Clinical trial NCT01688999
Conditions: Urothelial Carcinoma Urethral Neoplasms Urinary Bladder Neoplasms Kidney Neoplasms
Keywords: Kidney Cancer Tyrosine Kinase Inhibitor Bladder Cancer
Sponsor: National Cancer Institute (NCI)
Start date: 2012-09-11; Completion date: 2020-09-14
Enrollment: 69 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

\- Cabozantinib is a drug that slows the growth of blood vessels that feed tumors. It is approved for medullary thyroid cancer. However, studies have shown that prostate and ovarian tumors respond to it. Researchers want see if cabozantinib can be a safe and effective treatment for urothelial cancer.

Objectives:

\- To test the safety and effectiveness of cabozantinib for advanced urothelial cancer.

Eligibility:

\- Individuals at least 18 years of age who have advanced urothelial cancer that has not responded to standard treatments.

Design:

* Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. Tumor tissue samples will also be collected. Imaging studies will also be performed.
* Participants will take cabozantinib by mouth once per day on each day of a 28-day cycle.
* Treatment will be monitored with frequent blood tests and imaging studies.
* Participants will continue to take the study drug for as long as their cancer does not worsen and side effects are not too severe.

Detailed description:
Background:

* In the United States, urothelial carcinoma (UC) of the bladder is the fourth most common malignancy in men and the ninth most common in women with an estimated 69,250 new cases and 14,990 deaths in the year 2011
* There is no Food and Drug Administration (FDA)-approved second line drug for patients with metastatic Urothelial Cancer (UC)
* Multiple lines of evidence support targeting angiogenesis in UC
* In human bladder cancer, overexpression of tyrosine-protein kinase (c-Met)/Axl/platelet derived growth factor receptor- (PDGFR)-alpha or c-Met alone showed significant correlation with poor survival
* Cabozantinib is a new chemical entity that inhibits multiple receptor tyrosine kinases with growth-promoting and angiogenic properties.
* The primary targets of cabozantinib are mesenchymal epithelial transition factor (MET), vascular endothelial factor receptor 2 (VEGFR2), and rearranged during transfection (RET)

Objectives:

\- To determine the response rate of cabozantinib in patients with progressive urothelial cancer who have received prior cytotoxic chemotherapy

Eligibility:

* Patients in cohort 1 must have a histologically confirmed diagnosis of metastatic, progressive urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.
* Patients in cohort 2 must have a histologically confirmed diagnosis of bone only metastatic, urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.
* Patients in cohort 3 must have a histologically confirmed diagnosis of non-transitional cell carcinoma cancer (including but not limited to squamous cell, neuroendocrine, adenocarcinoma including urachal and sarcomatoid) of the bladder, urethra, ureter, or renal pelvis.
* Patients must have been previously treated, as defined by treatment with at least one prior cytotoxic chemotherapy regimen or agent. Patients may have received any number of prior cytotoxic agents.
* 18 years of age or older.

Design:

* A maximum of 71subjects will be enrolled in this open label, non-randomized, phase II trial of 60 mg each day of cabozantinib. Up to 50 patients will be accrued to cohort 1 (metastatic, progressive urothelial cancer. The remainder will be enrolled on exploratory cohorts 2 \& 3, bone only metastatic urothelial disease and non transitional cell carcinoma (TCC) bladder cancer respectively, during the time the study is accruing patients for cohort 1. Note: Patients who tolerate cabozantinib at 60 mg daily during the first 2 cycles (first restaging time period) without (Bullet) grade 2 toxicity may undergo dose escalation to 80 mg daily at the discretion of the Principal Investigator.
* A Simon 2 stage design with alpha=0.05 and beta = 0.10 as acceptable error probabilities. Initially 21 subjects will be enrolled and followed for progression. If 2 or more of cohort 1 subjects experiences a response, enrollment will continue until a total of 41 evaluable subjects with progressive urothelial cancer have been entered. 2-3 patients per month may enroll on this trial; thus, 2 to 3 years is anticipated as the accrual period.
* Each patient will undergo response evaluation assessments with chest abdomen pelvis computed tomography (CAP CT) (or magnetic resonance imaging (MRI)) with or without 18F-Sodium Fluoride (Na18F) positron emission tomography (PET CT) every 8 weeks while on active protocol therapy starting at baseline. Patients will undergo investigational Fludeoxyglucose, (FDG) PET/CT and PET/MRI (optional) at baseline, week 4 and week 8.

Arms: arm 1: Administered orally at a dose of 60 mg once daily on each day of a 28-day cycle.
Interventions: intervention 1: Cabozantinib
Intervention descriptions: intervention 1: 60 mg by mouth (PO) daily each 28 day cycle. Treatment continues until toxicity or disease progression.

Protocol documents:
Prot_SAP_002.pdf: 
Abbreviated Title: Ph 2 XL184 in urothelial CA 
 
CTEP Study #: 9236 
Version Date: 05/10/2019 
1 
 
Abbreviated Title: Ph 2 XL184 in urothelial CA 
CTEP Protocol #: 
9236 
CC Protocol #: 
12-C-0205 P 
Version Date: May 10, 2019 
NCT Number: NCT01688999 
 
Title: A Phase II Study of Cabozantinib (XL184) in Patients with Advanced/Metastatic Urothelial 
Carcinoma 
 
NCI Principal Investigator: Andrea B. Apolo, M.D. A-E 
Genitourinary Malignancies Branch (GMB) 
National Cancer Institute 
10 Center Drive Room 12N226 
Bethesda, MD 20892 
Phone: 301-480-0536 
Fax: 301-402-0172 
Email: andrea.apolo@nih.gov 
Lead Associate Investigator: William Dahut, M.D., GMB, CCR, NCI A-E 
NIH Associate Investigators: Peter Choyke, M.D., MIP, CCR, NCI B, E 
James Gulley, M.D., Ph.D., GMB, CCR, NCI A-E 
Ravi Madan, M.D., GMB, CCR, NCI A-E 
Howard Parnes, M.D., Prostate and Urologic Cancer Research 
Group A-E 
John Wright, M.D., Ph.D., IDB, CTEP, DCTD, NCI B, E 
*Donald Bottaro, Ph.D., UOB/CCR/NCI B, E 
*William Figg, Pharm.D., GMB, CCR, NCI B, E 
*Douglas Price, Ph.D., GMB, CCR, NCI B, E 
*Les R. Folio, D.O., MPH, MSc, MAS B, E 
*Jane Trepel, DTB, CCR, NCI B, E 
*Mark Raffeld, M.D., LP, CCR, NCI B, E 
*Maria Merino, M.D., LP, CCR, NCI B, E 
*Michael Dean, Ph.D., Laboratory of Translational Genomics, 
DCEG, NCI B, E 
Statistician: *Seth Steinberg, Ph.D. B, E 
Biostatistics and Data Management Section 
National Cancer Institute 
9609 Medical Center Drive, Room 2-W-334, MSC 9716 
Bethesda, MD 20892-9716 
Phone: 240-276-5563 
Email: steinbes@mail.nih.gov 
Responsible Research Nurse / 
Study Coordinator: 
Corrine M. Keen, R.N., M.S., CCRP A,B,C 
10 Center Drive, Room 13N230 


Abbreviated Title: Ph 2 XL184 in urothelial CA 
 
CTEP Study #: 9236 
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Phone: 240-760-6097 
Email: ckeen@mail.nih.gov 
Referral Contact: Corrine M. Keen, R.N., M.S., CCRP 
* not responsible for patient care 
 
Roles:  
A. Obtain information by intervening or interacting with 
living individuals for research purposes 
B. Obtaining identifiable private information about living 
individuals 
C. Obtaining the voluntary informed consent of 
individuals to be subjects 
D. Makes decisions about subject eligibility 
E. Studying, interpreting, or analyzing identifiable private 
information or data/specimens for research purposes 
F. Studying, interpreting, or analyzing coded, linked data 
or specimens for research purposes 
G. Some/all research activities performed outside NIH 
 
CTEP Supplied Agents:     
Drug Name: 
Cabozantinib (XL184) 
IND Number: 
116059 
NSC Number: 
761968 
Sponsor: 
CTEP 
Manufacturer: 
Exelixis 
Commercially available agents:   
18FDG and Na18F will be supplied from commercial sources by the NCI Molecular Imaging 
Program 


Abbreviated Title: Ph 2 XL184 in urothelial CA 
 
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PRÉCIS 
Background: 
x In the United States, urothelial carcinoma (UC) of the bladder is the fourth most common 
malignancy in men and the ninth most common in women with an estimated 69,250 new 
cases and 14,990 deaths in the year 2011  
x There is no FDA-approved second line drug for patients with metastatic UC 
x Multiple lines of evidence support targeting angiogenesis in UC 
x In human bladder cancer, overexpression of c-Met/Axl/PDGFR-α or c-Met alone showed 
significant correlation with poor survival  
x Cabozantinib is a new chemical entity that inhibits multiple receptor tyrosine kinases with 
growth-promoting and angiogenic properties.  
x The primary targets of cabozantinib are MET, VEGFR2, and RET 
Objectives: 
x To determine the response rate of cabozantinib in patients with progressive urothelial cancer 
who have received prior cytotoxic chemotherapy 
Eligibility: 
x Patients in cohort 1 must have a histologically confirmed diagnosis of metastatic, progressive 
urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis. 
x Patients in cohort 2 must have a histologically confirmed diagnosis of bone only metastatic, 
urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis. 
x Patients in cohort 3 must have a histologically confirmed diagnosis of non-transitional cell 
carcinoma cancer (including but not limited to squamous cell, neuroendocrine, 
adenocarcinoma including urachal and sarcomatoid) of the bladder, urethra, ureter, or renal 
pelvis. 
x Patients must have been previously treated, as defined by treatment with at least one prior 
cytotoxic chemotherapy regimen or agent.  Patients may have received any number of prior 
cytotoxic agents. 
x 18 years of age or older. 
Design: 
x A maximum of 71 subjects will be enrolled in this open label, non-randomized, phase II trial 
of 60 mg each day of cabozantinib.  Up to 50 patients will be accrued to cohort 1 (metastatic, 
progressive urothelial cancer).  The remainder will be enrolled on exploratory cohorts 2 & 3, 
bone only metastatic urothelial disease and non TCC bladder cancer respectively, during the 
time the study is accruing patients for cohort 1. Note: Patients who tolerate cabozantinib at 
60 mg daily during the first 2 cycles (first restaging time period) without ≥ grade 2 toxicity 
may undergo dose escalation to 80 mg daily at the discretion of the Principal Investigator. 
x A Simon 2 stage design with alpha=0.05 and beta = 0.10 as acceptable error probabilities.  
Initially 21 subjects will be enrolled and followed for progression.  If 2 or more of cohort 1 
subjects experiences a response, enrollment will continue until a total of 41 evaluable 


Abbreviated Title: Ph 2 XL184 in urothelial CA 
 
CTEP Study #: 9236 
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subjects with progressive urothelial cancer have been entered.  2-3 patients per month may 
enroll on this trial; thus, 2 to 3 years is anticipated as the accrual period. 
x Each patient will undergo response evaluation assessments with CAP CT (or MRI) with or 
without Na18F PET CT every 8 weeks while on active protocol therapy starting at baseline.  
Patients will undergo investigational FDG PET/CT and PET/MRI (optional) at baseline, 
week 4 and week 8. 
 
SCHEMA 
 
TREATMENT AND IMAGING SCHEDULE 
 
 
 
FDG PET CT/MRI 
 
 
CT CAP/MRI ± Na18F 
PET CT  
 
Baseline 
Week 4 
Week 8 
Week 16 
Week 24 
*Every 8 weeks 
after week 24 
* Every 12 weeks for patients on drug holiday.  
 
 
60 mg cabozantinib daily 


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TABLE OF CONTENTS 
PRÉCIS ............................................................................................................................................3 
SCHEMA .........................................................................................................................................4 
TABLE OF CONTENTS .................................................................................................................5 
1 
OBJECTIVES ...........................................................................................................................8 
1.1 
Primary Objective .......................................................................................................... 8 
1.2 
Secondary Objectives ..................................................................................................... 8 
1.3 
Exploratory Objectives................................................................................................... 8 
2 
BACKGROUND ......................................................................................................................8 
2.1 
Urothelial Cancer ........................................................................................................... 8 
2.2 
IND Agent - Cabozantinib (XL184) ............................................................................ 11 
2.3 
Rationale ...................................................................................................................... 18 
2.4 
Correlative Studies Background .................................................................................. 20 
3 
PATIENT SELECTION .........................................................................................................22 
3.1 
Eligibility Criteria ........................................................................................................ 22 
3.2 
Screening Evaluation ................................................................................................... 28 
4 
REGISTRATION PROCEDURES ........................................................................................29 
4.1 
Treatment Assignment Procedures .............................................................................. 29 
5 
TREATMENT PLAN .............................................................................................................29 
5.1 
Agent Administration ................................................................................................... 30 
5.2 
General Concomitant Medication and Supportive Care Guidelines ............................ 31 
5.3 
On Study Assessments ................................................................................................. 35 
5.4 
Duration of Therapy ..................................................................................................... 36 
5.5 
Duration of Follow Up ................................................................................................. 37 
5.6 
Criteria for Removal from Protocol Therapy and Off Study Criteria .......................... 37 
6 
DOSING DELAYS/DOSE MODIFICATIONS ....................................................................39 
6.1 
Cabozantinib ................................................................................................................ 39 
6.2 
Cabozantinib drug holiday ........................................................................................... 53 
7 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS .................................53 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) ........................... 53 
7.2 
Definitions .................................................................................................................... 58 
7.3 
Expedited Adverse Event Reporting to CTEP ............................................................. 60 
7.4 
Routine Adverse Event Reporting to CTEP................................................................. 61 
7.5 
NIH Intramural IRB and Clinical Director Reporting ................................................. 62 
7.6 
Secondary Malignancy ................................................................................................. 62 


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7.7 
Second Malignancy ...................................................................................................... 63 
7.8 
Data and Safety Monitoring Plan ................................................................................. 63 
8 
PHARMACEUTICAL AND IMAGING AGENT INFORMATION ...................................63 
8.1 
Cabozantinib (XL184) (NSC 761968) ......................................................................... 63 
9 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES .............................................66 
9.1 
Biomarker Studies ........................................................................................................ 66 
9.2 
Correlative Studies ....................................................................................................... 75 
9.3 
Sample Storage, Tracking and Disposition .................................................................. 75 
9.4 
Samples for Genetic/Genomic Analysis ...................................................................... 76 
10 STUDY CALENDAR ............................................................................................................80 
11 MEASUREMENT OF EFFECT ............................................................................................83 
11.1 Antitumor Effect – Solid Tumors ................................................................................ 83 
12 DATA COLLECTION / DATA REPORTING / REGULATORY REQUIREMENTS .......89 
12.1 Data Collection............................................................................................................. 89 
12.2 Genomic Data Sharing Plan ......................................................................................... 90 
12.3 Data Reporting ............................................................................................................. 90 
12.4 CTEP Multicenter Guidelines ...................................................................................... 91 
12.5 Collaborative Agreements Language ........................................................................... 91 
12.6 Material Transfer Agreement (MTA) for Samples Sent to HTG Molecular ............... 92 
12.7 MTA for Samples Sent to Baylor College ................................................................... 92 
13 STATISTICAL CONSIDERATIONS ...................................................................................93 
13.1 Study Design/Endpoints ............................................................................................... 93 
13.2 Sample Size/Accrual Rate ............................................................................................ 93 
13.3 Stratification Factors .................................................................................................... 94 
13.4 Analysis of Secondary Endpoints ................................................................................ 94 
13.5 Reporting and Exclusions ............................................................................................ 94 
14 HUMAN SUBJECTS PROTECTIONS .................................................................................95 
14.1 Rationale For Subject Selection ................................................................................... 95 
14.2 Participation of Children .............................................................................................. 95 
14.3 Participation of Subjects Unable to Give Consent ....................................................... 95 
14.4 Evaluation of Benefits and Risks/Discomforts ............................................................ 96 
14.5 Risks/Benefits Analysis ............................................................................................... 96 
14.6 Consent and Assent Process and Documentation ........................................................ 96 
15 REFERENCES .......................................................................................................................98 
16 APPENDICES ......................................................................................................................103 


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16.1 Appendix A: Performance Status Criteria.................................................................. 103 
16.2 Appendix B: Patient Information on Possible Drug Interactions............................... 104 
16.3 Appendix C: Patient Medication Diary ...................................................................... 106 
16.4 Appendix D:  CCR Patient Self-Administered Study Agent Compliance Log ......... 107 
16.5 Appendix E:  Blood Pressure Monitoring Form ........................................................ 109 
16.6 Appendix F: Sample Collection for Correlative Studies............................................ 110 
16.7 Appendix G: MDASI Quality of Life Assessment .................................................... 113 
 
 
 


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1 
OBJECTIVES 
1.1 
PRIMARY OBJECTIVE 
x To determine the response rate of cabozantinib in patients with progressive urothelial 
cancer who have received prior cytotoxic chemotherapy. 
1.2 
SECONDARY OBJECTIVES 
x To measure the PFS of cabozantinib as determined by RECIST (version 1.1). 
x To determine the safety and toxicity of cabozantinib in this previously treated patient 
population. 
x To estimate overall survival of patients with metastatic urothelial carcinoma of the 
bladder treated with cabozantinib.  
x To explore the relationship between the biodistribution changes in FDG PET/CT 
parameters and the clinical response. 
x To assess RECIST criteria semi-automated volume (SAV), SACT, MASS criteria and 
Choi criteria in metastatic target lesions. 
x To compare the change in Hounsfield units (HU) with the SUV change with treatment 
response in metastatic lesions. 
x To perform correlative studies assessing potential biomarkers of response to XL184. 
1.3 
EXPLORATORY OBJECTIVES 
x To perform exploratory evaluation of response criteria in urothelial cancer patients who 
have not progressed by RECIST, but have developed bone lesions. 
x To perform exploratory evaluation of response criteria in patients with non-transitional 
cell carcinoma of the bladder. 
x To conduct preliminary studies in genetic changes in tumor vs. normal tissue in order to 
begin to identify specific genetic or chromosomal changes that lead to cancer. 
x To assess quality of life in patients treated with cabozantinib. 
2 
BACKGROUND 
2.1 
UROTHELIAL CANCER 
In the United States, urothelial carcinoma (UC) of the bladder is the fourth most common 
malignancy in men and the ninth most common in women with an estimated 69,250 new cases and 
14,990 deaths in the year 2011.1  Worldwide, 386,300 new cases and 150,200 deaths occurred 
from bladder cancer in 20081. Although UC is a chemosensitive malignancy with response 
proportions of over 50% with conventional cytotoxic regimens, the response durations are short 
and the median survival of patients with metastatic disease is approximately 14 months2.  There is 
no FDA-approved second line drug for patients with metastatic UC and no standard conventional 
chemotherapy agent(s) have demonstrated a survival benefit in patients that have progressed after 
first line platinum-based chemotherapy.  Second-line trials with cytotoxic agents have generally 
yielded discouraging response rates (see Table 1 below) with a median progression-free survival 
between 2 to 3 months and a median survival in the range of 6 to 9 months3-6. Furthermore, many 
patients receive these agents as part of first-line therapy leaving few available options for patients 


Abbreviated Title: Ph 2 XL184 in urothelial CA 
 
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with progressive or recurrent disease.  This highlights the need for the development of novel 
therapies for the treatment of patients with metastatic UC. 
 
Table 1. Results with cytotoxic agents in patients with metastatic urothelial carcinoma 
who had received prior chemotherapy 
Agent 
Activity 
Overall Response 
95% CI 
Paclitaxel4,7,8 
9-10% 
0-17% 
Docetaxel3,9 
13% 
4-30% 
Ifosfamide10-12 
20% 
10-32% 
Gemcitabine13,14 
23% 
8-38% 
 
Targeting Angiogenesis in UC 
Several processes central to tumor progression, including tumor growth, invasion, and metastasis 
are dependent on an adequate blood supply. Angiogenesis, the process by which the neovascular 
blood supply is recruited, is orchestrated by a balance of stimulatory and inhibitory factors released 
by tumor and host cells. Over twenty years ago, Chodak et al first demonstrated that the urine of 
patients with UC contained pro-angiogenic substances 15. Multiple lines of evidence support 
targeting angiogenesis in UC: 
x Microvessel density, a histological measure of angiogenesis, has been correlated with 
stage, recurrence, and survival, in UC. 16,17, 18  
x Several reports have described increased expression of vascular endothelial growth factor 
(VEGF), a mediator of angiogenesis, in the tissue, serum, and urine of patients with UC 
and correlated these markers with stage and prognosis.19-21 
x Inhibitors of angiogenesis have shown activity in preclinical murine models of UC.22-24  
x A functional autocrine loop involving VEGF/VEGFR2 may be important in the 
pathogenesis of some bladder cancers. In a recent non-clinical study, 6 of 13 bladder 
tumor cell lines examined expressed VEGFR2 (Flk-1). Further analysis of the T24 
bladder tumor cell line revealed a functional autocrine loop involving VEGF and 
VEGFR2.25,26 
Clinical studies in bladder cancer with anti-angiogenic agents.  
A phase II study of single agent Sunitinib 27 in 77 patients on one of two schedules (50 mg per day 
for 4 weeks on and 2 weeks off [cohort A], 37.5 mg per day continuously [cohort B]), found a 
partial response in three of 45 patients in cohort A, and in one of 32 patients in cohort B. Clinical 
regression or stable disease was achieved in 33 of 77 patients (43%) with 29% of patients achieving 
stable disease lasting longer than 3 months. Antitumor responses were observed, identifying the 
vascular endothelial growth factor axis as a viable pathway for UC treatment. 
A phase II study of 43 metastatic or unresectable chemo naïve UC patients treated with cisplatin, 
gemcitabine, and bevacizumab as first-line chemotherapy reported complete response 19%, partial 
response 53%; with overall response rate of 72%. Stable disease lasting greater than 12 weeks was 


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observed in 9%.  With a median follow-up of 27.2 months (range, 3.5 to 40.9 months), median 
progression-free survival (PFS) was 8.2 months (95% CI, 6.8 to 10.3 months) with a median 
overall survival (OS) time of 19.1 months (95% CI, 12.4 to 22.7 months).  This combination 
demonstrates significant clinical activity in the first-line treatment of metastatic UC patients. A 
phase III trial to further define the toxicity risk vs. clinical benefit of bevacizumab addition to 
platinum-based doublets is currently ongoing in this population. 
Met expression in Bladder Cancer 
The c-met proto-oncogene encodes a receptor tyrosine kinase (Met) and has been shown to play a 
role in oncogenesis. High titers of hepatocyte growth factor, the specific ligand for Met, are 
excreted in the urine and tend to reflect disease activity of bladder cancer. The clinical significance 
of Met in human bladder cancer was examined in bladder cancer cell lines and human bladder 
cancer tumors. The mRNA expression and genomic alteration of c-met was studied in five bladder 
cancer cell lines. Met overexpression was then compared with p53 nuclear accumulation (TP53) 
in primary bladder cancer (n = 142 patients). Expression of c-met tended to correlate with 
differentiation of cancer cell lines in the absence of point mutations. Expression of Met was 
positively associated with histologic grade, stage classification, tumor size, and nodular tumor 
growth (P <.05, respectively). Indicators for poor long-term survival were invasive cancer, 
multiple tumors, and Met overexpression (P =.0006, .01, and.04, respectively). In these studies, 
the c-met proto-oncogene demonstrated that it plays an important role in the progression of bladder 
carcinogenesis28. 
The clinical significance of the expression of phosphorylated c-Met in bladder cancer, and its 
correlation with cancer cell progression-related molecules has also been investigated by Miyata et 
al.29. The expression levels of 2 tyrosine residues of c-Met (pY1234/1235 and pY1349) were 
examined immunohistochemically (IHC) in 133 specimens with non-metastatic bladder cancer and 
their correlation with matrix metalloproteinase–1, –2, –7, and –14; urokinase-type plasminogen 
activator; E-cadherin; CD44 standard, variant 3, and variant 6; and vascular endothelial growth 
factor. Expression of phosphorylated c-Met was detected in cancer cells, but was rare in normal 
urothelial cells. c-Met, pY1349 was associated with high pathologic T stage in a multivariate 
analysis. Expression of pY1349 c-Met was a marker of metastasis and (P = .001) and cause-
specific survival (P = .003). Expressions of matrix metalloproteinase–2, matrix metalloproteinase–
7, and E-cadherin correlated with pY1349 c-Met expression. This demonstrates that pY1349 c-
Met plays an important role in tumor development, and its expression is a significant predictor of 
metastasis and survival of patients with bladder cancer.  
A study using antibody arrays that selected antibodies against targets differentially expressed in 
bladder tumors, found serum protein, c-met, to be top ranked at identifying bladder cancer patients 
from controls30.  C-met expression was validated by immunohistochemistry of tissue microarrays 
containing bladder tumors (n = 173) and was associated with pathological stage and tumor grade 
(p<0.001), and over-all survival (P=0.044). 
NIH-Met5 and T24-Met3 cell lines harboring an inducible human c-Met gene were established. 
C-Met-related receptor tyrosine kinases were screened by microarray analysis. The potential 
clinical importance was examined in a cohort of 65 cases of locally advanced and metastatic 
bladder cancer patients.  A positive association of Axl or platelet-derived growth factor receptor-
alpha (PDGFR-α) with c-Met expression was demonstrated at translational level, and confirmed 
by specific siRNA knock-down. The transactivation of c-Met on Axl or PDGFR-α in vitro was 


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through a ras- and Src-independent activation of mitogen-activated protein kinase/extracellular 
signal-regulated kinase (MEK/ERK) pathway. In human bladder cancer, co-expression of these 
receptor tyrosine kinases was associated with poor patient survival (p < 0.05), and overexpression 
of c-Met/Axl/PDGFR-α or c-Met alone showed the most significant correlation with poor survival 
(p < 0.01)31. 
C-Met Inhibitor in Bladder Cancer Cell Lines 
Met overexpression occurs in bladder cancer28,29,31,32. The effects of a small, orally available, 
highly selective Met tyrosine kinase inhibitor, PF-2341066, was studied in a pre-clinical model of 
bladder cancer. Bladder cancer cell lines (HT 1376, T24 and TCC-sup) were treated with PF-
2341066 to determine its effects on cellular proliferation and migration. Migration was inhibited 
in a dose dependent manner when the cells were treated with PF-2341066 (Bottaro, NCI, UOB, 
unpublished). 
Dual Targeting VEGF and C-MET 
Hypoxia has been shown to result in the upregulation of both MET and VEGF, and activated MET 
can indirectly promote angiogenesis and tumor growth by upregulating VEGF expression 33,34. 
Evidence from the literature 34 also supports cooperative roles for MET and VEGFR2 in the 
proliferation and survival of the tumor endothelium. Thus, simultaneous inhibition of both MET 
and VEGFR2 should result in near-complete inhibition of major survival pathways that are induced 
in tumors by hypoxia.  
2.2 
IND AGENT - CABOZANTINIB (XL184)  
XL184 (cabozantinib) inhibits multiple receptor tyrosine kinases (RTKs) implicated in tumor 
growth, metastasis, and angiogenesis (Investigator’s Brochure, 2011).  The primary targets of 
XL184 are MET (c-MET) and vascular endothelial growth factor receptor 2 (VEGFR2); additional 
targets include RET, AXL, KIT, and TIE-2.  Both c-Met and VEGFR2 are important mediators of 
tumor growth and tumor angiogenesis, and in vivo pharmacodynamic activity of XL184 against c-
Met and VEGFR2 has been demonstrated in both preclinical and clinical studies.  
RTKs regulate many processes including cell growth and survival, organ morphogenesis, 
neovascularization, and tissue repair35.  Dysregulation of RTKs by mutation, gene rearrangement, 
gene amplification, and overexpression of both receptor and ligand has been implicated as 
causative factors in the development and progression of numerous human cancers. 
The RTK c-Met, encodes the high-affinity receptor for hepatocyte growth factor (HGF) or scatter 
factor (SF)35.  c-Met and HGF are each required for normal mammalian development and have 
been shown to be important in cell migration, morphogenic differentiation, and organization of 
three-dimensional tubular structures (e.g., renal tubular cells, gland formation, etc.), as well as cell 
growth, angiogenesis, and tumor invasiveness and metastasis.  Upregulation of MET is found in a 
wide range of malignancies including thyroid, prostate, ovarian, lung, and breast cancers, and is 
associated with more aggressive and invasive phenotypes of cancer cells in vitro and metastases 
in vivo (Investigator’s Brochure, 2011).  c-Met-driven metastasis may be exacerbated by a number 
of factors, including tumor hypoxia caused by selective inhibition of the VEGF pathway. 
Evidence linking c-Met and HGF as causative or progression factors in human cancers include:  
(1) the overexpression of both receptor and ligand in neoplasms relative to surrounding tissues; (2) 
the correlation of receptor and ligand overexpression with disease severity and outcome; (3) 


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genetic alteration of c-Met by mutation of gene amplification in multiple cancer types; (4) 
introduction of c-Met and HGF (or mutant c-Met) into cell lines, conferred the properties of 
tumorigenicity and metastatic propensity on engineered cells; (5) introduction of c-Met or HGF as 
transgenes into the germline of mice resulted in primary and secondary neoplasms; and (6) the 
inhibition of c-Met or HGF function with dominant-negative receptors, antibody antagonists (both 
Met and HGF), and biologic antagonists (e.g., NK4) have reversed cancer-associated phenotypes 
such as motility, invasion and proliferation of tumor cells, and tumor growth and dissemination in 
vivo35. 
A wide variety of human cancers, including brain, colorectal, gastric, and lung, demonstrate 
dysregulated c-Met activity36, either by means of c-Met kinase overexpression37, activating c-Met 
gene mutations and/or amplification37-39, or increased autocrine and/or paracrine secretion of the 
c-Met ligand, HGF/SF.  These alterations have been implicated in tumor progression and 
metastasis, and a high constitutive activation of c-Met has been correlated with poor clinical 
prognosis40. 
VEGFR2 is the predominant mediator of VEGF-stimulated endothelial cell migration, 
proliferation, survival, and enhanced vascular permeability41.  Increased expression of VEGFR2, 
often in combination with VEGFR3, has been observed in the tumor vascular endothelium in most 
common human solid tumor types, on tumor cells in melanoma and hematological malignancies, 
and in colitis-associated colon cancer42.  High VEGFR2 expression is an unfavorable prognostic 
biomarker in hepatocellular carcinoma (HCC), and correlated with triple-negative (i.e., therapy-
resistant) breast cancer and poor survival. 
Nonclinical Development of XL184   
In Vivo Activity 
Inhibition of VEGF signaling pathway was previously shown to result in more invasive tumors in 
the transgenic RIP-Tag2 mouse model of pancreatic neuroendocrine cancer that spontaneously 
develops aggressive tumors43.  In RIP-Tag2 transgenic mice, tumors treated with XL184 were 
smaller (P <0.05) than in mice treated with vehicle or an anti-VEGF antibody, but were also less 
invasive (P <0.05) and had no liver metastases 44.  All mice treated with XL184 (n = 6) survived 
until 20 weeks, but none treated with vehicle (n = 14) or anti-VEGF antibody (n = 8) reached that 
endpoint.  Tumor vascularity decreased after treatment, with reductions ranging from 67% at 3 
mg/kg to 83% at 30 mg/kg for 7 days 45.  Tumors were 35% smaller after XL184 treatment than 
corresponding values for vehicle control mice.  c-Met protein expression in tumors was slightly 
decreased, but phosphorylated c-Met was markedly reduced after treatment for 7 days.   
Mice bearing MDA-MB-231 cells (expressing MET and VEGF) were administered four oral doses 
of 100 mg/kg 46.  XL184 increased tumor hypoxia (13-fold) and apoptosis (TUNEL; 2.5-fold) at 8 
and 4 hours after the first and second doses, respectively, when compared to vehicle-treated 
tumors.  In addition, XL184 disrupted tumor vasculature by inducing endothelial cell death that 
negatively affected tumor viability.  XL184 treatment resulted in significant tumor growth 
inhibition of MDA-MB-231 tumors (P <0.001) at all doses (1, 3, 10, 30, or 60 mg/kg) when 
compared to vehicle-treated tumors.  Dose-dependent inhibition was observed for the 3 and 10 
mg/kg doses (P <0.01), and complete inhibition was observed at the 30 and 60 mg/kg doses.  A 
single 100 mg/kg dose resulted in sustained MDA-MB-231 tumor growth inhibition for ~8 days 
after which tumors began growing at a rate similar to vehicle-treated control tumors.  In addition, 
XL184 inhibited tumor growth (P <0.001) in the MET-expressing rat C6 glioma cell line for all 


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doses (1, 3, 10, 30, or 60 mg/kg) when compared with vehicle-treated tumors.  The 3 mg/kg and 
10 mg/kg doses resulted in significant tumor regression (62% and 85%, P <0.0001) when 
compared with predose tumor weights.  Subchronic administration of XL184 was well tolerated 
in mice and rats with no signs of toxicity, as determined by stable and/or increasing body weights 
during the treatment period. 
ARCaP-M is a human prostate cancer model which expresses both c-Met and VEGF co-receptor 
NP-1 used in a human prostate tumor xenograft study in mouse bone47.  ARCaP-M cells were 
injected into the tibia of nude mice on Day 1, and on Day 31 animals with established bone lesions 
were randomized to receive XL184 or vehicle daily (qd) for 7 weeks of treatment48. Tibiae from 
vehicle-treated animals exhibited both osteoblastic and osteolytic lesions, whereas tibiae from 
XL184 treated animals appeared mostly normal.  Thus, XL184 treatment blocked both osteoblastic 
and osteolytic progression of ARCaP-M xenograft tumors in bone. 
 
