 
Source Documents and Background Data ................................................................. 84 
17.3. 
Case Report Forms ..................................................................................................... 84 
18. 
PUBLICATIONS ........................................................................................................... 85 
19. 
REFERENCES ............................................................................................................... 86 
20. 
APPENDIX 1 - WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ................................................................................ 89 
20.1. 
Definitions .................................................................................................................. 89 
20.1.1. 
Woman of Childbearing Potential (WOCBP) ............................................................. 89 
20.2. 
Contraception Guidance for Females of Childbearing Potential ............................... 89 
20.3. 
Contraception Guidance for Males of Childbearing Potential .................................. 90 
21. 
APPENDIX 2 – GUIDELINES REGARDING RADIATION THERAPY ................................. 92 
 
List of Tables 
Table 1. Dose Levels of Cabozantinib ........................................................................................... 27 
Table 2. Schedule of Assessments ................................................................................................ 35 
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Table 3. Analyte Listing ................................................................................................................. 40 
Table 4 - Dose Levels for Cabozantinib ......................................................................................... 43 
Table 5 - Dose Modifications of Cabozantinib .............................................................................. 44 
Table 6  - Dose Modifications of Cabozantinib for Treatment-Related AEs ................................. 44 
Table 7 - Cabozantinib Tablet Components and Composition ..................................................... 49 
Table 8 - Management Guidelines for Adverse Events Possibly Related to Cabozantinib ........... 57 
 
LIST OF FIGURES 
No table of figures entries found. 
 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
adverse event 
ALP 
alkaline phosphatase  
ALT 
alanine transaminase (SGPT) 
ANC 
absolute neutrophil count 
AST 
aspartate transaminase (SGOT) 
AUC 
area under the time-concentration curve 
BSA 
body surface area 
Cmax 
maximum plasma drug concentration 
Cmin 
minimum plasma drug concentration 
CBC 
complete blood count 
CI 
confidence interval 
CNS 
central nervous system 
CR 
complete response 
CT 
computed tomography 
DLT 
dose-limiting toxicity 
DSMC 
Data safety monitoring committee 
DNA 
deoxyribonucleic acid 
DCR 
DOR 
disease control rate 
duration of response 
ECOG PS 
Eastern Cooperative Oncology Group performance status 
CRF 
electronic case report form 
EOS 
end of study 
EOT 
end of treatment 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte-colony stimulating factor 
ICH 
International Conference on Harmonisation  
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 
IND 
investigational new drug  
IP 
investigational product 
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IRB 
Institutional Review Board 
mg 
Milligram 
mL 
Milliliter 
MRI 
magnetic resonance imaging 
MTD 
maximum-tolerated dose 
mTOR 
mammalian target of rapamycin 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
ORR 
overall response rate 
OS 
overall survival 
PD 
progressive disease 
PFS 
Progression-free survival 
PK 
Pharmacokinetics 
PR 
partial response 
PTEN 
protein tyrosine phosphatase 
RECIST 
 
RFS 
Response Evaluation Criteria in Solid Tumors 
 
Relapse-Free Survival 
 
SAE 
serious adverse event 
SD 
stable disease 
SGOT 
serum glutamic oxaloacetic transaminase (AST) 
SGPT 
serum glutamic pyruvic transaminase (ALT) 
TBL 
total bilirubin level 
ULN 
upper limit of normal 
 
 
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Abbreviation or Term 
Definition/Explanation 
Study Day 1 
First day that protocol-specified IP is administered to the subject. 
End of Treatment 
The date of the last dose of cabozantinib therapy. 
End of Treatment Visit 
The date when safety assessments and procedures are performed 
after the last treatment, which should occur within 1 week (±3 days) 
after the last dose of cabozantinib.  
End of Study 
 
Either the date of the last visit of the last subject to complete the 
study, or the date of receipt of the last data point from the last 
subject that is required for primary, secondary, and/or exploratory 
analysis, as pre-specified in the protocol, whichever is later.  
Follow-up Period 
 
Follow-up period is the on-study time period after the EOT Visit. All 
subjects that discontinue study drug and have not withdrawn full 
consent to participate in the study will continue in the follow-up 
phase for disease recurrence. Follow up will continue approximately 
every 12 weeks (±2 weeks), until either one (1) year has elapsed since 
initiation of cabozantinib therapy (C1D1), death, withdrawal of 
consent, disease recurrence, or the study closes, whichever is the 
earliest. This will include a physical exam and imaging assessment.  
Thereafter, subjects who will be followed every 6 months (+/- 1 
month) until 3 years have elapsed since initiation of cabozantinib 
therapy (C1D1), end-of-study, death, or withdrawal of consent, 
whichever is earliest. This evaluation may be made by review of 
publicly available information, record review and/or telephone 
contact. 
Primary Analysis 
 
For this study will occur once all data for primary and secondary 
endpoints is collected. 
Efficacy Analysis 
Dataset  
 
This includes all subjects treated with at least one dose of 
cabozantinib at the recommended phase 2 dose, concurrently with 
neoadjuvant radiation therapy.  
Full Analysis Set 
All enrolled subjects who receive at least 1 dose of cabozantinib 
(treated population). Subjects enrolled to Phase 1 who withdraw for 
reasons other than toxicity during the DLT Period will be considered 
not evaluable and will be replaced. 
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Per-protocol 
Analysis 
Set 
All enrolled subjects who do not have any prospectively defined 
protocol violations. Subjects enrolled to Phase 1 or Phase 2 who are 
unable to tolerate cabozantinib monotherapy will not be considered 
evaluable for the Phase 1 or 2 component of the study and will be 
replaced.  Subjects enrolled to Phase 1 who withdraw for reasons 
other than toxicity during the DLT Period will be considered not 
evaluable and will be replaced. 
Progression-free 
survival 
The time from the first dose date to the first observation of a disease 
progression or death due to any cause.   
Overall survival 
The time from the first dose date to the date of death due to any 
cause. 
 