Nonclinical Pharmacodynamics 
In mice, the effective dose resulting in 50% inhibition (ED50) of targets was achieved at well 
tolerated doses of XL184 and at plasma exposures comparable to exposure observed in clinical 
trials49.  XL184 produced prolonged inhibition of receptor phosphorylation, such as sustained 
inhibition of c-Met and VEGFR2 for 10 hours after administration of a single dose of XL184.  This 
extended inhibition occurred in a manner that was generally predicted by plasma exposure, i.e., 
inhibition was diminished when plasma levels fell below approximately 20 μM for c-Met, 5 μM 
for VEGFR2, and 23 μM for TIE-2. 
Once daily administration of XL184 resulted in significant inhibition of c-Met phosphorylation in 
TT tumors, relative to tumors from vehicle control-treated mice, with maximal inhibition of 70% 
seen at 60 mg/kg49.  Dose-dependent inhibition of phosphorylation of c-Met and RET was 
observed among the 3, 10, and 30 mg/kg dose groups as well.   
c-Met phosphorylation was inhibited by a single 100 mg/kg oral dose of XL184, 2–8 hours post 
dose in H441 tumors (human lung papillary adenocarcinoma) that harbor constitutively 
phosphorylated c-Met 46.  This effect was reversible, as c-Met phosphorylation returned to basal 
levels by 48 hours after treatment.   
 
Nonclinical Pharmacokinetics 
In the various xenograft models, plasma exposures were similar and plasma concentrations in the 
range of 3 to 27 μM were associated with efficacy49.  In rats, plasma concentrations in the range 
of 5 to 15 μM were associated with maximal anti-tumor activity.  Despite the apparent requirement 
for high peak concentrations, trough concentrations as low as 0.1 μM were observed at highly 
efficacious doses in mice.  These results were consistent with in vivo target modulation studies in 
mice which demonstrated long (4- to 10-hour) durations of action, and indicated that continuous 
high exposure was not required to maintain efficacy.   
Dose proportional increases in exposure occurred at oral doses of 3–100 mg/kg in mice and at 3–
30 mg/kg in rats49.  In rats, the oral bioavailability of XL184 dosed as a solid was approximately 
100% of XL184 dosed as a liquid.  In comparison, oral bioavailability was much lower in dogs 
(20%) and monkeys (18%) for the solid versus liquid dosage forms. 


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Systemic drug exposure parameters (maximum plasma concentration [Cmax] and area under the 
time-concentration curve from 0 to t hours post-dose [AUC0-t] values) associated with single 
XL184 oral doses in rats increased less than dose-proportionally with increasing dose (100–900 
mg/kg) 49.  With repeat daily oral dosing in rats, systemic exposure (AUC0-t values) increased 
generally dose-proportionally following 14 and 178 dosing days (dose ranges 1–15 mg/kg/day and 
0.1–1 mg/kg/day, respectively).  The Cmax and AUC0-t values in rats administered 100 mg/kg were 
approximately 2-fold and 3-fold higher, respectively, than for dogs given 2000 mg/kg; therefore, 
the higher systemic exposure to XL184 in rats correlated with the greater toxicity observed in this 
species at lower administered doses. 
Systemic drug exposure parameters (Cmax and AUC0-t values) associated with single XL184 oral 
doses in dogs increased less than dose-proportionally with increasing XL184 dose (400–2000 
mg/kg), suggesting possible saturation of systemic absorption 48.  With repeat daily dosing, 
exposure (Cmax and AUC0-24 values) both increased greater than dose-proportionally from 10 to 
100 mg/kg and less than dose proportionally from 100 to 1000 mg/kg following 14 dosing days.   
 
Toxicology 
In rodents and non-rodents, histopathological changes associated with XL184 administration were 
observed in gastrointestinal (GI) tract, bone marrow, lymphoid tissues, kidney, and adrenal and 
reproductive tract tissues 48.  Histopathological changes present in the bone and pancreas were 
considered secondary to XL184 administration. Adverse effects following oral exposure to XL184 
were generally dose-related, clinically monitorable, and self-resolving upon discontinuation of 
dosing. In 6-month chronic toxicity studies, treatment-related changes were present only in kidney 
(rats) and reproductive tissues (dog).  In reproductive/developmental toxicity studies, XL184 
administration resulted in decreased fertility in male and female rats, in embryotoxicity when given 
to pregnant rats, and in a visceral tissue malformation (small spleen) when given to pregnant 
rabbits. The no-observable-adverse-effect-levels (NOAELs) for the chronic toxicity and 
reproductive/developmental toxicity studies occurred at plasma exposures (AUC) below steady-
state values measured in subjects with solid tumors administered 175 mg XL184 capsule form 
daily (Study XL184-001). 
In definitive genotoxicity bioassays, XL184 was negative in an S. typhimurium/E.coli bacterial 
mutagenicity study, an in vitro chromosome aberration study using human peripheral blood 
lymphocytes, and an in vivo mouse bone marrow micronucleus study49.  In safety pharmacology 
studies, no adverse effects occurred on neurobehavioral or respiratory functions in XL184-treated 
rats or on cardiovascular function in XL184-treated dogs. 
 
Clinical Experience 
As of May 4, 2011, 1003 patients have been studied in 12 ongoing Exelixis-sponsored clinical 
trials with XL184 treatment 1) as a single agent at does ranging from 0.08 to 11.52 mg/kg on an 
intermittent dosing schedule, 2) from 25 to 265 mg (19.7-209 mg freebase equivalent weight) on 
a fixed daily dosing schedule and 3) in combination with temozolomide (TMZ) and radiation 
therapy (RT), or with erlotinib (Exelixis Communication, 2011).  The maximum tolerated dose 
(MTD) on once daily (qd) by mouth (PO) dosing schedule was determined to be 175 mg L-malate 
salt (or approximately 138 mg freebase equivalent weight). 


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Detailed information for each of these studies, including pharmacokinetic data, can be found in 
the Investigator’s Brochure48.  Safety and efficacy information, from the 2011 Investigator’s 
Brochure, is summarized below.  
 
Phase I Studies 
Study XL184-001 was a phase 1 dose-escalation study in subjects with solid tumors.  Eighty-five 
subjects, across 13 dosing levels (DL) ranging from 0.08 mg/kg qd (using powder-in-bottle [PIB] 
suspension on a 5 days on, 9 days off schedule) to 265 qd (using capsules [25 and/or 100mg] for 
two, 14-day cycles) were enrolled.  The capsule MTD was determined to be 175 mg qd50.  Of the 
35 subjects with medullary thyroid cancer (MTC) and measureable disease enrolled in the dose 
expansion phase, 10 (29%, 95% CI) had confirmed partial responses (cPR) (with a duration up to 
48+ months), 17 (49%) had tumor shrinkage of ≥30%, and stable disease (SD) of at least 6 months 
was observed in 15/37 (41%) of the MTC subjects.   
In Study XL184-002, treatment of subjects with newly diagnosed glioblastoma (GB) consisted of 
cabozantinib in combination with TMZ with or without radiation therapy.  Enrollment has been 
terminated and no clinical efficacy data is presented in the 2011 Investigator’s Brochure.  All 
adverse events (AEs) were assessed with respect to combination treatment and not the individual 
components.  Nineteen patients were evaluated for AEs, the most common grade 3 or higher 
included neutropenia (21%), thrombocytopenia (16%), leucopenia (16%), and hypertension 
(11%).  Myelosuppression, including prolonged pancytopenia, is a dose-limiting toxicity (DLTs) 
associated with TMZ use.  The frequency at which bone marrow toxicity was observed in this 
study is consistent with the TMZ prescribing information.   
Study XL184-004 is a Phase 1, open-label, randomized, single-dose, two-treatment, two-way 
crossover study to assess the effect of food on the bioavailability of cabozantinib in healthy adult 
subjects.  According to a randomization scheme, 56 subjects received single oral doses of the 
assigned treatment of Test (175 mg cabozantinib, dosed as one 100-mg capsule and three 25-mg 
capsules 30 minutes after administration of a high-fat breakfast) or Reference (175 mg 
cabozantinib, dosed as one 100-mg capsule and three 25-mg capsules under fasting conditions).  
Blood samples were collected up to 504 hours post-dose for each subject after each treatment to 
assess plasma cabozantinib pharmacokinetics.  See “Pharmacokinetics” section for results. 
Study XL184-005 is a Phase 1, open-label, randomized, single-dose, two-treatment, two-way 
crossover comparative bioavailability study of cabozantinib tablet and capsule formulations in 
healthy volunteers.  Subjects received single oral doses of the assigned treatment of Test (100 mg 
cabozantinib, dosed as one 100-mg tablet) or Reference (100 mg cabozantinib, dosed as two 50-mg 
capsules), according to a randomization scheme.  Each dosing was administered under fasting 
conditions, and blood samples were collected up to 504 hours post-dose for each subject after each 
treatment to assess plasma cabozantinib PK.  See “Pharmacokinetics” section for results. 
In Study XL184-008, subjects with advanced solid tumors (particularly renal cell carcinoma 
[RCC] and differentiated thyroid cancer [DTC]) are evaluated for any potential clinically 
significant drug-drug interaction of cabozantinib on the CYP isozyme CYP2C8.  The effect of qd 
dosing of 175 mg cabozantinib and a single dose of rosiglitazone will be evaluated.  In 11 patients 


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evaluated for AEs, the most common grade 3 or higher AEs were fatigue (9%), hypophosphatemia 
(27%), blood amylase increase (9%), and hyponatremia (9%). 
In a phase 1 study, CA205-001, Japanese subjects with advanced or metastatic solid tumors for 
whom the standard of care is ineffective or inappropriate, received cabozantinib at a starting dose 
of 75 mg PO qd.  Two of the three subjects in the first cohort experienced DLTs of proteinuria and 
thrombocytopenia.  Because of a change in study sponsor, this study was reinitiated as XL184-
014.  One additional subject was enrolled as of May 2011 at 50 mg PO qd.   
Study XL184-202 was a phase 1b/2 trial that evaluated the safety and tolerability of cabozantinib 
and erlotinib administered in combination in non-small-cell lung cancer (NSCLC) subjects.  Of 
the 64 subjects enrolled in the phase 1 dose-escalation portion of the study, all but two had been 
previously treated with and progressed on erlotinib therapy.  A cPR was observed in 5 subjects 
(8%) and 24 subjects (37%) had SD/PR ≥4 months.  The most common grade 3 or higher AEs in 
the phase 1 portion included diarrhea (44%), fatigue (22%), hypokalemia (11%), decreased 
appetite (6%), dyspnea (14%), lipase increase (6%), hypomagnesemia (6%), and dehydration 
(5%).  Twenty-eight subjects were enrolled in the phase 2 portion of the study, in which subjects 
who had received clinical benefit from erlotinib and subsequently experienced progressive disease 
(PD), received single-agent cabozantinib or cabozantinib with erlotinib.  AEs ≥grade 3 included 
dehydration (8%) and hypertension (8%).  One patient, who was treated with single-agent 
cabozantinib, had a cPR. 
 
Phase 2 Studies 
In a phase 2 study, XL184-201, subjects with progressive or recurrent GB in first or second relapse 
were enrolled to receive cabozantinib qd as a single agent.  Group A received an initial dose of 
175 mg (Group A), subsequent cohorts (Groups B and C) received an initial dose of 125 mg.  
Forty-six subjects were enrolled in Group A, and a total of 176 subjects were enrolled in Groups 
B/C.  Fifty-seven subjects experienced one or more serious adverse events (SAEs) that were 
assessed to be related to treatment, including five fatal rSAEs. 
Study XL184-203 is a phase 2 randomized discontinuation trial.  Subjects are enrolled into one of 
nine tumor-specific cohorts: breast cancer, gastric/gastroesophageal (GEJ) cancer, hepatocellular 
carcinoma (HCC), melanoma, NSCLC, ovarian cancer, pancreatic cancer, prostate cancer, and 
small cell lung cancer (SCLC).  Eligible subjects with advanced solid tumors receive open-label 
cabozantinib at starting dose of 100 mg qd for 12 weeks.  Of the 531 subjects enrolled in this study 
as of May 2011, 92 experienced one or more SAEs that were assessed to be related to treatment 
with cabozantinib, including seven fatal SAEs. 
Study XL184-205 is a randomized phase 2 trial for subjects with grade IV astrocytic tumors in 
first or second relapse.  Subjects received one of four regimens: 25 mg qd (Arm 1) continuously, 
75 mg qd (Arm 2) continuously, 125 mg qd for 2 weeks followed by 50 mg qd continuously (Arm 
3), and 125 mg qd on an intermittent 3 week on/1 week off schedule (Arm 4).  A total of 19 subjects 
were accrued before the study was terminated.  Three subjects were rolled over to maintenance 
Study XL184-900.  One subject experienced an SAE assessed to be related to treatment with 
cabozantinib.  
Study XL184-301 is a blind trial for subjects with unresectable, locally advanced or metastatic 
MTC, randomized 2:1 to cabozantinib or placebo.  SAEs reported in Study XL184-301 are: one 


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grade 4 reversible posterior leukoencephalopathy syndrome (RPLS), one grade 5 cardiac arrest 
following asystolic vagal reaction after aspiration on study medication, and three SAEs of acquired 
trachea-esophageal fistula (two grade 3, one grade 5). 
Adverse Events 
The clinical studies with XL184 are ongoing and thus the AE data from the clinical database as of 
March 1, 2011 and May 4, 2011 do not yet include all SAEs (Exelixis Communication, 2011).  As 
of March 2011, AE data are available for 913 subjects who have been dosed with XL184 (806 in 
single-agent studies and 107 in combination studies of XL184 with erlotinib, rosiglitazone, or 
TMZ ± radiation) (Investigator’s Brochure, 2011).  Data from the 806 subjects who received 
single-agent XL184 show that the most frequently (>20%) observed AEs regardless of causality 
were fatigue, diarrhea, nausea, decreased appetite, constipation, palmar-plantar erythrodysesthesia 
(PPE) syndrome, vomiting, dysphonia, and hypertension.  Effects that may be related to the 
inhibition of VEGF, including hypertension, thromboembolic events, GI perforation, fistula 
formation, hemorrhage, wound dehiscence, and proteinuria, have been observed in the single-agent 
and combination XL184 studies.  The most commonly reported SAEs that were assessed as related 
to study treatment with XL184 (as a single-agent or combination) were pulmonary embolism (PE), 
diarrhea, dehydration, deep vein thrombosis (DVT), vomiting, nausea, thrombocytopenia, fatigue, 
wound dehiscence, and PPE syndrome. 
Grade 5 AE data are available for 1404 subjects who have been dosed with cabozantinib as a single 
agent (1286) or in combination (118) through June 1, 2012.  There have been 27 grade 5 AEs 
related to study treatment: GI hemorrhage (two subjects), pulmonary hemorrhage (one subject), 
esophageal hemorrhage (one subject), PE (two subjects), respiratory failure (three subjects), 
respiratory disorder (one subject), hemoptysis (one subject), death due to unknown cause (four 
subjects), intracranial hemorrhage (one subject), intestinal perforation (one subject), 
enterocutaneous fistula (one subject), tracheo-esophageal fistula (one subject), esophageal fistula 
(one subject), hemorrhage (two subjects), hepatic failure (one subject), bronchopneumonia (one 
subject) cardiac arrest (one subject), sepsis (one subject), and diverticular perforation, peritonitis 
(one subject) (Exelixis Communication).  The initial daily doses of drug in these subjects were 100 
mg (8 subjects), 125 mg (8 subjects), 175 mg (11 subjects).  In 2 subjects, the initial dose of 125 
mg was reduced to 50 and 75 mg respectively prior to death. 
Pharmacokinetics 
Pharmacokinetic analysis of 74 patients in trial XL184-001 showed dose proportional increases in 
maximum plasma concentration (Cmax) and AUC both for PIB (dose range 0.08-11.52 mg/kg) and 
the capsule formulation (dose range: 125 to 175 mg) (Kurzrock, 2011).  Terminal-phase half-life 
(t1/2,z) values were 59.1 to 136 hours (Investigator’s Brochure, 2011).  After repeat dosing, t1/2,z 
values (mean ± standard deviation) for XL184 were 91.3 ± 33.3 hours (n = 23), and apparent 
steady-state plasma levels were reached by Day 15 (Kurzrock, 2011).  Steady-state clearance for 
the 175 mg capsule dose derived from repeat dose data was 4.2 ± 1.5 L/h.  Patients who received 
175 mg capsules had four- to five-fold higher steady-state exposure (AUC) compared with Day 1 
(7.68 ± 2.85 mcg∙h/mL; n = 23 vs. 41.6 ± 15.3 mcg∙h/mL; n = 23), indicating that XL184 
accumulated with repeat daily dosing.  There was no significant difference in exposure between 
patients with MTC and those without MTC. 
Based on the preliminary PK data from 23 subjects in XL184-005 who completed both treatments, 
after a single oral dose of cabozantinib at 100 mg, the terminal t1/2, z of cabozantinib appeared to 


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be similar for both tablet and capsule formulations, with approximately mean values of 110 hours 
(Exelixis Communication, 2012).  The median time to the maximum plasma concentration (tmax) 
was 4 hours for the tablet formulation and 5 hours for the capsule formulation.  High inter-subject 
variability for Cmax and the area under the plasma drug concentration time curve (AUC) values 
were observed for both formulations (coefficient of variation [CV]% Cmax: 51% for the tablet 
formulation, 61% for the capsule formulation; CV% for the AUC from time zero to the last 
quantifiable timepoint or to infinity [AUC0-last or AUC0-inf]: 40-43% for the tablet formulation, 43% 
for the capsule formulation).  The geometric mean Cmax of the tablet formulation was 
approximately 39% higher than the value observed for the capsule formulation.  The geometric 
mean AUC0-last and AUC0-inf values for the tablet formulation were also higher (15% and 19%, 
respectively) than those observed for the capsule formulation.  However, due to the high within-
formulation variability observed, no statistical difference in exposure between the two 
formulations was apparent. 
Based on the preliminary PK data from 46 subjects who completed both treatments on trial XL184-
004, a high-fat meal did not appear to alter the terminal t1/2, z of cabozantinib [mean t1/2, z : 131 
hours (fed) vs. 128 hours (fasted)].  The high-fat meal significantly increased the median tmax to 6 
hours from 4 hours (fasted).  The high-fat meal also significantly increased both the cabozantinib 
Cmax and AUC values by 39% and 56%, respectively.  The geometric mean ratio of Cmax fed/fasted 
was 1.39 (90% CI: 1.16-1.67), and the geometric mean ratio of AUC0-last fed/fasted was 1.56 (90% 
CI: 1.34-1.80).  Based on this result, cabozantinib must be taken on an empty stomach (fasting is 
required 2 hours before and 1 hour after each cabozantinib dose). 
2.3 
RATIONALE 
2.3.1 Rationale for cabozantinib in UC 
Bladder cancer is a highly vascular malignancy that produces high levels of pro-angiogenic factors 
including VEGF, bFGF and IL-8. Microvessel density, a histological measure of angiogenesis, has 
been correlated with stage, recurrence, and survival in this disease. Clinical studies in bladder 
cancer with anti-VEGF pathway agents have shown anti-tumor activity. While these studies 
validate the potential for an anti-angiogenic approach to UC, they also indicate the need to 
investigate alternative ways to target the tumor vasculature. Of particular interest are agents that 
target more than one mechanism for tumor growth and development and have activity in tumors 
resistant to existing therapies. Cabozantinib is an oral, potent inhibitor of MET and VEGFR2 that 
produces robust antiangiogenic, antiproliferative, and antiinvasive effects in preclinical models. 
MET and VEGFR2 are key mediators of angiogenesis. Preliminary results of randomized phase II 
studies with cabozantinib in CRPC and ovarian cancer have demonstrated clinical activity. MET 
activation is common in solid tumors including UC and promotes proliferation, invasion, and 
metastasis. For these reasons, co-targeting of the MET and VEGF signaling pathways using 
cabozantinib may represent a promising treatment strategy. 
2.3.2 Rationale for a PFS Endpoint 
Pertinent to the issue of discovering new drugs active in urothelial cancers is that identifying 
clinical benefit should not be limited to response.  Some of the newer "targeted therapy" agents 
approved by the FDA have been approved on the basis of improved progression-free survival 
(PFS) and not response rate (e.g., sorafenib in renal cell carcinoma with a response rate of 
approximately 10% but a major impact in PFS and, eventually, an improvement in survival).  This 


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being said, the median progression-free survival for bladder cancer patients treated with 
chemotherapy is modest at only 2-3 months and response rates are in the 10-20% range.  In a 
second-line trial of weekly paclitaxel in 31 patients with progressive urothelial cancer, the median 
time to progression was 2.2 months4.  In an ECOG trial evaluating the epothilone analog BMS-
247550 in patients with relapsed urothelial cancer, the median progression-free survival was 2.7 
months (95% CI, 1.8, 4.1)5.  In a phase 3 randomized second-line trial of vinflunine versus best 
supportive care, the PFS for patients treated with vinflunine was 3.0 months (95% CI, 2.1, 4.0)51.  
Novel therapies are desperately needed for these patients and identifying activity in the refractory 
setting by using PFS is considered an acceptable approach with these new targeted agents. 
2.3.3 Rationale for Cabozantinib Dose Selection 
A cabozantinib starting dose of 100 mg qd has been studied in 171 CRPC subjects enrolled to the 
Phase 2 XL184-203 RDT. Despite relatively high rates of cabozantinib dose reductions to the next 
lowest dose of 60 mg qd within the first 12 weeks of therapy (51%), this starting dose resulted in 
high rates of pain relief, bone scan improvement, and overall disease control.  
Preliminary data from a separate and ongoing dose-ranging study looking at lower doses of 
cabozantinib in CRPC coupled with results from a retrospective review of the Phase 2 XL184-203 
RDT indicate that lower doses below 100 mg qd are likely to retain efficacy while improving upon 
tolerability: 
Preliminary results from an ongoing dose-ranging study: To date, 9 subjects with metastatic CRPC 
enrolled to the first cohort (starting dose of 40 mg qd) are evaluable for bone scan response. All 9 
subjects exhibit evidence of response on bone scan including two complete responses. Although 
most subjects did not have pain at baseline, one subject reported pain at baseline which resolved 
by Week 6. No dose reductions or interruptions have been reported to date, although one subject 
discontinued study treatment for fatigue that was present at baseline and another subject 
discontinued because of a pathologic fracture. This provides preliminary evidence that lower doses 
are pharmacologically active in a patient population with advanced CRPC.  
Retrospective review of Phase 2 XL184-203 RDT: While the overall rate of dose reduction from 
100 mg to 60 mg was 51%, only 14% required an additional reduction in dose from 60 mg to the 
next lowest dose of 40 mg, which is consistent with an overall improvement in tolerability profile 
at the 60-mg dose level. The majority (69%) of subjects with pain at baseline who experienced 
early dose reduction (before Week 6) to 60 mg went on to report pain improvement at Week 6. 
Moreover, 80% of these subjects remained progression-free and continued to report pain relief at 
the Week 12 time point. Thus the dose of 60 mg qd appears to offer improved tolerability while 
maintaining efficacy in a patient population with advanced CRPC and cancer-related pain at 
baseline.  
Further analysis of the timing of AEs that led to dose reductions or interruptions was conducted. 
The median time to first AE triggering a dose reduction or interruption at 100 mg qd was 29 days, 
with very few subjects experiencing significant toxicity in the first 2 weeks of study treatment. 
As such this study will adopt a starting cabozantinib dose of 60 mg qd. The goal of this regimen 
is to improve the overall tolerability of cabozantinib while maintaining efficacy in this patient 
population 


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2.4 
CORRELATIVE STUDIES BACKGROUND 
2.4.1 Circulating endothelial cells (CEC), circulating endothelial progenitor cells (CEP) and 
Circulating epithelial tumor cells (CTC) 
CEC, CEP and CTC may serve as markers for assessment of treatment's antiangiogenic activity. 
CEC, CEP and CTC will be analyzed by multiparameter flow cytometry.  Mononuclear cells will 
be isolated and run fresh or viably frozen.  Immune subsets, including MDSC and Tregs, may be 
analyzed if sample permits. 
2.4.2 c-Met analysis by real-time RT-PCR 
The c-met proto-oncogene encodes a receptor tyrosine kinase (Met) and has been shown to play a 
role in oncogenesis. The clinical significance of Met in human bladder cancer was examined in 
bladder cancer cell lines and human bladder cancer tumors. The mRNA expression and genomic 
alteration of c-met was studied in five bladder cancer cell lines. Met overexpression was then 
compared with p53 nuclear accumulation (TP53) in primary bladder cancer (n = 142 patients). 
Expression of c-met tended to correlate with differentiation of cancer cell lines in the absence of 
point mutations. Expression of Met was positively associated with histologic grade, stage 
classification, tumor size, and nodular tumor growth (P <.05, respectively). Indicators for poor 
long-term survival were invasive cancer, multiple tumors, and Met overexpression (P =.0006, .01, 
and.04, respectively). In these studies, the c-met proto-oncogene demonstrated that it plays an 
important role in the progression of bladder carcinogenesis28.  
We hypothesize that the c-Met analysis by real-time RT-PCR correlates with the C-met level found 
in the serum and is of prognostic significance.  
2.4.3 IL-8 circulating cytokine levels 
IL-8 is a proinflammatory chemokine, which belongs to the chemokine receptors family and which 
stimulates neutrophil chemotaxis and degranulation52,53. IL-8 is a potent pro-angiogenic factor, 
which has been shown to initiate tumor angiogenesis in xenograft models in which VEGF 
signaling was regulated54. Its expression has been reported to enhance angiogenesis through the 
induction of MMP-9 and to induce metastases of human transitional cancer cell lines55. In animal 
models of urothelial cancer, high expression of IL-8 was associated with a significant increase in 
tumor growth and metastases56 A recent study has associated increased IL-8 plasma levels in 
xenograft renal cell carcinoma (RCC) models with resistance to sunitinib treatment.57 In the same 
study, IL-8 was overexpressed in tumors from patients refractory to sunitinib. Increased expression 
of IL-8, MMP-9, and VEGF in non-small-cell lung cancer patients, treated with the oral inhibitor 
of VEGFR2 tyrosine kinase vandetanib, correlated with a higher risk of progression.58  In mRCC 
patients treated with pazopanib, baseline levels of IL-8 correlated with tumor burden,59 and 
different polymorphisms of the IL-8 gene were significantly associated with treatment activity.60 
The role for IL-8 baseline levels as a predictive serum biomarker of sunitinib activity in patients 
with urothelial cancer was studied and it was found that low IL-8 baseline levels were significantly 
associated with increased time to progression.61   
2.4.4 Genetic biomarkers 
Single nucleotide polymorphisms (SNPs) in genes that play an important role in the drug 
metabolism and disposition of cabozantinib (via cytochrome P450 3A4 and ABCB1-mediated 
pathways) will be evaluated to correlate with efficacy and clinical outcomes. Functional SNPs in 