 
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1. 
INTRODUCTION 
1.1. 
Soft Tissue Sarcoma 
1.1.1. 
Epidemiology 
Soft-tissue sarcomas (STS) are mesenchymally derived cancers, with an estimated incidence of 
13,040 new cases and 7,370 deaths in the United States in 20181.  Their impact is made greater 
by the relatively young age population affected by them: this magnifies the impact of these 
diseases in terms of years-of-life lost versus more common cancers affecting older subjects.  
STS are also characterized by great heterogeneity: at least 173 histologic entities are classified 
as STS2.  The combination of these factors has hindered progress in the management of these 
conditions.  Sarcomas remain an underserved area in oncology, as recognized by the National 
Cancer Institute’s “Roadmap for Sarcoma Research”3. 
Soft tissue sarcomas are the subject of a staging system proposed by the American Joint 
Commission on Cancer4.  This incorporates data regarding the tumoral grade (a measure of 
proliferative rate), tumor size, tumor depth, presence of nodal involvement, and presence of 
distant metastases.  These data yield a staging classification from I (earliest disease) to IV (most 
advanced).  Long-term survival segregates strongly by stage, from 90% 5-year survival for those 
with stage I disease, to less than 20% for those with stage IV disease. 
1.1.2. 
Standard Treatment 
The therapy of non-metastatic sarcomas is dominated by surgery.  In certain cases, definitive 
radiation therapy may be used, such as in subjects who are not candidates for surgery, or for 
whom the cosmetic or functional results of surgery are unacceptable.  Surgery may be 
supplemented by adjuvant or neoadjuvant radiation therapy5.  For certain subtypes of 
sarcomas (osteosarcoma, Ewing’s sarcoma, rhabdomyosarcoma), the use of chemotherapy, 
administered prior to or after definitive local therapy with surgery or radiation, has 
demonstrated survival benefits.  For most other types of sarcomas, the benefits of 
chemotherapy are unclear5. 
For unresectable or metastatic STS, treatment is palliative5.  Systemic chemotherapy remains 
the backbone of treatment.  Surgery and/or radiotherapy may be useful to relieve symptoms, 
or, in a limited number of cases with uni- or oligo-metastatic disease, to provide definitive 
control.  In subjects with unresectable disease, the life expectancy is limited, with median 
survival of approximately 12-18 months6,7. 
In treatment of primary disease, the surgical status of the tumoral margins (the presence of 
viable tumor at the edge of the resection specimen and the distance from the resection margin 
to the tumor) is an important indicator of outcome.  Several systems exist for classifying the 
marginal status of tumors.  One of the more widely used classifies tumor resection status into 
R0 (complete resection of grossly/macroscopically evident tumor, with no evidence of residual 
microscopic disease at the margins of resection); R1 (complete resection of 
grossly/macroscopically evident tumor, but with microscopically evident disease at the margins 
of resection); and R2 (gross/macroscopically evident disease remains after attempted 
resection).  
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Marginal status is a key factor in the primary treatment, with positive margins being associated 
with increased risk of local recurrence and sarcoma-specific death8.  Risk of distant metastasis 
of disease is not, however, determined by the extent of surgery, as demonstrated by a study of 
amputation for primary treatment of extremity sarcomas9.  In multivariable Cox analysis, the 
probability of distant metastasis was determined by tumor size and histologic grade, rather 
than the type of local surgery (amputation versus limb-sparing procedure) undertaken to 
control the primary tumor.  Limb-sparing procedures lead to improved functional outcomes 
versus amputation, but do not alter anticipated survival10. 
1.1.3. 
Use of radiotherapy in adjuvant and neo-adjuvant therapy 
While the traditional approach to soft tissue sarcoma surgery was amputation (in the 
extremities) or radical surgery in other locations, more conservative approaches, such as limb-
sparing approaches in STS of the extremities, have been adopted in recent decades11,12.  This 
has been facilitated by the widespread adoption of combined modality therapy, in which 
subjects with resectable or potentially resectable disease receive combination therapy with 
both surgery and radiation therapy.  Radiation therapy to the resection site may be 
administered post-operatively (known as “adjuvant” therapy”) or pre-operatively (known as 
“neoadjuvant” therapy). 
No clear difference in efficacy is apparent between neoadjuvant and adjuvant use of 
radiotherapy11,12,13,14.  However, pre-operative approaches allow use of lower doses of 
radiotherapy and smaller radiation fields15.  While associated with higher rates of complication 
in subsequent tumor surgery wound healing, pre-operative therapy yields lower rates of long-
term complications attributable to radiation therapy16.  This observation is consistent with the 
known radiobiology of late radiation toxicity, which exhibits a threshold effect17.  Small 
increases in radiation dose may be associated with marked increases in toxicity.  An increase in 
dose from a total of 50 Gy typically given neoadjuvantly to 60-66 Gy administered adjuvantly 
may explain the increase in late toxicity with adjuvant radiotherapy14,15,18. 
Two randomized trials comparing adjuvant (post-operative) radiation therapy to no adjuvant 
therapy have been reported19,20.  In one study, a limb-sparing surgical procedure combined with 
adjuvant radiotherapy was compared to amputation of the affected extremity19.  All subjects 
also received post-operative chemotherapy.  This was administered concurrently with 
radiotherapy in those undergoing limb-sparing procedures.  Local recurrence rates at the site of 
resection were higher in the group undergoing limb-sparing procedure (80% vs 0% at 5 years), 
although the study was quite small, with only 43 subjects enrolled.  No difference in disease-
free or overall survival was reported. 
The second study randomized subjects undergoing a limb-sparing procedure to receive 
adjuvant radiation therapy (n=70) or no additional local therapy (n=71) [19].  For those with 
high histological grade, chemotherapy was administered concurrently with radiation.  Local 
recurrence rates were suppressed, irrespective of histologic grade, with overall local recurrence 
of 1% in those treated with post-operative radiotherapy versus 24% in those not receiving 
radiotherapy.  In the subset with high-grade tumors, no difference in metastatic disease-free or 
overall survival was evident based on radiotherapy assignment status. 
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These studies have some limitations19,20.  Both studies had relatively small sample sizes, 
especially the earlier study enrolling only 43 subjects, and both included chemotherapy in 
addition to post-operative radiotherapy.  Local control was superior in both studies when 
radiation was included.  No survival difference was observed based on administration of 
radiotherapy, implying that local control did not necessarily determine survival.  The possibility 
of synergism between chemotherapy and radiation therapy was not addressed, nor were issues 
of toxicity.  Neoadjuvant radiotherapy has not been compared to surgery alone. 
The combination of surgery with either post-operative or pre-operative radiation therapy, the 
latter being the subject of this proposal, is quite effective in achieving local control of disease.  
One randomized study compared pre- and post-operative radiotherapy in treatment of 
extremity soft tissue sarcomas, with the primary endpoint of toxicity21.  Among the 186 subjects 
evaluable for secondary efficacy measures, there was no difference in rate of local control, 
development of regional/distant relapse, and progression-free survival (log rank p=0.70, 0.79 
and 0.83, respectively).  Survival for post-operatively treated subjects was inferior (median 
follow-up=3.3 year; 85% alive pre-operative vs. 72% post-operative, log rank p=0.0481).  This 
was due to an increased number of deaths due to sarcomas and to non-malignant causes in the 
post-operative group.   
A large retrospective analysis of 1225 sarcoma subjects treated over 39 years at a single major 
center supports these observations13.  Neither treatment sequence with respect to radiation 
therapy and surgery nor receipt of adjuvant chemotherapy was associated with local control, 
metastatic recurrence, disease-free survival, or disease-specific survival.  Tumor size and tumor 
grade were associated with all three of these efficacy outcomes, with large, high-grade tumors 
being unfavorable. 
1.1.4. 
Use of chemotherapy in adjuvant and neo-adjuvant therapy 
Administration of systemic chemotherapy in the primary treatment of STS could have several 
theoretical benefits.  First, chemotherapy may have a direct effect on the existing primary 
tumor, allowing complete resection with negative margins (an R0 resection).  The ability to 
achieve a negative marginal status is independently associated with local control, disease-free 
survival and disease-specific survival8,13.  Second, chemotherapy may be able to eradicate 
micrometastatic disease prior to it becoming clinically apparent (and generally ineradicable 
with current systemic therapies).  This is perhaps best exemplified by the experience with 
sarcomas of childhood, osteosarcoma, Ewing’s sarcoma and rhabdomyosarcoma22.  Finally, 
systemic therapy, given during or in the vicinity of radiation therapy, may enhance the effects 
of radiation therapy. 
The use of peri-operative chemotherapy has been assessed in a number of randomized trials, 
which have been the subject of meta-analyses23,24.  Specifically, these analyses include 
randomized trials employing anthracycline-based chemotherapy, primarily doxorubicin.  
Doxorubicin was administered alone, or in combination with other chemotherapy agents.  In 
both analyses, anthracycline-based chemotherapy was associated with improvement in risk of 
local, distant, and overall relapse.  Neither analysis indicated a survival benefit associated with 
doxorubicin therapy.  The analysis of Pervaiz and colleagues indicated that the combination of 
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doxorubicin and ifosfamide appeared to be associated with a survival benefit, estimated at an 
11% reduction in risk of recurrence23. 
A large study of adjuvant therapy in soft-tissue sarcomas with doxorubicin and ifosfamide was 
recently reported25.  This study enrolled 351 subjects. Neither relapse-free nor overall survival 
was improved by administration of chemotherapy.  Subgroup analysis suggested benefit in 
those with large, high-grade tumors.  An earlier randomized trial from the Italian Sarcoma 
Group suggested that subjects with large, high grade tumors might benefit from peri-operative 
chemotherapy26.  Participation was limited to those subjects with tumors at least 5 cm in 
maximal dimension and high histologic grade.  This study demonstrated an improvement in 
disease-free survival at two years, the primary endpoint of the study (72% chemotherapy 
versus 45% control, p=0.003).  Although an initial survival benefit was reported, this secondary 
outcome was not maintained with continued follow-up27. 
A retrospective study of French sarcoma subjects also identified tumor grade as a key factor in 
identifying benefit from adjuvant chemotherapy28.  In multivariable Cox regression analysis, 
adjuvant chemotherapy was associated with improved survival in those with grade 3 (high), but 
not grade 2 (intermediate) tumors.  Subject age, tumor size, and the presence of bone or 
neurovascular invasion were adverse in both grade 2 and 3 subjects, while anatomic site was a 
prognostic factor only in those with grade 3 tumors. 
Only one randomized study of neoadjuvant chemotherapy has been reported29.  This study 
enrolled subjects with high-risk sarcomas, defined as the following groups: those greater than 8 
cm in maximal dimension; those of intermediate (grade II) or high (grade III) histologic grade; 
grade II/III locally recurrent tumors; and grade II/III tumors inadequately treated within 6 weeks 
of randomization and requiring further surgery.  Eligible subjects were randomized to receive 
three pre-operative cycles of chemotherapy with doxorubicin and ifosfamide or no 
chemotherapy.  After surgery, subjects with selected high-risk features received adjuvant 
radiation therapy. 
This study was initially intended to allow feasibility assessment as part of a lead-in to a phase III 
assessment of the regimen.  The primary endpoint of the proposed phase III was detection of a 
15% improvement in 5-year survival.  This would have a required enrollment of 269 subjects.  
The study was closed due to slow accrual after enrollment of 134 evaluable subjects (67 per 
arm).  No improvement in disease-free or overall survival was observed.  The authors concluded 
that the negative results of this admittedly underpowered trial argued against a major survival 
benefit for the regimen.  Nevertheless, the results did not exclude the proposed 15% benefit 
that the phase III trial would have been powered to detect. 
At least four factors have been cited as possible reasons for the failure of peri-operative 
chemotherapy to improve outcome in subjects with primary soft tissue sarcomas27.  First, 
sarcomas represent a diverse group of related, but distinct, disease entities.  This may increase 
population heterogeneity, reducing the power of trials.  Combined with the reasonable size of 
the population available for participation, this may make detection of beneficial effects difficult 
with trials of the size that can reasonably be generated.  
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Second, the efficacy of local treatment with surgery and/or radiotherapy may also be improving 
over time, such as by the introduction of new radiotherapy techniques27.  This may produce 
better primary treatment results, making assumptions regarding anticipated treatment 
outcomes less reliable.  Power calculations based on earlier studies may therefore overestimate 
the relapse rate in the control group.  This again can lead the trials to be underpowered for 
their endpoints.  
Third, even using presently known criteria, there is heterogeneity with respect to the 
populations that are enrolled in trials27.  Two trials and a retrospective cohort analysis cited 
previously suggested that larger, high-grade tumors are most likely to benefit from peri-
operative chemotherapy25,26, 28.  Host factors may also be important in determining outcome. 
Fourth, most trials to date have been based on the use of anthracycline-based chemotherapy27.  
Although this class of drug has activity in sarcomas, there may be some sarcoma subtypes that 
are more or less sensitive to anthracycline effects5.  Furthermore, sarcoma subtypes have been 
identified which demonstrate non-responsiveness to cytotoxic chemotherapy but were 
previously included in clinical trials.  The exclusion of those subtypes, such as gastrointestinal 
stromal tumors (previously classified as a type of leiomyosarcoma), from trials of cytotoxic 
agents is important.  Such sarcoma subtypes would not respond to cytotoxic agents and would 
statistically minimize differences between intervention and control groups.    This further 
depresses the power of studies already struggling under the disease heterogeneity and 
relatively small pool of eligible subjects. 
1.1.5. 
Use of chemoradiotherapy in adjuvant and neo-adjuvant therapy 
Several studies have evaluated the use of neoadjuvant protocols combining pre-operative 
radiotherapy with chemotherapy.  One study assessed a regimen of three cycles of pre-
operative doxorubicin, ifosfamide and dacarbazine (“MAID”) chemotherapy, with radiation 
therapy.  Subjects with positive surgical margins received additional post-operative radiation, 
and subjects received an additional three cycles of post-operative MAID therapy30.  Subjects 
enrolled had intermediate or high-grade (grade II or III) tumors at least 8 cm in maximal 
dimension.  The treatment group of 48 subjects was compared to 48 historical controls, 12 of 
whom had received some form of adjuvant chemotherapy.  Controls were subjects from the 
same institution who were matched with respect to tumor size, grade, age at diagnosis, and era 
of treatment. 
While the primary endpoint was not explicitly stated, positive margins were observed in 15% 
(7/48) of the experimental treated subjects at the time of surgery versus 19% (9/48) of the 
matched controls.  There was no difference in the rate of local control between the two groups.  
Distant metastasis-free, disease-free and overall survival however heavily favored the group 
treated with the MAID regimen.  The non-randomized nature of the study implies that the 
results must be taken with caution. 
This regimen was assessed again in a retrospective review of subjects treated more recently at 
the same institution31.  No control group was presented in this analysis.  Surgical margins were 
positive in 11% of resection specimens.  Local and distant metastasis-free rate at 5 years was 91 
and 64%.  The authors attempted to identify factors associated with clinical outcomes using Cox 
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analysis but were unable to identify any factors in the dataset analyzed.  Again, it is difficult to 
evaluate the value of this chemoradiotherapy treatment regimen due to lack of an adequate 
control group. 
A prospective study from a single center evaluated pre-operative administration of doxorubicin, 
followed by a 10-day regimen of radiotherapy, in subjects to undergo sarcoma resection32.  75 
subjects were enrolled in the study.  Tumors were greater than 5 cm in 66% of the subjects and 
intermediate- or high-grade (grade II/III) in 71%.  In 11% (8/75), surgical margins were positive 
for residual sarcoma.  Subjects with positive margins had 5-year local control of only 50%, 
versus 97% for those with negative margins.  Tumor grade and tumor stage (reflecting tumor 
size, depth and anatomic extent of involvement) were associated with the risk of death in 
multivariable Cox analysis.  Wound complications occurred in 11 (15%) of the 75 subjects, 
including 3 subjects requiring re-operation.  Like the studies above, interpretation of this one is 
hampered by lack of a control group. 
A retrospective analysis examined results of 112 subjects treated with various neoadjuvant 
chemoradiotherapy regimens, neoadjuvant radiation, or with surgery alone33.  All three 
treatment groups had high rates of margin negativity at the time of surgery (86-91%).  For all 
subjects, there was no difference in rate of local control rate, distant metastasis free survival or 
overall survival.  For those with primary tumors greater than 5 cm, overall survival was superior 
when the radiation-treated groups were compared to those treated only with surgery.  
However, only 7 subjects treated with surgery alone fell into this group. 
A great deal of work has been undertaken, primarily using the anthracycline doxorubicin alone 
and in combinations (especially with ifosfamide), to evaluate the value of peri-operative 
cytotoxic therapy in soft tissue sarcomas.  Use of this drug in peri-operative setting is 
problematic.  While this drug is among the most active as monotherapy for sarcomas, it can 
cause a dose-dependent cardiomyopathy5.  This limits the lifetime dose of the drug, as 
excessive amounts can cause treatment-refractory heart failure.  Doxorubicin can also be 
associated with enhancement of radiation-associated skin toxicity34.  In the absence of proven 
peri-operative benefit, use of doxorubicin alternatives would be sensible: this would reserve 
the agent for treatment of metastatic disease in those later developing metastatic disease and 
avoid the risk of cardiotoxicity in the subjects who did not have recurrent disease.  Further, the 
results cited earlier indicating that tumoral biology is a key determinant of outcome suggest 
that agents exploiting sarcoma and radiation biology might be very desirable to explore in 
combination regimens of radiotherapy and systemic therapy. 
Even if a subject is ultimately cured of the condition, treatment can have lifelong impact.  
Surgery remains the mainstay of treatment.  Due to the relatively advanced condition that 
subjects often present with, surgery to render subjects disease-free is often cosmetically and 
functionally disfiguring.  While rehabilitation is a key component of the treatment process, it 
cannot entirely solve the deficits consequent to proper sarcoma treatment. 
Radiation therapy (RT) is a critical component of optimal sarcoma therapy.  While occasionally 
used as definitive therapy, RT is more often used in coordination with surgery.  Administered 
neoadjuvantly or adjuvantly, RT improves local control, and may allow tumors initially 
considered unresectable to be removed successfully.  Although based on retrospective analysis, 
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recent data from one group suggest that peri-operative RT may also convey a survival benefit.  
This remains to be confirmed by additional analyses. 
Surgery combined with radiation therapy provides excellent local disease control, providing 
definitive local control in about 85-90% of subjects.  Results with high-risk tumors are less 
successful.  “High-risk” tumors are those that are large (generally greater than 5 cm in maximal 
dimension), high histologic grade, and/or located in surgically challenging positions.  Further, 
these therapies do not address the major reason for the ultimate failure of treatment in most 
cases: distant metastasis.  Approaches to improve local control and simultaneously address 
distant treatment failure are needed.  Systemic therapy approaches may be most useful for 
this. 
Up to now, peri-operative systemic therapy of sarcomas has demonstrated clear benefit only in 
sarcomas associated with childhood: osteosarcoma, Ewing’s sarcoma, and rhabdomyosarcoma.  
In these diseases, this therapy has both a local control and distant control advantage, leading to 
marked improvements in survival over local therapy alone.  Similar benefits have not been 
demonstrated through use of current agents in the majority of STS. 
Systemic, peri-operative therapy of most STS is reserved for those with high-risk tumors likely 
to pose difficulties in complete surgical extirpation.  Combination therapy, typically with 
Adriamycin and ifosfamide (a regimen known as “AIM”), yields a significant response rate 
(estimated ORR about 26%).  A treatment response may improve the quality of subsequent 
local therapy with surgery and radiation therapy.  Whether such therapy impacts control of 
distant micro-metastatic disease is unclear. 
AIM poses several problems in this setting: 
i) 
While it has the highest documented response rate of any general STS 
regimen, it is still only 26%.  Benefit can only be determined empirically.  
Thus, subjects must suffer the significant toxicity and logistical complexity of 
the regimen in exchange for, more likely than not, no discernible benefit. 
ii) 
Adriamycin, an important component of the regimen, is incompatible with 
concurrent RT.  Thus, any possible synergism to be derived from concurrent 
chemoradiotherapy is lost. 
iii) 
Traditionally, peri-operative systemic therapy regimens have been derived 
from those with previously demonstrated activity in the metastatic setting.  
In the metastatic setting, a clear survival benefit for AIM therapy over 
Adriamycin monotherapy has been excluded.  Clear evidence of survival 
benefits for Adriamycin-based, peri-operative systemic therapy is lacking, 
despite significant efforts.  If such benefit exists, it is modest, at best.    
iv) 
 If effects on distant disease are a major focus of peri-operative systemic 
therapy, then Adriamycin monotherapy might be considered.  However, 
response rates for Adriamycin monotherapy are only about 10%.  
Administration of Adriamycin monotherapy as an alternative to AIM in the 
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peri-operative setting would sacrifice one of the few documented benefits of 
multi-agent therapy with AIM: its increased response rate. 
v) 
AIM is relatively toxic therapy.  Subjects must be in good physical condition 
with good performance status and end-organ function to be considered for 
this therapy.  Due to either disease status or co-morbidities, subjects may not 
be able to receive AIM therapy.   
New approaches to peri-operative systemic therapy of STS are desperately needed.   
1.2. 
Cabozantinib Background 
Cabozantinib (XL184) is an inhibitor of multiple receptor tyrosine kinases (RTKs). It is provided 
as both capsules and tablets, but the two formulations are not interchangeable. Cometriq® 
(cabozantinib capsules, 140 mg) was approved by the United States Food and Drug 
Administration (FDA) on 29 November 2012 for the treatment of subjects with progressive, 
metastatic medullary thyroid cancer (MTC). On 21 March 2014, cabozantinib capsules were 
approved by the European Commission for the treatment of adult subjects with progressive, 
unresectable locally advanced or metastatic MTC. Cabometyx™ (cabozantinib tablets, 60 mg) 
was approved by FDA on 25 April 2016 for subjects with advanced renal cell carcinoma (RCC) 
who have received prior anti-angiogenic therapy and by the European Commission on 09 
September 2016 for the treatment of advanced RCC in adults who have received prior vascular 
endothelial growth factor (VEGF)-targeted therapy. 
The targets of cabozantinib include several RTKs known to play important roles in tumor cell 
proliferation and/or tumor neovascularization, namely MET (hepatocyte growth factor [HGF] 
receptor), vascular endothelial growth factor receptor 2 (VEGFR2, also known as KDR), AXL, and 
RET. Other recognized targets of cabozantinib include ROS1, TRKA, TRKB, TYRO3, MER, two 
additional members of the VEGFR family (VEGFR1, VEGFR3), and the closely-related RTKs KIT 
and FLT-3. In vivo pharmacodynamic activity of cabozantinib against MET, VEGFR2, AXL, and 
RET has been demonstrated in preclinical studies and has been associated with tumor growth 
inhibition and tumor regression. In preclinical studies, cabozantinib treatment has also been 
shown to inhibit tumor angiogenesis and tumor invasiveness and metastasis. 
In nonclinical toxicology studies of cabozantinib in rodents and non-rodents, histopathological 
changes associated with cabozantinib administration were observed in gastrointestinal (GI) 
tract, bone marrow, lymphoid tissues, kidney, adrenal, and reproductive tract tissues, and 
secondary changes were observed in bone and pancreas. Cabozantinib tested negative in 
bacterial and mammalian cell genotoxicity assays in vitro. In reproductive toxicity studies, 
cabozantinib was embryotoxic in rats, produced fetal soft tissue changes in rabbits, produced 
fetal external malformations in rats, and decreased fertility in male and female rats. The 
metabolite present at highest concentrations in humans administered cabozantinib, EXEL-1644, 
was negative in an in vitro bacterial genotoxicity bioassay and caused no systemic tissue toxicity 
in rats. In a 2-year rat carcinogenicity study, cabozantinib-related neoplastic findings consisted 
of an increased incidence of benign pheochromocytoma, alone or in combination with 
malignant pheochromocytoma/complex malignant pheochromocytoma of the adrenal medulla 
in both sexes. No clinical cases of pheochromocytoma have occurred to date. No carcinogenic 
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signal was observed in a rasH2 transgenic mouse model following cabozantinib dosing for 26 
weeks. 
1.3. 
Rationale for Combination of Cabozantinib with Radiation Therapy for High-Risk 
Soft Tissue Sarcoma of the Extremities 
Given the established benefit of combination surgery and radiation therapy, systemic agents 
that increase the therapeutic index of radiotherapy in this relatively radio-resistant class of 
tumors would be desirable.  This would be most important in cases where surgical excision is 
likely to be complex.  In addition, agents that might treat pre-existing micro-metastatic disease 
would also be desirable. 
Targeting the MET oncogene represents a strategy to achieve some of these goals in the 
sarcoma setting.  MET dysregulation appears to be important and frequent in the STS 
pathogenesis, including in clear cell sarcoma35, synovial sarcoma36, leiomyosarcoma37, 
pleomorphic sarcoma37,38,39, rhabdomyosarcoma40,41, angiosarcoma38, epithelioid36, Ewing’s42, 
and alveolar soft part sarcoma43.  A phase II study was conducted with the MET inhibitor 
tivantinib, enrolling 47 subjects, primary with alveolar soft part sarcoma and clear cell 
sarcoma44.  These diseases were targeted due to their association with microphthalmia 
transcription factor (MiTF).  MiTF proteins lead to transcriptional activation of the MET gene.  
Among those with alveolar soft part sarcoma (n=27), median progression-free survival was 5.5 
months.  At least three studies are in progress to assess the activity of the MET inhibitor 
cabozantinib in advanced sarcomas (See ClinicalTrials.gov: NCT01755195, NCT01979393, 
NCT02867592).  None of these seek to assess administration of the agent in combination 
therapy regimens or with neoadjuvant intent. 
MET inhibitors also have documented radiosensitizing effects.  Pre-clinical studies 
demonstrating such effects have been undertaken in non-small cell lung cancer45,46 and 
prostate cancer47.   Several mechanisms have been invoked for these radiosensitizing effects.  
These include: prevention of radiation-induced MET expression via the ATM-NFκB pathway, 
thereby preventing MET-mediated cell invasion; and anti-apoptotic effects48 and down-
regulation of the ATR-CHK1-CDC25 pathway49.  Critically, the latter mechanism enhances 
radiosensitivity in p53-deficient cells, a common circumstance in sarcomas. 
This trial will examine cabozantinib in combination with radiotherapy in the neoadjuvant 
setting.  Because of concerns regarding potential toxicities of the combination of a multi-
targeted tyrosine kinase inhibitor like cabozantinib with radiotherapy (such as fistula 
formation50), this study will be restricted to those with sarcomas of the extremities.  Fistula 
formation has also been reported in studies of cabozantinib monotherapy51. The subject 
population to be enrolled will include all sarcoma subjects for whom neoadjuvant radiation to 
the extremities followed by surgical resection is planned.  
The results of this study may help to determine whether concurrent administration of 
cabozantinib and radiotherapy is feasible, and whether there is preliminary evidence of activity 
in this class of tumors.  Correlative studies will utilize specimens that are available pre-
treatment, at the time of resection, and at recurrence, if recurrence occurs.  These studies will 
investigate changes in molecular pathway activation during therapy; correlates of response or 
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lack thereof; and alterations in the immune microenvironment induced by this therapy.  In 
addition, these studies will investigate radiomic metrics correlating with treatment response 
and relapse-free survival. 
1.4. 
Rationale for Starting Dose Selection  
Cabozantinib is presently approved for the treatment of advanced renal cell carcinoma that has 
progressed despite prior anti-angiogenic therapy and hepatocellular carcinoma (HCC) that has 
been previously treated with sorafenib51.  Recommended dose is 60 mg daily.  The drug is 
available in 20 mg tablets.  Dose reductions to 40 mg and 20 mg daily are possible in response 
to toxicity in the currently approved setting.  Below 20 mg daily, the drug is discontinued in the 
currently approved setting. 
 
In this study, we propose to initiate treatment using a 21-day dosing schedule. The following 
dose levels will be assessed: 
 
Dose Level 
Daily Dose of Cabozantinib 
-1 
20 mg Daily 
0 
40 mg Daily 
+1 
60 mg Daily 
 
Dose level +1 is the presently approved target dose of cabozantinib51.  Based on the reported 
half-life of the drug (99 hours51), dose reductions below 40 mg daily would be reasonable to 
consider, if the initial 40 mg daily dosing is not tolerated.  These would result in lower steady 
state concentrations of the drug.  Since one of the primary endpoints is to assess the 
radiosensitizing effects of cabozantinib, it would still be reasonable to explore doses that are 
less than would be administered when the drug is being used as monotherapy, if the full dose is 
not tolerable. 
 
 
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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
2.1.1. 
Primary Objectives  
• Phase I: To determine if administration of cabozantinib is safe and feasible in 
combination with neoadjuvant radiation therapy. 
• Phase II: To assess the proportion of subjects alive and free of both local and distant 
disease recurrence (and progression after incomplete resection) one year after 
treatment initiation.   
2.1.2. 
Secondary Objective(s) 
• Rate of pathologic response. 
• Rate of surgical excision with negative margins. 
• Response rate (complete, partial, overall) of the combination therapy prior to surgery, 
as defined by RECIST 1.1 criteria. 
• Pattern of and time to local vs. distant recurrences. 
• Relapse-free and overall survival at various time points from study entry. 
• Safety and tolerability of combined treatment regimen, including the rate of 
discontinuation during the cabozantinib monotherapy component of the study. 
2.1.3. 
Exploratory Objective(s) 
• Comparison of pre- and post-treatment specimens to identify changes in activation of 
molecular pathways associated with MET genetic profiles associated with treatment 
response and with relapse-free survival. 
• Evaluation of pre- and post-treatment specimens for mutational status of signaling 
pathways, including MAP-Kinas and AKT/m-TOR pathways.   
• Explore changes in the immune microenvironment induced by this neoadjuvant 
treatment, in comparison to matched specimens obtained from the University of 
Washington pathology archives.  
• Radiomic studies to identify predictors of treatment response and relapse-free survival. 
2.2. 
Endpoints 
2.2.1. 
Primary Endpoints 
• Phase I: Recommended Phase 2 dose of cabozantinib in combination with radiation 
• Phase II: Rate of relapse at 12 months after treatment initiation. 
2.2.2. 
Secondary endpoints 
• Rate of pathologic response. 
• Rate of surgical excision with negative margins. 
• Response rate (complete, partial, overall) of the combination therapy prior to surgery, 
as defined by RECIST 1.1 criteria. 
• Pattern of and time to local vs. distant recurrences. 
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• Relapse-free and overall survival at various time points from study entry. 
• Safety and tolerability of combined treatment regimen. 
• Rate of treatment discontinuation prior to neoadjuvant radiation therapy. 
2.2.3. 
Exploratory endpoints 
• Assessment of changes in activation of molecular pathways associated with MET genetic 
profiles associated with treatment response and with relapse-free survival.   
• Assessment of mutational status of signaling pathways, including MAP-Kinas and 
AKT/m-TOR pathways.   
• Assessment of changes in infiltration of immune cell subsets (CD4, CD8, myeloid) in the 
immune microenvironment induced by this neoadjuvant treatment, in comparison to 
matched specimens obtained from the University of Washington pathology archives.  
• Radiomic studies to identify predictors of treatment response and relapse-free survival, 
when comparing pre-treatment imaging with imaging prior to surgery (after completion 
of radiotherapy and concurrent cabozantinib). 
 