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the VEGFR2 gene could alter antiangiogenic treatment response or outcome by affecting the 
VEGF signaling pathways. Thus, we will determine if VEGFR2 genetic variants may be correlated 
to toxicity and clinical outcomes as we have previously shown in patients treated with 
bevacizumab and sorafenib62. 
2.4.5 Angiogenesis Markers 
Plasma levels of several angiogenic biomarkers, including VEGF-A, soluble VEGFR2 
(sVEGFR2), and placental growth factor (PIGF), have been shown to be significantly altered after 
single agent cabozantinib treatment (Investigator’s brochure). Post-treatment changes in soluble 
MET (sMET), a potential biomarker for MET inhibition, were observed to be of statistical 
significance in clinical studies. Plasma samples will be obtained to measure changes in the 
molecular markers of angiogenesis, as well as sMET/KIT before and after administration of the 
combination. The potential relationship between biomarker expression and tumor response will be 
explored. 
2.4.6 Plasma and urinary HGF and MET  
We will collect urine and blood from patients on this study in order to determine whether urinary 
hepatocyte growth factor (HGF), urinary soluble MET receptor (sMet), plasma HGF and plasma 
Met levels are biomarkers of bladder cancer (transitional cell carcinoma; TCC) and/or response to 
systemic treatment with the experimental Met/VEGFR inhibitor cabozantinib. Soluble Met levels 
are determined by electrochemiluminescence immunoassay and normalized to urinary creatinine 
values. 
2.4.7 Met expression in tissue 
We will investigate the expression and prognostic role of the receptor tyrosine kinase MET, 
phosphorylated MET, and the ligand hepatocyte growth factor (HGF) in patients with urothelial 
cancer enrolled in this study. MET, pMET, and HGF expression will be assessed using 
immunohistochemistry. MET, pMET, and HGF will be correlated with extent of disease, therapy 
response rate, progression free and overall survival. 
Tissue blocks and slides obtained from outside pathology departments will be analyzed as 
available.  Tissue biopsies will be encouraged but done strictly on a voluntary basis.  Biopsies will 
be obtained from primary tumor sites and/or metastatic sites.   
2.4.8 Immune subsets and angiogenesis markers in plasma and tumor tissue 
Circulating and intratumoral immune subsets and other markers of the microenvironment, 
hypoxia-inducible factor (HIF) 1α and 2α and other angiogenesis and/or immunologic markers 
will be analyzed at baseline and 8-18 weeks after treatment.  At 8 weeks (after 2 cycles of 
treatment), the potential for biopsy will be discussed with the patient.  Tissue blocks and slides 
obtained from outside pathology departments will be analyzed as available.  Tissue biopsies will 
be encouraged but done strictly on a voluntary basis.  Biopsies will be obtained from primary 
tumor sites and/or metastatic sites. 
2.4.9 Imaging with PET/CT and optional PET/MRI:  
Fluorine-18 2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET)/computed 
tomography (CT) has been approved for imaging in many malignancies but not for bladder cancer. 
A retrospective analysis FDG-PET/CT in patients with metastatic urothelial cancer demonstrated 


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that it has excellent sensitivity and specificity in the detection of metastatic bladder cancer63.  FDG-
PET/CT scans may provide better accuracy in clinical information for directing therapy. We will 
prospectively explore the utility of FDG-PET CT and FDG-PET MRI in this study. 
2.4.10 Comparison of Target Lesion Volume/ Density and RECIST Measurements on CT of 
Metastatic Urothelial Cancer 
At present, conventional imaging evaluation of tumor burden in metastatic disease is limited to 
axial measurements of select target lesions, which serves as a surrogate assessment for three 
dimensional changes in tumor size. Rigorous quantitative assessment of tumor response to cancer 
therapy is dependent upon assessment of these three dimensional changes in size. Recent image 
processing algorithms allow for formal RECIST reporting within clinical radiology reports, as well 
as tumor volumetric assessment and HU analysis within PACS and radiologist workflow. 
Advanced algorithms allow for rapid SA volumetric and tumor density measurements that more 
accurately reflect tumor burden/ treatment response compared to single dimensional axial 
measurements alone. Radiologists and information processing IP technologists can use PACS to 
record RECIST reports that include this information as accurate as existing team measurements. 
RECIST and volumetric analysis with data integrated has the potential to improve metastatic lesion 
quantification over existing reporting standards.  Ability to produce RECIST and volumetric 
calculations in reports in PACS, RIS and HIS should improve quality of patient care in facilities 
treating cancer patients.  
2.4.11 Quality of Life Assessment 
In the second line setting, chemotherapy is given with the intent of hindering disease progression 
and prolonging quality of life. As more treatments for solid tumor malignancies evolve, 
particularly for the palliative setting, their efficacy will be measured and agents compared not only 
by the traditional overall and progression free survival standards, but by the effect upon patient 
quality of life64. “Symptom Inventory” developed by Charles Cleeland at MDACC is a 
questionnaire that attempts to assess the degree to which various symptoms “interfere with life.” 
This cancer symptom measurement tool will be utilized at baseline and following cycle 3 of XL-
184 to informally evaluate its impact upon health related quality of life parameters in this 
population, to better measure the benefit of therapy against the risk of decline is quality of life. 
3 
PATIENT SELECTION 
3.1 
ELIGIBILITY CRITERIA  
3.1.1 Inclusion Criteria 
Cohort 1 only (urothelial progressive disease) 
3.1.1.1 Patients must have a histologically confirmed diagnosis of urothelial carcinoma of the 
bladder, urethra, ureter, or renal pelvis. Confirmation may be obtained from any CLIA 
certified lab. 
3.1.1.2 Patients must have progressive metastatic disease. Progressive disease will be defined as 
new or progressive lesions on cross-sectional imaging.  
3.1.1.3 Patients must have at least one measurable site of disease (according to RECIST (version 
1.1) criteria)  


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Cohort 2 only (Bone-only) 
3.1.1.4 Patients must have a histologically confirmed diagnosis of urothelial carcinoma of the 
bladder, urethra, ureter, or renal pelvis. Confirmation may be obtained from any CLIA 
certified lab. 
3.1.1.5 Patients must not have measurable progressive disease (RECIST 1.1) 
3.1.1.6 Patient must have appearance of at least one new bone lesion. 
Cohort 3 (Rare histologies) 
3.1.1.7 Patient must have a histologically confirmed diagnosis of non-transitional cell carcinoma 
of the bladder, urethra, ureter, or renal pelvis including but not limited to squamous cell, 
neuroendocrine, adenocarcinoma including urachal and sarcomatoid. Confirmation may 
be obtained from any CLIA certified lab. 
3.1.1.8 Patients must have progressive metastatic disease. Progressive disease will be defined as 
new or progressive lesions on cross-sectional imaging.  
3.1.1.9 Patients must have at least one measurable site of disease (according to RECIST (version 
1.1) criteria)  
 
All cohorts 
3.1.1.10 Patients must have been previously treated, as defined by treatment with at least one prior 
cytotoxic regimen or agent. 
3.1.1.11 Age > 18 years.  Because no dosing or adverse event data are currently available on the 
use of cabozantinib in patients <18 years of age, children are excluded from this study, 
but may be eligible for future pediatric trials. 
3.1.1.12 ECOG performance status <2 (Karnofsky >60%, (see Appendix A) 
3.1.1.13 Adequate organ function as defined by the following criteria: 
x Hemoglobin ≥ 9 g/dL 
x Absolute neutrophil count (ANC) ≥ 1500/μL  
x Platelets ≥ 75,000/μL  
x Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase 
[SGOT]) and serum alanine transaminase (ALT; serum glutamic pyruvic 
transaminase [SGPT]) ≤3.0 x upper limit of normal (ULN); ≤ 5.0 x ULN in 
cases of liver metastases 
x Total serum bilirubin ≤ 1.5 u the upper limit of normal (ULN). For subjects 
with known Gilbert’s disease or similar syndrome with slow conjugation of 
bilirubin, total bilirubin ≤ 3.0 mg/dL 
x Serum creatinine ≤ 1.5 X institutional upper limits of normal or for patients 
with creatinine levels above 1.5 x institutional normal: creatinine clearance ≥ 
50 mL/min/1.73 m2 by 24 hour urine collection or estimated creatinine 
clearance of ≥ 50 mL/min.   For creatinine clearance estimation , the 
Cockcroft and Gault equation should be used:  
o Male: CrCl (mL/min) = (140 - age) × wt (kg) / (serum creatinine × 72)  
o Female: Multiply above result by 0.85 


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x Urine protein/creatinine ratio (UPCR) ≤ 2 
3.1.1.14 Patient must be able to provide either archival tumor samples (H&E slides and one 
paraffin block or 10 unstained slides) or undergo tumor biopsy. 
3.1.1.15 Patient must be capable of understanding and complying with protocol requirements and 
is willing to give informed consent 
3.1.1.16 The effects of XL184 on the developing human fetus are unknown.  For this reason and 
because tyrosine kinase inhibitors agents are known to be teratogenic, women of child-
bearing potential and men must agree to use adequate contraception (see below) prior to 
study entry and for the duration of study participation.  Should a woman become pregnant 
or suspect she is pregnant while she or her partner is participating in this study, she should 
inform her treating physician immediately.  Men treated or enrolled on this protocol must 
also agree to use adequate contraception prior to the study, for the duration of study 
participation, and 4 months after completion of XL184 administration. 
Sexually active subjects (men and women) must agree to use medically accepted barrier 
methods of contraception (e.g., male or female condom) during the course of the study 
and for 4 months after the last dose of study drug(s), even if oral contraceptives are also 
used.  All subjects of reproductive potential must agree to use both a barrier method and 
a second method of birth control during the course of the study and for 4 months after 
the last dose of study drug(s). 
3.1.1.17 Women of childbearing potential must have a negative pregnancy test at screening. 
Women of childbearing potential include women who have experienced menarche and 
who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal 
ligation, or bilateral oophorectomy) or are not postmenopausal. Postmenopause is defined 
as amenorrhea ≥ 12 consecutive months.  Note: women who have been amenorrheic for 
12 or more months are still considered to be of childbearing potential if the amenorrhea 
is possibly due to prior chemotherapy, antiestrogens, ovarian suppression or any other 
reversible reason. 
3.1.2 Exclusion Criteria 
3.1.2.1 The subject has received cytotoxic chemotherapy (including investigational cytotoxic 
chemotherapy) or biologic agents (eg, cytokines or antibodies) within 3 weeks, or 
nitrosoureas or mitomycin within 6 weeks before the first dose of study treatment. 
3.1.2.2 Prior treatment with cabozantinib 
3.1.2.3 Prior treatment with other small molecule inhibitors of VEGFR within ≤ 2 years of study 
enrollment. 
3.1.2.4 The subject has received radiation therapy: 
x to the thoracic cavity or gastrointestinal tract within 3 months before the first 
dose of study treatment 
x to brain metastases within 14 days before the first dose of study treatment 
x to any other site(s), with the exception of bone, within 28 days before the first 
dose of study treatment 
3.1.2.5 The subject has received radionuclide treatment within 6 weeks before the first dose of 
study treatment 


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3.1.2.6 The subject has received prior treatment with a small molecule kinase inhibitor or a 
hormonal therapy (including investigational kinase inhibitors or hormones) within 14 
days or five half-lives of the compound or active metabolites, whichever is longer, before 
the first dose of study treatment.  
3.1.2.7 The subject has received any other type of investigational agent within 28 days before the 
first dose of study treatment.  
3.1.2.8 The subject has not recovered to baseline or CTCAE ≤ Grade 1 from toxicity due to all 
prior therapies except alopecia and other non-clinically significant AEs. 
3.1.2.9 The subject has a primary brain tumor 
3.1.2.10 The subject has active brain metastases, leptomeningeal or epidural disease (Note: 
Subjects with brain metastases previously treated with whole brain radiation or 
radiosurgery or subjects with epidural disease previously treated with radiation or surgery 
who are asymptomatic and do not require steroid treatment for at least 2 weeks before 
starting study treatment are eligible. Neurosurgical resection of brain metastases or brain 
biopsy is permitted if completed at least 3 months before starting study treatment. 
Baseline brain scans are not required to confirm eligibility.) 
3.1.2.11 The subject has prothrombin time (PT)/ International Normalized Ratio (INR) or partial 
thromboplastin time (PTT) test ≥1.3 u the laboratory ULN within 7 days before the first 
dose of study treatment. 
3.1.2.12 The subject requires treatment, in therapeutic doses, with oral anticoagulants such as 
warfarin prior to initiation of protocol therapy. Low dose aspirin (≤81 mg/day), low-dose 
warfarin (≤1 mg/day), and low molecular weight heparin (LMWH) are permitted. 
Subjects will be permitted to use anticoagulation as described in section 5.2.2.6 if 
treatment is required while they are enrolled on the protocol. 
3.1.2.13 The subject requires chronic concomitant treatment of strong CYP3A4 inducers (e.g., 
dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, 
and St. John’s Wort).  
Because the lists of these agents are constantly changing, it is important to regularly 
consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/  
medical reference texts such as the Physicians’ Desk Reference may also provide this 
information.  As part of the enrollment/informed consent procedures, the patient will be 
counseled on the risk of interactions with other agents, and what to do if new medications 
need to be prescribed or if the patient is considering a new over-the-counter medicine or 
herbal product.  Please refer to patient information sheet in Appendix B. 
3.1.2.14 The subject has experienced any of the following within 3 months before the first dose of 
study treatment: 
x clinically-significant hematemesis or gastrointestinal bleeding 
x hemoptysis of ≥ 0.5 teaspoon (≥2.5 mL) of red blood 
x any other signs indicative of pulmonary hemorrhage  
3.1.2.15 The subject has tumor invading (or concern for invasion) major blood vessels 
3.1.2.16 Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality 
that may increase the risk associated with study participation or study drug 
administration, or may interfere with the interpretation of study results, and in the 


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judgment of the Investigator would make the patient inappropriate for entry into this 
study. 
3.1.2.17 The subject has evidence of tumor invading the GI tract (esophagus, stomach, small or 
large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor 
within 28 days before the first dose of cabozantinib.  
3.1.2.18 The subject has uncontrolled, significant intercurrent or recent illness including, but not 
limited to, the following conditions: 
a. Cardiovascular disorders including 
i. Congestive heart failure (CHF): New York Heart Association (NYHA) Class III 
(moderate) or Class IV (severe) at the time of screening 
ii. Concurrent uncontrolled hypertension defined as sustained BP > 150 mm Hg 
systolic, or > 90 mm Hg diastolic despite optimal antihypertensive treatment 
(BP must be controlled at screening) 
iii. Any history of congenital long QT syndrome 
iv. Any of the following within 6 months before the first  dose of study treatment: 
x unstable angina pectoris 
x clinically-significant cardiac arrhythmias 
x stroke (including TIA, or other ischemic event) 
x myocardial infarction 
b. Gastrointestinal disorders particularly those associated with a high risk of 
perforation or fistula formation including: 
i. Any of the following within 28 days before the first dose of cabozantinib 
x active peptic ulcer disease, 
x active inflammatory bowel disease (including ulcerative colitis and 
Crohn’s disease), diverticulitis, cholecystitis, symptomatic cholangitis or 
appendicitis 
x active malabsorption syndrome 
ii. Any of the following within 6 months before the first dose of study treatment: 
(1) abdominal fistula 
(2) gastrointestinal perforation 
(3) bowel obstruction or gastric outlet obstruction 
(4) intra-abdominal abscess. Note: Complete resolution of an intra-abdominal 
abscess must be confirmed prior to initiating treatment with cabozantinib 
even if the abscess occurred more than 6 months ago. 
c. Other disorders associated with a high risk of fistula formation including PEG tube 
placement within 3 months before the first dose of study therapy. 


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d. Other clinically significant disorders such as: 
i. No active systemic infection requiring parenteral antibiotics 
ii. serious non-healing wound/ulcer/bone fracture within 28 days before the first 
dose of study treatment 
iii. history of organ transplant 
iv. concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days 
before the first dose of study treatment 
v. history of major surgery as follows: 
(1) Major surgery within 3 months of the first dose of cabozantinib if there 
were no wound healing complications or within 6 months of the first dose 
of cabozantinib if there were wound complications. 
(2) Minor surgery  within 1 months of the first dose of cabozantinib if there 
were no wound healing complications or within 3 months of the first dose 
of cabozantinib if there were wound complications 
 
In addition, complete wound healing from prior surgery must be confirmed at 
least 28 days before the first dose of cabozantinib irrespective of the time 
from surgery 
3.1.2.19 The subject is unable to swallow tablets 
3.1.2.20 The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) >500 
ms within 28 days before treatment initiation. 
3.1.2.21 The subject has a previously identified allergy or hypersensitivity to components of the 
study treatment formulation.   
3.1.2.22 The subject is unable or unwilling to abide by the study protocol or cooperate fully with 
the investigator or designee. 
3.1.2.23 The subject has had within 2 years before the start of study treatment evidence of another 
malignancy which required systemic treatment 
3.1.2.24 HIV-positive patients on combination antiretroviral therapy are ineligible because of the 
potential for pharmacokinetic interactions with the study agents. In addition, these 
patients are at increased risk of lethal infections when treated with marrow-suppressive 
therapy.  Appropriate studies will be undertaken in patients receiving combination 
antiretroviral therapy when indicated. 
3.1.3 Inclusion of Women and Minorities 
Men and women of all races and ethnic groups are eligible for this trial. 


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3.1.3.1 Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
 
2 
+  
4 
=  
6 
Not Hispanic or Latino 
 
15 
+  
44 
=  
59 
Ethnic Category: Total of all subjects 
 
17 
(A1) + 
 
48 
(B1) = 
 
65 
(C1) 
Racial Category 
 
American Indian or Alaskan Native 
 
0 
+  
1 
=  
1 
Asian 
 
3 
+  
4 
=  
7 
Black or African American 
 
4 
+  
9 
=  
13 
Native Hawaiian or other Pacific Islander 
 
0 
+  
1 
=  
1 
White 
 
10 
+  
33 
=  
43 
Racial Category: Total of all subjects 
 
17 
(A2) + 
 
48 
(B2) = 
 
65 
(C2) 
 
(A1 = A2) 
 
(B1 = B2) 
 
(C1 = C2) 
 
3.1.4 Recruitment Strategies 
The study will be posted on the CCR website and on clinicaltrials.gov  
3.2 
SCREENING EVALUATION 
Study eligibility is based on meeting all of the study inclusion criteria and none of the exclusion 
criteria at screening before study treatment administration. Screening evaluations may be 
performed as part of an NIH Screening protocol. This does not include the baseline correlative 
studies that will only be performed after the patient has signed the consent form. 
The following assessments will be conducted prior to subjects receiving their first dose of 
cabozantinib on this protocol: 
x 
History including performance status assessment 
x 
Physical examination including height, weight, vital signs 
x 
Laboratory assessments: acute care panel (sodium, potassium, chloride, total CO2 
(Bicarbonate), creatinine, glucose, urea nitrogen), mineral panel (albumin, calcium total, 
magnesium total, phosphorus), hepatic panel(alkaline phosphatase, ALT/GPT, AST/GOT, 
total bilirubin, direct bilirubin), ionized calcium, amylase, lipase, LDH, total protein, GGT 
x 
24 hour urine collection if needed (see section 3.1.1.13)  
x 
Urinalysis including UPCR 
x 
PT/INR, PTT 
x 
Thyroid function tests – TSH, total T3, T4 


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x 
12 lead ECG 
x 
Urine or serum HCG (in women of childbearing potential) 
x 
CT Scan of chest, abdomen and pelvis (MRI may be performed in subjects unable to 
tolerate contrast for CT) 
x 
Pathology evaluation/confirmation of urothelial carcinoma  
4 
REGISTRATION PROCEDURES 
Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) 
within 24 hours of signing consent.  A registration Eligibility Checklist from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and sent via 
encrypted email to:  NCI Central Registration Office (HOIS) ncicentralregistration-
l@mail.nih.gov. After confirmation of eligibility at Central Registration Office, CRO staff will 
call pharmacy to advise them of the acceptance of the patient on the protocol prior to the release 
of any investigational agents.  Verification of Registration will be forwarded electronically via e-
mail to the research team. A recorder is available during non-working hours.  
4.1 
TREATMENT ASSIGNMENT PROCEDURES 
Cohorts 
Number 
Name 
Description 
1 
Cohort 1 (urothelial 
progressive disease) 
Patients with urothelial progressive disease of the bladder, urethra, 
ureter, or renal pelvis.  
2 
Cohort 2 (Bone-only) 
Patients with bone-only urothelial carcinoma of the bladder, 
urethra, ureter, or renal pelvis.  
3 
Cohort 3 (Rare histologies) 
Patients with non-transitional cell carcinoma of the bladder, 
urethra, ureter, or renal pelvis including but not limited to squamous 
cell, neuroendocrine, adenocarcinoma including urachal and 
sarcomatoid.  
 
Arms 
Number 
Name 
Description 
1 
Cabozantinib 
Administered orally at a dose of 60 mg once daily on each day of a 
28-day cycle.  
 
Randomization and Arm Assignment 
Patients in all cohorts are assigned to arm 1. 
5 
TREATMENT PLAN 
This is a Phase 2, single-arm, open-label study of cabozantinib in subjects with 
advanced/metastatic urothelial carcinoma that has progressed despite treatment with cytotoxic 
chemotherapy.  The primary endpoint is to determine the activity of cabozantinib as determined 
by response rate. A Simon 2-stage design will be used.  In the first stage, 21 subjects will be 


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accrued.  If there are at least 2 responses, accrual will continue to the second stage and an additional 
20 evaluable subjects will be enrolled.  If there are a total of 6 or more responses among the total 
of 41 evaluable subjects, Cabozantinib will be considered of clinical interest in progressive 
urothelial carcinoma.   
The primary objective of the study will be to determine the activity of cabozantinib as determined 
by progression free survival by Response Evaluation Criteria in Solid Tumors (RECIST) version 
1.1. Cabozantinib will be administered orally at a daily dose of 60 mg. Patients may continue on 
study as long as they are tolerating therapy. Patients who achieve and maintain a response of CR 
by RECIST per section 11.1.4.4 for over 3 years, may have the drug held (drug holiday) as 
described in section 6.2.  
5.1 
AGENT ADMINISTRATION 
5.1.1 Cabozantinib 
Treatment will be administered primarily on an outpatient basis.  Subjects will be instructed to 
take cabozantinib orally at a dose of 60 mg once daily on each day of a 28 day cycle. If a dose is 
missed, subjects should be instructed not to make it up on the following day.  Cabozantinib should 
be taken on an empty stomach; patients must fast for 2 hours before and 1 hour following each dose 
of cabozantinib.  Subjects should be instructed not to crush or chew and to avoid both grapefruit and 
Seville orange products while on the study drug. 
Patients will be provided a pill diary (Appendix C) to track the oral study agents, instructed in its 
use, and asked to bring it with them to each appointment. A new copy of the pill diary will be 
given to patients whose dose is reduced due to adverse events. Pill counts will also be maintained 
by study personnel. 
Subjects will be instructed to notify their physician immediately of any and all AEs. Subjects 
experiencing one or more AEs due to the study treatment may require a dosing delay or 
reduction(s) in their dose in order to continue with study treatment.  
Reported adverse events and potential risks are described in Section 0.  Appropriate dose 
modifications are described in Section 6.  No investigational or commercial agents or therapies 
other than those described below may be administered with the intent to treat the patient's 
malignancy.  
 
REGIMEN DESCRIPTION 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Cabozantinib 
none 
60 mg 
PO 
Daily 
28 days  
(4 
weeks) 
 


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Patients who tolerate cabozantinib at 60 mg daily during the first 2 cycles (first restaging time 
period) without ≥ grade 2 toxicity may undergo dose escalation to 80 mg daily at the discretion of 
the Principal Investigator. 
5.1.2 Study Drug Accountability & Compliance 
All oral self-administered investigational agents will be properly accounted for, handled, and 
disposed in accordance with existing federal regulations and principles of Good Clinical Practice.  
The investigator will maintain accurate records of receipt of all cabozantinib, including dates of 
receipt (compliance form available in Appendix D).  In addition, accurate records will be kept 
regarding when 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 unused 
cabozantinib will be returned to the NCI Clinical Repository for proper destruction as per the NCI 
guidelines. 
Drug accountability and subject compliance will be assessed with drug dispensing and return 
records.  
5.2 
GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES 
Because there is a potential for interaction of XL184 with other concomitantly administered drugs 
through the cytochrome P450 system, the case report form must capture the concurrent use of all 
other drugs, over-the-counter medications, or alternative therapies.  The Principal Investigator 
should be alerted if the patient is taking any agent known to affect or with the potential to affect 
selected CYP450 isoenzymes. 
5.2.1 Concurrent Medications/Interventions 
5.2.1.1 Anticancer therapy  
If a subject requires additional systemic anticancer treatment, study treatment must be 
discontinued.  Local intervention is discouraged unless medically unavoidable.  Subjects receiving 
local intervention (e.g., palliative radiation) are allowed to continue to receive study treatment at 
the investigator’s discretion.  
5.2.1.2 Other Medications 
Subjects must be instructed to inform the investigators of the current or planned use or all other 
medications during the study (including prescription medications, over-the-counter medications, 
vitamins and herbal and nutritional supplements).  It is the responsibility of the investigator to 
ensure that details regarding all medications are documented. 
Bisphosphonates started prior to screening activities or initiated during the course of the study to 
control bone pain may be used with caution. 
Colony stimulating factors (e.g., erythropoietin and granulocyte colony-stimulating factors) and 
pain medications administered as dictated by standard practice are acceptable while the subject is 
enrolled in the study.  However, colony stimulating factors should not be administered 
prophylactically prior to the first dose of study treatment.  
No concurrent investigational agents are permitted. 
5.2.1.3 Potential Drug Interactions 


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Cytochrome P450:  Preliminary 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 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 (but not a CYP2C9 or CYP2D6 substrate), based on data 
from in vitro studies using CYP-isozyme specific neutralizing antibodies.  
Preliminary results from a clinical pharmacology study, XL184-006, showed that concurrent 
administration of cabozantinib with the strong CYP3A4 inducer, rifampin, resulted in an 
approximately 80% reduction in cabozantinib exposure (AUC values) after a single dose of 
cabozantinib in healthy volunteers.  Co-administration of cabozantinib with strong inducers of the 
CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, 
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 (e.g., chronic use of modafinil) should be avoided because of its potential to reduce 
cabozantinib exposure.  Selection of alternate concomitant medications with no or minimal 
CYP3A4 enzyme induction potential is recommended.  In addition, 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.  
Preliminary results from a clinical pharmacology study, XL184-007, showed that concurrent 
administration of cabozantinib with the strong CYP3A4 inhibitor, ketoconazole, resulted in a 33-
39% 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., ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, and 
ritonavir) may increase cabozantinib concentrations.  Grapefruit / grapefruit juice and Seville 
oranges may also increase plasma concentrations of cabozantinib.  Strong CYP3A4 inhibitors 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.  
Because in vitro studies only assessed the metabolizing capacity of the CYP3A4, CYP2C9, and 
CYP2D6 pathways, the potential for drugs that inhibit/induce other CYP450 pathways (e.g., 
CYP2C8, CYP2C19, CYP2B6, CYP1A2) to alter cabozantinib exposure is not known.  Therefore, 
these drugs should be used with caution when given with cabozantinib.  
Please refer to the Flockhart drug interaction tables for lists of substrates, inducers, and inhibitors 
of selected CYP450 isozyme pathways (Flockhart 2007; 
http://medicine.iupui.edu/clinpharm/ddis/.   
Protein Binding:  Cabozantinib is highly protein bound (approximately 99.9%) 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 


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cabozantinib and/or a co-administered highly protein-bound drug (and a corresponding increase in 
pharmacologic effect).  Factors that influence plasma protein binding may affect individual 
tolerance to cabozantinib.  Therefore, concomitant medications that are highly protein bound (e.g., 
diazepam, furosemide, dicloxacillin, and propranolol) should be used with caution.  Because 
warfarin is a highly protein bound drug with a low therapeutic index, administration of warfarin at 
therapeutic doses should be avoided in subjects receiving cabozantinib due to the potential for a 
protein binding displacement interaction.  
Drugs Associated with QTc Prolongation:  Treatment with cabozantinib has been associated with 
a mild prolongation of the QTc interval.  Caution should be used when treating subjects on 
cabozantinib with other drugs associated with QTc prolongation (see http://www.qtdrugs.org).  
Additional QTc monitoring is suggested for subjects who are treated concomitantly with QTc 
prolonging drugs. 
Other Interactions: In a relative bioavailability study in dogs, cabozantinib exposure was not 
significantly affected by drugs that alter gastric pH. Nevertheless, drugs such as proton pump 
inhibitors (PPIs) and H2-antagonists produce profound suppression of gastric acid secretion and 
significant increases in gastric pH.  By elevating gastric pH, PPIs and H2-antagonists may decrease 
cabozantinib plasma exposure levels and its effectiveness in vivo, resulting in clinically significant 
drug interactions.  The use of PPIs (e.g., omeprazole, lansoprazole, rabeprazole, pantoprazole, and 
esomeprazole) and/or H2-antagonists (e.g., ranitidine, famotidine, and nizatidine) is discouraged 
during this study.  If antacids are not adequate, the use of H2 blockers is preferred over PPIs (Note: 
Cimetidine should be avoided because of its potential to interfere with CYP3A4 mediated 
metabolism of cabozantinib).  Antacids, H2 blockers, or PPIs should be taken at least 2 hours 
(preferably 4 hours) after taking cabozantinib but at least 14 hours before the next dose of 
cabozantinib if possible.  
In vitro data suggest that cabozantinib is unlikely to be a substrate for P glycoprotein (P-gp), but 
it does appear to have the potential to inhibit the P-gp transport activity.  
Additional details related to these overall conclusions are provided in the Investigators Brochure 
5.2.2 Supportive Care 
General guidelines for the management of non-hematologic and hematologic toxicities are 
provided in Sections 6.1.1 and 6.1.2, respectively. As a general approach, it is suggested that all 
AEs be managed with supportive care when possible at the earliest signs of toxicity. For more 
specific guidelines on gastrointestinal AEs (diarrhea, nausea/vomiting, stomatitis/mucositis), 
hepatobiliary disorders, skin disorders (PPE), embolism and thrombus, and hypertension, see 
below.   
5.2.2.1 Diarrhea 
Subjects should be instructed to notify their physician immediately at the first signs of poorly 
formed or loose stool or an increased frequency of bowel movements. Administration of 
antidiarrheal agents is recommended at the first sign of diarrhea as initial management. 
Loperamide is recommended as standard first line therapy. Alternatively, diphenoxylate/atropine 
can be used. Additional agents to consider in subjects with diarrhea that is refractory to the above 
include deodorized tincture of opium and octreotide65. Some subjects may require concomitant 
therapy with loperamide, diphenoxylate/atropine, and deodorized tincture of opium to control 
diarrhea. When combination therapy with antidiarrheal agents does not control the diarrhea to 


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tolerable levels, a dose reduction and/or dose interruption of cabozantinib should be implemented 
as described in Table 2.  In addition, general supportive measures should be implemented 
including continuous oral hydration, correction of fluid and electrolyte abnormalities, small 
frequent meals, and stopping lactose-containing products not including cabozantinib, high fat 
meals and alcohol.  
5.2.2.2 Nausea and Vomiting 
Anti-emetic agents along with supportive care are recommended as clinically appropriate at the 
first sign of nausea and vomiting.  A dose reductions and/or dose interruption of cabozantinib may 
be required as described in Section 6.1.1 if antiemetic treatment and/or prophylaxis alone is not 
adequate.  
Agents classified as having the highest therapeutic index (such as 5-HT3 receptor antagonists) per 
ASCO or MASCC/ESMO guidelines for anti-emetics in oncology or dexamethasone are 
recommended66-68. Caution is recommended with the use of aprepitant or fosaprepitant and 
nabilone as cabozantinib exposure may be affected by concomitant administration because 
aprepitant and fosaprepitant are both inhibitors and inducers of CYP3A4, and nabilone is a weak 
inhibitor of CYP3A4. 
5.2.2.3 Stomatitis and Mucositis 
Preventive measures may include a comprehensive dental examination to identify any potential 
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 cleansing, and oral rinses (eg, with a weak solution of salt and baking soda) 
should be maintained. The oral cavity should be rinsed and wiped after meals, and dentures should 
be cleaned and brushed often to remove plaque. Local treatment should be instituted at the earliest 
onset of symptoms. When stomatitis interferes with adequate nutrition and local therapy is not 
adequately effective, dose reduction or temporary withholding of cabozantinib should be 
considered. 
5.2.2.4 Hepatobiliary Disorders 
In general, it is recommended that subjects with elevation of ALT, AST, and/or bilirubin have 
more frequent laboratory monitoring of these parameters. If possible, hepatotoxic concomitant 
medications and alcohol should be discontinued in subjects who develop elevated transaminases.  
See section 6.1.4 for additional information. 
5.2.2.5 Skin Disorders 
All subjects on study should be advised on prophylactic measures for hand-foot syndrome 
including the use of emollients (Ammonium lactate 12% cream or heavy moisturizer twice daily), 
removal of calluses, avoidance of exposure of hands and feet to hot water leading to vasodilatation, 
protection of pressure-sensitive areas of hands and feet, and use of cotton gloves and socks to 
prevent injury and keep the palms and soles dry. 
The onset of PPE is variable with paresthesia (tingling, numbness) being the characteristic initial 
manifestation, which can be accompanied by slight redness or mild hyperkeratosis. PPE advances 
with symmetrical painful erythema and swollen areas (edema) on the palms and soles. The lateral 
sides of the fingers or periungual zones may also be affected. Adequate interventions are required 


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to prevent worsening of skin symptoms such as blisters, desquamations, ulcerations, or necrosis 
of affected areas. 
Urea 20% cream twice daily and clobetasol 0.05% cream once daily should be used in subjects 
that exhibit toxicity.  NSAIDS, GABA agonists and opioids may be used for pain control. 
Aggressive management of symptoms is recommended, including early dermatology referral. 
Subjects with skin disorders should be carefully monitored for signs of infection (eg, abscess, 
cellulitis, or impetigo). 
In the case of study treatment-related skin changes (eg, rash, hand-foot syndrome), the investigator 
may request that additional assessments be conducted with the subject’s consent. These 
assessments may include digital photographs of the skin changes and/or a biopsy of the affected 
skin and may be repeated until the skin changes resolve.  
5.2.2.6 Embolism and Thrombosis  
Low molecular weight heparin should be used to establish full anticoagulation in subjects on the 
first occurrence of a PE and/or DVT. Full anticoagulation with warfarin is not permitted and 
venous filters are not recommended. Treatment can be restarted at the discretion of the investigator.  
Subjects should permanently discontinue after a second thrombotic event.  
Although routine prophylactic anticoagulation is not necessary for all subjects, prophylactic 
anticoagulation is allowed for individual subjects at the discretion of the investigator. 
5.2.2.7 Hypertension 
See instructions in section 6.1.8. 
5.3 
ON STUDY ASSESSMENTS 
Please see study calendar (section 10) for schedule of the study assessments. 
5.3.1 Electrocardiogram (ECG) Assessments 
ECG assessments will be performed with standard 12-lead ECG equipment according to standard 
procedures. Pre-treatment ECGs should be performed after vital signs are obtained and before any 
blood draws. At any time point, if there is an increase in QTc interval to an absolute value > 500 
msec using the Fridericia correction formula, two additional ECGs should be performed 
approximately 2 minutes apart, within 30 minutes. If the average QTc interval calculated by the 
Fridericia formula from the three ECGs is > 500 msec, study treatment must be withheld and a 
cardiology consultation is recommended for evaluation and subject management. Study treatment 
may only be continued if the QTc resolves to 500msec or less and per investigator judgment that 
continued treatment is appropriate. Abnormalities in the ECG that lead to a change in subject 
management (eg, dose reduced or withheld, requirement for additional medication or monitoring) 
or result in clinical signs and symptoms are considered clinically significant for the purposes of 
this study and will be recorded on the AE CRF. If values meet criteria defining them as serious, 
they must be reported as SAEs. When an ECG time point coincides with other activities, the ECG 
will be collected first, followed by vital signs. 


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5.3.2 Vital Signs 
Vital signs (body temperature, respiratory rate, and blood pressure and pulse) will be conducted at 
regular intervals. Blood pressure and pulse will be measured after the subject has been sitting for 
at least 5 minutes. 
When vital signs are scheduled at the same time as blood draws, the blood draws will be obtained 
at the scheduled time point, and the vitals will be obtained as close to the scheduled blood draw as 
possible. 
5.3.3 Physical Examinations 
A physical examination will include assessments of general appearance, skin, HEENT, 
thorax/lungs, cardiovascular, abdominal, genitourinary, musculoskeletal and neurological 
findings. Any pertinent findings should be documented either in the subject’s medical history (if 
determined to be prior to the first dose of cabozantinib) or as an AE (if new or worsening after the 
first dose of cabozantinib). 
5.3.4 Laboratory Assessments 
Laboratory assessments will include the following: 
5.3.4.1 Hematology: 
 
CBC with differential 
 
Reticulocytes (if indicated) 
 
Erythrocyte sedimentation rate (if indicated) 
5.3.4.2 Serum chemistries: 
 
Hepatic panel (alkaline phosphatase, ALT/GPT, AST/GOT, total bilirubin, direct 
bilirubin) 
 
Acute care panel (sodium, potassium, chloride, total CO2 (Bicarbonate), creatinine, 
glucose, urea nitrogen) 
 
Mineral panel (albumin, calcium total, magnesium total, phosphorus) 
 
Ionized calcium 
 
Amylase 
 
Lipase 
 
Lactate dehydrogenase (LDH) 
 
Total protein 
 
J-glutamyltransferase (GGT) 
5.3.4.3 Urinalysis including urine creatinine and UPCR 
5.3.4.4 Thyroid function tests - TSH, total T3 and T4 
5.3.4.5 PT/INR or PTT 
5.3.4.6 24 hour urine collection for protein 
5.3.4.7 Urine or serum HCG (in women of childbearing potential) 
5.4 
DURATION OF THERAPY 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of the 
following criteria applies: 


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x 
Disease progression (unless patients are on drug holiday in which case disease 
progression will prompt resuming the treatment), 
x 
Intercurrent illness that prevents further administration of treatment, 
x 
Unacceptable adverse event(s), 
x 
Patient decides to withdraw from the study, or 
x 
General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
x 
Necessity for treatment with other anticancer treatment prohibited by the protocol, 
x 
Sexually active subjects who refuse to use medically accepted barrier methods of 
contraception (e.g., male condom, female condom) during the course of the study 
and for 4 months following discontinuation of study treatment, 
x 
Women who become pregnant or are breast feeding, 
x 
Request by regulatory agencies for termination of treatment of an individual 
subject or all subjects under the protocol, or 
x 
Significant noncompliance with the protocol schedule in the opinion of the 
investigator. 
x 
The minimum dose of study treatment will be 20 mg once per day. Subjects who 
cannot tolerate 20 mg once per day will have study treatment discontinued. 
5.5 
DURATION OF FOLLOW UP 
Patients will be contacted by telephone 30 – 37 days after the last dose of cabozantinib for a safety 
assessment. Patients on drug holiday do not need to be contacted.  
Any study drug remaining in the patient’s possession at this time will be returned by mail and 
treatment compliance will be documented.  Additional follow-up will occur for subjects with AEs 
related to study treatment that are ongoing at the time of this phone call, and for subjects with 
SAEs related to study treatment that occur after the time of this phone call. 
The Investigator or designees will make every possible attempt every 2 months (±7 days) after 
the follow-up phone call to contact the patient or family to obtain the survival information of the 
patient and start date of additional anticancer treatment. 
5.6 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
Prior to removal from study, effort must be made to have all subjects complete a safety phone call 
approximately 30 days following the last dose of study therapy.  
5.6.1 Criteria for removal from protocol therapy 
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.  


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In addition, any of the following conditions unless they occur during the drug holiday require 
withdrawal of the subject from study treatment: 
x An AE or intercurrent illness that in the opinion of the investigator warrants the 
subject’s withdrawal from treatment 
x Hemorrhage within 30 days of agent administration 
x Necessity for treatment with other investigational drug or other anticancer 
medications prohibited by protocol 
x Noncompliance with the protocol schedule 
x Participation in another clinical study using anticancer agent(s) 
x Occurrence of any grade 4 non hematologic AE unless the subject is unequivocally 
deriving clinical benefit 
x Occurrence of grade 4 febrile neutropenia unless the subject is unequivocally deriving 
clinical benefit 
x Inability to tolerate a 20 mg daily dose of cabozantinib 
x Request by regulatory agencies for termination of treatment of an individual subject 
or all subjects under this protocol 
x Sexually active subjects who refuse to use medically accepted barrier methods of 
contraception (eg, male condom, female condom) during the course of the study and 
for 4 months following discontinuation of study treatment 
x Women who become pregnant or are breast feeding 
x Cabozantinib treatment delays > 6 weeks unless the subject was unequivocally 
benefitting from cabozantinib treatment 
x Progressive disease (PD) 
x Investigator Discretion 
The reason for study treatment discontinuation will be documented. For subjects who discontinue 
or are withdrawn from study treatment, every effort must be made to undertake protocol-specified 
follow-up procedures and end-of-treatment assessments, if possible, unless consent to participate 
in the study is also withdrawn. 
If a subject fails to return for the protocol-defined visits, an effort must be made to determine the 
reason. If the subject cannot be reached by telephone, at the minimum a registered letter should be 
sent to the subject (or the subject’s legal guardian) requesting contact with the clinic. 
If a subject is discontinued from study treatment because of an AE considered to be related to 
study treatment and the event is ongoing 30 days after the last dose of study treatment, the event 
must be followed until resolution or determination by the investigator that the event has become 
stable or irreversible. 
5.6.2 Off Study Criteria 
x Investigator Discretion 
x Manufacturer no longer able to supply study agent 
x Participant requests to be withdrawn from study 


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x Death 
If a subject withdraws consent to participate in the study, the reason for withdrawal will be 
documented, no further study procedures or assessments will be performed, and no further study 
data will be collected for this subject, other than the determination of survival status from public 
records such as government vital statistics or obituaries.  
5.6.3 Off Protocol Therapy and Off Study Procedure 
Authorized staff must notify Central Registration Office (CRO) when a subject is off protocol 
therapy and when a subject is taken off-study. A Participant Status Update Form from the web 
site (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be completed and 
sent via encrypted email to:  NCI Central Registration Office ncicentralregistration-
l@mail.nih.gov. 
6 
DOSING DELAYS/DOSE MODIFICATIONS 
6.1 
CABOZANTINIB  
Subjects will be monitored continuously for AEs throughout the study and for 30 days after the 
last dose of study treatment and for any serious adverse event (SAE) assessed as related to study 
treatment or study procedures, even if the SAE occurs more than 30 days after the last dose of 
study treatment. 
Subjects will be instructed to notify their physician immediately of any and all AEs. Subjects 
experiencing one or more AEs due to the study treatment may require a dosing delay or 
reduction(s) in their dose in order to continue with study treatment.  
General guidelines for the management of non-hematologic and hematologic toxicities are 
provided in section 6.1.1 and section 6.1.2, respectively. As a general approach, it is suggested 
that all AEs be managed with supportive care when possible at the earliest signs of toxicity. 
Calcium, magnesium, potassium and phosphorus should be kept above the lower limits of the 
laboratory normal values. For more specific guidelines on gastrointestinal AEs (diarrhea, 
nausea/vomiting, stomatitis/mucositis), hepatobiliary disorders, pancreatic disorders including 
lipase and amylase elevations, skin disorders (PPE), embolism and thrombus, hypertension, 
proteinurea, hemorrhage, rectal and perirectal abscess, gastrointestinal (GI) perforation and GI 
fistula, non-GI fistula, wound healing and surgery, osteonecrosis of the jaw (ONJ),  endocrine 
disorders and management of treatment-emergent prolongation of the QTc interval, refer to the 
appropriate section below.  Guidance for the management of fatigue, anorexia, weight loss, eye 
disorders, musculoskeletal and connective tissue disorders, nervous system disorders, 
respiratory/thoracic/mediastinal disorders and congenital, familial and genetic disorders can be 
found in the Cabozantinib Investigator’s Brochure.  
Re-escalating study treatment after a dose reduction: 
x Subjects who required a dose reduction for Grade 4 non-hematologic toxicity should not be 
re-escalated 
x For other related AEs, subjects may be re-escalated to the previous dose at the discretion of 
the investigator but not sooner than 2 weeks after resolution to Grade ≤ 1 or to the baseline 
value of AEs. 


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x If a subject has been dose-reduced more than once, dose re-escalation can only occur to the 
next higher dose level. Further dose escalation to higher well-tolerated dose levels is allowed 
only if clinically indicated per investigator’s judgment and dose escalation criteria are met 
with each escalation (e.g. a minimum 2 week interval between escalations)  
x If the AEs that previously led to dose reduction(s) recur upon re-escalation, the dose should 
be reduced again and no further dose escalation will be permitted.  
x Dose re-escalation is not allowed for dose reduction triggered by neutropenia or 
thrombocytopenia.  
Dosing may need to be interrupted for AEs considered not related to cabozantinib if this is 
clinically indicated or if causality is initially uncertain. Study treatment may be resumed at the 
same dose (or a lower dose per investigator judgment) if the AE is determined not to be related to 
cabozantinib once the investigator determines that retreatment is clinically appropriate and the 
subject meets the protocol re-treatment criteria. 
Dosing delays and modification instructions for cabozantinib hematologic and non-hematologic 
toxicities are below.  Please consult Table 2 for the appropriate dose at each dose reduction.  If 
study treatment of cabozantinib is restarted after being withheld or interrupted, the subject should 
be instructed not to make up the missed doses of cabozantinib.  
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.  Baseline CT and bone scans must be repeated at the time the study drug 
is reinitiated. 
The minimum dose of study treatment will be 20 mg daily. Subjects who cannot tolerate 20 mg 
daily will have study treatment discontinued. 
Table 2: Dose Levels 
Dose Level  
Cabozantinib dose 
-2 
20 mg 
-1 
40 mg 
1 
60 mg 
2 
80 mg 
 
The reason for treatment delay and reduced dose must be recorded on the case report form (CRF). 
6.1.1  General Guidelines for other Non-Hematologic Toxicities 
CTCAE Version 5 Grade  
Guidelines/Intervention 
Grade 1: 
Add supportive care as indicated.  Continue study treatment at 60 mg 
daily. 


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CTCAE Version 5 Grade  
Guidelines/Intervention 
Grade 2: 
Grade 2 AEs considered related to 
study treatment that are subjectively 
tolerable or easily managed 
Add supportive care as indicated.  Continue study treatment at 60 mg 
daily. 
Grade 2 AEs considered related to 
study treatment that are intolerable to 
the subject or deemed unacceptable in 
the investigator’s judgment; or are not 
easily managed or corrected 
Dose reduce 
x 
If the AE dose not resolve to Grade ≤ 1 or baseline in 7 to 10 days 
or worsens at any time, cabozantinib dosing should then be 
interrupted.  Then upon resolution to baseline or Grade ≤ 1, the 
reduced dose should be restarted. 
x 
If the AE resolves to Grade ≤ 1 or baseline without a dose 
interruption, continue the reduced dose. 
Grade 3: 
 
Grade 3 AEs considered related to 
study treatment which occurred 
without optimal prophylaxis or which 
is easily managed by medical 
intervention or resolved quickly 
x 
Interrupt study treatment and add supportive care as indicated 
x 
For AEs that are easily managed (e.g., correction of electrolytes) 
with resolution to baseline or Grade ≤ 1 within 24 hours,  
treatment may be resumed at either the same dose or with a dose 
reduction at the discretion of the investigator unless this is a 
recurring event at which time the dose should be reduced 
x 
For AEs that require supportive care, the dose should be held 
while supportive care is initiated and optimized.  Then upon 
resolution of the AE to baseline or Grade ≤ 1, treatment should be 
restarted with a dose reduction.  Note: if the investigator believes 
the likelihood of a reoccurrence of the same Grade 3 AE is small 
due to continued prophylaxis or other effective intervention, 
treatment may be resumed without a dose reduction and with very 
careful monitoring of the subject.   
Grade 3 AEs considered related to 
study treatment that occurred despite 
optimal prophylaxis or is not easily 
managed by medical intervention  
Interrupt study treatment until recovery to ≤ Grade 1 or baseline, and 
resume treatment with a dose reduction 
Grade 4: 
 
Grade 4 AEs considered related to 
study treatment 
Permanently discontinue study treatment unless determined that the 
subject is unequivocally deriving clinical benefit.  In this case, upon 
recovery to Grade ≤ 1 or baseline, the subject may be re-treated at a 
reduced dose that is to be determined by the investigator. 
Dose reductions or delays may occur in the setting of lower grade toxicity than defined above if the 
investigator believes that it is in the interest of the subject’s safety.  
 


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6.1.2 Hematologic Toxicities 
CTCAE Version 5 Grade 
Intervention 
Neutropenia 
Grade 3 neutropenia with documented 
infection 
Grade 3 neutropenia ≥ 5 days 
Grade 4 neutropenia   
Interrupt cabozantinib treatment until resolution to Grade ≤ 1, and 
resume cabozantinib treatment at a one dose level reduction.  
Thrombocytopenia 
Grade 3 thrombocytopenia with clinically 
significant bleeding or Grade 4 
thrombocytopenia 
Interrupt cabozantinib treatment until resolution to ≤ Grade 1, and 
resume cabozantinib treatment at a one dose level reduction 
Febrile Neutropenia 
Grade 3 febrile neutropenia 
Interrupt cabozantinib treatment until recovery of ANC to Grade ≤ 1 
and temperature to ≤ 38.0°C and resume cabozantinib treatment at a 
one dose level reduction. 
Grade 4 febrile neutropenia 
Permanently discontinue study treatment unless determined that the 
subject is unequivocally deriving clinical benefit.  In this case, upon 
recovery to Grade ≤ 1 or baseline, the subject may be re-treated at a 
reduced dose that is to be determined by the investigator and 
sponsor, but only with sponsor approval. 
Other Grade 4 Hematologic Toxicities 
Grade 4 hematologic toxicities  
other than anemia 
Permanently discontinue study treatment unless determined that the 
subject is clearly deriving clinical benefit. In this case, upon 
recovery to Grade ≤1 or baseline, the subject may be re-treated at a 
reduced dose that is to be determined by the investigator and 
sponsor and only with approval by the sponsor. 
Grade 4 anemia 
Permanent discontinuation for Grade 4 anemia is not mandated. 
Dose reductions or dose delays for anemia should be applied as 
clinically indicated. Supportive care such as red blood cell 
transfusions should be managed according to institutional 
guidelines. 
 
ANC, absolute neutrophil count; LLN, lower limit of normal 
Neutropenia: Grade 1 (LLN ≤ ANC < 1.5 u 109/L; Grade 2 (1 u 109/L ≤ ANC <1.5 x 109/L),  
Grade 3 (0.5 u 109/L ≤ ANC < 1 u 109/L), Grade 4 (ANC < 0.5 u 109/L). 
Febrile Neutropenia: Grade 3 (present); Grade 4 (Life-threatening consequences; urgent intervention indicated). 
Thrombocytopenia: Grade 1 (<LLN – 75 x 109/L); Grade 2 (<75.0 – 50.0 x 109/L);   
Grade 3 (Platelet count ≤ 50 - 25 u 109/L); Grade 4 (Platelet count < 25 x 109/L). 
 
No dose modifications are required for grade 1, grade 2 or other grade 3 hematological toxicities.   
6.1.3 Diarrhea, Nausea, Vomiting,  Stomatitis, and Mucositis 
6.1.3.1 Diarrhea 


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Subjects should be instructed to notify their physician immediately at the first signs of poorly 
formed or loose stool or an increased frequency of bowel movements.  Administration of 
antidiarrheal agents is recommended at the first sign of diarrhea as initial management.  
Loperamide is recommended as standard first line therapy.  Alternatively, diphenoxylate/atropine 
can be used.  Additional agents to consider in subjects with diarrhea that is refractory to the above 
include deodorized tincture of opium and octreotide (Benson et al., 2004).  Some subjects may 
require concomitant therapy with loperamide, diphenoxylate/atropine, and deodorized tincture of 
opium to control diarrhea.  The dose modification guidance in Table 6-1 should be followed.  In 
addition, general supportive measures should be implemented including continuous oral hydration, 
correction of fluid and electrolyte abnormalities, small frequent meals, and stopping lactose-
containing products, high fat meals and alcohol.  
6.1.3.2 Nausea and Vomiting 
Anti-emetic agents along with supportive care are recommended as clinically appropriate at the 
first sign of nausea and vomiting.  The dose modification guidance in Table 6.1.1 should be 
followed. 
The 5-HT3 receptor antagonists are recommended over chronic use of NK-1 receptor antagonists 
and dexamethasone (NK-1 receptor antagonists can induce or inhibit CYP3A4, and 
glucocorticoids induce CYP3A4 and thus could lower cabozantinib exposure.  Caution is also 
recommended with the use of nabilone, which is a weak inhibitor of CYP3A4. 
6.1.3.3 Stomatitis and Mucositis 
Preventive measures may include a comprehensive dental examination to identify any potential 
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 cleansing, and oral rinses (e.g., with a weak solution of salt and baking soda) 
should be maintained.  The oral cavity should be rinsed and wiped after meals, and dentures should 
be cleaned and brushed often to remove plaque. Local treatment should be instituted at the earliest 
onset of symptoms.  When stomatitis interferes with adequate nutrition and local therapy is not 
adequately effective, dose reduction or temporary withholding of cabozantinib should be 
considered. 
6.1.4 Hepatobiliary Disorders 
Elevations of transaminases have also been observed during treatment with cabozantinib.  In 
general, it is recommended that subjects with elevation of ALT, AST, and/or bilirubin have more 
frequent laboratory monitoring of these parameters.  If possible, hepatotoxic concomitant 
medications and alcohol should be discontinued in subjects who develop elevated transaminases.  
Since subjects may enter the study with elevations of AST/ALT at baseline, the following 
guideline should be used for dose modifications: 
Transaminase elevation 
CTCAE v5.0 
 
Intervention 
Subjects with AST and ALT less than or equal to the ULN at baseline 
Grade 1  
Continue cabozantinib with weekly monitoring of liver function tests (LFTs) for at 
least 4 weeks. Then resume the standard protocol-defined monitoring of LFTs. 


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Cabozantinib treatment should also be interrupted when transaminase increases are accompanied 
by progressive elevations of total bilirubin, and/or elevations of coagulation tests (e.g., 
International Normalized Ratio [INR]).  Monitoring of transaminases should be intensified (2–3 
times per week) and cabozantinib should be held until the etiology of the abnormalities is 
determined and these abnormalities are corrected or stabilize at clinically acceptable levels (INR 
< 1.5 u ULN, total bilirubin < 1.5 u ULN, aminotransferases ≤ baseline grade).  
Subjects must have cabozantinib permanently discontinued if transaminase elevations are 
accompanied by evidence of impaired hepatic function (bilirubin elevation >2 uULN), in the 
absence of evidence of biliary obstruction (i.e., significant elevation of alkaline phosphatase) or 
some other explanation of the injury (e.g., viral hepatitis, alcohol hepatitis), as the combined 
finding (i.e., Hy’s Law cases) represents a signal of a potential for the drug to cause severe liver 
injury. 
Grade 2 
Continue cabozantinib with at least twice weekly monitoring of LFTs for 2 weeks. 
Then weekly for 4 weeks.  If LFTs continue to rise within Grade 2, interrupt 
cabozantinib treatment.   Then continue with at least weekly LFTs until resolution 
to Grade ≤ 1.  Study treatment may then be resumed at a one-dose-level reduction 
of cabozantinib 
Grade 3  
Interrupt cabozantinib treatment and monitor with at least twice weekly LFTs until 
Grade ≤ 2.  Then continue with at least weekly LFTs until resolution to Grade ≤ 1.  
Cabozantinib may then be resumed at a one-dose-level reduction.  
Grade 4 
Discontinue study treatment permanently. LFTs should be monitored as clinically 
indicated, at least 2-3 times per week, until resolution to Grade ≤ 1.   If the subject 
was unequivocally deriving clinical benefit, the subject may be able to resume 
treatment at a lower dose of cabozantinib as determined by the investigator and 
sponsor but only with sponsor approval. 
Subjects with AST or ALT above the ULN  but ≤ 3.0 x ULN (i.e., Grade 1) at  baseline   
≥ 1.5 fold increase of AST or 
ALT AND both AST and 
ALT are ≤ 5.0 x ULN 
Continue cabozantinib treatment with at least twice weekly monitoring of LFTs 
for 4 weeks and weekly for 4 weeks.  If LFTs continue to rise, interrupt study 
treatment.   Then continue with at least weekly LFTs until resolution to Grade ≤ 1.  
Study treatment may then be resumed at a one-dose-level reduction of 
cabozantinib 
≥ 1.5 fold increase of AST or 
ALT and at least one of 
AST or ALT is Grade 3 (i.e. 
AST or ALT > 5.0 but ≤ 
20.0 x ULN) 
Interrupt study treatment and monitor with at least twice weekly LFTs until 
Grade ≤ 2.  Then continue with at least weekly LFTs until resolution to Grade ≤ 1.  
Study treatment may then be resumed at a one-dose-level reduction of 
cabozantinib. 
Grade 4  
Discontinue study treatment permanently. LFTs should be monitored as clinically 
indicated, at least 2-3 times per week, until resolution to Grade ≤ 1.  If the subject 
was unequivocally deriving clinical benefit, the subject may be able to resume 
treatment at a lower dose as determined by the investigator and sponsor but only 
with sponsor approval. 


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All subjects who develop isolated bilirubin elevations of Grade 3 should have study treatment held 
until recovered to Grade ≤1 or baseline (or lower).  If this occurs within 6 weeks of the dosing 
delay, study treatment may continue at a reduced dose. In subjects without biliary obstruction and 
Grade 4 bilirubin elevation, or with recurrence of Grade 3 bilirubin elevation after a dose reduction, 
study treatment must be discontinued.  
6.1.5 Pancreatic Conditions 
Amylase and lipase elevations have been observed in clinical studies with cabozantinib.  The 
clinical significance of asymptomatic elevations of enzymes is not known but in general has not 
been associated with clinically apparent sequelae.  It is recommended that subjects with lipase 
elevation and/or symptoms of pancreatitis have more frequent laboratory monitoring of lipase 
and/or amylase (2-3 times per week). Subjects with symptomatic pancreatitis should be treated 
with standard supportive measures. 
6.1.5.1 Asymptomatic Lipase or Amylase Elevations 
Asymptomatic Lipase or Amylase Elevations 
Grade 1 or Grade 2 
Continue at current dose level.  More frequent monitoring is recommended 
Grade 3 
x 
Interrupt treatment 
x 
Monitor lipase and amylase twice weekly 
x 
Upon resolution to Grade ≤1 or baseline, cabozantinib may be restarted 
at the same dose or at a reduced dose provided that this occurs within 6 
weeks. 
x 
If retreatment following Grade 3 lipase or amylase elevation is at the 
same dose and Grade 3 or Grade 4 elevations recur, then treatment must 
be interrupted again until lipase and amylase  levels have resolved to 
Grade ≤1 or baseline and retreatment must be at a reduced dose. 
Grade 4 
x 
Interrupt treatment 
x 
Monitor lipase and amylase twice weekly 
x 
Upon resolution to Grade ≤1 or baseline and if resolution occurred 
within 4 days, cabozantinib may be restarted at the same dose or a 
reduced dose.  If resolution took more than 4 days, the dose must be 
reduced upon retreatment provided that resolution occurred within 6 
weeks. 
x 
If retreatment following Grade 4 lipase or amylase elevation is at the 
same dose and Grade 3 or 4 elevations recur, then treatment must be 
interrupted again until lipase and amylase have resolved to Grade ≤1 or 
baseline and retreatment must be at a reduced dose. 
 