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3. 
STUDY DESIGN 
This is an open label, dose-finding, single-arm, prospective phase 1/2 study to identify the 
recommended dose of cabozantinib given orally, once daily, in a 21-day cycle, plus radiation 
therapy in subjects with high-risk soft tissue sarcoma of the extremities.  
The study will be conducted in compliance with International Conference on Harmonization (ICH) 
Good Clinical Practices (GCPs). 
3.1. 
Dose-finding Phase 1 Portion of the Study:   
Dose levels of cabozantinib will be tested in cohorts of 3 subjects each using the 3+3 dose-finding 
design.  
Table 1. Dose Levels of Cabozantinib 
Dose Levels 
Daily Dose of Cabozantinib 
-1 
20 mg daily 
0 
40 mg daily 
+1 
60 mg daily 
In the dose-finding Phase 1 portion of the study, subjects will receive one week of therapy at the 
planned starting dosage as monotherapy prior to initiation of radiotherapy.  Starting at Cycle 1 
Day 8, subjects will initiate therapy concurrently with radiation therapy.  Subjects enrolled to 
phase 1 who withdraw prior to initiation of radiation therapy for any reason, or during the DLT 
period for reasons other than toxicity will be considered non-evaluable and will be replaced. A 
window of + 7 days is permitted for initiation of RT in relation to C1D8. It is recommended that 
subjects begin treatment on a Monday due to radiation scheduling, however this is not 
mandatory. At least 7 days must pass between C1D1 and initiation of radiation therapy. 
In the dose-finding Phase 1 portion of the study, dose levels of cabozantinib will be tested in 
cohorts of 3 subjects each using the 3+3 dose-finding design, with the starting dose of 40mg once 
daily, with potential dose escalation to 60 mg, or de-escalating to 20 mg daily. The daily dose of 
cabozantinib will not be increased to more than 60 mg per day. The DLT period will include all 
subjects enrolled to the phase 1 component of the study. The DLT period is defined as beginning 
on C1D8 and continuing until 28 days after completion of concurrent radiation therapy and 
cabozantinib. If no dose-limiting toxicity (DLT) is observed at the starting dose in the first 3 
subjects, the next dose cohort would enroll subjects at 60 mg. If 1 DLT is observed any dose 
cohorts in the first 3 subjects, then additional 3 subjects will be enrolled at that dose level. If ≤1 
of 6 subjects experience a DLT at the starting dose or higher, enrollment would continue to the 
next higher dose level. The first 3 subjects of each cohort must complete their DLT period prior 
to expanding the cohort to include additional subjects to ensure a second DLT is not seen in the 
first 3 subjects. If ≤1 of 6 subjects experience a DLT at the starting dose or higher, enrollment 
would continue to the next higher dose level. 
If ≥2 subjects experience a DLT at dose level higher than the starting dose, enrollment will be 
discontinued for that dose cohort and the previous dose level would be declared the maximum 
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tolerated dose (MTD). If ≥2 subjects experience a DLT at the starting dose of 40 mg once daily 
(and any lower dose level), further enrollment at that dose level will be discontinued and 
cabozantinib will be reduced to the next planned dose level.  
If a subject is considered Not Evaluable due to withdrawal for reasons other than toxicity during 
the DLT Period, they will be replaced. 
The MTD of cabozantinib is the highest dose level at which ≤1 of 6 (or 0 out of 3) subjects 
experienced a DLT, thus a target DLT rate of roughly 17%. It is possible that the MTD is not 
reached in this study (e.g., if no DLT observed in the first 3 subjects at 60 mg daily). Recommended 
Phase 2 dose (RP2D) is identified based of the totality of safety and efficacy data. Once the dose-
finding portion of the study is concluded and RP2D is identified, subjects receiving a lower dose 
may be allowed to receive cabozantinib at the RP2D, based on the investigator judgment. 
3.2. 
Dose Expansion Phase 2 Portion of the Study:  
The dose-expansion Phase 2 will be conducted using an open-label, single stage design. Subjects 
enrolled in the Phase 1 dose-escalation component of the study at the RP2D level and meeting 
all inclusion/exclusion criteria for the Phase 2 component of the study will be included for efficacy 
and safety evaluation in the Phase 2 efficacy component of the study.  
Subjects enrolled to the dose-expansion Phase 2 portion of the study will receive one week of 
cabozantinib monotherapy at the RP2D prior to initiating radiation therapy. Starting at Cycle 1 
Day 8, subjects will initiate therapy concurrently with radiation therapy.  Subjects enrolled to 
phase 2 who withdraw prior to initiation of radiation therapy will not be considered evaluable 
and will be replaced. A window of + 7 days is permitted for initiation of RT in relation to C1D8. It 
is recommended that subjects begin treatment on a Monday due to radiation scheduling, 
however this is not mandatory. At least 7 days must pass between C1D1 and initiation of radiation 
therapy. 
3.3. 
Study Duration, End of Study, End of Treatment, End of Treatment Visit, Follow-up 
Period 
The study is expected to take approximately 60 months from first subject enrolled to last subject 
follow-up, including approximately 36 months of enrollment period, an estimated 5 months of 
treatment (or until treatment is no longer tolerated).   
End of Treatment (EOT) for a subject is defined as the date of the last dose of cabozantinib. End 
of Treatment Visit for a subject is when safety assessments and procedures are performed after 
the date of the last dose of cabozantinib.   
30-Day Follow-Up for a subject is defined as 30 days (+/- 1 week) after the last dose of 
cabozantinib. This visit will include safety assessments.  
Follow-up period is the on-study time period after the EOT Visit.  
The End of Study (EOS) defined as either the date of the last visit of the last subject to complete 
the study, or the date of receipt of the last data point from the last subject that is required for 
primary, secondary, and/or exploratory analysis, as pre-specified in the protocol, whichever is 
later.  
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4. 
STUDY POPULATION 
4.1. 
Number of Subjects 
Phase 1: Up to 12 subjects to identify the MTD, but the MTD may be reached with as few as 5 
subjects. Subjects enrolled to Phase 1 or Phase 2 who are unable to tolerate cabozantinib 
monotherapy will not be considered evaluable for the Phase 1 or 2 component of the study and 
will be replaced.  Subjects enrolled to Phase 1 who withdraw for reasons other than toxicity 
during the DLT Period will be considered not evaluable and will be replaced. 
Phase 2: An anticipated 34 subjects will accrue in Phase 2 of study. 
Assuming a 10% drop-out/non-evaluable rate, 44 total subjects would be accrued to the efficacy 
component for the study to yield 40 evaluable subjects. Subjects enrolled to Phase 2 who 
withdraw prior to initiation of radiation therapy will be determined to be not evaluable and 
replaced. 
4.2. 
Inclusion Criteria  
A subject will be eligible for inclusion in this study only if all the following criteria are met: 
1. Subjects, ≥18 years old, must have a histologically confirmed diagnosis of sarcomas 
of the extremities (which may include gluteal muscle involvement) for which 
neoadjuvant radiation therapy followed by surgical resection is a planned 
intervention.  
a. Subjects whose bowel cannot be completely protected from radiation 
exposure due to primary tumor location (e.g., proximal lower extremity) will 
be excluded. 
2. Subjects must have one or more measurable target lesions by RECIST v1.1, assessed 
via CT scan or MRI. 
3. At the time of study enrollment, subjects must have a tumor burden that is judged 
to be surgically resectable. 
4. Subjects must have adequate organ function and blood chemistry and blood count 
parameters: 
a. Absolute neutrophil count (ANC) ≥ 1500/mm3 (≥ 1.5 GI/L) without 
granulocyte colony-stimulating factor support in the last 28 days. 
b. White blood cell count ≥ 2500/mm3 (≥ 2.5 GI/L). 
c. Platelets ≥ 100,000/mm3 (≥ 100 GI/L) without transfusion in the last 28 days. 
d. Hemoglobin ≥ 9 g/dL (≥ 90 g/L) without transfusion in the last 28 days. 
e. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and 
alkaline phosphatase (ALP) ≤ 3 x upper limit of normal (ULN).  
i. ALP ≤ 5 x ULN is permitted in subjects with documented bone 
metastases (Phase 1 only). 
f. Total bilirubin ≤ 1.5 x ULN (for subjects with Gilbert’s disease ≤ 3 x ULN). 
g. Serum albumin ≥ 2.8 g/dl. 
h. Serum creatinine ≤ 2.0 x ULN or calculated creatinine clearance ≥ 30 mL/min 
(≥ 0.5 mL/sec) using the Cockcroft-Gault equation: 
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Males: (140 – age) x weight (kg)/(serum creatinine [mg/dL] × 72) 
Females: [(140 – age) x weight (kg)/(serum creatinine [mg/dL] × 72)] × 0.85 
i. Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol). 
5. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 
6. Male or non-pregnant and non-breast feeding female: 
a. Females of child-bearing potential (FOCBP) must agree to use highly effective 
contraception without interruption from initiation of therapy and continue 
until 4 months (120 days) after last dose of study therapy.  FOCBP must have 
a negative serum pregnancy test (β -hCG) result at screening and agree to 
ongoing pregnancy testing during the study, and at the end of study 
treatment. A highly effective method of contraception is defined as one that 
results in a low failure rate (that is, <1% per year), when used consistently 
and correctly, such as implants, injectables, combined oral contraceptives, 
some intrauterine contraceptive devices, sexual abstinence, or a 
vasectomized partner (APPENDIX 1 - WOMEN OF CHILDBEARING POTENTIAL 
DEFINITIONS AND METHODS OF CONTRACEPTION).  
b. Male subjects must practice abstinence or agree to use a condom during 
sexual contact with a pregnant female or a female of childbearing potential 
while participating in the study (APPENDIX 1 - WOMEN OF CHILDBEARING 
POTENTIAL DEFINITIONS AND METHODS OF CONTRACEPTION). 
7. Life expectancy of >3 months, as determined by the investigator. 
8. Ability to understand and sign informed consent. 
9. Willingness and ability to comply with scheduled visits, laboratory tests, and other 
study procedures. 
4.3. 
Exclusion Criteria  
A subject will not be eligible for inclusion in this study if any of the following criteria apply: 
1. Receipt of any type of cytotoxic, biologic, or other systemic anticancer therapy (including 
investigational) for the investigational diagnosis. 
2. Receipt of any prior radiation therapy for the investigational diagnosis. 
3. Known central nervous system (CNS) metastases.  
4. Concomitant anticoagulation with oral anticoagulants (e.g., warfarin, direct thrombin and 
Factor Xa inhibitors) or platelet inhibitors (e.g., clopidogrel). Allowed anticoagulants are 
the following: 
• Low-dose aspirin for cardioprotection (per local applicable guidelines) is 
permitted. 
• Low-dose low molecular weight heparins (LMWH) are permitted. 
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• Anticoagulation with therapeutic doses of LMWH is allowed in subjects without 
known brain metastases who are on a stable dose of LMWH for at least 6 weeks 
before first dose of study treatment, and who have had no clinically significant 
hemorrhagic complications from the anticoagulation regimen or the tumor.  
Subjects with hemoptysis, central nervous system hemorrhage or gastrointestinal 
hemorrhage within the last 6 months prior to treatment are excluded. 
5. The subject has uncontrolled, significant intercurrent or recent illness including, but not 
limited to, the following conditions: 
• Cardiovascular disorders: 
i. Congestive heart failure New York Heart Association Class 3 or 4, unstable 
angina pectoris, serious cardiac arrhythmias. 
ii. Uncontrolled hypertension defined as sustained blood pressure (BP) > 150 
mm Hg systolic or > 100 mm Hg diastolic despite optimal antihypertensive 
treatment. 
iii. Stroke (including transient ischemic attack [TIA]), myocardial infarction 
(MI), or other ischemic event, or thromboembolic event (e.g., deep venous 
thrombosis, pulmonary embolism) within 6 months before first dose. 
Uncontrolled serious medical or psychiatric illness.  
• Gastrointestinal (GI) disorders including those associated with a high risk of 
perforation or fistula formation: 
i. The subject has evidence of tumor invading the GI tract, active peptic ulcer 
disease, inflammatory bowel disease (e.g., Crohn’s disease), diverticulitis, 
cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis, 
acute obstruction of the pancreatic duct or common bile duct, or gastric 
outlet obstruction. 
ii. Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal 
abscess within 6 months before first dose. 
iii. Note: Complete healing of an intra-abdominal abscess must be confirmed 
before first dose. 
• Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon 
(2.5 ml) of red blood, or other history of significant bleeding (e.g., pulmonary 
hemorrhage) within 12 weeks before first dose. 
• Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease 
manifestation. 
• Lesions invading or encasing any major blood vessels. 
• Other clinically significant disorders that would preclude safe study participation. 
i. Serious non-healing wound/ulcer/bone fracture. 
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ii. Uncompensated/symptomatic hypothyroidism. 
iii. Moderate to severe hepatic impairment (Child-Pugh B or C). 
6. Major surgery (e.g., GI surgery, removal or biopsy of brain metastasis) within 8 weeks 
before first dose of study treatment. Complete wound healing from major surgery must 
have occurred at least 30 days before first dose, and from minor surgery (e.g., simple 
excision, tooth extraction) at least 10 days before first dose. Subjects with clinically 
relevant ongoing complications from prior surgery are not eligible. 
7. Corrected QT interval calculated by the Bazett’s formula (QTc) > 480 ms per 
electrocardiogram (ECG) within 28 days before first dose of study treatment. 
• Note: If a single ECG shows a QTc with an absolute value > 480 ms, two additional 
ECGs at intervals of approximately 3 min must be performed within 30 min after 
the initial ECG, and the average of these three consecutive results for QTc will be 
used to determine eligibility. 
8. Pregnant or lactating females. 
9. Inability to swallow tablets. 
10. Previously identified allergy or hypersensitivity to components of the study treatment 
formulations. 
11. Diagnosis of another malignancy within 2 years before first dose of study treatment, 
except for superficial skin cancers, or localized, low-grade tumors deemed cured and not 
treated with systemic therapy. 
12. Concurrent use of medications (especially those interacting with CYP3A417) that 
potentially interact unsafely with cabozantinib which cannot be discontinued or 
substituted 
13. Subjects with a sarcoma which has other, defined treatments or biology distinctly 
different from those of soft tissue sarcomas in general.  Including, but not limited to, 
Ewing’s sarcoma, rhabdomyosarcoma, gastrointestinal stromal tumors, Kaposi’s 
sarcoma, Wilms’ tumor. 
14. Transfusion of blood product or G-CSF support factor within the last 28 days. 
15. Recent infection requiring systemic anti-infective treatment that was completed ≤14 days 
prior to enrollment (except for uncomplicated urinary tract infection or upper respiratory 
tract infection). 
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5. 
TABLE OF EVENTS 
The schedule of assessments in Table 2 outlines the specific time points for study assessments.

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Table 2. Schedule of Assessments 
 Assessments a 
Baseline 
Screening b 
Treatment Phase Cycle 1-3 
 
 
Treatment Phase 
Cycle 4+ 
 
End of 
Treatment 
(EOT) Visit d 
30 Day 
Safety 
Follow-Upp Survival Follow-
up  
 
D1 
D8 c  
D15 c 
D1 
 
(+/- 7 d) 
Informed Consent 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Hepatitis and HIV 
Screen e 
X 
 
 
 
 
 
 
 
Urinalysis w/micro 
X 
X 
X 
X 
X 
X 
 
 
Urine Protein / 
Creatinine Ratio q 
X 
 
 
 
 
 
 
 
TSH, Free T4 
X 
X 
 
 
X 
X 
 
 
Pregnancy Test f 
X 
X 
 
 
X 
X 
 
 
LVEF (echo or MUGA) 
X 
 
 
 
 
 
 
 
12-lead ECG 
X 
X 
 
 
X 
X 
X 
 
Physical Exam/ECOG 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signs, height, and 
weight g 
X 
X 
X 
X 
X 
X 
X 
 
CBC/Diff/Blood Chem e 
X 
X 
X 
X 
X 
X 
X 
 
Lipid Panel m 
X 
X 
 
 
X 
X 
 
 
Tissue Sample n 
Xn 
 
 
 
 
Xn 
 
 
Imaging h 
X 
Every 12 weeks (±2 week). 
Cabozantinib i 
 
Daily 
 
 
 
Radiation Therapy r 
 
Administered per SOC. Radiation therapy to initiate within +7 days of C1D8. 
 AE/Con Med 
Assessment j 
X 
Continuous from C1D1 through 30-day follow-up.  
 
Long Term Follow-up k 
 
 
X 

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a All treatment visits are allowed to occur in a window of ±3 days unless otherwise specified.  
b Baseline screening visit will be done within 28 days prior to enrollment.  
c Day 8 and Day 15 visit is only in Cycle 1-3. Cycle 4+ will have visits on Day 1 only. 
d End of Treatment (EOT) Visit should be within 7 days of last study treatment (±3 days).  
e Baseline HIV and Hepatitis screening to include HIV, HBV sAg, HBV cAb, and HCV Ab. See Table 3 for full Analyte Listing for CBC and chemistry panels. 
f For all female subjects of childbearing potential (see Inclusion 6), a serum pregnancy test will be done at all indicated timepoints. Pregnancy tests conducted 
after screening will be recorded in the source documentation only.  
g Height is measured only at screening. Vitals signs to include respiration rate, temperature, systolic/diastolic blood pressure, and pulse. 
h Baseline scans should be done within 28 days prior to enrollment, preferably as close to C1D1 as possible. Repeat imaging should be completed every 12 weeks 
from C1D1 (+/- 2 weeks) for one year after initiation of protocol therapy based on the date of the C1D1 visit, or until disease recurrence/progression, 
withdrawal of consent, death, or end of study (whichever comes first) regardless of missed or out of window doses. MRI may be used if CT is contra indicated 
for a subject. The same mode of imaging at screening must be used consistently throughout the study. Baseline imaging must include CAP and the affected 
extremity. If subjects do not have disease in the A/P, imaging moving forward after baseline may omit those areas.  
i Cabozantinib will be administered daily. Subjects will complete a daily drug diary during treatment, to be reviewed on Day 1 of each cycle. Subjects with at least 
stable disease at the first post-RT imaging timepoint may continue to receive cabozantinib therapy for a maximum of 6 cycles, with treatment ending at least 28 
days prior to any scheduled surgery, including dental surgery. 
j Prior and concomitant medications, as well as any recent procedures should be documented at baseline. Prior medications/procedures include any medications 
or procedures completed ≤ 28 days prior to informed consent. 
k Follow up will continue to monitor disease status by imaging assessment of, at minimum, CT Chest and the affected extremity approximately every 12 weeks 
(±2 weeks), until either one (1) year has elapsed since initiating cabozantinib therapy based on the date of the C1D1 visit, death, withdrawal of consent, disease 
recurrence, or the study closes, whichever is the earliest. Thereafter, subjects will be followed for survival every 6 months (+/- 1 month) until 3 years have 
elapsed since initiating cabozantinib therapy based on the date of the C1D1 visit, disease recurrence, end-of-study, death, or withdrawal of consent, whichever 
is earliest. This evaluation may be made by review of publicly available information, record review and/or telephone contact.  
m Lipid panel should be fasting. 
n Optional tissue samples will be collected from archival tissue. Pre-treatment tissue should have been collected within 12 months prior to initiating protocol 
therapy. End of Treatment tissue samples may be collected from surgical resection, if applicable. If there is no surgical resection for any reason, end of 
treatment tissue samples will not be collected. No biopsies will occur solely for research collection.  
p 30 Day Follow-Up visit must occur 30 days from the date that the subject was last administered cabozantinib therapy. This visit has a window of +/- 7 days.  
q If urine protein/creatinine ratio is abnormal, a 24-hour urine collection should be collected for repeat UPC Ratio.   
r Radiation therapy may not be initiated prior to Cycle 1 Day 8. Radiation therapy must initiate within +7 days of the Cycle 1 Day 8 visit. All treatment plans for 
subjects that are not treated at the main study site will be submitted for review to the Sponsor-Investigator at least 1 week prior to the subject starting 
radiotherapy. It is recommended that outside treatment plans are received and reviewed as part of study eligibility and screening review. Review and approval 
of treatment plans for subjects receiving radiotherapy locally must be reviewed and approved by a radiation oncologist sub-investigator prior to initiation of 
radiotherapy.   