6.1.5.2 Pancreatitis 


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Pancreatitis 
Grade 2 and asymptomatic 
x 
Continue at current dose level. More frequent monitoring of lipase and 
amylase and radiographic evaluation is recommended. 
Grade 2 symptomatic and 
Grade 3 
x 
Interrupt treatment 
x 
Monitor lipase and amylase twice weekly 
x 
Upon resolution to Grade ≤1 or baseline , cabozantinib may be restarted 
at a reduced dose if resolution occurred within 6 weeks 
Grade 4 
Permanently discontinue treatment.  However, if the subject was unequivocally 
deriving benefit from cabozantinib therapy, treatment may resume at a reduced at 
a reduced dose agreed to by the investigator and sponsor but only with sponsor 
approval. 
 
6.1.6 Skin Disorders 
Palmar-plantar erythrodysesthesia syndrome (PPE; also known as hand-foot syndrome), skin rash 
(including blister, erythematous rash, macular rash, skin exfoliation, dermatitis acneiform, and 
papular rash), pruritus, dry skin, erythema, pigmentary changes, and alopecia have been reported 
in cabozantinib-treated subjects.  All subjects on study should be advised to use prophylactic 
measures for skin care.  These measures includes the use of hypoallergenic moisturizing creams, 
ointment for dry skin, sunscreen with SPF ≥30; avoidance of exposure of hands and feet to hot 
water; protection of pressure-sensitive areas of hands and feet; and use of thick cotton gloves and 
socks to prevent injury and to keep the palms and soles dry. Subjects with skin disorders should 
be carefully monitored for signs of infection (e.g., abscess, cellulitis, or impetigo). 
Early signs of hand-foot syndrome can include tingling, numbness, and slight redness or mild 
hyperkeratosis.  Early manifestations include painful, symmetrical red and swollen areas on the 
palms and soles.  The lateral sides of the fingers or periungual zones may also be affected.  
Adequate interventions are required to prevent worsening of skin symptoms such as blisters, 
desquamations, ulcerations, or necrosis of affected areas.  Aggressive management of symptoms 
is recommended, including early dermatology referral. 
Treatment guidelines for PPE related to study treatment are presented in the table below. 
In the case of study treatment-related skin changes (e.g., rash, hand-foot syndrome), the 
investigator may request that additional assessments be conducted with the subject’s consent.  
These assessments may include digital photographs of the skin changes and/or a biopsy of the 
affected skin and may be repeated until the skin changes resolve.  


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6.1.6.1 Hand-Foot Skin Reaction and Hand Foot Syndrome (PPE) 
Grade 1 
Continue cabozantinib at current dose.  Start urea 20% cream twice daily AND 
clobetasol 0.05% cream once daily. Assess subject at least weekly for changes in 
severity.  Subjects should be instructed to notify investigator immediately if 
severity worsens.   
Grade 2 
If tolerable, continue cabozantinib at current dose.  If intolerable, reduce 
cabozantinib dose to next lower level and/or interrupt dosing. Start/continue urea 
20% cream twice daily AND clobetasol 0.05% cream once daily. Add analgesics 
for pain control with NSAIDs/GABA agonists/narcotics if needed. Assess subject 
at least weekly for changes in severity.  If treatment was interrupted (but not 
reduced), treatment may be restarted at the same dose or at one dose level lower 
when reaction decreases to Grade 1 or 0.  If a treatment interruption is again 
required, the dose must be reduced when treatment resumes. Subjects should be 
instructed to notify investigator immediately if severity worsens.  If severity 
worsens at any time, or affects self-care, proceed to the management guidelines 
for Grade 3 PPE.   
Grade 3 
Interrupt study treatment until severity decreases to Grade 1 or 0.  Start/continue 
urea 20% cream twice daily AND clobetasol 0.05% cream once daily. Pain 
control with NSAIDs/GABA agonists/narcotics.  Treatment may restart at one 
dose level lower when reaction decreases to Grade 1 or 0. Permanently 
discontinue subject from study if reactions worsen or do not improve within 6 
weeks.  
GABA, γ-aminobutyric acid; NSAID, nonsteroidal anti-inflammatory drugs; PPE, palmar-plantar erythrodysesthesia 
 
6.1.7 Embolism and Thrombosis  
Deep vein thrombosis and PE have been observed in clinical studies with cabozantinib; including 
fatal events (please refer to the IB).  Subjects who develop a PE or DVT should have study 
treatment held until therapeutic anticoagulation with heparins is established.  Study treatment may 
be resumed with a one dose-level reduction in subjects who have uncomplicated PE or DVT and 
are deriving clinical benefit from study treatment.  During treatment with anticoagulants, subjects 
need to be monitored on an ongoing basis for bleeding risk and signs of bleeding.  Subjects with 
life-threatening PE or DVT should have study treatment discontinued unless toxicity can be 
managed and subject is deriving clear clinical benefit as determined by the investigator and agreed 
by the Sponsor.  Venous filters (e.g. vena cava filters) are not recommended due to the high 
incidence of complications associated with their use.  Once a subject is fully anticoagulated, 
treatment can be restarted per investigator judgment at one dose lower.  Subjects should 
permanently discontinue after a second thrombotic event.  Although routine prophylactic 
anticoagulation is not necessary for all subjects, prophylactic anticoagulation is allowed for 
individual subjects at the discretion of the investigator. 
Arterial thrombotic events (e.g., transient ischemic attack, myocardial infarction) have been 
observed rarely in studies with cabozantinib.  Cabozantinib should be discontinued in subjects who 
develop an acute MI or any other clinically significant arterial thromboembolic complication. 


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6.1.8 Hypertension 
Hypertension is a relatively common complication of other VEGF-pathway inhibitors and has been 
observed in cabozantinib clinical studies. 
Decisions to decrease or hold the dose of study treatment must be based on BP readings taken by 
a medical professional and must be confirmed with a second measurement at least 5 minutes 
following the first measurement.  Subjects with known hypertension should be optimally managed 
prior to study entry.  Clinical judgment should be used in deciding whether new or worsened 
hypertension emerging during treatment with cabozantinib requires immediate therapy, or whether 
therapeutic intervention can be delayed in order to confirm the finding of new or worsened 
hypertension at a second visit before taking new therapeutic action.  It is recommended that this 
second visit occur within 1 week.  Blood pressure should be monitored in a constant position visit 
to visit, either sitting or supine.  Cabozantinib dosing should be interrupted in subjects with severe 
hypertension (≥180 mm Hg systolic or ≥120 mm Hg diastolic; or sustained ≥160 mm Hg systolic 
or ≥110 diastolic) who cannot be controlled with medical interventions and discontinued in 
subjects with hypertensive crises or hypertensive encephalopathy (see next Table below). 
 
6.1.8.1 Management of Hypertension Related to Cabozantinib 
Criteria for Dose Modifications 
Treatment/cabozantinib Dose Modification 
Subjects not receiving optimized anti-hypertensive therapy 
> 140 mm Hg (systolic) and < 160 mm Hg 
OR 
> 90 mm Hg (diastolic) and < 110 mm Hg 
 
 
x Increase antihypertension therapy  (i.e., increase dose of 
existing medications and/or add new antihypertensive 
medications)  
x Maintain dose of cabozantinib 
x If optimal antihypertensive therapy (usually to include 
3 agents) does not result in blood pressure < 140 systolic or < 
90 diastolic, or if the subject is symptomatic, the dose of 
cabozantinib should be reduced. 
≥ 160 mm Hg (systolic) and < 180 mm Hg 
OR 
≥ 110 mm Hg (diastolic) and < 120 mm Hg 
x Reduce cabozantinib by one dose level. 
x Increase antihypertension therapy  (i.e., increase dose of 
existing medications and/or add new antihypertensive 
medications)  
x Monitor subject closely for hypotension. 
x If optimal antihypertensive therapy (usually to include 
3 agents) does not result in blood pressure < 140 systolic or < 
90 diastolic, dose of cabozantinib should be reduced further. 


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Criteria for Dose Modifications 
Treatment/cabozantinib Dose Modification 
≥ 180 mm Hg (systolic) OR 
≥ 120 mm Hg (diastolic) 
x Interrupt treatment with cabozantinib Add new or additional 
anti-hypertensive medications and/or increase dose of 
existing medications. 
x Monitor subject closely for hypotension. 
x When SBP < 140 and DBP < 90, restart cabozantinib 
treatment at one dose level lower 
x If optimal antihypertensive therapy (usually to include 
3 agents) does not result in blood pressure < 140 systolic or < 
90 diastolic, dose of cabozantinib should be reduced further. 
Hypertensive crisis or hypertensive 
encephalopathy 
Discontinue all study treatment 
BP, blood pressure, SBP systolic blood pressure, DBP diastolic blood pressure 
NOTE:  If SBP and DBP meet different criteria in table, manage per higher dose-modification criteria 
 
 
Patients with a history of hypertension should be instructed to record their blood pressure once per 
week during each cycle of cabozantinib on the form provided in Appendix E and to bring the form 
with them at each clinic visit.   
6.1.9 Proteinuria 
Proteinuria has been reported with approved drugs that inhibit VEGF pathways as well as with 
cabozantinib.  Any level of proteinuria diagnosed by dipstick should be quantified by a UPCR 
(mg/dL protein / mg/dL creatinine).  When a UPCR exceeds 2, a repeat UPCR or a 24-hour urine 
protein and creatinine should be performed to confirm the result. Cabozantinib should be 
discontinued in subjects who develop nephrotic syndrome (proteinuria >3.5 g/day in combination 
with hypoalbuminemia, edema and hyperlipidemia) or any other relevant renal disease.  Also, 
given the nephrotoxic potential of bisphosphonates, these agents should be used with caution in 
patients receiving treatment with cabozantinib.  Details of management are described in the next 
Table below. 
Management of Treatment Emergent Proteinuria 
 Urine Protein/Creatinine Ratio 
Action To Be Taken 
≤ 2 
x 
No change in treatment or monitoring 
> 2 and < 3.5 
 
x 
No change in study treatment required  
x 
Consider confirming with a 24-hour protein excretion within 7 
days 
x 
Repeat UPCR within 7 days and once every week. If UPCR is < 
2 on two consecutive readings, then UPCR monitoring can revert 
to protocol specific time points. (The second reading is a 
confirmatory reading and can be done within 1 week of the first 
reading.). 


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 Urine Protein/Creatinine Ratio 
Action To Be Taken 
≥ 3.5 
 
x 
Hold cabozantinib immediately and confirm with 24 hour urine 
protein excretion.  
x 
Evaluate for nephrotic syndrome. If present, discontinue 
cabozantinib treatment permanently, and monitor subject for 
resolution of nephrotic syndrome.  
x 
If proteinuria of ≥ 3.5 g/24 hours is confirmed without diagnosis 
of nephrotic syndrome, continue to hold cabozantinib and 
monitor UPCR weekly. If UPCR decreases to < 2.5, restart 
cabozantinib at a reduced dose.  Continue monitoring UPCR 
once every week until two consecutive readings are < 2, then 
revert to UPCR monitoring frequency specified in the protocol. 
UPCR, urine protein/urine creatinine ratio 
 
6.1.10 Guidelines for the Prevention of Hemorrhagic Events 
Hemorrhagic events have been reported with approved drugs that inhibit VEGF pathways as well 
as with cabozantinib.  As preventive measures, subjects should be evaluated for potential bleeding 
risk factors prior to initiating cabozantinib treatment and monitored for bleeding events with serial 
complete blood counts and physical examination while on study.  Risk factors for hemorrhagic 
events may include (but may not be limited to) the following: 
x Tumor lesions with cavitations or tumor lesions which invade, encase, or abut major 
blood vessels.  The anatomic location and characteristics of primary tumors or 
metastases as well as the medical history should be carefully reviewed in the selection 
of subjects for treatment with cabozantinib. 
x Recent or concurrent radiation to the thoracic cavity.  
x Active peptic ulcer disease, ulcerative colitis, and other inflammatory GI diseases. 
x Underlying medical conditions which affect normal hemostasis (e.g., deficiencies in 
clotting factors and/or platelet function, or thrombocytopenia). 
x Concomitant medication with anticoagulants or other drugs which affect normal 
hemostasis. 
x History of clinically significant hemoptysis. 
 
Cabozantinib should be discontinued in subjects with serious and life-threatening bleeding events 
or recent hemoptysis (≥0.5 teaspoon (2.5mL) of red blood).  Treatment with cabozantinib should 
be interrupted if less severe forms of clinically significant hemorrhage occur and may be restarted 
after the cause of hemorrhage has been identified and the risk of bleeding has subsided at a dose 
agreed to by the sponsor and the investigator.  Therapy of bleeding events should include 
supportive care and standard medical interventions.  
Furthermore, subjects who develop tumors invading a major blood vessel while on study treatment 
must be discontinued from cabozantinib treatment. 


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6.1.11 Rectal and Perirectal Abscess 
Rectal and perirectal abscesses have been reported, sometimes in subjects with concurrent 
diarrhea. These should be treated with appropriate local care and antibiotic therapy. Cabozantinib 
should be held until adequate healing has taken place.  
6.1.12 Guidelines for Prevention of GI Perforation/Fistula and Non-GI Fistula Formation 
GI perforation/fistula and Non-GI fistula formation have been reported with approved drugs that 
inhibit VEGF pathways as well as with cabozantinib. Carefully monitor for episodes of abdominal 
pain, especially in subjects with known risk factors for developing GI perforation/fistula or non-
GI fistula, to allow for early diagnosis. Such risk factors include (but may not be limited to) the 
following: 
6.1.12.1 GI-perforation/fistula: 
x Intra-abdominal tumor/metastases invading GI mucosa.  
x Active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, 
diverticulitis, cholecystitis or symptomatic cholangitis, or appendicitis . 
x History of abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal 
abscess 
x Prior GI surgery (particularly when associated with delayed or incomplete healing). 
Complete healing following abdominal surgery or resolution of intra-abdominal 
abscess must be confirmed prior to initiating treatment with cabozantinib. 
Additional risk factors include concurrent chronic use of steroid treatment or non-steroidal 
anti-inflammatory drugs.  Constipation indicative of bowel obstruction should be monitored and 
effectively managed.  
6.1.12.2 Non-GI fistula: 
x Radiation therapy has been identified as a possible predisposing risk factor for non-GI 
fistula formation in subjects undergoing treatment with drugs that inhibit VEGF 
pathways.  In addition, subjects who have undergone extensive surgery may be at 
increased risk of developing a fistula of the involved organs Non-GI fistula should be 
ruled out as appropriate in cases of onset of mucositis after start of therapy. 
Discontinue all study treatment in subjects who have been diagnosed with GI or non-GI 
perforation/fistula. 
6.1.13 Wound Healing and Surgery 
VEGF inhibitors can cause wound healing complications and wound dehiscence which may occur 
even long after a wound has been considered healed. Therefore, surgical and traumatic wounds 
must have completely healed prior to starting cabozantinib treatment and be monitored for wound 
dehiscence or wound infection while the subject is being treated with cabozantinib.  
Treatment with cabozantinib must be interrupted for any wound healing complication which needs 
medical intervention. Treatment with cabozantinib can be resumed once wound healing has 
occurred unless otherwise prohibited in specific protocols. Cabozantinib should be discontinued 
in subjects with serious or chronic wound healing complications. 


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The appropriate dose hold interval prior to elective surgery to reduce the risk for wound healing 
complications has not been determined. In general, cabozantinib should be stopped at least 3 weeks 
(5 half lives) prior to elective surgery.  
6.1.14 Endocrine Disorders 
Prospective studies of markers of thyroid functions are currently ongoing in two single-agent 
studies to characterize the effects of cabozantinib on thyroid function. Preliminary data indicate 
that cabozantinib affects thyroid function tests (TFTs) in a high number of subjects (see 
Cabozantinib Investigator’s Brochure).  Routine monitoring of thyroid function and assessments 
for signs and symptoms associated with thyroid dysfunction is recommended for subjects treated 
with cabozantinib. Management of thyroid dysfunction (e.g., symptomatic hypothyroidism) 
should follow accepted clinical practice guidelines. 
Other endocrine disorders such as hypocalcemia and hyperglycemia, and associated laboratory 
changes, have been observed in less than 10% of subjects.  Monitoring with standard laboratory 
tests for endocrine disorders and clinical examination prior to initiation and during treatment with 
cabozantinib is required. Cabozantinib should be discontinued in subjects with severe or life-
threatening endocrine dysfunction. 
6.1.15 Guidelines for Prevention of Osteonecrosis of the Jaw 
Osteonecrosis of the jaw (ONJ) has been reported with use of antiangiogenic drugs and 
bisphosphonates and denosumab in cancer patients.  Additional risk factors for ONJ have been 
identified such as use of corticosteroids, chemotherapy, local radiotherapy, poor oral hygiene, 
smoking, dental or orofacial surgery procedures, and cancer disease itself.  Cases of osteonecrosis 
have been reported in subjects treated with cabozantinib, the details of which are provided in the 
current version of Investigator’s Brochure.  As a preventive measure, invasive dental procedures 
should be avoided if possible in subjects who have previously been treated with or concomitantly 
receive bisphosphonates or denosumab. In cases where dental procedures are unavoidable, the 
risks and benefits of a dental procedure and the extent of the procedure as well as the risk of 
developing osteonecrosis of the jaw need to be considered when deciding on the duration of a 
temporary treatment interruption of cabozantinib.  If clinically possible, treatment with 
cabozantinib should be held for at least 2 weeks prior to a dental procedure and resumed after 
complete wound healing occurred. 
Subjects with any documented case of osteonecrosis should have study treatment interrupted, and 
appropriate clinical management should be initiated.  Reinitiation of study treatment must be 
discussed with and approved by the Sponsor on a case by case basis. 
6.1.16 Guidelines for Management of Treatment-Emergent Corrected QT (QTc) Prolongation 
Treatment with cabozantinib has been associated with a mild prolongation of the QTc interval.  
Other factors which may contribute to QTc prolongation include 
x Treatment with other drugs associated with QTc prolongation (see 
http://www.qtdrugs.org)  
x Treatment with CyP 3A4 inhibitors (which may increase cabozantinib drug levels) 
x Electrolyte changes (hypokalemia, hypocalcemia, hypomagnesemia). 


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x Medical conditions which can alter electrolyte status e.g., severe or prolonged 
diarrhea. 
Subjects having any of these additional risk factors while on cabozantinib must have ECGs 
performed approximately one week after the onset of these factors. 
If at any time on study there is an increase in QTc interval to an absolute value >500 msec, two 
additional ECGs should be performed within 30 minutes after the initial ECG with intervals not 
less than 3 minutes apart.  If the average QTcF from the three ECGs is >500 msec, study treatment 
must be withheld and the following actions should be taken: 
x Check electrolytes, especially potassium, magnesium and calcium.  Correct 
abnormalities as clinically indicated. 
x If possible, discontinue any QTc-prolonging concomitant medications. 
x Repeat ECG triplets hourly until the average QTcF is ≤500 msec or otherwise 
determined by consultation with a cardiologist. 
The Sponsor should be notified immediately of any QTc prolongation event.  
 
Subjects with QTc prolongation and symptoms must be monitored closely until the QTc elevation 
has resolved.  Cardiology consultation is recommended for evaluation and subject management.  
Symptomatic subjects must be treated according to standard clinical practice.  No additional study 
treatment is to be given to the subject until after the event has resolved, the subject has been 
thoroughly evaluated, and further treatment has been agreed to by the Sponsor.  If any additional 
study treatment is given (e.g., after correction of electrolyte abnormalities and normalization of 
QTcF), it will be at a reduced dose as agreed to by the investigator and the Sponsor. 
6.2 
CABOZANTINIB DRUG HOLIDAY 
Patients who achieve a complete response by RECIST lasting > 3 years, can have study therapy 
held (drug holiday) until they relapse. Scan intervals for patients achieving a complete response 
for > 3years will be changed from every 8 weeks to every 12 weeks. At the time of progressive 
disease, cabozantinib will be resumed and scan showing progressive disease will become the new 
baseline scan.  
7 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The following 
list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2.1.1) will determine 
whether the event requires expedited reporting (via CTEP-AERS) in addition to routine reporting. 
7.1 
COMPREHENSIVE ADVERSE EVENTS AND POTENTIAL RISKS LIST (CAEPR) 
7.1.1 Comprehensive Adverse Events and Potential Risks list (CAEPR) XL184 (Cabozantinib 
s-malate, NSC 761968) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the Specific 
Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and is 
identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 


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54 
 
protocol specific exceptions to expedited reporting to NCI (except as noted below). Refer to the 
'CTEP, 
NCI 
Guidelines: 
Adverse 
Event 
Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
for 
further clarification. Frequency is provided based on 3219 patients. Below is the CAEPR for 
XL184 (Cabozantinib s-malate). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to 
the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades to 
determine if expedited reporting is required. 
Version 2.4, December 17, 20181 
 
 Adverse Events with Possible  
 Relationship to XL184 (Cabozantinib) 
 (CTCAE 5.0 Term) 
[n= 3219] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
  
ENDOCRINE DISORDERS 
  
 
Hypothyroidism 
 
 Hypothyroidism (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 3) 
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
 
 
Gastrointestinal fistula2 
  
 
 
Gastrointestinal hemorrhage3 
  
 
 
Gastrointestinal perforation4 
  
 
Mucositis oral 
 
 Mucositis oral (Gr 3) 
Nausea 
 
 
 Nausea (Gr 3) 
 
Oral pain 
 
 Oral pain (Gr 2) 
Vomiting 
 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema limbs 
 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
INFECTIONS AND INFESTATIONS 
  
 
Infection5 
 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
 
Wound complication 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase increased  
 Alanine aminotransferase increased 
(Gr 3) 
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase increased 
(Gr 3) 
 
Lipase increased 
 
 Lipase increased (Gr 4) 
 
Platelet count decreased 
 
 Platelet count decreased  
(Gr 3) 
Weight loss 
 
 
 Weight loss (Gr 3) 
METABOLISM AND NUTRITION DISORDERS 
  


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 Adverse Events with Possible  
 Relationship to XL184 (Cabozantinib) 
 (CTCAE 5.0 Term) 
[n= 3219] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
Anorexia 
 
 
 Anorexia (Gr 3) 
 
Dehydration 
 
  
 
Hypocalcemia 
 
  
 
Hypokalemia 
 
  
 
Hypomagnesemia 
 
  
 
Hypophosphatemia 
 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Generalized muscle weakness 
 
  
 
Muscle cramp 
 
  
 
 
Osteonecrosis of jaw 
  
 
Pain in extremity 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
  
Dysgeusia 
 
 
 Dysgeusia (Gr 2) 
 
Headache 
 
  
 
 
Intracranial hemorrhage  
  
 
 
Ischemia cerebrovascular 
  
 
 
Reversible posterior 
leukoencephalopathy syndrome 
  
 
 
Stroke 
  
 
 
Transient ischemic attacks 
  
RENAL AND URINARY DISORDERS 
  
 
Hematuria 
 
  
 
 
Proteinuria 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
  
 
Dyspnea 
 
  
 
 
Pneumothorax6 
  
 
 
Respiratory fistula7 
  
 
Respiratory hemorrhage8 
 
  
 
Voice alteration 
 
 Voice alteration (Gr 3) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
  
 
Dry skin 
 
 Dry skin (Gr 2) 
 
Hair color changes 
 
 Hair color changes (Gr 1) 
Palmar-plantar erythrodysesthesia 
syndrome 
 
 
 Palmar-plantar erythrodysesthesia 
syndrome (Gr 3) 
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 3) 
VASCULAR DISORDERS 
  
Hypertension 
 
 
 Hypertension (Gr 3) 
 
Thromboembolic event9 
 
  
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all Principal 
Investigators at the time of revision.  The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV. 
Your name, the name of the investigator, the protocol and the agent should be included in the e-mail. 


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2Gastrointestinal fistula includes Anal fistula, Colonic fistula, Duodenal fistula, Esophageal fistula, Enterovesical 
fistula, Gastric fistula, Gastrointestinal fistula, Ileal fistula, Jejunal fistula, Oral cavity fistula, Pancreatic fistula, Rectal 
fistula, and Salivary gland fistula under the GASTROINTESTINAL DISORDERS SOC. 
3Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, Duodenal 
hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal 
hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower gastrointestinal hemorrhage, 
Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, and Upper gastrointestinal 
hemorrhage under the GASTROINTESTINAL DISORDERS SOC. 
4Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, Gastric 
perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal perforation under the 
GASTROINTESTINAL DISORDERS SOC. 
5Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
6Pneumothorax has been observed at a higher than expected frequency (15-20%) in a study treating patients with 
relapsed Ewing sarcoma and osteosarcoma all of whom had pulmonary metastases. 
7Respiratory fistula includes Bronchial fistula, Bronchopleural fistula, Laryngeal fistula, Pharyngeal fistula, 
Pulmonary fistula, and Tracheal fistula under the RESPIRATORY, THORACIC AND MEDIASTINAL 
DISORDERS SOC. 
8Respiratory hemorrhage includes Bronchopulmonary hemorrhage, Epistaxis, Hemoptysis, Laryngeal hemorrhage, 
Mediastinal hemorrhage, Pharyngeal hemorrhage, and Pleural hemorrhage under the RESPIRATORY, THORACIC 
AND MEDIASTINAL DISORDERS SOC. 
9Thromboembolic event includes pulmonary embolism which may be life-threatening. 
Adverse events reported on XL184 (Cabozantinib) trials, but for which there is insufficient evidence to suggest 
that there was a reasonable possibility that XL184 (Cabozantinib) caused the adverse event: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(pancytopenia); Disseminated intravascular coagulation; Eosinophilia; Febrile neutropenia; Hemolytic uremic 
syndrome 
CARDIAC DISORDERS - Atrial fibrillation; Atrioventricular block complete; Cardiac arrest; Cardiac disorders - 
Other (hypokinetic cardiomyopathy); Chest pain - cardiac; Heart failure; Left ventricular systolic dysfunction; 
Myocardial infarction; Myocarditis; Sinus bradycardia; Sinus tachycardia; Supraventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Hearing impaired; Vertigo 
ENDOCRINE DISORDERS - Endocrine disorders - Other (autoimmune thyroiditis); Endocrine disorders - Other 
(thyroiditis); Endocrine disorders - Other (thyrotoxicosis); Hyperthyroidism; Hypopituitarism 
EYE DISORDERS - Blurred vision; Cataract; Eye disorders - Other (corneal epithelium defect) 
GASTROINTESTINAL DISORDERS - Abdominal distension; Anal fissure; Anal mucositis; Anal pain; Anal ulcer; 
Cheilitis; Colitis; Colonic obstruction; Duodenal ulcer; Dysphagia; Enterocolitis; Esophageal ulcer; Esophagitis; 
Flatulence; Gastric ulcer; Gastroesophageal reflux disease; Gastrointestinal disorders - Other (glossitis); 
Gastrointestinal disorders - Other (pneumoperitoneum); Gastrointestinal pain; Gingival pain; Hemorrhoids; Ileus; 
Pancreatitis; Periodontal disease; Rectal pain; Rectal ulcer; Toothache 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Death NOS; Edema face; 
Fever; Gait disturbance; General disorders and administration site conditions - Other (general physical health 
deterioration); General disorders and administration site conditions - Other (implant site inflammation); Hypothermia; 
Malaise; Multi-organ failure; Non-cardiac chest pain; Pain; Sudden death NOS 
HEPATOBILIARY DISORDERS - Budd-Chiari syndrome; Cholecystitis; Hepatic failure; Hepatobiliary disorders 
- Other (cholelithiasis); Hepatobiliary disorders - Other (hepatic cirrhosis); Hepatobiliary disorders - Other (hepatic 
thrombus); Hepatobiliary disorders - Other (hepatitis toxic); Hepatobiliary disorders - Other (hepatorenal syndrome); 
Portal vein thrombosis 
IMMUNE SYSTEM DISORDERS - Allergic reaction; Anaphylaxis; Autoimmune disorder 


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INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fall; Injury, poisoning and procedural 
complications - Other (post procedural hemorrhage); Injury, poisoning and procedural complications - Other (tendon 
injury); Wound dehiscence; Wrist fracture 
INVESTIGATIONS - Alkaline phosphatase increased; Blood bilirubin increased; Blood lactate dehydrogenase 
increased; CPK increased; Cardiac troponin I increased; Creatinine increased; Ejection fraction decreased; 
Electrocardiogram QT corrected interval prolonged; GGT increased; Investigations - Other (D-dimer); Investigations 
- Other (urine ketone body present); Lymphocyte count decreased; Neutrophil count decreased; Serum amylase 
increased; Thyroid stimulating hormone increased; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Glucose intolerance; Hyperglycemia; Hypernatremia; 
Hyperuricemia; Hypoalbuminemia; Hyponatremia; Metabolism and nutrition disorders - Other (failure to thrive); 
Metabolism and nutrition disorders - Other (hypoproteinemia) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Buttock pain; Chest wall pain; 
Flank pain; Muscle weakness lower limb; Musculoskeletal and connective tissue disorder - Other (muscle 
hemorrhage); Myalgia; Neck pain; Osteonecrosis; Osteoporosis; Rhabdomyolysis 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (lip and/or oral cavity cancer); Tumor hemorrhage; 
Tumor pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Concentration impairment; Dysarthria; 
Dysesthesia; Dysphasia; Encephalopathy; Lethargy; Memory impairment; Nervous system disorders - Other 
(hemiparesis); Nervous system disorders - Other (vocal cord paralysis); Peripheral motor neuropathy; Peripheral 
sensory neuropathy; Presyncope; Seizure; Somnolence; Spinal cord compression; Syncope 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Delirium; Depression; Hallucinations; Insomnia; Psychiatric 
disorders - Other (mental status changes) 
RENAL AND URINARY DISORDERS - Acute kidney injury; Chronic kidney disease; Glucosuria; Renal and 
urinary disorders - Other (hemorrhage urinary tract); Urinary tract obstruction 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Pelvic pain; Reproductive system and breast 
disorders - Other (scrotal ulcer/erythema/edema); Scrotal pain; Vaginal fistula; Vaginal inflammation; Vaginal 
perforation 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Allergic rhinitis; Aspiration; Atelectasis; Hoarseness; Hypoxia; Laryngeal edema; Oropharyngeal pain; Pharyngeal 
mucositis; Pleural effusion; Pneumonitis; Productive cough; Pulmonary hypertension; Respiratory failure; 
Respiratory, thoracic and mediastinal disorders - Other (nasal septum perforation); Respiratory, thoracic and 
mediastinal disorders - Other (pneumomediastinum); Respiratory, thoracic and mediastinal disorders - Other (rales); 
Sore throat 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Erythema multiforme; Nail changes; Pain of skin; 
Pruritus; Rash acneiform; Skin and subcutaneous tissue disorders - Other (pain, sloughing of skin and erythema); Skin 
and subcutaneous tissue disorders - Other (psoriasis); Skin hypopigmentation; Skin ulceration 
VASCULAR DISORDERS - Hematoma; Hypotension; Superior vena cava syndrome; Vascular disorders - Other 
(bleeding varicose vein); Vasculitis 
 
Note: XL184 (Cabozantinib) in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never previously associated 
with either agent. 
 