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6. 
PROCEDURES 
6.1. 
Screening Evaluations 
This study will be conducted at the University of Washington, Seattle, USA. Each subject who 
enters into the screening period for the study receives a unique subject identification number 
before any study-related procedures are performed. The subject identification number will be 
assigned. This number will be used to identify the subject throughout the clinical study and must 
be used on all study documentation related to that subject.  
The subject identification number must remain constant throughout the entire clinical study; it 
must not be changed after initial assignment, including if a subject is rescreened.  
Before subjects may be entered into the study, Exelixis requires a copy of the sites’ written 
IRB/IEC approval of the protocol, informed consent form, and all other subject information 
and/or recruitment material, if applicable. A signed and dated Institutional Review Board (IRB) 
approved informed consent form (latest approved version) must be obtained from each subject 
prior to performing any study-specific procedures. All subjects or legally acceptable 
representatives must personally sign and date the consent form before commencement of study-
specific procedures. Adverse events are to be collected for a subject once they have signed the 
informed consent.  
Screening evaluations will be performed for all subjects to determine study eligibility.  These 
evaluations must be obtained ≤28 days prior to enrollment, unless otherwise indicated. Baseline 
imaging should be obtained as close to initiation of protocol therapy as possible.  
The following procedures are to be completed during the 28-day screening period, after signed 
informed consent has been obtained, designated in the Schedule of Assessments found in Table 
2. 
• Demographics (if allowed by local regulations, date of birth, sex, race, and ethnicity) 
• Physical examination (including physical exam, medical/cancer history, ECOG 
performance status assessment)  
• Prior/concomitant medications and procedures evaluation: all medications taken, and 
procedures completed within ≤28 days prior to signing of informed consent  
• Vital signs (height [screening only], weight, temperature, sys/dias blood pressure, 
respiration rate, and pulse) 
• 12-lead Electrocardiogram single tracing 
• Left ventricular ejection fraction (LVEF, by echocardiogram or MUGA) 
• Adverse event assessment 
• Local Laboratory Assessments: blood chemistry, complete blood count (CBC) + 
differential, complete urinalysis with microscopic evaluation, urine protein/creatinine 
ratio (UPCR), pregnancy test (women of child-bearing potential), HIV, hepatitis B 
surface antigen, hepatitis C antibody, fasting lipids, thyroid function 
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• CT or MRI must be done within the 28-day screening period, but preferably should be 
done as close to enrollment as possible 
• Archival tissue collection (optional) 
A subject is considered enrolled when the investigator decides that the subject has met all 
eligibility criteria. The investigator is to document this decision and date, in the subject’s medical 
record and/or in/on the electronic case report form (eCRF). Subjects should initiate treatment 
within 14 days of being enrolled to the study (28-day screening window from date of consent to 
enrollment date, plus up to an additional 14 days from enrollment date to C1D1 [total elapsed 
time from initiating screening to initiating therapy may not exceed 42 days]).  
6.2. 
Treatment Period 
A subject is considered on treatment on study day 1 when the IP, cabozantinib, is first 
administered. Subjects should initiate treatment within 14 days of being enrolled to the study. 
Cabozantinib is to be administered after all other protocol-specified pre-dose assessments have 
been performed during each visit that it is required. Subjects will continue therapy until 
completion of planned course of treatment, disease progression, or unacceptable AEs. Subjects 
should be instructed to immediately inform the principal investigator (PI) of any AEs. Subjects 
experiencing dizziness, sleepiness, or other symptoms that could influence alertness or 
coordination should be advised not to drive or operate other heavy machinery. 
6.2.1. 
Duration of Treatment 
One week of neoadjuvant therapy with cabozantinib will be administered prior to initiation of 
radiotherapy. Initiation of radiation therapy should occur within +7 days of C1D8.  
Typically, RT regimens for neoadjuvant treatment of STS are 5-6 weeks, though may vary based 
on institutional preference.  Typically, an interval of 4-6 weeks exists between completion of RT 
and time of surgery.  Subjects with at least stable disease at the first post-RT imaging timepoint 
may continue to receive cabozantinib therapy for a maximum of 6 cycles, with treatment 
ending at least 28 days prior to any scheduled surgery, including dental surgery. 
6.2.2. 
Day 1 Assessment 
The following assessments will be performed on Day 1 of each cycle, unless otherwise specified: 
• Physical examination  
• Concomitant medication and procedures evaluation  
• Vital signs (weight, temperature, sys/dias blood pressure, respiration rate, and pulse) 
• ECOG performance status 
• CBC, differential  
• Clinical chemistry panel including fasting lipid panel and thyroid function tests 
• Serum pregnancy test (women of child-bearing potential only) 
• ECG  
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• Urinalysis with microscopic evaluation 
• Adverse Event assessment 
All Day 1 evaluations for Cycle 1 may be omitted if screening evaluations are performed within 
72 hours of Cycle 1 Day 1.  
6.2.3. 
Day 8 Assessment 
The following assessments will be performed on Day 8 of Cycles 1-3 only: 
• Physical evaluation 
• Vital signs (weight, temperature, sys/dias blood pressure, respiration rate, and pulse) 
• Urinalysis with microscopic evaluation 
• Concomitant medication and procedures evaluation 
• ECOG performance status 
• CBC, differential 
• Clinical chemistry panel (Day 8 assessments do not include fasting lipid or thyroid 
studies) 
• Adverse Event assessment 
6.2.4. 
Day 15 Assessment 
The following assessments will be performed on Day 15 of Cycles 1-3 only:  
• Physical evaluation 
• Vital signs (weight, temperature, sys/dias blood pressure, respiration rate, and pulse) 
• Concomitant medication and procedures evaluation 
• ECOG performance status 
• CBC, differential 
• Urinalysis with microscopic evaluation 
• Clinical chemistry panel (Day 15 assessments do not include fasting lipid or thyroid 
panel)  
• Adverse Event assessment 
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Table 3. Analyte Listing 
Chemistry 
Hematology 
 Urinalysis 
Other Labs 
Sodium 
WBC 
 Specific gravity 
Pregnancy test (WOCBP only) 
Potassium 
RBC 
 pH 
HIV 
Bicarbonate 
Hemoglobin 
 Blood 
HBV sAg 
Chloride 
Hematocrit 
 Protein 
HBV cAb 
Total protein 
MCV 
 Glucose 
HCV Ab 
Albumin 
MCH 
 Ketones 
Total Cholesterol  
Calcium 
MCHC 
 Microscopic 
HDL 
Glucose (fasting) 
RDW 
  
LDL 
BUN 
Platelets 
  
Triglyceride 
Creatinine 
Differential: 
  
TSH, Free T4 
Total bilirubin 
-Neutrophils 
  
 
Alkaline 
phosphatase 
-Lymphocytes   
 
AST (SGOT) 
-Monocytes 
  
 
ALT (SGPT) 
-Eosinophils 
  
 
Amylase 
-Basophils 
  
 
Lipase 
GGT 
Lactate 
Dehydrogenase 
 
  
 
6.2.5. 
Disease Assessment  
Disease status will be assessed by CT or MRI scan. At baseline, imaging must include chest, 
abdomen, and pelvis (CAP), in addition to pertinent area of the extremity being treated (per 
institutional guidelines). If no disease is present in the abdomen/pelvis, these areas may be 
excluded from repeat imaging. Image preparation and evaluation will follow the specifications 
provided in the RECIST version 1.1. The same modality (CT or MRI) must be used at screening and 
throughout the study.  
CT/MRI scans to be performed at the following frequency: 
• ≤28 days prior to enrollment 
• Followed by every 12 weeks (± 2 weeks) from C1D1 for 12 months after initiation of 
protocol therapy (based on the date of C1D1) until disease recurrence, withdrawal of 
consent, end of study, completion of protocol participation, or death – whichever 
occurs first.  
An unscheduled scan for suspected disease recurrence/progression may be performed at any 
time at investigator discretion.  
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6.3. 
End of Treatment Visit Assessment 
The EOT Visit is a safety follow-up visit that is to be performed within 7 days (+/- 3 days) after the 
last dose of cabozantinib. All efforts should be made to conduct this visit. If it is not possible to 
conduct the EOT Visit, documentation of efforts to complete the visit should be provided. 
The following procedures will be completed at the EOT Visit as designated in the Schedule of 
Assessments in Table 2. 
• Physical examination  
• Concomitant medication and procedures evaluation  
• Vital signs (weight, temperature, sys/dias blood pressure, respiration rate, and pulse) 
• ECOG performance status 
• CBC, differential  
• Clinical chemistry panel including fasting lipid panel and thyroid function tests 
• Serum pregnancy test (women of child-bearing potential only) 
• ECG  
• Urinalysis with microscopic evaluation 
• Adverse Event assessment 
• Archival tumor collection (optional, for subjects undergoing clinical surgical resection) 
6.4. 
Follow-up Period for Survival and Initiation of Anticancer Therapy  
Adverse events will be monitored through 30 days after the subject’s last dose of investigational 
product.  
6.4.1. 
30 Day Follow-Up Visit Therapy  
The 30 day follow up visit should be completed 30 days after the subject’s last dose of 
cabozantinib therapy (+/- 1 week).  
The following procedures will be completed at the 30 day follow-up visit, as designated in the 
Schedule of Assessments in Table 2. 
• Physical examination  
• Concomitant medication and procedures evaluation  
• Vital signs (weight, temperature, sys/dias blood pressure, respiration rate, and pulse) 
• ECOG performance status 
• Clinical chemistry panel including fasting lipid panel and thyroid function tests 
• ECG 
• Adverse Event assessment 
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6.4.2. 
Long Term Follow-Up 
Disease status and any subsequent anticancer therapy information status will continue to be 
monitored. All subjects that discontinue study drug and have not withdrawn full consent to 
participate in the study will continue in the follow-up phase. Follow up will continue to monitor 
disease status approximately every 12 weeks (±2 weeks), until either one (1) year has elapsed 
since initiating cabozantinib therapy based on the date of C1D1, death, withdrawal of consent, 
disease recurrence, or the study closes, whichever is the earliest. This will include a physical 
exam and imaging assessment.   
Thereafter, subjects will be followed for survival every 6 months (+/- 1 month) until 3 years 
have elapsed since initiating cabozantinib therapy based on the date of C1D1, disease 
recurrence, end-of-study, death, or withdrawal of consent, whichever is earliest. This 
evaluation may be made by review of publicly available information, record review and/or 
telephone contact. 
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7. 
DESCRIPTION OF STUDY TREATMENTS  
7.1. 
Cabozantinib 
7.1.1. 
Cabozantinib Dosage, Administration, and Schedule 
Subjects will receive cabozantinib orally at a (starting) dose of 40 mg once daily.  
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 (e.g., if a subject is scheduled to take their dose at 8AM but misses it, they may 
take that missed dose any time before 8PM that day).  If a subject vomits the dose after taking 
it, skip the dose and resume the next dose at the regularly scheduled time.  
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. 
In all subjects, dose reductions and delays to manage toxicity are allowed under the guidelines in 
7.1.2 below. 
Table 4 - Dose Levels for Cabozantinib 
Dose Levels 
Cabozantinib in mg 
-1 
20 mg daily 
0 
40 mg daily 
+1 
60 mg daily 
7.1.2. 
Cabozantinib Dose Modification and Stopping Rules 
The following should be taken into consideration in decisions regarding dose modifications 
(reductions or interruption): 
• As a general approach all AEs should be managed with supportive care at the earliest 
signs of toxicity considered related to the study treatment. Should this be ineffective, 
dose interruptions and/or reductions should be considered to prevent worsening of 
toxicity.  
• The assigned starting dose for cabozantinib is 40 mg/day. The dose level may go to -1 as 
seen in Table 4. Further dose reductions beyond 20 mg daily are not permitted.  
• Dose modification criteria for cabozantinib are shown in Table 5 and 6. Dose 
interruptions and/or reductions should be implemented for unacceptable toxicity. Doses 
may be modified at any time while a subject is on treatment. 
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• Dose reductions or interruptions may also occur in the setting of lower grade toxicity if 
the investigator feels it is in the interest of a subject’s safety and will optimize drug 
tolerability. 
• Interruption of cabozantinib treatment for cabozantinib-related AEs may occur at any 
time per investigator discretion. If treatment is interrupted due to related AEs for more 
than 6 weeks, cabozantinib should be discontinued. 
Dose interruptions for reason(s) other than treatment-related AEs (e.g., surgical procedures, 
upper respiratory infection, common cold) can be longer than 6 weeks per the discretion of the 
investigator. 
Guidelines for the management of specific AEs are provided in Section 10.2.2.  
 
Table 5 - Dose Modifications of Cabozantinib 
Assigned Dose 
First Dose Level Reduction 
Second Dose Level Reduction 
60-mg cabozantinib oral qd* 
40-mg cabozantinib oral qd 
20-mg cabozantinib oral qd 
40-mg cabozantinib oral qd 
20-mg cabozantinib oral qd 
No further dose reductions 
20-mg cabozantinib oral qd** No further dose reductions 
No further dose reductions 
*qd, once daily 
**Cabozantinib will be discontinued if a qd dose of 20-mg cabozantinib daily (minimum dose) 
is not tolerated 
 
Table 6  - Dose Modifications of Cabozantinib for Treatment-Related AEs 
CTCAE v.5.0 Grade 
Recommended Guidelines for Management a 
Grade 1 AEs 
Add supportive care as indicated. Continue cabozantinib 
treatment at the current dose level if AE is manageable and 
tolerable. 
Grade 2 AEs which are 
tolerable and are easily 
managed 
 
Grade 2 AEs which are 
intolerable and cannot be 
adequately managed  
Continue cabozantinib treatment at the current dose level with 
supportive care. 
 
 
At the discretion of the investigator, cabozantinib should be 
dose reduced or interrupted. 
Note: It is recommended that dose holds be as brief as possible.  
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Grade 3 AEs (except 
clinically non-relevant 
laboratory abnormalities) 
Cabozantinib should be interrupted unless the toxicity can be 
easily managed with a dose reduction and optimal medical care.  
Note: It is recommended that dose holds be as brief as possible. 
Grade 4 AEs (except 
clinically non-relevant 
laboratory abnormalities) 
Subjects should have cabozantinib interrupted immediately.  
Discontinue cabozantinib unless the following criteria are met:  
• Subject is deriving clear clinical benefit as determined by 
the investigator 
• Toxicity can be managed with a dose reduction following 
recovery to Grade 1 (or baseline) and optimal medical care  
Note: The dose delay and modification criteria for specific medical conditions are provided in 
Section 10.2.2. 
a Study treatment dose adjustment is only needed if the toxicity was deemed related to 
cabozantinib treatment or had an unclear relationship to cabozantinib treatment. 
 