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7.2 
DEFINITIONS 
7.2.1 Adverse Event  
Any untoward medical occurrence in a human subject, including any abnormal sign (for example, 
abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with 
the subject’s participation in research, whether or not considered related to the subject’s 
participation in the research. 
7.2.1.1 Adverse Event Characteristics: 
x CTCAE term (AE description) and grade:  The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 will be utilized for AE reporting.  All appropriate treatment 
areas should have access to a copy of the CTCAE version 5.0.  A copy of the 
CTCAE version 5.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.    
x 
For expedited reporting purposes only:   
o AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in 
the SPEER column, Section 7.1.1) should be reported through CTEP-AERS only 
if the grade is above the grade provided in the SPEER. 
x 
Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
7.2.2 Suspected adverse reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship between the drug and the 
adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug. 
7.2.3 Unexpected adverse reaction 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in the 
investigator brochure or is not listed at the specificity or severity that has been observed; or, if an 
investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application. "Unexpected”, 
also refers to adverse events or suspected adverse reactions that are mentioned in the investigator 
brochure as occurring with a class of drugs or as anticipated from the pharmacological properties 
of the drug, but are not specifically mentioned as occurring with the particular drug under 
investigation. 


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7.2.4 Serious  
An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of a Serious 
Adverse Event or if it compromises the safety, welfare or rights of subjects or others. 
7.2.5 Serious Adverse Event 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
x 
Death, 
x 
A life-threatening adverse drug experience 
x 
Inpatient hospitalization or prolongation of existing hospitalization 
x 
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
x 
A congenital anomaly/birth defect. 
x 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
7.2.6 Disability 
A substantial disruption of a person’s ability to conduct normal life functions. 
7.2.7 Life-threatening adverse drug experience 
Any adverse event or suspected adverse reaction that places the patient or subject, in the view of 
the investigator or sponsor, at immediate risk of death from the reaction as it occurred, i.e., it does 
not include a reaction that had it occurred in a more severe form, might have caused death. 
7.2.8 Protocol Deviation (NIH Definition) 
Any change, divergence, or departure from the IRB-approved research protocol.   
7.2.9 Non-compliance (NIH Definition) 
The failure to comply with applicable NIH Human Research Protections Program (HRPP) policies, 
IRB requirements, or regulatory requirements for the protection of human research subjects. 
7.2.10 Unanticipated Problem 
Any incident, experience, or outcome that: 
x  Is unexpected in terms of nature, severity, or frequency in relation to  
(a) the research risks that are described in the IRB-approved research protocol and 
informed consent document; Investigator’s Brochure or other study documents, and 
(b) the characteristics of the subject population being studied; AND 
x Is related or possibly related to participation in the research; AND 


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x Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
7.3 
EXPEDITED ADVERSE EVENT REPORTING TO CTEP 
7.3.1 Reporting via CTEP-AERS 
Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event Reporting 
System), accessed via the CTEP Web site (http://ctep.cancer.gov). The reporting procedures to be 
followed are presented in the “NCI Guidelines for Investigators: Adverse Event Reporting 
Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs” which can be downloaded 
from the CTEP Web site (http://ctep.cancer.gov).  These requirements are briefly outlined in the 
tables below (Section 7.3.3). 
7.3.2 In the Event of Lost Internet Connectivity 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be made to 
CTEP by telephone at 301-897-7497. Once Internet connectivity is restored, the 24-hour 
notification phoned in must be entered electronically into CTEP-AERS by the original submitter 
at the site. 
7.3.3 Expedited Reporting Guidelines  
Use the NCI protocol number and the protocol-specific patient ID assigned during trial registration 
on all reports. 
Note:  A death on study requires both routine and expedited reporting regardless of 
causality, unless as noted below.  Attribution to treatment or other cause must be provided. 
Death due to progressive disease should be reported as Grade 5 “Neoplasms benign, malignant 
and unspecified (including cysts and polyps) - Other (Progressive Disease)” under the system 
organ class (SOC) of the same name.  Evidence that the death was a manifestation of underlying 
disease (e.g., radiological changes suggesting tumor growth or progression: clinical deterioration 
associated with a disease process) should be submitted.  
Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or 
not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 
24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 


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hospitalization may be considered serious when, based upon medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed 
in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-
AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 
1 
Timeframes 
Grade 
2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific Protocol 
Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of learning of the 
AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of learning 
of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention and have 
an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
x 
All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
x 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
x 
Grade 3 adverse events 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, rounded UP to the 
nearest whole day, after the agent/intervention was last administered.  Footnote “1” above applies after this reporting period. 
Effective Date:  May 5, 2011 
 
7.4 
ROUTINE ADVERSE EVENT REPORTING TO CTEP 
All Adverse Events must be reported in routine study data submissions.  AEs reported through 
CTEP-AERS must also be reported in routine study data submissions. 


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7.5 
NIH INTRAMURAL IRB AND CLINICAL DIRECTOR REPORTING 
7.5.1 NIH Intramural IRB and NCI CD Expedited Reporting of Unanticipated Problems 
and Deaths 
The Protocol PI will report in the NIH Problem Form to the NIH Intramural IRB and NCI Clinical 
Director: 
x All deaths, except deaths due to progressive disease  
x All Protocol Deviations 
x All Unanticipated Problems 
x All non-compliance 
Reports must be received within 7 days of PI awareness via iRIS. 
7.5.2 NIH Intramural IRB Requirements for PI Reporting at Continuing Review 
The protocol PI will report to the NIH Intramural IRB:  
1. A summary of all protocol deviations in a tabular format to include the date the deviation 
occurred, a brief description of the deviation and any corrective action. 
2. A summary of any instances of non-compliance 
3. A tabular summary of the following adverse events: 
x 
All Grade 2 unexpected events that are possibly, probably or definitely related to the 
research;  
x 
All Grade 3 and 4 events that are possibly, probably or definitely related to the 
research;  
x 
All Grade 5 events regardless of attribution;  
x 
All Serious Events regardless of attribution.  
NOTE: Grade 1 events are not required to be reported.  
7.5.3 NIH Intramural IRB Reporting of IND Safety Reports 
Only IND Safety Reports that meet the definition of an unanticipated problem will need to be 
reported to the  NIH Intramural IRB. 
7.6 
SECONDARY MALIGNANCY 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., treatment 
with investigational agent/intervention, radiation or chemotherapy). A secondary malignancy is 
not considered a metastasis of the initial neoplasm.  
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported via CTEP-AERS. Three options are available to describe the event:  
x Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic 
leukemia [AML])  


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x Myelodysplastic syndrome (MDS)  
x Treatment-related secondary malignancy  
Any malignancy possibly related to cancer treatment (including AML/MDS) should 
also be reported via the routine reporting mechanisms outlined in each protocol.  
7.7 
SECOND MALIGNANCY 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine reporting via 
CDUS unless otherwise specified.  
7.8 
DATA AND SAFETY MONITORING PLAN 
7.8.1 Principal Investigator/Research Team  
The clinical research team will meet on a regular basis when patients are being actively treated on 
the trial to discuss each patient. Decisions about dose level enrollment and dose escalation if 
applicable will be made based on the toxicity data from prior patients.  
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Adverse events will be reported as required above. Any safety concerns, 
new information that might affect either the ethical and or scientific conduct of the trial, or protocol 
deviations will be immediately reported to the IRB using iRIS.  
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.  
7.8.2 Sponsor Monitoring Plan 
See section 12.3.1. 
8 
PHARMACEUTICAL AND IMAGING AGENT INFORMATION 
8.1 
CABOZANTINIB (XL184) (NSC 761968) 
Chemical Name: N-[4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl]-N’-(4-
fluorophenyl)cyclopropane-1,1-dicarboxamide, (2S)-hydroxybutanedioate  
Other Names: Cabozantinib, EXEL-7184, EXEL-02977184  
Classification: Receptor Tyrosine Kinases Inhibitor (RTK) 
CAS Registry Number: 1140909-48-3  
Molecular Formula: C28H24FN3O5.C4H6O5  
 
M.W.: 635.6  
Mode of Action: XL184 inhibits multiple RTKs implicated in tumor growth (progression of 
tumors in bone), metastasis, and angiogenesis, and targets primarily MET and VEGFR2.  Other 
targets are RET, AXL, KIT, TIE-2, and FLT-3.  


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How Supplied:  XL184 is supplied by Exelixis and distributed by the DCTD.  XL184 is available 
in 20 mg and 60 mg tablet.  The tablets are yellow film coated containing cabozantinib malate 
equivalent to 20 mg and 60 mg of cabozantinib.  The 20 mg tablets have a round shape and the 60 
mg tablets have an oval shape, and they are packaged as 30 tablets per bottle.   
XL184 Tablet Components and Composition 
Ingredient  
Function 
% w/w 
Cabozantinib malate (25% drug load as cabozantinib) 
Active Ingredient 
31.7 
Microcrystalline Cellulose (Avicel PH-102) 
Filler 
38.9 
Lactose Anhydrous (60M) 
Filler 
19.4 
Hydroxypropyl Cellulose (EXF) 
Binder 
3.0 
Croscarmellose Sodium (Ac-Di-Sol) 
Disenegrant 
6.0 
Colloidal Silicon Dioxide, 
Glidant 
0.3 
Magnesium Stearate 
Lubricant 
0.75 
Opadry Yellow Film Coating which includes: 
- 
HPMC 2910 / Hypromellose 6 cp  
- 
Titanium dioxide  
- 
Triacetin  
- 
Iron Oxide Yellow 
Film Coating 
4.00 
 
Storage:  Store intact bottles at controlled room temperature, 200 to 250C. 
Stability:  XL184 should be dispensed in its original container.  XL184 tablets are stable for up to 
24 hours when dispensed in an open container, such as in a pill cup, and are stable for up to 7 days 
when dispensed in a closed container, such as a pharmacy dispensing bottle. 
Route of Administration: Oral. 
Method of Administration: Take cabozantinib on an empty stomach, (fasting is required 2 hours 
before and 1 hour after each cabozantinib dose).  Do not crush or chew. 
Potential Drug Interactions: XL184 is a substrate of CYP3A4.  Coadministration of XL184 with 
medications that are strong inhibitors/inducers of CYP3A4 should be avoided. Examples of strong 
CYP3A4 inducers are rifampin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifampentin, 
Phenobarbital, and St. John’s Wort. Strong CYP3A4 inhibitors are ketoconazole, itraconazole, 
clarithromycin, indinavir, nefazodone, nelfinavir, and ritonavir. Use alternative medications. 
Avoid grapefruit/ grapefruit juice and Seville oranges while participating in this trial. 
In vitro data, XL184 is not a P-gp substrate but may inhibit the P-gp transport activity. 
XL184 is highly protein bound, 99.9%.  Use caution when coadminister XL184 with medications 
that are highly protein-bound (e.g., diazepam, furosemide, dicloxacillin, and propranolol).  Avoid 
administration of warfarin with XL184 as warfarin is highly protein-bound and has a very narrow 
therapeutic index. 
Avoid concomitant use of XL184 with proton pump inhibitors (PPIs) and H2 -antagonists if 
possible.  The PPIs and H2 –antagonists decrease XL184 plasma exposure levels and its 
effectiveness in vivo.  Examples of PPIs are omeprazole, lansoprazole, rabeprazole, pantoprazole, 


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and esomeprazole; examples of H2 –antagonists are ranitidine, famotidine, and nizatidine.  
Cimetidine is a moderate CYP3A4 inhibitor.  Avoid using cimetidine with XL184.  If antacids, H2 
blockers, or PPIs are needed, take them at least 2 hours (preferably 4 hours) after taking 
cabozantinib but at least 14 hours before the next dose of cabozantinib if possible. 
Patient Care Implications:  Do not take grapefruit/ grapefruit juice or Seville oranges while 
participating in this trial.  Inform physician and study healthcare team about current medications 
including over the counter drugs, herbals, or natural medicines. Cimetidine or omeprazole is also 
available over-the-counter (OTC).  Do not use cimetidine.   If need an antacid, take it at least 2 
hours (preferably 4 hours) after taking XL184 but at least 14 hours before the next dose of XL184 
if possible. 
Availability 
XL184 (cabozantinib) is an investigational agent supplied to investigators by the Division of 
Cancer Treatment and Diagnosis (DCTD), NCI. 
XL184 (cabozantinib) is provided to the NCI under a Collaborative Agreement between the 
Pharmaceutical Collaborator and the DCTD, NCI (see Section 12.5). 
8.1.1 Agent Ordering and Agent Accountability 
8.1.1.1 NCI-supplied agents may be requested by the Principal Investigator (or their authorized 
designee) at each participating institution.  Pharmaceutical Management Branch (PMB) 
policy requires that agent be shipped directly to the institution where the patient is to be 
treated.  PMB does not permit the transfer of agents between institutions (unless prior 
approval from PMB is obtained).  The CTEP-assigned protocol number must be used for 
ordering all CTEP-supplied investigational agents.  The responsible investigator at each 
participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA Form 1572 (Statement of Investigator), Curriculum Vitae, 
Supplemental Investigator Data Form (IDF), and Financial Disclosure Form (FDF).  If 
there are several participating investigators at one institution, CTEP-supplied 
investigational agents for the study should be ordered under the name of one lead 
investigator at that institution. 
Active CTEP-registered investigators and investigator-designated shipping designees 
and ordering designees can submit agent requests through the PMB Online Agent Order 
Processing 
(OAOP) 
application 
(https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx). Access to OAOP requires the establishment 
of a CTEP Identity and Access Management (IAM) account (https://eapps-
ctep.nci.nih.gov/iam/) and the maintenance of an “active” account status and a “current” 
password.  For questions about drug orders, transfers, returns, or accountability, call 
(240) 276-6575 Monday through Friday between 8:30 am and 4:30 pm (ET) or email 
PMBAfterHours@mail.nih.gov anytime. 
8.1.1.2 Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the inventory and disposition of all agents 
received from DCTD using the NCI Drug Accountability Record Form (DARF).  (See 
the NCI Investigator’s Handbook for Procedures for Drug Accountability and Storage.) 


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9 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
(Please see Appendix F for the blood and tissue collection schedule in chart form) 
9.1 
BIOMARKER STUDIES 
All collection pre-treatment collection times are within 5 days prior to treatment; all other 
collection times and within ± 5 days of stated collection.  The blood biomarker studies will be 
prioritized as follows: Plasma HGF and MET, VEGF levels, immune subset, genetic biomarker, 
IL-8 circulating cytokine levels, c-Met analysis by real-time RT-PCR and CTC/CEC. 
9.1.1 Circulating endothelial cells (CEC), circulating endothelial progenitor cells (CEP) and 
Circulating epithelial tumor cells (CTC)    
CEC, CEP and CTC will be analyzed by multiparameter flow cytometry.  Mononuclear cells will 
be isolated and run fresh or viably frozen.  Immune subsets, including MDSC and Tregs, may be 
analyzed if sample permits.  
9.1.1.1 Collection & Handling of Specimens: 
Collect 2 times: at C1D1 pre-treatment and C3D1 pre-treatment 
Draw whole blood into three 8 mL BD Vacutainer Cell Preparation Tube (CPT) with Sodium 
Citrate and two 10 mL EDTA lavender top tubes. 
x Immediately after collection, mix the blood sample by gentle inversion several times.  
x The date and exact time of each blood draw should be recorded on the tube. 
x Please email Jane.Trepel@nih.hhs.gov, lees@pop.nci.gov and 
leemin@mail.nih.gov about expected samples and call Jane Trepel’s lab at 240-
760-6330 to arrange for immediate pick-up. 
9.1.1.2 Site Performing the Assay 
The assays will be performed by Dr. Min-Jung Lee and Dr. Yeong Sang Kim in Jane Trepel’s 
laboratory in the Medical Oncology Branch, Building 10, Room 12N218.  
9.1.2 c-Met analysis by real-time RT-PCR 
9.1.2.1 Collection & Handling of Specimens: 
x Peripheral blood for analysis of c-Met mRNA will be collected in a PAXgene tube on 
C1D1 pre-treatment and C3D1 pre-treatment  
x (PreAnalytix; 2.5 cc peripheral blood per tube) per the manufacturer’s instructions.  
x After the blood is drawn, the tube should be inverted several times, placed at 4°C.  RNA 
will be isolated using the PAXgene Blood RNA Kit according to the manufacturer’s 
instructions. The first strand cDNA will be synthesized from total RNA by using a HC 
reverse transcription kit (Applied Biosystems). The reaction mixture is diluted to 100 μL 
with TE. PCR will be performed using the c-met primers).   
x Please email Jane.Trepel@nih.hhs.gov, lees@pop.nci.gov and leemin@mail.nih.gov 24 
hours prior to anticipated collection and call Jane Trepel’s lab at 240-760-6330 to arrange 
for immediate pickup when drawn. 


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9.1.2.2 Site Performing the Assay 
cMet mRNA levels in peripheral blood will be analyzed by the Trepel Lab, Medical Oncology 
Branch, Building 10, Room 12N218.  
9.1.3 IL-8 circulating cytokine levels 
We will be collecting blood samples to determine whether IL-8 levels are associated with 
cabozantinib treatment outcome measures.  
9.1.3.1 Collection & Handling of Specimens: 
x Peripheral blood will be drawn in a 5 mL red top tube pretreatment on C1D1, cycle 1 day 
15 and at cycle 2 day 1. 
x The date and exact time of each blood draw should be recorded on the tube. 
x Please email Jane.Trepel@nih.hhs.gov, lees@pop.nci.gov and leemin@mail.nih.gov 24 
hours prior to anticipated collection and call Jane Trepel’s lab at 240-760-6330 to arrange 
for immediate pickup when drawn. 
9.1.3.2 Site Performing the Assay 
Il-8 levels in peripheral blood will be analyzed using the ELISA technique by the Trepel Lab, 
Medical Oncology Branch, Building 10, Room 12N218 
9.1.4 Genetic biomarkers 
We will determine if VEGFR2 genetic variants may be correlated to toxicity and clinical outcomes 
as we have previously shown in patients treated with bevacizumab and sorafenib62. 
9.1.4.1 Collection and Handling of Specimens 
x 
One 10 mL EDTA lavender top tube will be collected on day 1 of cycle 2. 
x Immediately after collection, invert the blood tube 8-10 times. 
x 
Place the tube on wet ice and then store at 4rC in the refrigerator until processing. 
x 
The date and exact time of each blood draw should be recorded on the tube. 
x 
Please email NCIBloodcore@mail.nih.gov 24 hours prior to anticipated collection and 
page 102-11964 for immediate pickup. 
9.1.4.2 Site Performing the Assay 
These studies will be done by the Molecular Pharmacology Program, under the direction of Dr. 
Figg.  
9.1.5 Angiogenesis Markers 
Plasma levels of several angiogenic biomarkers, including VEGF-A, soluble VEGFR2 
(sVEGFR2), and placental growth factor (PIGF), have been shown to be significantly altered after 
single agent cabozantinib treatment (Investigator’s brochure).  
The analysis will be done with assays developed on electrochemiluminescence platform that 
provides ultra-high sensitivity and very large signal dynamic range. 
9.1.5.1 Collection and Handling of Specimens 


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Serum VEGF 
x Collect on cycle 1 day 1 pretreatment, cycle 1 day 15 pretreatment, cycle 2 day 1 and at 
the time of progression. 
x Venous blood samples will be collected in one 6mL EDTA tube per protocol time points.   
x Immediately after collection, invert the EDTA tube 2-4 times and place the tube on wet ice 
and store at 4qC in the refrigerator until processing for a maximum of 30-60 minutes.   
x The date and exact time of each blood draw should be recorded on the tube. 
x Please email NCIBloodcore@mail.nih.gov 24 hours prior to anticipated collection and 
page 102-11964 for immediate pick-up.   
9.1.5.2 Sample Processing 
Upon arrival in the Blood Processing Core (BPC), blood samples will be centrifuged for 5 minutes 
at 1200 x g, at 4qC. The serum will be transferred into two cryovials and immediately frozen. 
Serum samples will be stored at -80qC until the time of analysis. 
9.1.5.3 Site Performing the Assay 
These studies will be done by the Molecular Pharmacology Program, under the direction of Dr. 
Figg.  
9.1.6 Plasma and Tissue HGF and MET and urinary MET and spot creatinine 
To determine whether urinary hepatocyte growth factor (HGF), urinary soluble MET receptor 
(sMet), plasma HGF and plasma Met levels are biomarkers of bladder cancer (transitional cell 
carcinoma; TCC) and/or response to systemic treatment with the experimental Met/VEGFR 
inhibitor cabozantinib. 
In fresh frozen tissue (FFT), HGF, and the cabozantinib targets MET, phosphoMET, VEGFR2, 
RET, KIT, AXL and FLT3 will be quantitatively analyzed using two-site electrochemiluminescent 
immunoassays developed for use with a Meso Scale Discovery (MSD) SectorImager 2400 plate 
reader at baseline from patients on study with cabozantinib. Use of purified recombinant protein 
standards permits quantitation of receptor mass per mass total extracted cell protein.  
9.1.6.1 Sample Collection Protocols 
A. URINE SAMPLES 
1. Collect at least 2 mL of urine prior to treatment at every visit while on study The 
source of the urine will need to be documented i.e. normally voided urine, without 
internal stent, Foley, percutaneous nephrostomy, ileal conduit, Indian pouch or 
neobladder. 
2. Determine urine creatinine values per standard clinical laboratory testing protocol. 
3. The date and exact time of the urine collection should be recorded on the tube. 
4. Please email NCIBloodcore@mail.nih.gov 24 hours prior to anticipated collection 
and page 102-11964 for immediate pick-up.   
5.  sMet analysis requires 1-2 ml per sample.  Adjust urine to pH 7.5 with Trizma-
HCl (Sigma, St. Louis, MO), 2 mol/L, pH 7.5 using 50 microliters per 2 ml urine 
volume. 


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6. Centrifuge urine samples at 3000 x g for 10 min at room temperature to remove 
cells and debris; store samples in appropriately sized plastic cryovials (Nunc or 
Sargent; bar coded vials are preferred for optimal sample identification) at -80°C. 
B. PLASMA SAMPLES 
1. Blood samples should be collected in a 3 mL EDTA tube at every visit while on 
study.    
2. The date and exact time of the urine collection should be recorded on the tube. 
3. Blood samples should be centrifuged within 30 min at 1,300 RCF at room 
temperature for 10 minutes.  Do not use braking to stop the centrifuge.  This will 
give three layers: (from top to bottom) plasma, leucocytes (buffy coat), 
erythrocytes.  
4. Carefully aspirate the supernatant (plasma) at room temperature and transfer to a 
new centrifuge tube. Take care not to disrupt the cell layer or transfer any cells.  
5. Inspect the plasma for turbidity. Turbid samples should be centrifuged and the 
clarified supernatant should be transferred to cryovials and stored at –80°C.  Ensure 
that the cryovials are properly labeled.  
6. Please email NCIBloodcore@mail.nih.gov 24 hours prior to anticipated collection 
and page 102-11964 for immediate pickup. 
C. FRESH TISSUE SAMPLES 
1. A post treatment biopsy (as referenced in section 9.1.8.1.2) will be performed on a 
voluntary basis, and cabozantinib target levels will be compared to baseline 
measurements on fresh tissue (see collection in section 9.1.7). MET and HGF 
expression by IHC will be compared to MET, phosphoMET, and HGF expression 
by quantitative two-site electrochemiluminescent immunoassay. Results will be 
correlated with baseline prognostic factors such as tumor grade, stage, size, sites of 
metastatic disease, response to prior cisplatin therapy, response to cabozantinib, 
progression free survival and overall survival. 
2. Please contact Dr. Bottaro to notify of biopsy date and time (301-402-6499) and to 
arrange for pick up of sample during biopsy. 
3. Fresh tissue samples should be collected in empty cryovials on dry ice. The 
minimum tissue volume required for HGF or Met analysis is 50 ul (approx 50 ug); 
analysis for phospho-Met requires 100 ul. 
4. The interval between sample acquisition and freezing on dry ice must not exceed 2 
minutes. Frozen, vialed samples should be transferred to -80°C storage within 2 
hours. Stored vials must be bar coded ONLY for sample identification. 
 
9.1.6.2 HGF and Met Electrochemiluminescent Immunoassay Protocols 
A. DETECTION OF HUMAN MET ECTODOMAIN (sMet) 


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1. Block with I Block solution (1X) 300 ul/well for 1 h at RT.  Use 300 ul multi-
channel pipette and disposable trough. 
2. Wash 3 times with 150ul/well Ca2+/Mg2+ free PBS. 
3. Add capture antibody at 5 ug/ml, 25 ul/well and shake for 1 h. 
4. Put out 20 previously frozen samples to thaw on ice at this time. 
5. Wash 3 times with 150ul/well Ca2+/Mg2+ free PBS. 
6. Add samples and standards at 25 ul/well for 1 h with shaking.  Adding the standards 
first; when the standards are done, mix the thawed samples well before adding to 
wells.  If volume is insufficient to fill triplicate wells at 25 ul/well, note any lesser 
amount added. 
7. Wash 3 times with 150ul/well Ca2+/Mg2+ free PBS. 
8. Add detection antibody at 1ug/ml, 25 ul/well for 1 h with shaking. 
9. Wash 4 times with 150ul/well Ca2+/Mg2+ free PBS. 
10. Set up the MSD Sector 2400’s computer for reading the plates. 
11.  Add MSD Read Buffer T with Surfactant (1X) 150ul/well, read plate immediately 
in MSD Sector 2400. 
 
B. DETECTION OF HUMAN HGF 
1. To a standard MSD streptavidin-coated 96-well plate, add biotinylated capture 
antibody diluted in 0.5% BSA in Ca2+/Mg2+ free PBS at 5 mcg/ml final, 25 
mcL/well for 1 hour at RT with shaking. 
2. Wash three times with 150 mcL/well Ca2+/Mg2+ free PBS. 
3. Block with 5% BSA in Ca2+/Mg2+ free PBS, 300 mcL/well for 1 hour at RT. 
4. Wash three times with 150 mcL/well Ca2+/Mg2+ free PBS. 
5. Add samples and standards: 100 ul/well for 1 hour at RT with shaking. 
6. Wash three times with 150 mcL/well Ca2+/Mg2+ free PBS. 
7. Add detection antibody diluted in 0.5% BSA in Ca2+/Mg2+ free PBS) 1 ug/ml 
final, 25 ul/well for 1 hour at RT with shaking. 
8. Wash four times with 150 mcL/well Ca2+/Mg2+ free PBS. 
9. Add MSD Read Buffer T with Surfactant, 150 mcL/well, read plate in MSD Sector 
2400. 
C. REAGENTS 
sMet DETECTION 
1. MSD streptavidin-coated 96-well plate catalog no. L15SA-1. 


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2. Capture antibody: R&D BAF358 biotinylated anti-Met antibody diluted in 
Ca2+/Mg2+ free PBS + 0.5% BSA.  
3. Standards: R&D 358-MT purified recombinant human Met ectodomain-Ig fusion 
protein diluted in Ca2+/Mg2+ free PBS + 0.5% BSA. 
4. Detection antibody: R&D AF276 anti-Met antibody labeled w/ MSD Sulfotag.  
Sulfo-tagging is performed per the manufacturer’s protocol.  
5. MSD Read Buffer T with Surfactant: prepare 20 ml of Read Buffer for 1 plate, 
using 5 ml of 4X Read Buffer and 15 ml of ultra pure water.  
HGF DETECTION 
1. MSD streptavidin-coated 96-well plate catalog no. L15SA-1. 
2. Capture antibody: R&D Systems MAB694, biotinylated using Pierce EZ-Link 
Maleimide-PEO Solid Phase Biotinylation Kit, catalog no. 21920. 
3. Standards: R&D Systems 294-HG purified recombinant human HGF diluted in 
0.5% BSA in Ca2+/Mg2+ free PBS, standard curve covers range from 0.003 ng/ml 
to 3 ng/ml in semi-log increments. 
4. Detection antibody: R&D Systems AF294NA, tagged with MSD Sulfo-Tag NHS 
Ester, catalog no. R91AN-1, per the manufacturer’s protocol. 
5. MSD Read Buffer T with Surfactant, catalog no. R92TC-3; 4x. 
9.1.6.3 Site Performing the Assay 
These studies will be done by the Urologic Oncology Branch, under the direction of Dr. Donald 
Bottaro. 
9.1.7 Met expression in Tissue 
All patients will have their tumors analyzed for Met expression by immunohistochemistry (IHC) 
either with a tumor block, 10 unstained slides or a fresh tumor biopsy.  Fresh biopsies, if archival 
samples are unavailable, will be obtained at baseline from primary tumor sites (bladder) and/or 
metastatic visceral sites.  4 - 6 core biopsies (or as available) will be taken from a single site. 
Please 
contact 
trepel@helix.nih.gov, 
lees@pop.nci.gov, 
leemin@mail.nih.gov 
and 
maria_merino@nih.gov when scheduled and call the Trepel Lab (240) 760 6330 for pickup.   
All material will be obtained for review. H&E slides, and one paraffin block or 10 unstained slides 
will be requested. In house tissue biopsies or resections will be obtained when indicated and tissues 
process routinely. Immunohistochemistry will be performed. For this procedure, 5-Pm, formalin 
fixed, paraffin-embedded sections will be deparaffinized, and used. Antigen retrieval will be 
utilized using a microwave oven. Antibodies against c-MET will be used with proper positive and 
negative controls. 
Tissue blocks from outside pathology departments will be stored in the NIH pathology department 
with attention to Dr. Maria Merino. Unstained slides will be stored by Dr. Andrea Apolo for 
staining. Biopsies obtained by surgery or interventional radiology will be processed for IHC met 
staining.  