7.2. 
Radiation Therapy 
Subjects will receive planned radiation as part of standard clinical care. The typical pre-
operative radiotherapy dose will range from 5000 – 5040 cGy delivered with conventional 
fractionation (180 – 200 cGy per fraction). Other details of the radiation treatment, such as 
scheduling, are to be completed per institutional standard, at the discretion of the treating 
radiation oncologist. Radiation oncologists seeking further guidance in radiation planning (i.e. 
RTOG Consensus Sarcoma Target Volume Definitions) may refer to Appendix 2. 
7.2.1. 
Simulation 
Subjects will be immobilized in a safe and reproducible position to allow accurate delivery of 
radiotherapy.  Understanding that the anatomic considerations for immobilization may vary 
depending on the location of the tumor, a variety of immobilization devices may be used 
including: vacuum-bags, Alpha Cradles, thermoplastic casts, customized molds.  Aquaplast 
molds are recommended for reliable immobilization of distal extremities (hands or feet). 
Positioning for immobilization will also be chosen to minimize radiation dose to non-target 
critical structures (for instance, a contralateral limb, torso, pelvis, head, etc). 
CT Simulation will be performed for all subjects.  When possible, appropriate diagnostic studies 
will be fused with the simulation CT to aid in target delineation (MRI T1 contrast-enhanced and 
T2 sequences, PET CT).  Administration of IV contrast during simulation is optional at the 
discretion of the treating radiation oncologist.  If IV contrast is administered, the density of the 
contrast should be overridden on the planning scan to provide more accurate dose calculation.  
Alternately a separate non-contrast scan can be obtained and used for dose calculation and 
planning. 
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7.2.2. 
Planning 
Treatment will be delivered using 3D conformal radiotherapy, IMRT, or proton therapy.  CT 
based planning is required. Target expansion guidelines are to follow protocol-defined 
parameters regardless of treatment modality. 
IMRT is the preferred radiotherapy technique and anticipated to be the most likely treatment 
modality for extremity tumors that approximate critical structures (bone, lymphatics) or involve 
a significant portion of the circumference of the extremity (with IMRT utilized to reduce 
lymphedema risk).   
For peripheral tumors that do not approximate critical structures, 3D conformal radiotherapy 
may be appropriate.   
Proton therapy may be utilized for tumors that approximately critical structures that cannot be 
adequately protected using 3D conformal radiotherapy or IMRT.  
Normal structure dose constraints: 
Long bones (i.e. femur, radius, ulna, humerus, etc):  
• Max dose 5500 cGy 
• Mean dose < 3700 cGy.   
• 5000 cGy line should not cover the entire circumference of a long bone unless the tumor 
encases said bone. 
Femoral neck (right or left):   
• Max dose 5000 cGy 
• Mean dose < 4500 cGy 
Every effort should be made to avoid treating the entire circumference of a limb to avoid risk of 
lymphedema. 
Skin:   
• Skin will be defined as a 5mm rind 
• V2000 cGy (volume of skin receiving 2000 cGy) should be < 50% 
• Max dose to the skin surface should be kept below 3000 cGy when possible.   
• However, if the PTV extends close to the skin surface then PTV coverage will be 
prioritized over the skin dose constraint. 
• The use of bolus is discouraged unless it is used to ensure coverage of tumor that 
invades to the surface of the skin (as in fungating tumors). 
Other normal anatomy should follow standard QUANTEC dose constraints. 
7.2.3. 
Prescription Guidelines 
The targets will be specified as: 
• GTV_5000 or GTV_5040: This is the gross tumor seen on CT as well as MRI T1 
contrast enhanced images.  Fusion of MRI and CT is recommended when possible. 
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• CTV_5000 or CTV_5040: This target includes the gross tumor and an additional 
margin to account for microscopic disease.  This is defined as the GTV with a 3 cm 
longitudinal margin and 1.5 cm radial margin.  All edema concerning for tumor 
involvement as identified on T2 weighted MRI should be included in the CTV.  CTV 
borders can be trimmed at anatomic barriers to tumor spread such as bone, the 
edges of a muscle compartment, other fascial planes, or skin surface.   
• PTV_5000 or PTV_5040: This is a 5mm expansion of the CTV to account for setup 
error and organ motion.  The PTV does not extend beyond the skin surface.  Daily 
image guidance (IGRT) through cone beam CT or kilovoltage imaging should be 
performed.  If daily IGRT is not feasible, the use of an expanded PTV margin may be 
utilized on a per-subject basis per approval by the delegated radiation oncologist 
investigator.   
PTV coverage guidelines (5000 cGy in 25 fractions): 
• Minimum dose: 
4650 cGy, and at least 95% of the PTV_5000 receives 4750 cGy 
• Maximum dose:  5650 cGy, and no more than 15% of PTV_5000 receives > 5500 
cGy. 
• If PTV_5000 extends to the skin surface but there is no direct tumor involvement at 
the skin surface, then a PTV eval can be created as a copy of PTV_5000 subtracted 
3mm beneath the skin surface.  PTV eval can then be used to evaluate target 
coverage. 
PTV coverage guidelines (5040 cGy in 28 fractions): 
• Minimum dose: 
4687 cGy, and at least 95% of the PTV_5040 receives 4788 cGy 
• Maximum dose:  5695 cGy, and no more than 15% of the PTV receives > 5544 cGy. 
• If PTV_5040 extends to the skin surface but there is no direct tumor involvement at 
the skin surface, then a PTV eval can be created as a copy of PTV_5040 subtracted 
3mm beneath the skin surface.  PTV eval can then be used to evaluate target 
coverage. 
7.2.4. 
Treatment Delivery 
Treatment will be delivered daily, typically Monday through Friday, over 25-28 fractions. Use of 
bolus is discouraged unless tumor directly involves the overlying skin surface. 
7.2.5. 
Treatment Interruption and Dose Modifications 
Treatment interruptions should be minimized. Any treatment interruption of > 3 days (not 
including holidays or weekends) must be reported to the Sponsor-Investigator. 
7.2.6. 
Quality Assurance 
Subject specific treatment plan QA measurements are required for IMRT and proton treatment 
plans.  Secondary monitor unit calculations are required for all 3D conformal treatment plans. 
All treatment plans for subjects that are not treated at the main study site will be submitted for 
review to the Sponsor-Investigator at least 1 week prior to the subject starting radiotherapy. It 
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is recommended that outside treatment plans are submitted and reviewed as part of study 
eligibility and screening. Review and approval of treatment plans for subjects receiving 
radiotherapy locally must be reviewed and approved by a radiation oncologist sub-investigator 
prior to initiation of radiotherapy.  DICOM plan data is preferred but a printed or electronic 
copy of the plan document is also acceptable. 
 
 
 
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8. 
STUDY DRUG MANAGEMENT  
8.1. 
Description of Study Drugs  
8.1.1. 
Cabozantinib Packaging, Labeling, and Storage 
At the study site, all study medication will be stored at 20°C to 25°C (68°F to 77°F); excursions are 
permitted from 15°C to 30°C (59°F to 86°F) and inventoried in accordance with applicable 
Washington state and federal regulations. 
Subjects will need to be instructed to store the IP at controlled room temperature, away from 
direct sunlight or appliances/items that give off heat and to not store the study drug in a hot, 
unventilated car for a long period of time.  
Cabozantinib tablets are supplied as film coated tablets containing cabozantinib malate 
equivalent to 20 mg of cabozantinib and contain microcrystalline cellulose, lactose anhydrous, 
hydroxypropyl cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate 
and Opadry® yellow. The 20-mg tablets are round. Doses of 40 mg will comprise two 20-mg 
tablets, and doses of 60-mg will comprise of three 20-mg tablets. The components of the tablets 
are listed in the table below. 
Refer to the Pharmacy Manual for details on storage and handling of cabozantinib. 
Table 7 - Cabozantinib Tablet Components and Composition 
Ingredient  
Function 
% w/wa 
Cabozantinib Drug Substance (25% drug load as free base) 
Active 
Ingredient 
31.68 
Microcrystalline Cellulose (Avicel® PH-102) 
Filler 
38.85 
Lactose Anhydrous (60M) 
Filler 
19.42 
Hydroxypropyl Cellulose (EXF) 
Binder 
3.00 
Croscarmellose Sodium (Ac-Di-Sol®) 
Disintegrant 
6.00 
Colloidal Silicon Dioxide 
Glidant 
0.30 
Magnesium Stearate 
Lubricant 
0.75 
Opadry® yellow film coating which includes  
HPMC 2910/Hypromellose 6 cp, titanium dioxide, triacetin, and 
iron oxide yellow 
Film 
Coating 
4.00 
a weight fraction, expressed in percentage; HPMC, hydroxypropyl methylcellulose 
8.1.2. 
Study Treatment Accountability 
The investigator or designee will maintain accurate records of receipt of all study treatment 
including dates of receipt. In addition, accurate records will be kept regarding the date, lot 
number, and how much study treatment is dispensed and used by each subject in the study. 
Reasons for deviation from the expected dispensing regimen must also be recorded. At 
completion of the study, to satisfy regulatory requirements regarding drug accountability, all 
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unused study treatment will be reconciled and destroyed according to applicable state, federal, 
and local regulations. 
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9. 
SAFETY 
9.1. 
Adverse Events and Laboratory Abnormalities 
9.1.1. 
Adverse Events (AEs) 
An AE is any untoward medical occurrence in a subject or clinical trial subject administered a 
medicinal product and which does not necessarily have a causal relationship with this 
treatment. An adverse event can therefore be any unfavorable and unintended sign (e.g. an 
abnormal laboratory finding), symptom, or disease temporarily associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. An adverse 
event can arise from any use of the drug (e.g. off-label use, use in combination with another 
drug) and with any route of administration, formulation, or dose, including an overdose. This 
definition also includes AEs associated with medication errors and uses of the investigational 
product outside what is in the protocol, including misuse and abuse. Pre-existing medical 
conditions that worsen during the study should be recorded as AEs. Abnormal laboratory 
values, ECG findings, or vital signs are to be recorded as AEs if they meet the criteria described 
in this protocol. All untoward events that occur after informed consent through 30 days after 
the decision to discontinue study treatment are to be recorded by the investigational site. This 
requirement includes AEs from unscheduled as well as scheduled visits and includes the new 
onset of or increase in pain during this period. 
Seriousness, severity grade, and relationship to study treatment will be assessed by the 
investigator. Severity grade and adverse event term will be defined by the current version of 
the National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE), 
version 5.0. 
For management of Adverse Events and Serious Adverse Events, refer to Section 10. 
9.1.2. 
Serious Adverse Events (SAEs) 
The SAE definition and reporting requirements are in accordance with the International 
Conference of Harmonisation (ICH) Guideline for Clinical Safety Data Management: Definitions 
and Standards for Expedited Reporting, Topic E2A. 
An SAE is defined as any untoward medical occurrence that at any dose:  
• Result in death; 
• Is life-threatening (i.e., in the opinion of the investigator, the AE places the subject at 
risk of death; it does not include an event that, had it occurred in a more severe form, 
might have caused death); 
• Requires subject hospitalization or results in prolongation of an existing hospitalization; 
o Note: While most hospitalizations necessitate reporting of an SAE, some 
hospitalizations do not require SAE reporting, as follows: elective or previously 
scheduled surgeries or procedures for pre-existing conditions that have not 
worsened after initiation of treatment (e.g., a previously scheduled ventral 
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hernia repair); pre-specified study hospitalizations for observation; or events 
that result in hospital stays of fewer than 24 hours and that do not require 
admission (e.g., an ER visit for hematuria that results in a diagnosis of cystitis and 
discharge home on oral antibiotics).  SAEs must, however, be reported for any 
surgical complication resulting in prolongation of the hospitalization. 
• Results in persistent or significant disability or incapacity: 
o Note: The term “disability” refers to events that result in a substantial disruption 
of a subject’s ability to conduct normal life function. 
• Is a congenital anomaly or birth defect; 
• Is an important medical event (IME):  
o Note: The term “important medical event” refers to an event that, based upon 
appropriate medical judgment, 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 other serious outcomes listed. Examples of 
IMEs include intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias, or convulsions that do not result in 
hospitalization; or development of product dependency or product abuse. 
 
9.1.3. 
Relationships to Study Treatment 
Assessment of the relationship of the AE to the study treatment by the investigator is based on 
the following two definitions: 
• Not Related: A not-related AE is defined as an AE that is not associated with the study 
treatment and is attributable to another cause or there is no evidence to support a 
causal relationship. Unrelated and unlikely related AEs should be documented as not 
related. 
• Related: A related AE is defined as an AE where a causal relationship between the event 
and the study treatment is a reasonable possibility. A reasonable causal relationship is 
meant to convey that there are facts (e.g., evidence such as dechallenge/rechallenge) or 
other clinical arguments to suggest a causal relationship between the AE and study 
treatment. Possibly and probably related AEs should be documented as related. 
9.1.4. 
Serious Adverse Event Reporting 
As soon as an investigator becomes aware of an AE that meets the definition of ‘serious,’ this 
must be documented on an SAE Report Form or in an electronic database and include the 
following:  
(i) 
all SAEs that occur after starting cabozantinib and through 30 days after the decision 
to discontinue study treatment and  
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(ii) 
any SAEs assessed as related to study treatment or study procedures, from the time 
of informed consent, even if the SAE occurs more than 30 days after the decision to 
discontinue study treatment. 
All SAEs that are assessed by the Sponsor-Investigator as related to drug or study procedure 
and all pregnancy/lactation reports regardless of outcome must be sent to Exelixis within one 
(1) business day of the Sponsor-Investigator’s knowledge of the event. The reports must be sent 
to drugsafety@exelixis.com or fax 650-837-7392. 
• The Sponsor-Investigator will perform adequate due diligence regarding obtaining 
follow-up information on incomplete reports. All follow-up information must be sent to 
Exelixis within one (1) business day of the Sponsor-Investigator’s receipt of the new 
information. Upon Exelixis request, the Sponsor-Investigator will query for follow-up 
information. 
9.1.5. 
Regulatory Reporting 
The treating Sub-Investigator or Sponsor-Investigator will assess the expectedness of each 
related SAE. The current cabozantinib Reference Safety Information (Appendix K of the most 
recent approved Investigator Brochure) will be used as the reference document for assessing 
the expectedness of the event regarding cabozantinib. All serious, unexpected, suspected 
adverse drug reactions (SUSARs) will be reported to FDA by the Sponsor-Investigator as 
required by 21 CFR 312.32: 
• These reports are to be filed utilizing the Form FDA 3500A (MedWatch Form). 
• Exelixis, upon review, reserves the right to upgrade the Sponsor-Investigator assessment 
of an SAE for their own safety data and reporting purposes based on Exelixis 
assessment. This assessment will be communicated to the Sponsor-Investigator. 
• The Sponsor-Investigator shall promptly provide all information requested by Exelixis 
regarding all adverse events occurring during the conduct of the study.  
• The Sponsor-Investigator is responsible for complying with all regulatory authority 
reporting requirements for the study that are applicable to the sponsor of a clinical trial. 
The Sponsor-Investigator shall provide a copy of all responses to regulatory agency 
requests, periodic reports, and final study reports to Exelixis within one (1) business day 
of the submission.   
• Exelixis will provide relevant product safety updates and notifications, as necessary.  
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9.2. 
Other Safety Considerations 
9.2.1. 
Laboratory Data 
All laboratory data required by this protocol and any other clinical investigations should be 
reviewed per standard clinical practice. Formal source documentation by the investigator of 
clinical significance for each abnormal laboratory value will not be collected. Grade 1 laboratory 
abnormalities will not be considered an Adverse Event unless a clinical intervention is taken to 
directly treat that lab abnormality, or if that lab abnormality results in a modification, delay, or 
discontinuation of study drug. All lab abnormalities Grade 2 or higher, regardless of clinical 
significance or intervention, will be captured as AE/SAE as appropriate, and recorded on the 
subject-specific adverse event log.   
9.2.2. 
Pregnancy/Lactation Exposure 
If a subject becomes pregnant during the study, she will be taken off study treatment and will 
be followed through the end of her pregnancy. Pregnancy (in subject or partner) or lactation 
exposure, although not an SAE, should be reported to Exelixis. Forms will be provided to the 
study sites upon request. The outcome of a pregnancy (for a subject or for the partner of a 
subject) and the medical condition of any resultant offspring must be reported to Exelixis. Any 
birth defect or congenital anomaly must be reported as an SAE, and any other untoward events 
occurring during the pregnancy must be reported as AEs or SAEs, as appropriate. 
9.2.3. 
Follow-Up of Adverse Events 
Any related SAEs or any AEs assessed as related that led to treatment discontinuation, including 
clinically significant abnormal laboratory values that meet these criteria, ongoing 30 days after 
the decision to discontinue study treatment must be followed until either resolution of the 
event or determination by the investigator that the event has become stable or irreversible. 
This follow-up guidance also applies to related SAEs still ongoing 30 days after the decision to 
discontinue study treatment. This does not apply to subjects who screen-fail. The status of all 
other continuing AEs will be documented as of 30 days after the decision to discontinue study 
treatment. 
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10. 
MANAGEMENT OF TOXICITY AND COMPLICATIONS 
10.1. 
Guidelines for Management of Potential Adverse Events 
Subjects will be monitored for AEs from the time of signing informed consent through 30  days 
after the date of the last dose of cabozantinib treatment. Subjects will be instructed to notify 
their physician immediately at the onset of any AE. Seriousness, severity grade, and relationship 
to study treatment of AEs will be determined by the investigator. AE severity will be graded by 
the investigator in accordance with CTCAE v.5.0.  
Management of severe or intolerable adverse reactions may require temporary dose reduction 
and/or interruption for cabozantinib. 
10.2. 
Cabozantinib Related Toxicity 
10.2.1. 
Dose-Limiting Toxicity 
The most frequent AEs experienced by ≥ 20% of subjects treated with cabozantinib in 
descending order of frequency were diarrhea, fatigue, decreased appetite, nausea, weight 
decreased, PPES, vomiting, constipation, hypertension, dysgeusia, dysphonia, asthenia, and 
dyspnea. For a full description of the safety profile of cabozantinib, refer to the cabozantinib 
Investigator’s Brochure. 
Other medically important but less frequent AEs including arterial thrombotic AEs (e.g., 
transient ischemic attack [TIA], and myocardial infarction [MI]) and venous thrombotic AEs 
(e.g., deep vein thrombosis [DVT] and pulmonary embolism), severe hemorrhagic events, 
proteinuria, wound healing complications, gastrointestinal (GI) perforation, abscesses including 
intra-abdominal and pelvic abscess, GI and non-GI fistula formation, osteonecrosis, and 
reversible posterior leukoencephalopathy syndrome (RPLS). 
Adverse events associated with laboratory abnormalities experienced by ≥ 5% of subjects 
treated with cabozantinib in descending order of frequency were anemia, AST increased, ALT 
increased, hypothyroidism, hypokalemia, hypomagnesemia, thrombocytopenia, hypocalcemia, 
hypophosphatemia, lactate dehydrogenase (LDH) increased, lipase increased, neutropenia, 
hyponatremia, ALP increased, leukopenia, and hyperglycemia. 
Adverse events may occur within the first few weeks during treatment with cabozantinib, as 
cabozantinib is expected to reach steady state exposure at approximately 2 weeks following 
first dose. Events that generally have an early onset include hypocalcemia, hypokalemia, 
thrombocytopenia, hypertension, PPES, abdominal pain, mucosal inflammation, constipation, 
diarrhea, and vomiting. Adverse events should be managed with supportive care at the earliest 
signs of toxicity. Dose reductions and treatment interruptions should be considered. Dose 
reductions are recommended for events that, if persistent, could become serious or intolerable. 
Cabozantinib should be discontinued for the following AEs: visceral perforation or fistula 
formation, severe hemorrhage, serious arterial thromboembolic events, nephrotic syndrome, 
hypertensive emergency, persistent uncontrolled hypertension despite optimal medical 
management, and RPLS. 
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Determination and attribution of DLT are critical for determining the RP2D for this study.  The 
DLT period will include all subjects enrolled to the phase 1 component of the study who receive 
cabozantinib in combination with radiation therapy. The DLT period is defined as beginning on 
C1D8 and continuing until 28 days after completion of concurrent radiation therapy and 
cabozantinib.  Cabozantinib is anticipated to have systemic effects at sites distant from that 
receiving neoadjuvant radiation treatment.  It may also interact loco-regionally at the site of 
radiation administration.  However, as the objective of this study is to assess the impact of the 
cabozantinib/radiotherapy combination, only those effects in the region subject to radiation 
therapy are considered pertinent and will be considered DLT.  
DLT are defined as any Grade 3 or greater AE, occurring in the region subject to radiation 
therapy, at least possibly related (per investigator attribution) to concurrent radiation therapy 
and cabozantinib therapy. Toxicities with a clearly identified and documented alternative 
explanation may be deemed non-DLT. Toxicities which are clearly identified and documented as 
related to cabozantinib therapy only or radiation therapy only may be deemed non-DLT. Only 
toxicities observed in the region subject to radiation therapy will be considered DLT.   
Toxicities that are Grade 3 or greater that meet the following will always be considered DLT: 
1. Occur after the initiation of concurrent cabozantinib/radiation therapy until 28 days 
after completion of radiation therapy; 
a. Involve the region of a subject’s body that is receiving concurrent radiation 
therapy; and  
b. Are of a degree or character inconsistent with anticipated radiation effects. 
Dose modification guidelines are outlined in Table 5, Table 6, and Table 8 for clinically 
significant toxicities that are deemed to have a relation to cabozantinib. Clinically significant 
toxicities that are deemed to have a relationship to radiation therapy only will be managed per 
standard institutional practice, additional information is available in Section 10.3. 
 