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9.1.8 Immune subsets, angiogenesis and other markers in plasma and tissue  
9.1.8.1 Collection and Handling 
Circulating and intratumoral immune subsets and other markers of the microenvironment, 
hypoxia-inducible factor (HIF) 1α and 2α and other angiogenesis and/or immunologic markers 
will be analyzed at 8-18 weeks after treatment. 
9.1.8.1.1 Blood 
x Blood will be collected in a 6 mL EDTA lavender top tube at baseline and at 8 – 18 weeks 
after treatment.  Blood should only be collected at these timepoints if a tumor biopsy is 
also performed.   
x Please email Jane.Trepel@nih.hhs.gov, lees@pop.nci.gov and leemin@mail.nih.gov 24 
hours prior to anticipated collection and call Jane Trepel’s lab at 240-760-6330 to arrange 
for immediate pickup when drawn. 
9.1.8.1.2 Tissue 
Tissue will be analyzed 8 – 18 weeks after treatment.  Any remaining tissue from biopsies obtained 
on this protocol will also be evaluated.  Tissue blocks and slides obtained from outside pathology 
departments will be analyzed as available.  Tissue biopsies, limited to 4 – 6 cores, will be 
encouraged but done strictly on a voluntary basis.  Biopsies will be obtained from primary tumor 
sites and/or metastatic sites.   
9.1.8.2 Processing 
Samples will be processed immediately by the Trepel laboratory.  Biospecimens will be collected 
and processed using validated SOPs that will ensure both specimen quality and patient 
confidentiality. Using a computerized inventory system and a backup hardcopy process, all 
specimen collection and processing steps will be documented and the specific location of each 
specimen will be tracked. Each new specimen collected will be assigned a unique barcode 
identifier that can be linked to the original specimen collected and other relevant information 
within the inventory system.  Specimen labels will indicate: protocol number, order in which the 
patient enrolled on the trial, type of sample, collection time, and total volume collected, as 
appropriate.  The inventory process contains other security provisions sufficient to safeguard 
patient privacy and confidentiality. Access to the inventory system and associated documents will 
be restricted to appropriate individuals. Requests to use specimens stored in the repository must 
be approved. SOPs ensure that any changes in informed consent made by a patient and relayed to 
the PI will be reflected in the inventory system to ensure that specimens are destroyed as 
appropriate. All laboratory personnel will be trained to adhere to SOPs and will be monitored for 
high-quality performance. As soon as possible after the patient is scheduled please send email 
notification to the Trepel lab at trepel@helix.nih.gov, lees@pop.nci.gov and leemin@mail.nih.gov 
that the biopsy is scheduled. A member of the Trepel Lab will come to the OR/IR suite as soon as 
the biopsy is available for optimally rapid procurement to maximize tumor viability 
 
9.1.9 Imaging with PET/CT and optional PET/MRI  
Patients will undergo a baseline FDG PET/CT of metastatic lesions only along with standard 
imaging-CT of the chest abdomen and pelvis with or without Na18F PET CT. FDG-PET/CT of 
metastases will be repeated after 4 (alone) and 8 weeks (along with CT CAP) or until progression 


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(whichever comes first). The FDG-PET CT will be required, but may be waived at the discretion 
of the PI. The rationale for an FDG-PET at 4 weeks is that little is known about FDG-PET response 
to therapy in UC. We believe this is an important potential use of PET given the low objective 
RECIST response rate in studies in UC. The 8 week scan is taken to assess response to therapy 
and to assure that we capture progression of disease. The PET will be correlated with standard 
imaging modality. 
Patients will have the option of also undergoing a FDG PET/MR the same day of the PET/CT. 
PET-MR is a new technology that has recently become available at NIH.  Unlike PET-CT, PET-
MRI fuses the PET image to an MRI for attenuation correction.  In order to explore the value of 
this technology the patient may be asked whether they are willing to undergo a PET-MRI after 
completion of their standard PET-CT.  After the patient has completed the PET-CT examination, 
they will be offered additional scanning on a PET-MRI scanner located in the CC/DRD 
emphasizing that this is optional.   No additional injections of radioactivity will be administered 
and, because the MRI does not utilize ionizing radiation, there will be no additional exposure to 
the patient.   The patient will be escorted to Radiology.  The post-injection scan time for PET/MR 
will be 2 to 2.5 hours.  Approximately 1 hour of additional scanning (PET and MR obtained 
simultaneously) will be performed.  Results of the PET-CT and PET-MRI will be compared. 
These studies will be done by the Molecular Imaging Program, under the direction of Dr. Peter 
Choyke. 
9.1.10 Comparison of Target Lesion Volume/ Density and RECIST Measurements on CT of 
Metastatic Urothelial Cancer 
We will compare RECIST with semi-automated volume (SAV) / HU measurements, size and 
attenuation criteria (SACT), mass, attenuation, size and structure (MASS) criteria and Choi criteria 
in metastatic urothelial lesions.  SAV will be measured and standardized utilizing the Lesion 
Management Application (LMA) of CareStream experimental PACS algorithm.  The LMA results 
will be assessed by two independent radiologists.  Differing assessments will be resolved by a third 
radiologist who will review the results. We will correlate SAV/HU, SACT, MASS and Choi 
criteria to therapeutic response and determine the practicability of PACS to extract measurement 
markups that create RECIST reports. 
9.1.11 HTG Molecular 1,3,78 
HTG Molecular has a platform to obtain RNA from FFPE tissues and from Paxgene tubes. NCI 
would send HTG Molecular paired coded samples of pre treatment and post treatment Paxgene 
samples and FFPE slides (H&E and serial unstained slides) for analysis. 
In this study, we will access the performance of the HTG EdgeSeq Immuno-Oncology Assay and 
OBP Assays on 20 trial cases with both pre and post treatment samples. Each case will have FFPE 
tissue and matched PaxGene samples to be assessed.  A small number of additional samples 
corresponding to atypical histologies and MET lesions will also be analyzed in parallel as 
additional data points and controls. 
Our priority is to demonstrate the performance of FFPE and Paxgene samples for further utilization 
in clinical trials and secondary to determine if pathway and immune expression biomarkers are 
differentially expressed between pre and post treated samples.   


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9.1.11.1 Processing at HTG: 
Lysates: 
x Lysis method.  Sample lysis shall be performed in accordance to OP-00034, HTG EdgeSeq 
Processing. 
x Sample input volumes for each sample type: Cells = 20,000/well, FFPE = 5mm2/well 
x Unstained slides to be macro-dissected per NIH pathology recommendations, focusing on 
tumoral and peritumoral regions. 
x Lysates shall be aliquoted into several tubes so in order to minimize freeze/thaw cycles 
throughout the experiment and store sample for further analysis via OBP, IO assays and if 
required re-runs. 
Specimens, data or information will be coded so that the provider of the samples/data can link 
them to specific individuals but the receiver will not be able to do so. 
Coded samples will be sent under an MTA to: 
TG Molecular Diagnostics, Inc. 
Attention:  
Mark Stern, Ph.D. 
Vice President, Head of Immuno-Oncology Franchise 
HTG Molecular Diagnostics 
3430 E Global Loop 
Tucson, AZ 85706 
C: (848) 213-5051 
T: (877) 289-2615 
F: (520) 547-2837 
9.1.12 Xenobiotic Metabolism 
Previously we have identified the role of hypermethylation in decreasing the expression of 
cytochromes P450 1A1 (CYP1A1) and P450 1B1 (CYP1B1) in tumors compared to matched 
benign tissues. Furthermore, using a data mining approach on the TCGA data, we have recently 
uncovered yet another enzyme involved in xenobiotic metabolism, aldehyde oxidase (AOX1), as 
being progressively down-regulated during progression of bladder cancer through various clinical 
stages (T2-T4). AOX1 is known to play an essential role in amino acid synthesis and xenobiotic 
metabolism and metabolizes N-heterocycles and nitrosamines, azo dyes or nitropolycyclic 
aromatic hydrocarbons, many of which are known to increase the risk for bladder cancer. 
Importantly, using Tissue Microarrays on 190 BCa patients we confirmed a loss of AOX1 protein 
expression in advanced stages of bladder cancer. Based on all of the above data, we hypothesize 
that xenobiotic metabolism plays a key role in bladder cancer progression, its enzymes like AOX1 
regulate tumor progression and xenobiotic metabolites could function as non-invasive markers to 
monitor tumor progression. Our aims include: 
x Define stage-specific profiles of key xenobiotic metabolites in bladder cancer plasma 
samples. 
x Develop a first-generation multiplex panel of tissue-derived xenobiotic metabolites in 
plasma that correlates with clinical staging of the disease. 


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Other aims included  
x Identify race specific metabolic markers in bladder cancer plasma. 
x Identify a metabolic signature for the bladder cancer smoker 
 
9.1.12.1 Sample Processing 
Plasma - 100 uL  
Please aliquot in Eppendorf tube – Prefer not to have EDTA. Please store in -80 and ship on dry 
ice. 
Specimens, data or information will be coded so that the provider of the samples/data can link 
them to specific individuals but the receiver will not be able to do so.  
Shipping: 
Nagireddy Putluri, Ph.D  
Associate Professor  
120D, Jewish Building 
One Baylor Plaza, Houston, TX, 77030 
 
9.2 
CORRELATIVE STUDIES 
9.2.1 Quality of Life Questionnaire 
Patients will be asked to complete the MDA Anderson Symptom Inventory (MDASI) Core items 
(See Appendix G) in order to assess their symptoms.  Surveys will be completed at baseline and 
on day 1 (± 5 days) of cycle 3 of cabozantinib.  Each survey should take about 5 – 10 minutes to 
complete. 
9.3 
SAMPLE STORAGE, TRACKING AND DISPOSITION 
Samples will be ordered and tracked in CRIS and tracked through a Clinical Trial Data 
Management system.  Should a CRIS screen not be available, the CRIS downtime procedures will 
be followed.  Samples will not be sent outside NIH without IRB notification and an executed MTA.  
9.3.1 Blood Processing Core (BPC)   
Please e-mail NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples (the 
Friday before is preferred). 
For sample pickup, page 102-11964. 
For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 
240-760-6190 (main clinical pharmacology lab number). 
For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov. 
Sample Data Collection 
All samples sent to the Blood Processing Core (BPC) will be bar-coded, with data entered and 
stored in the LABrador (aka LabSamples) utilized by the BPC. This is a secure program, with 
access to  LABrador limited to defined Figg lab personnel, who are issued individual user accounts. 


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Installation of LABrador is limited to computers specified by Dr. Figg. These computers all have 
a password restricted login screen. All Figg lab personnel with access to patient information 
annually complete the NIH online Protection of Human Subjects course.  
LABrador creates a unique barcode ID for every sample and sample box, which cannot be traced 
back to patients without LABrador access. The data recorded for each sample includes the patient 
ID, name, trial name/protocol number; time drawn, cycle time point, dose, material type, as well 
as box and freezer location. Patient demographics associated with the clinical center patient 
number are provided in the system. For each sample, there are notes associated with the processing 
method (delay in sample processing, storage conditions on the ward, etc.). 
Sample Storage and Destruction 
Bar-coded samples are stored in bar-coded boxes in a locked freezer at either -20° or -80qC 
according to stability requirements.  These freezers are located onsite in the BPC and offsite at 
NCI Frederick Central Repository Services in Frederick, MD.  Saliva samples will be stored at 
room temperature.  Samples will be stored until requested by a researcher named on the protocol. 
All requests are monitored and tracked in LABrador. All researchers are required to sign a form 
stating that the samples are only to be used for research purposes associated with this trial (as per 
the IRB approved protocol) and that any unused samples must be returned to the BPC. 
Following completion of this study, samples will remain in storage as detailed above. Access to 
these samples will only be granted following IRB approval of an additional protocol, granting the 
rights to use the material.  
If, at any time, a patient withdraws from the study and does not wish for their existing samples to 
be utilized, the individual must provide a written request. Following receipt of this request, the 
samples will be destroyed (or returned to the patient, if so requested), and reported as such to the 
IRB. Any samples lost (in transit or by a researcher) or destroyed due to unknown sample integrity 
(i.e. broken freezer allows for extensive sample thawing, etc.) will be reported as such to the IRB. 
Sample barcodes are linked to patient demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use of the 
LABrador. It is critical that the sample remains linked to patient information such as race, age, 
dates of diagnosis and death, and histological information about the tumor, in order to correlate 
genotype with these variables. 
9.4 
SAMPLES FOR GENETIC/GENOMIC ANALYSIS 
9.4.1 Saliva 
9.4.1.1 Collection and handling 
x 3 mL of saliva will be collected using the Oragene saliva collection kit (DNA Genotek). 
The sample may be collected at any time after informed consent has been obtained, but 
collection is preferred at baseline. 
x Ideally, the patient should be advised not to eat or drink anything 30 minutes prior to 
collection. 
x Once the sample is obtained, the top of the device is closed, releasing a preservative, the 
top is removed and a cap is placed on the tube. 


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x The date and exact time of the collection should be recorded on the sample. 
x Please email NCIBloodcore@mail.nih.gov 24 hours prior to anticipated collection and 
page 102-11964 for immediate pick-up.   
9.4.1.2 Handling 
As described in section 9.3, samples will be relabeled with barcoded labels generated by LABrador 
on arrival in the Figg Lab. 
9.4.1.3 Site performing the analysis 
Genetic/genomic studies will be performed in the laboratory of Michael Dean, Ph.D., CCR, NCI. 
9.4.2 Tumor Biopsy 
9.4.2.1 Collection and handling 
x Biopsy material remaining from either the baseline collection (see section 9.1.7) or the 
collection at 8 – 18 weeks (see section 9.1.8) should be placed on ice or frozen as soon as 
possible after collection.   
In the case that there is limited biopsy material, tissue distribution should be prioritized as 
follows: 
1. Analysis of met expression (Dr. Maria Merino) 
2. HGF and cabozantinib target analysis  (Dr. Donald Bottaro) 
3. Immune subset analysis (Jane Trepel) 
4. Genetic/Genomic Analysis (Dr. Michael Dean) 
5. HTG Analysis (Dr. Stern) 
9.4.2.2 Processing  
The sample will be processed in the Trepel lab as described in section 9.1.8.2.  DNA will be 
extracted from leftover tissue per Trepel lab procedures and will be assigned a unique barcode that 
can be linked to the original specimen collected, annotated with clinical information.  The DNA 
extracted from the samples will be sent to the Dean lab for analysis. 
9.4.2.3 Site performing the analysis 
Genetic/genomic studies will be performed in the laboratory of Michael Dean, Ph.D., CCR, NCI 
and HTG Molecular as per section 9.1.11.  
9.4.2.4 Shipping 
Extracted DNA from biopsies should be sent to: 
Julie Sawitzke 
Center for Cancer Research, NCI 
Building 560, Room 21-43 
Frederick, MD 21702 
Phone:  301 845 1997 
Email: sawitzkej@mail.nih.gov  
9.4.3 Scope of analysis 
Tumor samples will be used as a source of DNA for genetic/genomic studies.  Saliva samples will 
be used as a source of genomic (germline DNA) from the patients to compare with tumor DNA 


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for somatic mutations.  Whole genome and whole exome studies may be conducted using the 
material collected.  Studies for the analysis of chromosomal abnormalities may also be performed. 
9.4.4 Confidentiality of medical information/biological specimens 
Samples will be labeled with unique identifiers generated in the Figg or Trepel labs respectively 
and transferred to the Dean lab for analysis.  No patient identifiers (e.g., medical record number, 
patient name or initials) will be included with the sample.  Dr. Dean’s lab will create a separate 
unique sample ID using Labmatrix that can be linked to the clinically annotated identifiers from 
the source labs.  Samples will be stored in coded, locked freezers in a room that is locked when 
unoccupied.  The storage facility is located in a building that is key card secured.  Raw and 
analyzed sequencing data will be stored on dedicated server and on a hard drive in the 
investigator’s locked office.  Analyzed data will also be uploaded into the secure Labmatrix 
database. 
Only the PI and study personnel who interact directly with the patients will have access to patient 
records which include personally identifiable information. Investigators conducting the individual 
sample testing will only have access to coded identification numbers and coded patient information 
(i.e. treatment regimens, treatment responses, diagnoses, pathology information). 
No personally identifiable information will be released to third parties and samples and data will 
only be shared with other researchers with the permission of the IRB and under the proper Material 
Transfer Agreements. 
Sometimes, because a group collaboration or journal policy requires it, a subject’s genetic data 
may be deposited in a database such as dbGaP. Although there is controlled access to such a 
database, such a submission carries theoretical risks of revealing the identity of the subject. This 
is discussed in the consent. 
9.4.4.1 Certificate of Confidentiality 
As part of study efforts to provide confidentiality of subject information, this study will obtain a 
Certificate of Confidentiality which helps to protect personally identifiable research information.  
The Certificate of Confidentiality allows investigators on this trial to refuse to disclose identifying 
information related to the research participants, should such disclosure have adverse consequences 
for subjects or damage their financial standing, employability, insurability or reputation.  The 
informed consent includes the appropriate coverage and restrictions of the Certificate of 
Confidentiality. 
9.4.5 Management of Results 
In the unlikely event that clinically actionable incidental findings are discovered, living patients 
will be contacted and asked if they would like to submit a blood sample to be tested at a CLIA 
certified lab and meet with a certified genetic health care provider to discuss the implications of 
this type of testing.  Patients will be offered the option for a legal next of kin to be contacted if 
they are deceased at the time of the research finding.  The legal next of kin would be offered 
genetic counseling that would include the distinction between a clinical and research finding and 
would be offered the opportunity to have those findings confirmed in a living relative of the patient. 
Note: Clinically actionable findings for the purpose of this study are defined as disorders 
appearing in the American College of Medical Genetics and Genomics recommendations for the 
return of incidental findings that is current at the time of primary analysis. (A list of current 


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guidelines is maintained on the CCR intranet: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Incidental+Findings+Lists). 
Incidental findings will only be reported to the patient within the first 5 years of signing the 
consent.  
9.4.6 Genetic Counseling 
Should any significant incidental findings be discovered, genetic counseling will be provided on a 
consultation basis by the NHGRI, NIH. Any genetic counseling or testing at a CLIA certified lab 
will be funded by the Center for Cancer Research at the time of the event (s).   
 


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10 STUDY CALENDAR 
Baseline evaluations are to be conducted within 1 week prior to start of protocol therapy.  Scans and x-rays must be done <4 weeks prior 
to the start of therapy.  In the event that the patient’s condition is deteriorating, laboratory evaluations should be repeated within 48 
hours prior to initiation of the next cycle of therapy. 
The following schedule of assessments applies to all subjects.  More frequent assessments should be obtained if clinically indicated.   
Procedure 
Study Treatment Period 
Post-Treatment Period 
Within 28 days prior to 1st 
Dose of Study Treatment 
Within 1 week prior to 
the first dose of Study 
Treatment 
Day 1 of Weeks  3, 5, 7, 9,  
11, 13,  and 15 then every 4 
weeks 
(± 7 days) 
30 - 37 Days 
after last dose 
Long Term 
Follow Up9 
Informed consent 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical and cancer 
history/demographics 
X 
 
 
 
 
Dental examination 
(baseline)1 
X 
 
 
 
 
24 hour urine collection 
if needed (see section 
3.1.1.13) 
X 
 
 
 
 
Physical examination 
X 
X 
X 
 
 
Height 
X 
 
 
 
 
Weight 
X 
X 
X 
 
 
Vital signs 
X 
X 
X 
 
 
ECOG performance 
status 
X 
X 
X 
 
 
Clinical laboratory 
tests2  
X 
X 
X 
 
 
Urinalysis (including 
UPCR) 
X 
X 
X 
 
 


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Procedure 
Study Treatment Period 
Post-Treatment Period 
Within 28 days prior to 1st 
Dose of Study Treatment 
Within 1 week prior to 
the first dose of Study 
Treatment 
Day 1 of Weeks  3, 5, 7, 9,  
11, 13,  and 15 then every 4 
weeks 
(± 7 days) 
30 - 37 Days 
after last dose 
Long Term 
Follow Up9 
PT/INR, PTT 
X 
X 
X3 
 
 
TFTs  
X 
X 
X3 
 
 
12-lead ECG4 
X 
X 
X3 
 
 
Cabozantinib 
administration 
 
 
X (daily) 
 
 
Pregnancy test (in 
women of childbearing 
potential) 
X 
X 
X3 
 
 
Tumor assessment: CT 
CAP or MRI scan ± 
NaF PET CT 5 
X 
 
X (every 8 weeks)11 
 
 
Concomitant 
medications  
 
 
X 
 
 
Investigational FDG 
PET/CT8 
X 
 
X (weeks 4, 8) 
 
 
Research blood, saliva 
and urine  
X6 
 
X6 
 
 
Biopsy/archival tissue 
obtained7 
X 
 
X (optional, week 8 – 
18) 
 
 
QOL Assessment10 
X 
 
X (week 9 only) 
 
 
Adverse events 
 
Continuous 
 
 
Follow-up phone call 
 
 
 
X 
X 
ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; UPCR, urine protein/urine creatinine ratio 
1 Dental examination required at baseline in patients that have been treated with or are currently taking bisphosphonates 


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2 Clinical laboratory tests include:  a standard hematology panel (CBC, differential, platelets) and chemistry panel (albumin, alkaline phosphatase, ALT, amylase, AST, 
bicarbonate, bilirubin, blood urea nitrogen, calcium, chloride, creatinine, γ-glutamyltransferase (GGT), glucose, lactate dehydrogenase, lipase, magnesium, phosphorus, potassium, 
sodium, total bilirubin, total protein).  Refer to section 5.3.4)  
3 Every 4 weeks 
4 Three ECGs should be obtained within 30 minutes but at least 2 minutes apart if there is an increase in QTc to an absolute value > 500 msec using the Fridericia correction 
formula. See section 5.3.1 
5 All sites of known disease must be assessed.  Baseline scans must be repeated if patient is off of study drug for > 6 weeks. 
6 Please see section 9 or Appendix F for research blood and urine collection   
7 Please see sections 9.1.7, 9.1.8.1.2 and 9.4.2 or Appendix F for biopsy or archival tissue specifications 
8 Performed on patients with metastatic disease. See section 9.1.9.  
9 Will attempt patient contact every 2 months after 30 – 37 day phone call to determine survival status 
10 QOL assessments will be performed at baseline and after cycle 3 of cabozantinib. Please see section 9.2.1 for further details. 
11 Patients who are off treatment due to complete response after 3 years will have their assessments every 12 weeks. 
  


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11 MEASUREMENT OF EFFECT 
11.1 ANTITUMOR EFFECT – SOLID TUMORS 
Patients with measurable disease will be assessed primarily by CT scan of the chest, abdomen and 
pelvis.  MRI may be used in subjects unable to tolerate contrast.  For the purposes of this study, 
patients should be re-evaluated every 8 weeks. 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1). [Eur J Ca 45:228-247, 2009] and Prostate Cancer Clinical Trials Working Group 
criteria (PCWG2)79.  Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST 
criteria. 
11.1.1 Definitions 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their first 
treatment with study agents. 
Evaluable for objective response. All of the patients who met the eligibility criteria and who have 
received at least 8 weeks of therapy are evaluable for response. Patients that have: progressive 
disease, early death from malignant disease, early death from toxicity, early death because of other 
cause, or unknown (not assessable, insufficient data) should be considered to have a treatment 
failure (disease progression). Thus, an incorrect treatment schedule or drug administration does 
not result in exclusion from the analysis of the response rate. 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle 
of therapy, and have had their disease re-evaluated will be considered evaluable for non-target 
disease.  The response assessment is based on the presence, absence, or unequivocal progression 
of the lesions.  
11.1.2 Disease Parameters 
Measurable disease.  Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as >20 mm by chest x-ray or as >10 mm 
with CT scan, MRI, or calipers by clinical exam.  All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph node 
must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will be measured 
and followed. 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 


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effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable. 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if 
they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline.  Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements.  It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion which can be measured reproducibly should be selected.  A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated 
and reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, then 
only the short axis is added into the sum.  The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the disease. 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up.  
11.1.3 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical lesions Clinical lesions will only be considered measurable when they are superficial (e.g., 
skin nodules and palpable lymph nodes) and t10 mm diameter as assessed using calipers (e.g., 
skin nodules).  In the case of skin lesions, documentation by color photography, including a ruler 
to estimate the size of the lesion, is recommended.  
Chest x-ray Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
Conventional CT and MRI This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice thickness greater 


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than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  MRI is 
also acceptable in certain situations (e.g. for body scans).   
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal resolution; 
however, there are many image acquisition variables involved in MRI, which greatly impact image 
quality, lesion conspicuity, and measurement.  Furthermore, the availability of MRI is variable 
globally.  As with CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of disease.  Furthermore, 
as with CT, the modality used at follow-up should be the same as was used at baseline and the 
lesions should be measured/assessed on the same pulse sequence.  It is beyond the scope of the 
RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image acquisition 
protocol should be followed as closely as possible to prior scans.  Body scans should be performed 
with breath-hold scanning techniques, if possible. 
PET-CT At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements.  However, if the 
site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to 
a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for 
RECIST measurements and can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time.  Note, however, that the PET portion of the CT introduces 
additional data which may bias an investigator if it is not routinely or serially performed.   
Ultrasound Ultrasound is not useful in assessment of lesion size and should not be used as a method 
of measurement.  Ultrasound examinations cannot be reproduced in their entirety for independent 
review at a later date and, because they are operator dependent, it cannot be guaranteed that the 
same technique and measurements will be taken from one assessment to the next.  If new lesions 
are identified by ultrasound in the course of the study, confirmation by CT or MRI is advised.  If 
there is concern about radiation exposure at CT, MRI may be used instead of CT in selected 
instances. 
Endoscopy, Laparoscopy The utilization of these techniques for objective tumor evaluation is not 
advised.  However, such techniques may be useful to confirm complete pathological response 
when biopsies are obtained or to determine relapse in trials where recurrence following complete 
response (CR) or surgical resection is an endpoint. 
Tumor markers Tumor markers alone cannot be used to assess response.  If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response.  Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and 
PSA response (in recurrent prostate cancer) have been published [JNCI 96:487-488, 2004; J Clin 
Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  In addition, the Gynecologic 
Cancer Intergroup has developed CA-125 progression criteria which are to be integrated with 
objective tumor assessment for use in first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
Cytology, Histology These techniques can be used to differentiate between partial responses (PR) 
and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell 
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The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
FDG-PETWhile FDG-PET response assessments need additional study, it is sometimes reasonable 
to incorporate the use of FDG-PET scanning to complement CT scanning in assessment of 
progression (particularly possible 'new' disease).  New lesions on the basis of FDG-PET imaging 
can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not 
PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively described 
in the protocol and supported by disease-specific medical literature for the indication.  
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
11.1.4 Response Criteria 
11.1.4.1 Evaluation of Target Lesions 
Complete Response (CR): 
Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have 
reduction in short axis to <10 mm. 
Partial Response (PR): 
At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum 
diameters. 
Progressive Disease (PD): 
At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on 
study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.  (Note:  the appearance of one 


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or more new lesions is also considered progressions). 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference 
the smallest sum diameters while on study. 
 
11.1.4.2 Evaluation of Non-Target Lesions 
Complete Response (CR): 
Disappearance 
of 
all 
non-target 
lesions 
and 
normalization of tumor marker level.  All lymph nodes 
must be non-pathological in size (<10 mm short axis). 
Note:  If tumor markers are initially above the upper 
normal limit, they must normalize for a patient to be 
considered in complete clinical response 
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal 
limits. 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  
Unequivocal progression should not normally trump 
target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.     
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed at 
a later time by the review panel (or Principal Investigator). 
11.1.4.3 Metastatic bone lesions 
Two new bone lesions on Na18F PET CT that is associated with characteristic bone changes on CT 
will be defined as progressive disease (PD).79  Na18F uptake changes including changes in SUV or 
flares of known lesions will not be counted as PD. Only new lesions with associated CT changes 
will be counted as PD. 
11.1.4.4 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started).  The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 


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For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-
Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall 
Response when 
Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. 
Confirmation** 
CR 
Non-
CR/Non-
PD 
No 
PR 
>4 wks. 
Confirmation** 
CR 
Not 
evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least 
once >4 wks. from 
baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence 
of a new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-
target lesions may be accepted as disease progression. 
 
Note: Patients with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease 
progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 


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For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease 
since SD is increasingly used as an endpoint for assessment of efficacy in some 
trials so to assign this category when no lesions can be measured is not advised 
 
11.1.5 Duration of Response 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease or death is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  
11.1.6 Progression Free Survival 
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first. 
12 DATA COLLECTION / DATA REPORTING / REGULATORY REQUIREMENTS 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 0 
(Adverse Events: List and Reporting Requirements). 
12.1 DATA COLLECTION 
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system NCI CCR C3D database within 14 days of collection and ensuring data accuracy, 
consistency and timeliness. The principal investigator, associate investigators/research nurses 
and/or a contracted data manager will assist with the data management efforts.  All data obtained 
during the conduct of the protocol will be kept in secure network drives or in approved alternative 
sites that comply with NIH security standards. Primary and final analyzed data will have identifiers 
so that research data can be attributed to an individual human subject participant. 