 
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10.2.2. 
Adverse Event Management Algorithms 
Table 8 - Management Guidelines for Adverse Events Possibly Related to Cabozantinib 
System/Organ 
Adverse Event 
CTCAE Grade 
v5.0 
Dose modification Algorithm 
Skin/Mucosa 
Palmar-plantar 
Erythrodysesthesia 
Syndrome 
Grade 1 
If PPES is clinically insignificant and tolerable, cabozantinib may be 
continued at current dose, otherwise reduce by one dose level.  
Urea 20% cream twice daily and Clobetasol 0.05% cream once daily to be 
reassessed at least weekly. If PPES does not improve, or worsens after 2 
weeks, follow intervention guidelines for grade 2.  
Grade 2 
Cabozantinib treatment may be continued if PPES is tolerated.  
Cabozantinib should be dose reduced or interrupted if PPES is intolerable.  
Continue urea 20% cream twice daily AND high potency steroid cream 
(e.g., clobetasol 0.05%) once daily and add analgesics (e.g., 
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 cabozantinib treatment until severity decreases to Grade 1 or 0.  
Continue treatment of skin reaction with high potency steroid cream (e.g., 
clobetasol 0.05%) 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. 

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Stomatitis and/or 
Mucositis 
Any Grade 
No change in cabozantinib treatment. Preventive measures may include a 
comprehensive oral examination to identify and treat any potential risk for 
complications before study treatment is initiated. Appropriate correction 
of local factors should be instituted as indicated, such as modification of ill-
fitting dentures and appropriate care of gingivitis. During treatment with 
cabozantinib, good oral hygiene and standard local treatments such as 
non-traumatic and non-irritating cleansing, and oral rinses (e.g., with a 
weak solution of salt and baking soda) should be maintained. Lips should 
be kept moisturized with lip balm. The use of lipstick, lip-gloss, and 
Vaseline should be avoided. 
Local treatment should be instituted at the earliest onset of symptoms. 
Obtain bacterial/viral culture if oral infection is suspected and treat 
infection as clinically indicated. 
Lab Abnormalities 
Proteinuria 
UPC Ratio ≤ 1 
mg/mg 
(≤ 113.1 
mg/mmol) 
No change in cabozantinib treatment or monitoring 
For UPC Ratio 
>1 and <3.5 
mg/mg 
(>113.1 and 
<395.9 
mg/mmol) 
Consider confirming with a 24-h protein assessment within 7 days 
No change in cabozantinib treatment required if UPCR ≤ 2 mg/mg or urine 
protein ≤ 2 g/24 h on 24-h urine collection. 
Dose reduce or interrupt cabozantinib treatment if UPCR > 2 mg/mg on 
repeat UPCR testing or urine protein >2 g/24 h on 24-h urine collection.  
Continue cabozantinib on a reduced dose if UPCR decreases to < 2 mg/mg.  

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Consider interrupting cabozantinib treatment if UPCR remains > 2 mg/mg 
despite a dose reduction until UPCR decreases to < 2 mg/mg. Restart 
cabozantinib treatment at a reduced dose after a dose interruption. 
Repeat UPCR within 7 days and once per week. If UPCR < 1 mg/mg on 2 
consecutive readings, UPCR monitoring can revert to protocol-specific 
times. (Second reading is confirmatory and can be done within 1 week of 
first reading.)  
If UPCR remains > 1 mg/mg and < 2 mg/mg for 1 month or is determined 
to be stable (< 20% change) for 1 month, check urine protein/creatinine 
per protocol or as clinically indicated. 
UPC Ratio ≥ 
3.5 mg/mg 
(≥ 395.9 
mg/mmol) 
Interrupt cabozantinib treatment pending repeat UPCR within 7 days 
and/or 24 h urine protein.  
If ≥ 3.5 mg/mg on repeat UPCR, continue to interrupt cabozantinib 
treatment and check UPCR every 7 days. If UPCR decreases to < 2 mg/mg, 
restart cabozantinib treatment at a reduced dose and monitoring of urine 
protein/creatinine should continue weekly until the UPCR decreases to < 1 
mg/mg.  
If UPCR remains > 1 mg/mg and < 2 mg/mg for 1 month or is determined 
to be stable (< 20% change) for 1 month, check urine protein/creatinine 
per protocol or as clinically indicated. 
Nephrotic 
Syndrome 
Discontinue cabozantinib. 

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Elevated 
Aminotransferases 
(ALT/AST) 
Grade 3 or 4 
Interrupt cabozantinib treatment if ALT/AST elevations are also 
accompanied by progressive elevation of total bilirubin and/or elevations 
of coagulation tests.  
Transaminases should be monitored weekly if elevated to Grade 3+, in 
combination with total bilirubin and coagulation tests.  
Cabozantinib should be discontinued if hepatic dysfunction does not 
resolve to Grade 1 or better within two weeks of interrupting therapy.  
Elevations >3 × ULN of ALT or AST concurrent with >2 × ULN total bilirubin 
without other explanation (such as initial findings of cholestasis and 
obstructive disease, viral hepatitis, pre-existing or acute liver disease, or 
another drug capable of causing the observed injury) can indicate drug-
induced liver injury (DILI) and study drug should be permanently 
discontinued.  
Cardiac Toxicity 
Hypertension 
Grade 2 
(Systolic 140-
159 or 
Optimize antihypertensive medications by adding new or additional 
antihypertensive medications and/or increase dose of existing 
medications. 

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Diastolic 90-
99) 
Reduce cabozantinib treatment by one dose level if optimal 
antihypertensive therapy (usually to include 3 agents) does not result in BP 
<150 mm Hg systolic or <100 mm Hg diastolic 
If subject is symptomatic interrupt cabozantinib treatment 
Grade 3 
(Systolic ≥ 160 
or Diastolic ≥ 
100) 
Reduce cabozantinib by one dose level or interrupt cabozantinib treatment 
per investigator discretion 
Add new or additional anti-hypertensive medications and/or increase dose 
of existing medications and monitor subject closely for hypotension. If 
optimized antihypertensive therapy (usually to include 3 agents) does not 
result in BP < 150 mm Hg systolic or < 100 mm Hg diastolic, cabozantinib 
treatment should be dose reduced further or interrupted 
Cabozantinib treatment should be dose interrupted if upper limits of 
systolic BP (≥ 160 mm Hg) are sustained and not adequately manageable 
or if systolic BP is > 180 mm Hg or diastolic BP > 110 mm Hg, or if subject is 
symptomatic 
Re-start cabozantinib treatment at the most tolerable dose only if BP falls 
to and is sustained at < 150 mm Hg systolic and < 100 mm Hg diastolic 
Grade 4 
Permanently discontinue cabozantinib 
Arterial 
Thromboembolic 
Events 
Any Grade 
Discontinue cabozantinib. 
 
ECG QTc (QT 
Corrected) 
Grade 3 
Perform two additional ECGs not less than 3 minutes apart, within 30 
minutes after the initial ECG. If the average of the QTcF of the three ECGs 

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Interval 
Prolonged 
is >500ms, interrupt cabozantinib treatment. Symptomatic subjects should 
be hospitalized for a thorough cardiology evaluation.  
Regardless of symptom presentation, check magnesium, potassium, and 
calcium levels, correcting as clinically indicated. Repeat ECG triplicates 
hourly until average QTcF is <500ms, or otherwise determined by 
consultation with cardiologist or appropriate expert.  
Cabozantinib treatment should be interrupted for a minimum of 1 week 
following the return of the QTcF to <500ms. Cabozantinib treatment may 
be resumed at one dose level reduction. Following reinitiation of study 
treatment, ECGs must be repeated weekly for 2 weeks, then every 2 weeks 
for 1 month, then may return to the regularly defined timepoints.  
If there are development of prolonged symptoms that are the result of QT 
interval prolongation or if a recurrence of QTcF prolongation occurs after 
reinitiation of treatment at a reduced dose, cabozantinib should be 
permanently discontinued.  
Grade 4 
Discontinue cabozantinib. 
Gastrointestinal 
Disorders 
Diarrhea 
Grade 1-2 
lasting < 48h 
Continue with study treatment and consider dose reduction 
Initiate treatment with an antidiarrheal agent (e.g., loperamide 4 mg 
followed by 2 mg after each episode of diarrhea [maximum: 16 mg 
loperamide per day]) 
Dietary modifications (e.g., small lactose-free meals, bananas and rice) 
Intake of isotonic fluids (1-1.5 L/day) 
Re-assess after 24 hours: 

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• Diarrhea resolving to baseline bowel habits: gradually add solid 
foods and discontinue or decrease antidiarrheal treatment after 
12 h diarrhea-free interval 
• Diarrhea not resolving: Continue/resume antidiarrheal treatment 
and hold cabozantinib therapy until diarrhea resolves to Grade 1 or 
Baseline 
Grade 2 lasting 
>48h, Grade 3 
Interrupt study treatment 
Rule out infection (e.g., stool sample for culture) 
Administer antibiotics as needed (e.g., if fever or Grade 3-4 neutropenia 
persists > 24 h) 
Administer fluids (1-1.5 L/day orally or IV, as appropriate) for hydration or 
to correct electrolyte abnormalities 
For Grade 3-4 or complicated lower grade diarrhea consider hospitalization 
and IV hydration 
Diarrhea resolving to baseline bowel habits or Grade ≤ 1: consider 
restarting study treatment at reduced dose 
Diarrhea not resolving: Start and or continue antidiarrheal treatment (e.g., 
loperamide 4 mg followed by 2 mg after each episode of diarrhea 
[maximum: 16 mg loperamide per day]). Consider starting second line 
antidiarrheal or referral to gastroenterologist 
Grade 4 
Permanently discontinue cabozantinib 
Fistula, 
perforations, 
bowel 
Any Grade 
For any grade perforation of any organ, GI leak, or any fistula, discontinue 
cabozantinib. 

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obstruction, 
intra-abdominal 
and pelvic 
abscesses 
For any grade bowel obstruction requiring medical intervention, delay 
cabozantinib until obstruction resolves completely, and then resume 
cabozantinib at the previous dose. For obstruction requiring surgery delay 
cabozantinib until full recovery from surgery, then resume cabozantinib at 
the previous dose. 
Other 
Reversible Posterior 
Leukoencephalopathy 
Syndrome 
Any Grade 
Permanently discontinue cabozantinib 
Nervous System 
Disorders (Other) 
Any Grade 
Cabozantinib appears to represent minimal risk of adverse neurological 
effects based on nonclinical Good Laboratory Practice (GLP)-compliant 
toxicology studies. Dysphonia, dysgeusia, headache, dizziness, confusional 
state, convulsion, depression, memory impairment, hypoesthesia, 
peripheral neuropathy, insomnia, ataxia, and encephalopathy have been 
observed in clinical studies with cabozantinib. The development of any 
new or progressive, unexplained neurological symptoms should be 
assessed for underlying causes. 
Non-CNS, Non-
Pulmonary 
bleeding 
Grade 2  
Delay cabozantinib until ≤ grade 1, then resume with one dose level 
reduction. 
Grade 3 or 4 
Permanently discontinue cabozantinib 
Fistula, 
perforations, 
bowel 
obstruction, or 
wound 
dehiscence 
Any Grade 
For any grade perforation of any organ, GI leak, or any fistula, discontinue 
cabozantinib. 
For any grade bowel obstruction requiring medical intervention, delay 
cabozantinib until obstruction resolves completely, and then resume 
cabozantinib at the previous dose. For obstruction requiring surgery delay 

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cabozantinib until full recovery from surgery, then resume cabozantinib at 
the previous dose. 
For wound dehiscence requiring medical or surgical intervention 
discontinue cabozantinib. 
Complications from radiation therapy especially of the thoracic cavity 
including mediastinum have been identified as a possible predisposing risk 
factor for non-GI fistula formation in subjects undergoing treatment with 
VEGF pathway inhibitors. 
Discontinue cabozantinib and initiate appropriate management in subjects 
who have been diagnosed with a non-GI fistula. 
Wound healing 
and surgery 
Any Grade 
Cabozantinib has the potential to cause wound healing complications and 
wound dehiscence which may even occur long after a wound has been 
considered healed. Therefore, surgical and traumatic wounds must not 
only be completely healed prior to starting cabozantinib treatment but 
must also be monitored for wound dehiscence, wound infection and other 
signs of impaired wound healing while the subject is being treated with 
cabozantinib. If dehiscence occurs, cabozantinib treatment should not be 
restarted until complete healing has taken place.  
Treatment with cabozantinib should be stopped at least 28 days prior to 
scheduled surgery. The decision to resume treatment with cabozantinib 
after surgery should be based on clinical judgment of adequate wound 
healing. 
Hemorrhage 
Any Grade 
Hemorrhagic events, including serious and sometimes fatal events, have 
been reported with cabozantinib. Subjects should be monitored for 
bleeding events with serial complete blood counts and physical 

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examination while on study. The risk of hemorrhage in cabozantinib-
treated subjects with brain metastases has not been thoroughly analyzed. 
Subjects enrolled with treated and stable brain metastases should be 
monitored with a high index of suspicion if symptoms that could be due to 
a CNS hemorrhage occur. 
Cabozantinib should be discontinued in subjects with serious and life-
threatening bleeding events or recent hemoptysis (≥ 2.5 mL of red blood). 
Thromboembolic 
event 
Any Grade 
Subjects who develop a pulmonary embolism and/or DVT should have 
study treatment interrupted until therapeutic anticoagulation is 
established.  
Treatment with cabozantinib may be resumed in subjects with pulmonary 
embolism or DVT if it is determined that the event is uncomplicated and 
that the subject is deriving clinical benefit from cabozantinib treatment 
and that anticoagulation does not place them at a significant risk that 
outweighs the benefit of resuming treatment. 
Low molecular weight heparins are the preferred management for 
thrombotic events. 
Oral anticoagulants (e.g., warfarin or other coumarin-related agents, direct 
thrombin or direct FXa inhibitors, or antiplatelet agents, or chronic use of 
aspirin above low dose levels for cardioprotection per local applicable 
guidelines) are not allowed. 
Further treatment with cabozantinib should be discontinued in subjects 
who develop an acute MI, cerebral infarction, or any other clinically 
significant arterial thromboembolic complication. 

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Osteonecrosis 
Any Grade 
Osteonecrosis of the jaw (ONJ) occurred in <1% of subjects treated with 
cabozantinib. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone 
erosion, tooth or periodontal infection, toothache, gingival ulceration or 
erosion, persistent jaw pain or slow healing of the mouth or jaw after 
dental surgery.  
Perform an oral examination prior to initiation of cabozantinib and 
periodically during cabozantinib treatment. Advise subjects regarding good 
oral hygiene practices. Withhold cabozantinib treatment for at least 28 
days prior to scheduled dental surgery or invasive dental procedures, if 
possible. Withhold cabozantinib for development of ONJ until complete 
resolution.  
 
Infections and/or 
Infestations 
Any Grade 
Infections are commonly observed in cancer subjects. Predisposing risk 
factor include a decreased immune status (e.g., after myelosuppressive 
anticancer therapies, splenectomy), destructive growth of the underlying 
malignancy including bone marrow infiltration with suppression of normal 
hematopoiesis, as well as the presence of IV devices.  
Infections and abscesses should be treated with appropriate local care and 
systemic therapy. Cabozantinib should be interrupted until adequate 
healing has taken place. 
Blood and 
Lymphatic System 
Disorders 
Any Grade 
Hematological toxicities (i.e., neutropenia and thrombocytopenia) and 
associated complications have been observed after administration of 
cabozantinib and may be managed with dose interruptions and/or dose 
reductions. Subjects with hematologic toxicities may require additional or 
more frequent laboratory tests according to institutional guidelines. 

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Dose reductions or dose interruptions for hematological toxicities are not 
mandated but can be applied as clinically indicated. Supportive care for 
thrombocytopenia or anemia, such as transfusions, may be managed 
according to institutional guidelines. The use of colony-stimulating growth 
factors should be considered. Febrile neutropenia or evidence of infection 
associated with neutropenia must be assessed immediately and treated 
appropriately and in a timely manner according to institutional guidelines. 
Fatigue 
Any Grade 
Common causes of fatigue, such as anemia, deconditioning, emotional 
distress (depression and/or anxiety), poor nutrition, dehydration, sleep 
disturbance, and hypothyroidism should be ruled out and treated 
according to standard of care. Pharmacological management should be 
considered after disease specific morbidities have been excluded when not 
prohibited. 
Weight Loss 
Any Grade 
Anorexia and weight loss should be managed according to local standard 
of care including nutritional support. Pharmacologic therapy should be 
considered for appetite enhancement when not prohibited by a protocol. 
Electrolyte 
Disorders 
Any Grade 
Serum electrolyte disorders including hyponatremia, hypokalemia, 
hypomagnesemia, and hypophosphatemia have been reported during 
treatment with cabozantinib, and serum electrolyte levels should be 
monitored frequently while receiving cabozantinib. Clinically relevant 
electrolyte disorders should be managed according to the dose 
modification guidelines as clinically indicated. Standard clinical practice 
guidelines should be used for management of electrolyte disorders and 
may include oral or intravenous replacement. 

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Endocrine 
Disorders 
Any Grade 
Treatment-emergent elevation of thyroid-stimulating hormone (TSH) has 
been observed with cabozantinib treatment. Currently available data are 
insufficient to determine the mechanism of thyroid function test 
alterations and its clinical relevance. Management of thyroid dysfunction 
(e.g., symptomatic hypothyroidism) should follow accepted clinical 
practice guidelines. 
Angioedema 
Any Grade 
Angioedema should be managed according to standard practice. The 
subject should be observed until symptoms resolve, with attention to 
maintaining an open airway. 
Other Non-
Hematologic 
Grade 3 or 4 
Toxicity 
Grade 3 or 4 
For other grade 3 or 4 non-hematologic toxicity not described above, 
(excluding nausea, vomiting, and diarrhea; unless refractory to anti-
emetics and/or antidiarrheals) and considered at least possibly related to 
treatment, delay cabozantinib treatment until toxicity improves to ≤ grade 
1, then resume treatment with one dose level reduction. 

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10.2.3. 
Cabozantinib Dose Reinstitution and Reescalation 
If the subject recovers from his or her toxicities to CTCAE v.5.0 Grade ≤ 1 or to the baseline 
value (or lower) and the toxicity was unrelated to study treatment, then study treatment may 
be restarted with no change in dose.  
If the subject recovers from his or her toxicities to Grade ≤ 1 or to the baseline value (or lower) 
the toxicity was deemed possibly related to study treatment, then study treatment may be 
restarted as outlined in Table 5 and 6.  
Subjects receiving a dose of 20 mg daily may be restarted at the same dose if deemed safe at 
the discretion of the Sponsor-Investigator or treating Sub-Investigator. Subjects unable to 
tolerate a dose of 20 mg daily should discontinue study treatment. 
10.2.4. 
Dose re-escalation is not permitted. Overdose  
Any overdose, or study drug administration error that results in an AE, even if it does not meet 
the definition of serious, requires reporting within one (1) business day to Exelixis. 
10.3. 
Radiation Therapy Related Toxicity 
The expected toxicities related to radiation therapy may vary in relation to the site of 
irradiation. The most commonly observed toxicities include fatigue (Grade 3), and skin toxicities 
(Grade 3) such as rash, color changes, burning, blistering, or desquamation. Skin toxicities 
should be managed by radiation-oncology staff utilizing standard of care protocols.  
The radiation oncologist may list expected toxicities for a given radiation treatment prior to 
administration of radiation treatment in the subject’s medical record. Strict prospective quality 
assurance of all radiation plans will be performed prior to initiation of radiotherapy, per 
institutional standards, to minimize risk of serious toxicity. 
Toxicities of radiation should be treated according to standard institutional practices, including 
the prescription of steroids, if appropriate. Subjects will continue study treatment if steroids 
are used to treat radiation-associated toxicity. 
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11. 
CONCOMITANT MEDICATIONS AND PROCEDURES 
All concomitant treatments, including blood and blood products, must be reported on the eCRF. 
Throughout the study, investigators may prescribe any concomitant medications or treatments 
deemed necessary to provide adequate supportive care except for those listed in Section 11.2. 
Concomitant therapies are to be collected from enrollment/randomization through the EOT Visit. 
Therapy name including indication, dose, frequency, route, start date and stop date will be 
recorded on each subject’s CRF(s). 
11.1. 
Permitted Medications and Procedures 
The investigator must be informed as soon as possible about any medication taken from the time 
of screening until the 30 Day Follow-Up visit. Any concomitant medication(s), including herbal 
preparations, taken during the study will be recorded in the CRF. The minimum requirement is 
that drug name, dose, and the dates of administration are to be recorded. Additionally, a 
complete list of all prior cancer therapies will be recorded in the CRF. 
Subjects should receive full supportive care during the study, including transfusions of blood and 
blood products, and treatment with antibiotics, anti-emetics, anti-diarrheas, and analgesics, and 
other care as deemed appropriate, and in accordance with their institutional guidelines. WBC 
growth factors may be administered at the discretion of the investigator, consistent with 
institutional guidelines. 
Extreme precaution must be taken with contraceptives (either combined or progesterone only), 
as it is not known if there is the potential of inhibition/induction of enzymes that affect the 
metabolism of estrogens and/or progestins.  
• Antiemetics and antidiarrheal medications are allowed prophylactically according to 
standard clinical practice if clinically indicated.  
• Granulocyte colony-stimulating factors (G-CSF or GM-CSF) are allowed if used per clinical 
guidelines (e.g., ASCO or ESMO guidelines).  
• Bisphosphonates can be used to control bone loss or hypocalcemia if the benefit 
outweighs the risk per the investigator’s discretion. 
• Transfusions and hormone replacement should be utilized as indicated by standard 
clinical practice. 
• Individualized anticoagulation therapy with heparin is allowed if it can be provided safely 
and effectively under the following circumstances:  
o Low dose heparins for prophylactic use are allowed if clinically indicated and the 
benefit outweighs the risk per the investigator’s discretion.  
o Therapeutic doses of LMWH at the time of the first dose of study treatment are 
allowed if the subject has no evidence of brain metastasis, has been on a stable dose 
of LMWH for at least 6 weeks, and has had no complications from a thromboembolic 
event or the anticoagulation regimen.  
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o Therapeutic doses of LMWH after first dose of study treatment are allowed if 
clinically indicated (e.g., for the treatment of deep venous thrombosis), and the 
benefit outweighs the risk per the investigator’s discretion. For management of 
thromboembolic complications while on study, refer to Section 10.2.2.  
o Accepted clinical guidelines regarding appropriate management while receiving 
anticoagulation therapy with heparins must be followed. This includes, but is not 
limited to, subject education regarding potential adverse drug reactions, monitoring 
laboratory parameters, dose adjustments (e.g., due to kidney dysfunction).  
o For restrictions on oral anticoagulants see Section 11.2. 
Potential drug interactions with cabozantinib are summarized in Section 11.3. 
 
11.2. 
Prohibited Medications and Procedures 
The use of certain medications, and illicit drugs within 5 half-lives or 28 days, whichever is shorter 
prior to the first dose of study drug and for the duration of the study will not be allowed. If a 
prohibited medication is required for single use (such as for a procedure) while study drug is held, 
the Sponsor-Investigator and Exelixis can approve such use. 
The following therapies are prohibited until study treatment has been permanently 
discontinued: 
• Any investigational agent or investigational medical device. 
• Oral anticoagulants (e.g., warfarin or other coumarin-related agents, direct thrombin or 
direct FXa inhibitors, or antiplatelet agents such as clopidogrel, or chronic use of aspirin 
above low dose levels for cardioprotection per local applicable guidelines). 
• Any non-protocol systemic anticancer treatment (e.g., chemotherapy, immunotherapy, 
radionuclides, drugs or herbal products used specifically for the treatment of the cancer 
under investigation). 
The following therapies should be avoided until study treatment has been permanently 
discontinued or until otherwise specified: 
• Erythropoietic stimulating agents (e.g., epoetin alfa and darbepoetin alfa) should not be 
used based on a report of increased risk of tumor recurrence/progression associated 
with erythropoietin. 
• Concomitant medications that are known to prolong the QTc interval should be avoided 
in subjects who receive cabozantinib until they have permanently discontinued 
cabozantinib treatment (refer to http://www.qtdrugs.org for a list of drugs which have 
the potential to prolong the QTc interval). 
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• Chronic co-administration of cabozantinib with strong inducers of the CYP3A4 family 
(e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. 
John’s Wort) may significantly decrease cabozantinib concentrations and should be 
avoided. Selection of alternate concomitant medications with no or minimal CYP3A4 
enzyme induction potential is recommended.  
• Caution must be used when discontinuing treatment with a strong CYP3A4 inducer in a 
subject who has been concurrently receiving a stable dose of cabozantinib, as this could 
significantly increase the exposure to cabozantinib.  
• Co-administration of cabozantinib with strong inhibitors of the CYP3A4 family 
(e.g., boceprevir, conivaptan, posaconazole, ketoconazole, itraconazole, clarithromycin, 
atazanavir, indinavir, nefazodone, nelfinavir, saquinavir, ritonavir, lopinavir, telaprevir, 
telithromycin, and voriconazole) may increase cabozantinib concentrations and should 
be avoided. Grapefruit, star fruit, and Seville oranges may also increase plasma 
concentrations of cabozantinib and should be avoided. 
Additional information on potential drug interactions with cabozantinib is provided in Section 
11.3. 
11.3. 
Potential Drug Interactions with Cabozantinib 
Cytochrome P450: Data from a clinical drug interaction study (Study XL184-008) show that 
clinically relevant steady-state concentrations of cabozantinib appear to have no marked effect 
on the area under the plasma concentration-vs-time curve (AUC) of co-administered 
rosiglitazone, a CYP2C8 substrate. Therefore, cabozantinib is not anticipated to markedly inhibit 
CYP2C8 in the clinic, and by inference, is not anticipated to markedly inhibit other CYP450 
isozymes that have lower [I]/Ki values compared to CYP2C8 (i.e., CYP2C9, CYP2C19, CYP2D6, 
CYP1A2, and CYP3A4). In vitro data indicate that cabozantinib is unlikely to induce cytochrome 
P450 enzymes, except for possible induction of CYP1A1 at high cabozantinib concentrations 
(30 μM).  
Cabozantinib is a CYP3A4 substrate and a weak substrate for CYP2C9 (but not a CYP2D6, 
CYP2C8, CYP2C19, CYP2B6, or CYP1A2 substrate), based on data from in vitro studies. Results 
from a clinical pharmacology study, XL184-006, showed that concurrent administration of 
cabozantinib with the strong CYP3A4 inducer, rifampin, resulted in an approximately 77% 
reduction in cabozantinib exposure (AUC values) after a single dose of cabozantinib in healthy 
volunteers. Chronic co-administration of cabozantinib with strong inducers of the CYP3A4 
family (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. 
John’s Wort) may significantly decrease cabozantinib concentrations. The chronic use of strong 
CYP3A4 inducers should be avoided. Other drugs that induce CYP3A4 should be used with 
caution because these drugs have the potential to decrease exposure (AUC) to cabozantinib. 
Selection of alternate concomitant medications with no or minimal CYP3A4 enzyme induction 
potential is recommended.  
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Results from a clinical pharmacology study, XL184-007, showed that concurrent administration 
of cabozantinib with the strong CYP3A4 inhibitor, ketoconazole, resulted in a 38% increase in 
the cabozantinib exposure (AUC values) after a single dose of cabozantinib in healthy 
volunteers. Co-administration of cabozantinib with strong inhibitors of the CYP3A4 family 
(e.g., boceprevir, conivaptan, posaconazole, ketoconazole, itraconazole, clarithromycin, 
atazanavir, indinavir, nefazodone, nelfinavir, saquinavir, ritonavir, lopinavir, telaprevir, 
telithromycin, and voriconazole) may increase cabozantinib concentrations. Grapefruit, star 
fruit and Seville oranges may also increase plasma concentrations of cabozantinib and should 
be avoided. Strong CYP3A4 inhibitors should be avoided and other drugs that inhibit CYP3A4 
should be used with caution because these drugs have the potential to increase exposure (AUC) 
to cabozantinib. Selection of alternate concomitant medications with no or minimal CYP3A4 
enzyme inhibition potential is recommended.  
Please refer to the drug interaction tables at the following websites for lists of substrates, 
inducers, and inhibitors of selected CYP450 isozyme pathways: 
Http://medicine.iupui.edu/clinpharm/ddis/table.aspx 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInterac
tionsLabeling/ucm080499.htm).  
Protein Binding: Cabozantinib is highly bound (≥ 99.7%) to human plasma proteins. Therefore, 
highly protein bound drugs should be used with caution with cabozantinib because there is a 
potential displacement interaction that could increase free concentrations of cabozantinib 
and/or a co-administered highly protein-bound drug (and a corresponding increase in 
pharmacologic effect). 
Other Interactions: Food may increase exposure levels of cabozantinib by 57%, fasting 
recommendations should be followed. In vitro data suggest that cabozantinib is unlikely to be a 
substrate for P-glycoprotein, but it does appear to have the potential to inhibit the P-
glycoprotein transport activity. Therefore, cabozantinib may have the potential to increase 
plasma concentrations of co-administered substrates of P-glycoprotein. Additional details 
related to these overall conclusions can be found in the investigator brochure. 
Administration of the proton pump inhibitor (PPI) esomeprazole resulted in no clinically-
relevant effect on cabozantinib plasma PK in healthy volunteers. Therefore, concomitant use of 
gastric pH modifying agents (i.e., PPIs, H2 receptor antagonists, and antacids) is not 
contraindicated in subjects administered cabozantinib. 
Additional details regarding potential drug interactions with cabozantinib can be found in the 
investigator brochure. 
Cabozantinib was shown to be a substrate of drug transporter MRP2 in an in vitro assay. 
Administration of MRP2 inhibitors to subjects may result in increases in cabozantinib plasma 
concentrations. 
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12. 
STATISTICAL CONSIDERATIONS 
12.1. 
Safety Analysis 
The safety analysis set includes all treated subjects. 
Safety and tolerability will be monitored through continuous reporting of treatment-emergent 
and TRAEs, AEs of special interest, laboratory abnormalities, and incidence of subjects 
experiencing dose modifications, dose delay/dose not given, dose interruptions, and/or 
premature discontinuation of IP due to an AE. All AEs will be recorded by the investigator from 
the time the subject signs informed consent until 30 days after the last dose of IP. Adverse events 
will be graded by NCI CTCAE v5.0. 
Physical examination, vital signs, laboratory assessments (e.g., serum chemistry, hematology), 
and ECOG performance status will be monitored. All SAEs (regardless of relationship to IP) will be 
followed until resolution or sequelae. Local laboratory analysis will be performed as per study 
schedule. 
12.2. 
Efficacy Analysis  
Assessment of the primary efficacy analysis will take place in real time.  Based on anticipated 
accrual of 40 evaluable subjects, if 9 or more have relapsed or died due to any cause (unless 
clearly documented as unrelated to investigational diagnosis, e.g., car accident) at or before one 
year after cabozantinib initiation, then the study will be closed to further accrual, and data will 
simply be collected on the remaining subjects, as specified in the protocol. 
12.3. 
Exploratory Analysis 
Appropriate specimens will be collected in anticipation of the exploratory/correlative studies.  
Analysis will be undertaken once provision for conduct of planned analyses is made. 
12.4. 
Sample Size Considerations 
Phase 1: up to 12 subjects to identify the MTD, but the MTD may be reached with as few as 5 
subjects.  
Phase 2: For sample size determination, we assume the following: 
• Null hypothesis: 1-yr relapse-free survival (local and distant) =75% 
• Alternative hypothesis: 1-yr relapse-free survival (local and distant) =90% 
• Alpha=0.1 (one-sided).  
• Beta=0.1 (power=90%) 
Total accrual=40 evaluable subjects. 
Anticipate accrual of 6 evaluable subjects from phase I component of study. Therefore, 34 
evaluable subjects to accrue in phase II portion of study. Subjects who withdraw for reasons other 
than toxicity during the DLT Period will be determined to be not evaluable and will be replaced. 
Subjects are evaluated for efficacy assessment if they receive at least one dose of cabozantinib 
in combination with neoadjuvant radiation therapy.  
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Assuming a 10% drop-out/non-evaluable rate, 44 total subjects would be accrued to the efficacy 
component for the study to yield 40 evaluable subjects. 
From the perspective of efficacy, this study is intended as a screening study of activity.  Thus, 
avoiding a type II error (rejecting the proposed regimen as inactive, when it is an active regimen) 
is a major consideration.  This study is not intended to provide definitive evidence of activity.  
Therefore, a type I error (false positive) is not considered as critical.  For these reasons, we have 
chosen to increase the power of the study to 90% (minimizing type II errors), while relaxing 
constraints regarding type I.  Specifically, we use a one-sided alpha of 0.10 for rejection of the 
null hypothesis.  Use of a one-sided value is justified based on the high efficacy for local control 
of soft tissue sarcoma provided by the combination of surgery and neoadjuvant radiation therapy 
(~90%).  It is not anticipated that distant disease control would be worsened by addition of 
cabozantinib to neoadjuvant radiation therapy. 
An early stopping rule for accrual to the efficacy component of the study is to be undertaken.  If 
9 (nine) or more evaluable subjects are found to have died or demonstrated disease recurrence 
at or before 1 (one) year after cabozantinib initiation, then the efficacy component of the study 
will be discontinued.  This assumes of a binomial probability for the primary endpoint, with a 
target probability of 0.90 for evaluable subjects to be alive and disease-free at one-year after 
initiation of cabozantinib therapy.  When 9 subjects demonstrate failure with respect to the 
primary endpoint (disease recurrence or death from any cause), then the upper bound of the 
95% confidence interval for the binomial probability distribution would no longer encompass the 
target probability of 0.90 (31/40=0.775, 95%CI:0.62-0.89).  At this point, the study would be 
considered negative with respect to the primary endpoint, and further accrual will be 
discontinued. 
12.5. 
Primary Analysis 
This will occur once all data for primary and secondary endpoints is collected. 
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13. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY 
13.1. 
Discontinuation from Investigational Product or Study 
Subjects may discontinue study treatment or withdraw their consent to participate in the study 
at any time without prejudice. The investigator may withdraw a subject from study treatment 
or from the study if, in his or her clinical judgment, it is in the best interest of the subject or if 
the subject cannot comply with the protocol.  
In addition, any of the following conditions require discontinuation of the subject from study 
treatment: 
• An AE or intercurrent illness that in the opinion of the investigator warrants the 
subject’s withdrawal from study treatment; 
• The investigator believes it is not in the best interest of the subject to continue on study 
• Specific conditions described in the Management of Adverse Events Section 10.2.2; 
• Necessity for treatment with other anticancer treatment prohibited by protocol; 
• Sexually active subjects who refuse to use medically accepted barrier methods of 
contraception (e.g., male condom, female condom) during the study and for 4 months 
after discontinuation of study treatment; 
• Women who become pregnant or are breastfeeding; 
• If the subject does not recover from his or her toxicities to tolerable Grade ≤ 2 within 6 
weeks, the subject will have study treatment discontinued unless there is unequivocal 
evidence that the subject is benefitting. In this situation, a subject may be able to restart 
therapy with a dose reduction upon resolution of the toxicity and with agreement of the 
principal investigator; 
• Request by regulatory agencies for termination of treatment of an individual subject or 
all subjects under the protocol; 
• Significant noncompliance with the protocol schedule in the opinion of the investigator; 
• Subjects who cannot tolerate the minimum protocol-specified dose of study treatment 
will have study treatment discontinued; 
• Progressive disease (PD) or the subject no longer experiences clinical benefit as 
determined by the investigator 
13.2. 
Sponsor-Investigator Decision to Withdraw or Terminate Subject’s Participation 
Prior to Study Completion 
The Sponsor-Investigator can decide to withdraw a subject(s) from Investigational Product 
and/or other protocol-required therapies, protocol procedures, or the study as a whole at any 
time prior to study completion.    
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Subjects may be eligible for continued treatment with Exelixis’ Investigational Product and/or 
other protocol-required therapies by a separate protocol or as provided for by the local country’s 
regulatory mechanism. 
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14. 
REGULATORY OBLIGATIONS 
14.1. 
Informed Consent 
The Sponsor-Investigator is responsible for preparing the informed consent document to be used 
at the study site. Updates to the template are to be communicated formally in writing from the 
investigator to Exelixis. The written informed consent document is to be prepared in the 
language(s) of the potential subject population. 
Before a subject’s participation in the clinical study, the investigator is responsible for obtaining 
written informed consent from the subject after adequate explanation of the aims, methods, 
anticipated benefits, and potential hazards of the study and before any protocol-specific 
screening procedures or the IP is administered.  
The acquisition of informed consent and the subject’s agreement or refusal of his/her notification 
of the primary care physician is to be documented in the subject’s medical records, and the 
informed consent form to be signed and personally dated by the subject or a legally acceptable 
representative and by the person who conducted the informed consent discussion. The original 
signed informed consent form is to be retained in accordance with institutional policy, and a copy 
of the signed consent form is to be provided to the subject or legally acceptable representative. 
If a potential subject is illiterate or visually impaired and does not have a legally acceptable 
representative, the investigator must provide an impartial witness to read the informed consent 
form to the subject and must allow for questions. Thereafter, both the subject and the witness 
must sign the informed consent form to attest that informed consent was freely given and 
understood.   
If new safety information results in significant changes in the risk/benefit assessment, the 
consent form should be reviewed and updated as necessary. All subjects (including those 
already being treated) should be informed of the new information, should be given a copy of 
the revised form, and should give their consent to continue in the study. 
 
14.2. 
Institutional Review Board/Independent Ethics Committee  
A copy of the protocol, proposed informed consent form, other written subject information, and 
any proposed advertising material must be submitted to the IRB for written approval. A copy of 
the written approval of the protocol and informed consent form must be received by Exelixis 
before recruitment of subjects into the study and shipment of Exelixis IP. 
The investigator must submit and, where necessary, obtain approval from the IRB for all 
subsequent protocol amendments and changes to the informed consent document.  The 
investigator is to notify the IRB of deviations from the protocol or SAEs occurring at the site and 
other AE reports received from Exelixis, in accordance with local procedures. 
The investigator is responsible for obtaining annual IRB approval [IRBs only]/renewal [IRBs and 
IECs] throughout the duration of the study. Copies of the investigator’s reports and the IRB 
continuance of approval must be sent to Exelixis. 
This study is being conducted under a United States Investigational New Drug application.  
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14.3. 
Subject Confidentiality 
The Sponsor-Investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Exelixis. 
• Subjects are to be identified by a unique subject identification number. 
• Where permitted, date of birth is to be documented and formatted in accordance 
with local laws and regulations. 
• On the CRF demographics page, in addition to the unique subject identification 
number, include the age at time of enrollment. 
• For SAEs reported to Exelixis, subjects are to be identified by their unique subject 
identification number, initials (for faxed reports, in accordance with local laws and 
regulations), and date of birth (in accordance with local laws and regulations). 
• Documents that are not submitted to Exelixis (e.g., signed informed consent forms) 
are to be kept in confidence by the investigator, except as described below. 
14.4. 
Protocol Amendments   
Protocol modifications (including protocol amendments) may be made and will be prepared, 
reviewed, and approved by representatives of the Sponsor-Investigator. Protocol modifications 
or amendments must be reviewed and approved by Exelixis prior to implementation. 
All protocol modifications must be submitted to the IRB/EC for information and approval in 
accordance with local requirements and to regulatory agencies if required. Approval must be 
obtained before any changes can be implemented, except for changes necessary to eliminate an 
immediate hazard to study subjects or those that involve only logistical or administrative aspects 
of the trial (e.g., change in monitor or change of telephone number). 
14.5. 
Termination of the Study 
Both Exelixis and the Sponsor-Investigator reserve the right to terminate the study according to 
the study contract. The Sponsor-Investigator is to notify the IRB in writing of the study’s 
completion or early termination and send a copy of the notification to Exelixis. At any time, the 
study may be terminated by the -Sponsor-Investigator, the FDA, the IRB, or by Exelixis. Should 
this be necessary, Exelixis and the Sponsor-Investigator will arrange the procedures on an 
individual study basis after review and consultation. In terminating the study, Exelixis and the 
Sponsor-Investigator will ensure that adequate consideration is given to the protection of the 
subjects’ interests. Upon study termination, the Sponsor-Investigator shall cease enrolling 
subjects into the study and shall discontinue conduct of the study as soon as is medically 
practicable. 
 
 
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15. 
DATA HANDLING AND RECORDKEEPING 
15.1. 
Data Quality Assurance 
Accurate and reliable data collection will be ensured by verification and crosscheck of the eCRFs 
against the investigator’s records by the study monitor (source document verification) to the 
extent described the Fred Hutch/UW Cancer Consortium Data and Safety Monitoring Plan and 
the Sarcoma Group Standard Operating Procedure 005 Clinical Trial Monitoring and Follow-Up 
and by the maintenance of a drug–dispensing log by the investigator or designee. 
15.2. 
Data/Documents 
The investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the investigational product are complete, accurate, filed, and 
retained. Examples of source documents include: hospital records; clinic and office charts; 
laboratory notes; memoranda; checklists; dispensing records; recorded data from automated 
instruments; copies or transcriptions certified after verification as being accurate copies; 
microfiche; x-ray film and reports; and records kept at the pharmacy; and the laboratories, as 
well as copies of CRFs or CD-ROM. 
15.3. 
Data Management 
Data will be collected via electronic medical record and subject shadow chart and entered into 
RedCAP. These data will be electronically verified through use of programmed edit checks 
specified by the clinical team. Discrepancies in the data will be brought to the attention of the 
clinical team, and investigational site personnel, if necessary. Resolutions to these issues will be 
reflected in the database. An audit trail within the system will track all changes made to the data. 
15.4. 
Investigator Responsibilities for Data Collection 
The investigator is responsible for complying with the requirements for all assessments and data 
collection (including subjects not receiving protocol-required therapies) as stipulated in the 
protocol for each subject in the study. For subjects who withdraw prior to completion of all 
protocol-required visits and are unable or unwilling to continue the Schedule of Assessments (in 
Table 2, the investigator can search publicly available records (where permitted) to ascertain 
survival status.  
This ensures that the data set(s) produced as an outcome of the study is/are as comprehensive 
as possible. 
15.5. 
Sample Storage and Destruction 
Tumor samples collected according to the Schedule of Assessments in Table 2 can be analyzed 
for any of the tests outlined in the protocol, for any tests necessary to minimize risks to study 
subjects, and in any other method determined to be appropriate by the Sponsor-Investigator to 
evaluate a primary, secondary, or exploratory endpoint. Results from this analysis are to be 
documented and maintained but are not necessarily reported as part of this study.  
The records should be retained by the Investigator according to ICH, local regulations, or as 
specified in the Clinical Trial Agreement, whichever is longer; but at a minimum, all study 
documentation must be retained for 2 years after the last marketing application approval in an 
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ICH region or after at least 2 years have elapsed since formal discontinuation of clinical 
development of cabozantinib. 
Since the evaluations are not expected to benefit the subject directly or to alter the treatment 
course, the results of other exploratory studies are not placed in the subject’s medical record and 
are not to be made available to the subject, members of the family, the personal physician, or 
other third parties, except as specified in the informed consent. 
The subject retains the right to request that the sample material be destroyed by contacting the 
Investigator.  Following the request from the subject, the investigator is to ensure that any 
remaining blood or tumor samples and any other components from the cells can be located and 
destroyed. Samples will be destroyed once all protocol-defined procedures are completed.   
The Sponsor-Investigator is responsible for the destruction of the sample(s) at the request of the 
subject through the Investigator, at the end of the storage period, or as appropriate (e.g., the 
scientific rationale for experimentation with a certain sample type no longer justifies keeping the 
sample). If a commercial product is developed from this research project, the subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample.  
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16. 
QUALITY CONTROL AND QUALITY ASSURANCE 
16.1. 
Study Monitoring 
Institutional support of trial monitoring will be in accordance with the FHCRC/University of 
Washington Cancer Consortium Institutional Data and Safety Monitoring Plan. Under the 
provisions of this plan, FHCRC Clinical Research Support (CRS) coordinates data and compliance 
monitoring conducted by consultants, contract research organizations, or FHCRC employees 
unaffiliated with the conduct of the study. Independent monitoring visits occur at specified 
intervals determined by the assessed risk level of the study and the findings of previous visits per 
the institutional DSMP.  
In addition, protocols are reviewed at least annually and as needed by the Consortium Data and 
Safety Monitoring Committee (DSMC), FHCRC Scientific Review Committee (SRC) and the 
FHCRC/University of Washington Cancer Consortium Institutional Review Board (IRB). The review 
committees evaluate accrual, adverse events, stopping rules, and adherence to the applicable 
data and safety monitoring plan for studies actively enrolling or treating subjects. The IRB reviews 
the study progress and safety information to assess continued acceptability of the risk-benefit 
ratio for human subjects. Approval of committees as applicable is necessary to continue the 
study.  
The trial will comply with the standard guidelines set forth by these regulatory committees and 
other institutional, state and federal guidelines. 
16.2. 
Audits and Inspections 
In accordance with ICH GCP, this study may be selected for audit by the US Food & Drug 
Administration for inspection of site facilities (e.g., pharmacy, protocol-required therapy storage 
areas, laboratories) and review of study-related records will occur to evaluate the study conduct 
and compliance with the protocol, ICH GCP, and applicable regulatory requirements. The 
investigator should understand that source documents for this study must be made available, 
after appropriate notification, to qualified health authority inspectors. The verification of the CRF 
data must be by direct inspection of source documents.  
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17. 
STUDY DOCUMENTATION AND RECORD-KEEPING 
17.1. 
Investigator’s Files and Retention of Documents 
The Sponsor-Investigator must maintain adequate and accurate records to enable the conduct 
of the study to be fully documented and the study data to be subsequently verified. These 
documents should be classified into two separate categories as follows: (1) the investigator’s 
study file, and (2) subjects’ clinical source documents. 
The investigator’s study file will contain the protocol and protocol amendments, CRFs, query 
forms, IRB/EC and governmental approvals with correspondence, sample informed consent, 
drug records, staff curriculum vitae and authorization forms, any other records required under 
the Protocol, and other appropriate documents and correspondence. 
Subjects’ clinical source documents include the subjects’ hospital/clinic records; physicians’ and 
nurses’ notes; the appointment book; original laboratory, ECG, electroencephalogram, X-ray, 
pathology and special assessment reports; signed informed consent forms; consultant letters; 
and subject screening and enrollment logs.  
The investigator must keep these two categories of documents on file for at least the latest of 
(a) 2 years following the marketing application approval date for the study treatment in the 
indication being investigated, or (b) 2 years after the investigation is completed or 
discontinued, or (c) for a period of time consistent with local regulatory requirements, 
whichever is longest. After that period, the documents may be destroyed subject to local 
regulations. 
17.2. 
Source Documents and Background Data 
Upon request, the Sponsor-Investigator will supply its licensees and collaborators with any 
required background data from the study documentation or clinic records. This is particularly 
important when CRFs are illegible or when errors in data transcription are suspected. In case of 
special problems or governmental queries or requests for audit inspections, it is also necessary 
to have access to the complete study records, provided that subject confidentiality is protected. 
17.3. 
Case Report Forms  
For enrolled subjects, all and only data from the procedures and assessments specified in this 
protocol and required by the eCRFs should be entered on the appropriate eCRF. Data from 
some procedures required by the protocol, such as physical examinations and laboratory 
results, will be recorded only on the source documents and will not be transcribed to eCRFs. 
Additional procedures and assessments may be performed as part of the investigator’s 
institution or medical practice standard of care and may not be required for eCRF entry.  
For each subject enrolled, the eCRF must be completed and signed by the PI or authorized 
delegate from the study staff. 
The investigator should ensure the accuracy, completeness, legibility, and timeliness of the data 
in the eCRFs and in all required reports. 
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18. 
PUBLICATIONS 
The Sponsor-Investigator holds the primary responsibility for publication of the study results; 
provided that the Sponsor-Investigator will provide Exelixis with a copy of any proposed 
publication or release: (a) for abstracts, slide presentations or posters, at least five (5) business 
day prior to submission (in the case of abstracts) or first public presentation (in the case of slide 
presentations and posters); and (b) at least thirty (30) days in advance of first submission and 
each subsequent submission in the case of manuscripts and also comply with any provisions 
regarding publication that are agreed to between the University of Washington and Exelixis, Inc. 
in the Clinical Trial Agreement related to this study.  
Public presentation of data in any form will be thoroughly de-identified to ensure confidentiality. 
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19. 
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35. Cornillie J, van Cann T, Wozniak A, Hompes D, Schoffski P. Biology and management of clear 
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40. Skrzypek K, Kusienicka A, Szewczyk B, et al. Constitutive activation of MET signaling impairs 
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41. Miekus K, Lukasiewicz E, Jarocha D, Sekula M, Drabik G, Majka M. The decreased metastatic 
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43. Covell DG, Wallqvist A, Kenney S, Vistica DT. Bioinformatic analysis of subject-derived ASPS 
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44. Wagner AJ, Goldberg JM, Dubois SG, et al. Tivantinib (ARQ 197), a selective inhibitor of MET, 
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45. Bhardwaj V, Zhan Y, Cortez MA, et al. C-Met inhibitor MK-8003 radiosensitizes c-Met-
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47. Yu H, Li X, Sun S, Gao X, Zhou D. c-Met inhibitor SU11274 enhances the response of the 
prostate cancer cell line DU145 to ionizing radiation. Biochem Biophys Res Commun 
2012;427:659-65. 
48. De Bacco F, Luraghi P, Medico E, et al. Induction of MET by ionizing radiation and its role in 
radioresistance and invasive growth of cancer. J Natl Cancer Inst 2011;103:645-61. 
49. Mikami K, Medova M, Nisa L, et al. Impact of p53 Status on Radiosensitization of Tumor 
Cells by MET Inhibition-Associated Checkpoint Abrogation. Mol Cancer Res 2015;13:1544-53. 
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antiangiogenic tyrosine kinase inhibitor therapy for thyroid cancer. Thyroid 2014;24:918-22. 
51. Exelixis. Cabozantinib package insert. 2016. 
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20. 
 APPENDIX 1 - WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND METHODS 
OF CONTRACEPTION 
20.1. 
Definitions 
20.1.1. 
Woman of Childbearing Potential (WOCBP) 
 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy. 
 
Women in the following categories are not considered WOCBP 
 
• Premenarchal 
• Premenopausal female with 1 of the following: 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s review of the 
participant’s medical records, medical examination, or medical history interview. 
• Postmenopausal female 
o A postmenopausal state is defined as 12 months of amenorrhea in a woman over 
age 45 years in the absence of other biological or physiological causes.  
20.2. 
Contraception Guidance for Females of Childbearing Potential 
 
One of the highly effective methods of contraception listed below is required during study 
duration and until the end of relevant systemic exposure, defined as 4 months after last 
treatment. Local laws and regulations may require use of alternative and/or additional 
contraception methods. 
 
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of < 1% per year when used consistently and correctly.a 
• Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation 
o oral 
o intravaginal 
o transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation 
o oral 
o injectable 
 
Highly Effective Methods That are User Independent 
• Implantable progestogen-only hormonal contraception associated with inhibition of 
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Ovulation  
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
• Vasectomized partner 
• Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
treatment. The reliability of sexual abstinence needs to be evaluated in related to the 
duration of the study and the preferred and usual lifestyle of the participant. 
o It is not necessary to use any other method of contraception when complete 
abstinence is elected. 
• WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests as specified in study calendar. 
• Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence. 
 
a Typical use failure rates may differ from those when used consistently and correctly. Use 
should be consistent with local regulations regarding the use of contraceptive methods for 
participants participating in clinical studies. 
 
Less Than Highly Effective Contraceptive Methods That are User Dependent 
 
Failure rate of > 1% per year when used consistently and correctly. 
• Male or female condom with or without spermicide. Male and female condoms cannot 
be used simultaneously. 
• Diaphragm with spermicide 
• Cervical cap with spermicide 
• Vaginal sponge with spermicide 
• Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action 
 
Unacceptable Methods of Contraception 
• Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
• Withdrawal (coitus interruptus) 
• Spermicide only 
• Lactation amenorrhea method (LAM) 
20.3. 
Contraception Guidance for Males of Childbearing Potential 
 
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to the following during the treatment and until the end of relevant systemic 
exposure. 
 
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• Inform any and all partner(s) of their participation in a clinical drug study and the need 
to comply with contraception instructions as directed by the investigator. 
 
• Male participants are required to use a condom for study duration and until the end of 
relevant systemic exposure defined as 4 months after last systemic dose. 
 
• Female partners of males participating in the study to consider use of effective methods 
of contraception until the end of relevant systemic exposure, defined as 4 months after 
last systemic dose. 
 
• Male participants with a pregnant or breastfeeding partner must agree to remain 
abstinent from penile vaginal intercourse or use a male condom during each episode of 
penile penetration during the treatment and until 4 months after last systemic dose. 
 
• Refrain from donating sperm for the duration of the study treatment and for 4 months 
after last systemic dose. 
 
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21. 
APPENDIX 2 – GUIDELINES REGARDING RADIATION THERAPY 
Radiation needs may vary considerably from subject to subject. There is significant flexibility 
regarding potential radiation regimens. 
Radiation needs may vary considerably from subject to subject. Treatments for an individual 
subject may deviate from the standard approach described below at the discretion of the 
radiation oncology investigator.  
Tumors targeted for treatment with radiotherapy should be discussed with Dr. Ed Kim, co-
investigator and radiation oncologist for this trial prior to initiating therapy. A gross tumor 
volume (GTV) should be delineated based on radiographic appearance on radiation planning CT 
and relevant diagnostic imaging. Clinical Target Volume (CTV) should include the GTV and sites 
of potential tumor involvement based on consensus guidelines (i.e. RTOG Consensus Sarcoma 
Target Volume Definitions), adjusted per discretion of treating physician.  For extremity 
sarcomas, the CTV should include the “reactive zone” as seen on T2-weighted MRI sequences.  
Longitudinal margins of 3cm and radial margins of 1.5 cm will be utilized in most cases, per 
institutional standards (adjusting for normal barriers to tumor growth such as bone, muscle 
compartments, and fascial planes). A planning target volume (PTV) of at least 5mm is 
recommended to account for tumor motion. The PTV expansion may be individualized based on 
the anatomic location, subject immobilization, and (if relevant) motion-management strategy 
chosen. 
Image guidance (typically cone-beam CT) may be utilized prior to each treatment to verify 
accurate targeting and sparing of normal tissue. 
The RTOG Contouring Atlas can be found here: 
https://www.rtog.org/CoreLab/ContouringAtlases/RTOGExtremitySoftTissueSarcomaAtlas.aspx 
 
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