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All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event. Patients 
will be followed for adverse events for a minimum of 30 days after removal from study treatment 
or until off-study, whichever comes first. 
An abnormal laboratory value will be considered an AE if the laboratory abnormality is 
characterized by any of the following: 
x 
Results in discontinuation from the study 
x 
Is associated with clinical signs or symptoms  
x 
Requires treatment or any other therapeutic intervention 
x 
Is associated with death or another serious adverse event, including hospitalization.  
x 
Is judged by the Investigator to be of significant clinical impact 
x 
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome. 
Quality assurance complete records must be maintained on each patient treated on the protocol.  
These records should include primary documentation (e.g.: laboratory report slips, X-ray reports, 
scan reports, pathology reports, physician notes, etc.) which confirm that: 
x The patient met all eligibility criteria 
x Signed informed consent was obtained prior to treatment 
x Treatment was given according to protocol (dated notes about doses given, 
complications, and clinical outcomes) 
x Toxicity was assessed according to protocol (laboratory report slips, etc.) 
x Response was assessed according to protocol (X-ray, scan, lab reports, date noted on 
clinical assessment, as appropriate) 
All data will be kept secure. Personal identifiers will not be used when collecting and storing data. 
An enrollment log will be maintained in the regulatory binder/file which is the only location of 
personal identifiers with unique subject identification number. 
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable.  
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, the IRB will be notified. 
12.2 GENOMIC DATA SHARING PLAN 
Unlinked genomic data will be deposited in public genomic databases such as dbGaP in 
compliance with the NIH Genomic Data Sharing Policy. 
12.3 DATA REPORTING 
12.3.1 Method 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  The C3D 
data management system will be used to capture data and report to the clinical data update system 


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(CDUS).  Cumulative protocol- and patient-specific CDUS data will be submitted electronically 
to CTEP on a quarterly basis, either by FTP burst of data or via the CDS web application.  Reports 
are due January 31, April 30, July 31, and October 31.  Instructions for submitting data using the 
CDUS can be found on the CTEP Web site (http://ctep.cancer.gov/reporting/cdus.html).  
Note:  If your study has been assigned to CDUS-Complete reporting, all adverse events (both 
routine and expedited) that have occurred on the study and meet the mandatory CDUS reporting 
guidelines must be reported via the monitoring method identified above.  If your study has been 
assigned to CDUS-Abbreviated reporting, no adverse event reporting (routine or expedited) is 
required to be reported via CDUS. 
12.4 CTEP MULTICENTER GUIDELINES 
N/A 
12.5 COLLABORATIVE AGREEMENTS LANGUAGE 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and 
shall be maintained as such by the investigators.  The protocol documents for studies 
utilizing Agents contain confidential information and should not be shared or distributed 
without the permission of the NCI.  If a copy of this protocol is requested by a patient or 
patient’s family member participating on the study, the individual should sign a 
confidentiality agreement.  A suitable model agreement can be downloaded from: 
http://ctep.cancer.gov.  
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to 
and use of data by each Collaborator shall be as follows (data pertaining to such 
combination use shall hereinafter be referred to as "Multi-Party Data”): 
a. NCI will provide all Collaborators with prior written notice regarding the existence 
and nature of any agreements governing their collaboration with NCI, the design of 
the proposed combination protocol, and the existence of any obligations that would 
tend to restrict NCI's participation in the proposed combination protocol. 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical 
trial by any other Collaborator solely to the extent necessary to allow said other 
Collaborator to develop, obtain regulatory approval or commercialize its own Agent. 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-


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Party Data solely for development, regulatory approval, and commercialization of its 
own Agent. 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available to Collaborator(s), the NCI, and the FDA, as 
appropriate and unless additional disclosure is required by law or court order as 
described in the IP Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the protection 
of human subjects, including, if applicable, the Standards for Privacy of Individually 
Identifiable Health Information set forth in 45 C.F.R. Part 164. 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to 
the NCI, who will then notify the appropriate investigators (Group Chair for Cooperative 
Group studies, or PI for other studies) of Collaborator's wish to contact them. 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is 
a DMC for this clinical trial. 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by 
the Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review 
and comment prior to submission for publication.  Collaborator(s) will have 30 days from 
the date of receipt for review.  Collaborator shall have the right to request that publication 
be delayed for up to an additional 30 days in order to ensure that Collaborator’s 
confidential and proprietary data, in addition to Collaborator(s)’s intellectual property 
rights, are protected.  Copies of abstracts must be provided to CTEP for forwarding to 
Collaborator(s) for courtesy review as soon as possible and preferably at least three (3) 
days prior to submission, but in any case, prior to presentation at the meeting or 
publication in the proceedings.  Press releases and other media presentations must also be 
forwarded to CTEP prior to release.  Copies of any manuscript, abstract and/or press 
release/ media presentation should be sent to: 
Email: ncicteppubs@mail.nih.gov  
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/ proprietary information. 
12.6 MATERIAL TRANSFER AGREEMENT (MTA) FOR SAMPLES SENT TO HTG MOLECULAR  
An MTA is to be filed for samples to be sent to HTG Molecular as outlined in section 9.1.11.  
12.7 MTA FOR SAMPLES SENT TO BAYLOR COLLEGE 
An MTA for samples to be sent to Nagireddy Putluri Ph.D at Baylor College as outlined in section 
9.1.12, will be finalized upon approval of the amendment O dated 11/08/2017. 


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13 STATISTICAL CONSIDERATIONS 
13.1 STUDY DESIGN/ENDPOINTS 
The primary objective of this study is to determine if patients with advanced or metastatic bladder 
cancer will exhibit responses to XL184. 
The study will be conducted as an optimal two-stage phase II trial (Simon R, Controlled Clinical 
Trials 10:1-10, 1989), in order to rule out an unacceptably low 5% overall response rate (ORR; 
p0=0.05), in favor of a modest response rate of 20% (p1=0.20). With alpha=0.05 (probability of 
accepting a poor treatment=0.05) and beta = 0.10 (probability of rejecting a good treatment=0.10), 
the study will initially enroll 21 evaluable patients and if 0 to 1 of the 21 have a response by 
RECIST version 1.1, then no further patients will be accrued. If 2 or more the first 21 have a 
response, then accrual would continue until a total of 41 patients have enrolled. As it may take 
several weeks to determine if a patient has experienced a response, a temporary pause in the accrual 
to the trial may be necessary to ensure that enrollment to the second stage is warranted. If there 
are 2 to 4 responses in 41 patients, this would be an uninterestingly low response rate, while if 
there were 5 or more responses in 41patients, then this would be sufficiently interesting to warrant 
further study in later trials. Under the null hypothesis (5% response rate), the probability of early 
termination is 72%. 
Patients with bone-only disease will be accrued and evaluated separately from all other patients, 
as they cannot be evaluated with the same methods or same degree of accuracy as all other patients 
with this disease. It is expected that only 15-20% of all patients enrolling on the trial will have 
bone-only disease. The patients which would be expected to enroll while awaiting enrollment of 
the main set of 41 patients will be considered a hypothesis generating cohort to determine if any 
patients show some evidence of avoiding worsening disease while receiving XL184. They will be 
evaluated using Na18F PET CT scans in addition to standard CT CAP (or MRI) and FDG PET and 
will be considered to have favorable results if additional lesions are not noted compared to 
baseline. As this is a small set of patients, the results will be used to determine if a more definitive 
subsequent study in these patients would be warranted. 
Patients with non transitional cell carcinoma will be accrued and evaluated separately from all 
other patients.  Because no data for an expected response rate for comparison currently exist with 
regard to this group of patients, this will be an exploratory study. The patients which would be 
expected to enroll while awaiting enrollment of the main set of 41 patients will be considered a 
hypothesis generating cohort to determine if any patients show some evidence of avoiding 
worsening disease while receiving XL184. They will be evaluated using standard CT CAP (or 
MRI) and FDG PET and will be considered to have favorable results if additional lesions are not 
noted compared to baseline. As this is a small set of patients, the results will be used to determine 
if a more definitive subsequent study in these patients would be warranted. 
 
13.2 SAMPLE SIZE/ACCRUAL RATE 
In order to allow for up to 41 evaluable patients plus up to 21 patients with either bone only or non 
TCC bladder, urethra, ureter, or renal pelvis cancer who will be evaluated in separate cohorts, the 
accrual ceiling will be 71 patients.  This will allow enrollment of up to 8-9 patients who may be 
considered inevaluable.  It is anticipated that 2-3 patients per month may enroll on this trial; thus, 


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2 to 3 years is anticipated as the accrual period for this study.  Subjects will be accrued into the 
exploratory cohorts (cohorts 2 and 3) for only as long as subjects are being accrued onto the 
hypothesis generating cohort (cohort 1). 
13.3 STRATIFICATION FACTORS 
N/A 
13.4 ANALYSIS OF SECONDARY ENDPOINTS 
The secondary endpoint of progression free survival and survival will also be analyzed via a 
Kaplan-Meier curve. This latter, secondary, evaluation will be based on all patients who are able 
to be assessed in either the first (retrospectively) or second stage of accrual.  The secondary 
endpoint of the assessment of non RECIST imaging criteria and association with treatment 
response (RECIST) will be analyzed via appropriate non-parametric methods, such as a Wilcoxon 
rank sum test to compare parameters between responders and non-responders. 
Toxicity and safety are also a primary consideration for use of this agent in this population. The 
worst grade of each type of toxicity noted per patient will be tabulated and reported according to 
the NCI Common Toxicity Criteria, version 4.0. 
Evaluations of any laboratory and correlative parameters obtained will be done using exploratory 
techniques. Comparisons of parameters between patients who do and do not respond to therapy 
will be done using non-parametric methods such as a Wilcoxon rank sum test. The results will be 
reported without any formal adjustment for multiple comparisons. 
For the secondary objective of FDG PET scan evaluation we will examine the change of uptake of 
FDG over time and explore its relationship with response to therapy. Descriptive statistics such as 
percent changes of FDG over time and its overall trend in relation to the clinical endpoints will be 
reported.  The data obtained from this study will be used for hypothesis generating and sample 
size planning for the main study. 
13.5 REPORTING AND EXCLUSIONS 
13.5.1 Evaluation of toxicity 
All patients will be evaluable for toxicity from the time of their first treatment with cabozantinib. 
13.5.2 Evaluation of response 
All patients included in the study must be assessed for response to treatment, even if there are 
major protocol treatment deviations or if they are ineligible.  Each patient will be assigned one of 
the following categories:  1) complete response, 2) partial response, 3) stable disease, 4) 
progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early 
death because of other cause, or 9) unknown (not assessable, insufficient data).  [Note:  By 
arbitrary convention, category 9 usually designates the “unknown” status of any type of data in a 
clinical database.] 
All of the patients who met the eligibility criteria (with the possible exception of those who 
received no study medication) should be included in the main analysis of the response rate.  
Patients in response categories 4-9 should be considered to have a treatment failure (disease 
progression).  Thus, an incorrect treatment schedule or drug administration does not result in 


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exclusion from the analysis of the response rate.  Precise definitions for categories 4-9 will be 
protocol specific.  
All conclusions should be based on all eligible patients.  Subanalyses may then be performed on 
the basis of a subset of patients, excluding those for whom major protocol deviations have been 
identified (e.g., early death due to other reasons, early discontinuation of treatment, major protocol 
violations, etc.).  However, these subanalyses may not serve as the basis for drawing conclusions 
concerning treatment efficacy, and the reasons for excluding patients from the analysis should be 
clearly reported.  The 95% confidence intervals should also be provided.  
14 HUMAN SUBJECTS PROTECTIONS  
14.1 RATIONALE FOR SUBJECT SELECTION 
Subjects with progressive urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis will 
be eligible for participation in this study.  Individuals of any race or ethnic group will be eligible 
for this study.  Eligibility assessment will be based solely on the patient’s medical status.  
Recruitment of patients onto this study will be through standard CCR mechanisms.  No special 
recruitment efforts will be conducted. 
14.2 PARTICIPATION OF CHILDREN 
Individuals under the age of 18 will not be eligible to participate in this study because they are 
unlikely to have urothelial cancer, and because of unknown toxicities of this agent in the pediatric 
patient. 
14.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT 
Adults unable to give consent are excluded from enrolling in the protocol.  However re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (section 14.4), all subjects ≥ age 18 will be offered the opportunity to fill in 
their wishes for research and care, and assign a substitute decision maker on the “NIH Advance 
Directive for Health Care and Medical Research Participation” form so that another person can 
make decisions about their medical care in the event that they become incapacitated or cognitively 
impaired during the course of the study. Note: The PI or AI will contact the NIH Ability to Consent 
Assessment Team (ACAT) for evaluation as needed for the following: an independent assessment 
of whether an individual has the capacity to provide consent; assistance in identifying and 
assessing an appropriate surrogate when indicated; and/or an assessment of the capacity to appoint 
a surrogate. For those subjects that become incapacitated and do not have pre-determined 
substitute decision maker, the procedures described in NIH HRPP SOP 14E for appointing a 
surrogate decision maker for adult subjects who are (a) decisionally impaired, and (b) who do not 
have a legal guardian or durable power of attorney, will be followed. 


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14.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
14.4.1 Benefits 
The potential benefit to a patient on this study is a reduction in the bulk of their tumor and 
improvement in cancer lesions, which may or may not have favorable impact on symptoms and/or 
survival.   
14.4.2 Risks 
Radiation Risks 
Undergoing the research FDG PET CT scans will cause subjects to be exposed to approximately 
3.2 rem which is below the guideline of 5 rem per year allowed for adult research subjects by the 
NIH Radiation Safety Committee. 
Other Risks 
Additional risks include the possible occurrence of any of a range of side effects which are listed 
in the Consent Document.  Frequent monitoring for adverse effects will help to minimize the risks 
associated with administration of cabozantinib. 
14.5 RISKS/BENEFITS ANALYSIS 
Although urothelial cancer is a chemosensitive malignancy with response proportions of over 50% 
with conventional cytotoxic regimens, the response durations are short and the median survival of 
patients with metastatic disease is approximately 14 months.  There is no FDA-approved second 
line drug for metastatic urothelial cancer.  Inhibition of angiogenesis has demonstrated antitumor 
efficacy in patients with metastatic UC.  Cabozantinib inhibits multiple receptor kinases with 
growth promoting and angiogenic properties, including MET and VEGF, which are known to be 
over-expressed in bladder cancer. 
The use of cabozantinib as a second line agent in metastatic urothelial cancer has the potential to 
improve outcomes in this patient population.  Given the efforts to minimize risk with the 
administration of this combination, this protocol involves greater than minimal risk, but presents 
the potential for direct benefit to individual subjects. 
14.6 CONSENT AND ASSENT PROCESS AND DOCUMENTATION 
The principal investigator or a designee will obtain written informed consent from each subject 
participating in this study after adequate explanation of the aims, methods, anticipated benefits, 
and potential hazards of the study. In the case where the subject is unable to read, an impartial 
witness will be present during the entire informed consent discussion. After the subject has orally 
consented to participation in the trial, the witness’s signature on the form will attest that the 
information in the consent form was accurately explained and understood. 
If new safety information results in significant changes in the risk/ benefit assessment, the consent 
form will be reviewed and updated as necessary. All subjects (including those already being 
treated) will be informed of the new information, be given a copy of the revised form, and be asked 
give their consent to continue in the study. 
It will be documented on the case report form that informed consent has been obtained. 


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14.6.1 Telephone re-consent  
Reconsent on this study may be obtained via telephone according to the following procedure: the 
informed consent document will be sent to the subject.  An explanation of the study will be 
provided over the telephone after the subject has had the opportunity to read the consent form.  
The subject will sign and date the informed consent.   
The original informed consent document will be sent back to the consenting investigator who will 
sign and date the consent form with the date the consent was obtained via telephone.   
A fully executed copy will be returned via mail for the subject’s records.   
The informed consent process will be documented in the medical record. 


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79. 
Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for patients 
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the Prostate Cancer Clinical Trials Working Group. J Clin Oncol. 2008;26(7):1148-1159. 
 
 


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


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16.2 APPENDIX B: PATIENT INFORMATION ON POSSIBLE DRUG INTERACTIONS 
 
Information on Possible Interactions with Other Agents for Patients and Their Caregivers 
and Non-Study Healthcare Team 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental cabozantinib.  This clinical trial is sponsored by the National Cancer Institute.  This 
form is addressed to the patient, but includes important information for others who care for this 
patient.  
Cabozantinib interacts with many drugs that are processed by your liver.  Because of this, it is very 
important to tell your study doctors about all of your medicine before you start this study.  It is 
also very important to tell them if you stop taking any regular medicine, or if you start taking a 
new medicine while you take part in this study.  When you talk about your medicine with your 
study doctor, include medicine you buy without a prescription at the drug store (over-the-counter 
remedy), or herbal supplements such as St. John’s wort.  
 
Many health care prescribers can write prescriptions.  You must also tell your other prescribers 
(doctors, physicians’ assistants or nurse practitioners) that you are taking part in a clinical trial. 
Bring this paper with you and keep the attached information card in your wallet.  These are 
the things that you and they need to know:  
 
Cabozantinib interacts with (a) certain specific enzyme(s) in your liver.  
x The enzyme(s) in question is CYP3A4.  This enzyme breaks down cabozantinib, gradually 
reducing the level of the active drug in your system.    
x Other medicines may affect the activity of the enzyme.  Cabozantinib must be used very 
carefully with these medicines, or you may need to switch to alternate medications. 
o Substances that increase the enzyme’s activity (“inducers”) could reduce the 
effectiveness of the drug, while substances that decrease the enzyme’s activity 
(“inhibitors”) could result in high levels of the active drug, increasing the chance 
of harmful side effects. 
x You and healthcare providers who prescribe drugs for you must be careful about adding or 
removing any drug in this category.  
x Before you start the study, your study doctor will work with your regular prescriber to 
switch any medicines that are considered “strong inducers/inhibitors or substrates of 
CYP3A4.” 
x Your prescribers should look at this web site http://medicine.iupui.edu/clinpharm/ddis/ or 
consult a medical reference to see if any medicine they want to prescribe is on a list of 
drugs to avoid.   
x Please be very careful!  Over-the-counter drugs have a brand name on the label—it’s 
usually big and catches your eye.  They also have a generic name—it’s usually small and 
located above or below the brand name, and printed in the ingredient list.  Find the 
generic name and determine, with the pharmacist’s help, whether there could be an 
adverse interaction.   


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x Be careful:  
o If you take acetaminophen regularly:  You should not take more than 4 grams a 
day if you are an adult or 2.4 grams a day if you are older than 65 years of age.  
Read labels carefully!  Acetaminophen is an ingredient in many medicines for 
pain, flu, and cold. 
o If you drink grapefruit juice or eat grapefruit or Seville orange:  Avoid these until 
the study is over.  
o If you take herbal medicine regularly:  You should not take St. John’s wort while 
you are taking cabozantinib 
o For indigestion, take antacid at least 2 hours (preferably 4 hours) after taking 
cabozantinib and at least 14 hours before the next dose of cabozantinib if possible.  
Avoid using ranitidine, famotidine, omeprazole, lansoprazole, rabeprazole, 
pantoprazole, or esomeprazole. If antacids are not adequate, please contact the 
research team member before taking any other medications. 
 
Other medicines can be a problem with your study drugs.  
x You should check with your doctor or pharmacist whenever you need to 
use an over-the-counter medicine or herbal supplement.  
x Your regular prescriber should check a medical reference or call your 
study doctor before prescribing any new medicine for you.  Your study 
doctor’s name is Dr. Andrea Apolo and she can be contacted at 301-480-
0536. 
 
 
 
 
INFORMATION ON POSSIBLE DRUG INTERACTIONS  
You are enrolled on a clinical trial using the experimental agent XL184 
(cabozantinib).  This clinical trial is sponsored by the NCI.  XL184 
(cabozantinib) interacts with drugs that are processed by your liver.  
Because of this, it is very important to: 
¾ Tell your doctors if you stop taking regular medicine or if you start 
taking a new medicine. 
¾ Tell all of your prescribers (doctor, physicians’ assistant, nurse 
practitioner, pharmacist) that you are taking part in a clinical trial. 
¾ Check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement. 
INFORMATION ON POSSIBLE DRUG INTERACTIONS  
You are enrolled on a clinical trial using the experimental agent XL184 
(cabozantinib).  This clinical trial is sponsored by the NCI.  XL184 
(cabozantinib) interacts with drugs that are processed by your liver.  
Because of this, it is very important to: 
¾ Tell your doctors if you stop taking regular medicine or if you start 
taking a new medicine. 
¾ Tell all of your prescribers (doctor, physicians’ assistant, nurse 
practitioner, pharmacist) that you are taking part in a clinical trial. 
¾ Check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement. 


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16.3 APPENDIX C: PATIENT MEDICATION DIARY 
Cycle #_____________________ 
Patient Name________________________________   
INSTRUCTIONS TO THE PATIENT: 
1. Complete one form for each Cycle. 
2. You will take ___ cabozantinib pills once each day.   
3. Record the date, the number of pills you took, and when you took them.   
4. If you have any comments or notice any side effects, please record them in the Comments column. 
5. Please bring your pill bottles and this form to your physician when you go for your next appointment. 
 
Date 
 
Day 
Cabozantinib  
(taken once a day) 
 
# pills, 
when taken 
# pills  
missed 
Comments 
 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
12 
 
 
 
 
13 
 
 
 
 
14 
 
 
 
 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
22 
 
 
 
 
23 
 
 
 
 
24 
 
 
 
 
25 
 
 
 
 
26 
 
 
 
 
27 
 
 
 
 
28 
 
 
 
Patient’s Signature: ___________________________________  Date: ____________________ 
 


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16.4 APPENDIX D:  CCR PATIENT SELF-ADMINISTERED STUDY AGENT COMPLIANCE LOG 
This form is to be updated at every study contact where patient receives or returns study drug.  This form may be used for multiple self-administered study agents. 
This form is to be used in conjunction with a note in CRIS about study drug self-administration and case report form and will be maintained in the research record.  
If patient is bringing back their study drug and you will not be returning that to the pharmacy, rather, the patient will be taking it back home with them, please use 
the form entitled ‘CCR Patient Self-Administered Study Agent Interim Compliance Form’. 
 
CC Protocol Number:_________________________             Principal Investigator:______________________ 
 
Protocol Title:_____________________________________________________________________________ 
 
Patient’s Medical Record Number:____________________   Patient’s Name:___________________________ 
 
Patient Study ID:  ________________ 
Cycle Number_____     
 
Date Dispensed 
Amount 
Dispensed 
Dose Form 
(e.g., tablets, 
pills, bottles, 
capsules,  vials) 
Date Returned 
Actual 
Amount 
Returned 
Expected 
Amount 
Taken 
Expected 
Amount 
Returned 
Reason for difference 
between actual and expected 
amount returned, if 
applicable 
Site Staff 
Initials 
____/_____/20_____ 
(mm/dd/yyyy) 
 
  
____/_____/20______ 
(mm/dd/yyyy) 
 
 
 
 
 
____/_____/20_____ 
(mm/dd/yyyy) 
 
 
____/_____/20______ 
(mm/dd/yyyy) 
 
 
 
 
 
____/_____/20_____ 
(mm/dd/yyyy) 
 
 
____/_____/20______ 
(mm/dd/yyyy) 
 
 
 
 
 
____/_____/20_____ 
(mm/dd/yyyy) 
 
 
____/_____/20______ 
(mm/dd/yyyy) 
 
 
 
 
 
____/_____/20_____ 
 
 
____/_____/20______ 
 
 
 
 
 


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Date Dispensed 
Amount 
Dispensed 
Dose Form 
(e.g., tablets, 
pills, bottles, 
capsules,  vials) 
Date Returned 
Actual 
Amount 
Returned 
Expected 
Amount 
Taken 
Expected 
Amount 
Returned 
Reason for difference 
between actual and expected 
amount returned, if 
applicable 
Site Staff 
Initials 
(mm/dd/yyyy) 
(mm/dd/yyyy) 
____/_____/20_____ 
(mm/dd/yyyy) 
 
 
____/_____/20______ 
(mm/dd/yyyy) 
 
 
 
 
 
____/_____/20_____ 
(mm/dd/yyyy) 
 
 
____/_____/20______ 
(mm/dd/yyyy) 
 
 
 
 
 


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16.5 APPENDIX E:  BLOOD PRESSURE MONITORING FORM 
For use in patients with a history of hypertension 
 
Instructions 
1. Take your blood pressure once per week during each cycle of cabozantinib 
2. Record the date you took your blood pressure and your blood pressure below 
3. Bring this form with you at your next study visit 
Week 
Date 
Blood Pressure 
1 
 
 
 
 
 
 
/ 
 
 
2 
 
 
 
 
 
 
/ 
 
 
3 
 
 
 
 
 
 
/ 
 
 
4 
 
 
 
 
 
 
/ 
 
 
 
 


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16.6 APPENDIX F: SAMPLE COLLECTION FOR CORRELATIVE STUDIES 
Test 
description 
Amount/Type/T
ube/Handling 
Collection 
Timing 
Contact 
Special 
Instructions 
Saliva 
Oragene saliva 
collection kits 
(DNA Genotek) 
At any time after 
consent is signed, 
but preferably at 
baseline 
Please email 
NCIBloodcore@mail.nih.gov 
24 hours prior to anticipated 
collection and page 102-11964  
for pickup. 
store at room temp 
Met expression 
in tissue 
4-6 cores, Tumor 
block, 10 unstained 
slides, or a fresh 
tumor biopsy 
Pre-treatment 
When scheduled email Jane 
Trepel (trepel@helix.nih.gov), 
Sunmin Lee 
(lees@pop.nci.gov), Mi-Jung 
(leemin@mail.nih.gov, and 
Maria Merino 
Analyzed by 
immunohistochemi
stry and flow 
cytometry as 
appropriate 
 
 
  
When patient arrives at IR call 
Jane Trepel (240) 760-6330 
and Maria Merino 
Tissue biopsies 
strictly on 
voluntary basis 
HTG EdgeSeq 
Immuno-
Oncology and 
OBP Assays 
H&E and serial 
unstained slides 
 
HTG Molecular Diagnostics, 
Inc. 
3430 E. Global Loop 
Tucson, AZ 85706 
T: (877) 289-2615 
F: (520) 547-2837 
 
CEC, CEP, and 
CTC 
Two 10cc Lavender 
top EDTA tube 
Three 8mL blue-
tiger top BD 
Vacutainer 
Preparation tube 
with sodium citrate 
Pre-treatment 
When scheduled email Jane 
Trepel (trepel@helix.nih.gov), 
Sunmin Lee 
(lees@pop.nci.gov), Mi-Jung 
(leemin@mail.nih.gov) 
Gently invert 
sample several 
times immediately 
after collection, 
store at room temp 
 
Date and Time tube 
C3D1 
When drawn call Trepel lab 
(240) 760-6330 for immediate 
pick up 
  
C-Met analysis 
by real-time 
RT-PCR 
PAXgene tube 
(PreAnalytix; 2.5cc 
blood per tube) 
Pre-treatment 
When scheduled email Jane 
Trepel (trepel@helix.nih.gov), 
Sunmin Lee 
(lees@pop.nci.gov), Mi-Jung 
(leemin@mail.nih.gov)  
invert several 
times and place at 
room temp or 
refrigerate 
 
Date and Time tube 
C3D1 
When drawn call Trepel lab 
(240) 760-6330 for immediate 
pick up 
 
IL-8 circulating 
cytokine levels 
One 5mL red top 
tube 
C1D1, C1D15,       
C2D1 
When scheduled, email Jane 
Trepel (trepel@helix.nih.gov), 
Sunmin Lee 
(lees@pop.nci.nih.gov), Min-
Jung Lee 
(leemin@mail.nih.gov)  
store at room temp 


Abbreviated Title: Ph 2 XL184 in urothelial CA 
 
CTEP Study #: 9236 
Version Date: 05/10/2019 
111 
 
Test 
description 
Amount/Type/T
ube/Handling 
Collection 
Timing 
Contact 
Special 
Instructions 
 
Date and Time tube 
 
When drawn call (240) 760-
6330 (Trepel lab) for 
immediate pick up 
  
Genetic 
biomarkers 
(VEGFR2) 
One 10mL EDTA 
lavender top tube 
C2D1 
e-mail 24 hr prior, Please page 
102-11964  - Figg lab 
Invert 8-10 times, 
place on wet ice 
and store at 4°C in  
refrigerator until 
procession 
 
Date and Time tube 
  
 
 
Angiogenesis 
markers 
4mL EDTA tube 
C1D1, C1D15,         
C2D1,    
progression 
E-mail 24hr prior, Please page 
102-11964 - Figg lab 
Invert EDTA tube 
2-4 times, place on 
wet ice and store at 
4°C in the 
refrigerator until 
processing for a 
maximum of 30-60 
min. 
 
Date and Time tube 
 
 
 
Plasma HGF 
and MET 
One 3mL EDTA 
tube 
prior to treatment, 
every visit 
Email 24 hr prior, Please page 
102-11964  - Figg lab 
Should be 
centrifuged within 
30 min  
 
Date and Time tube 
 
 
Refrigerate 
samples 
Analysis of 
tissue HGF and 
cabozantinib 
targets 
4-6 cores of fresh 
tumor biopsy 
x Pre-treatment  
x 8 – 18 weeks 
When scheduled, contact Dr. 
Bottaro to notify of biopsy 
date and time (301-402-6499) 
and to arrange for pick up of 
sample during biopsy 
The interval 
between sample 
acquisition and 
freezing on dry ice 
must not exceed 2 
minutes. 
 
Tissue biopsies 
strictly on 
voluntary basis 
Urinary MET 
and urine spot 
creatinine 
Collect at least 2mL 
of urine 
prior to treatment, 
every visit 
Email 24 hr prior, Please page 
102-11964  - Figg lab 
Note urine source: 
void, percutaneous 
stent, Foley, 
neobladder, Indian 
pouch, or ileal 
conduit 


Abbreviated Title: Ph 2 XL184 in urothelial CA 
 
CTEP Study #: 9236 
Version Date: 05/10/2019 
112 
 
Test 
description 
Amount/Type/T
ube/Handling 
Collection 
Timing 
Contact 
Special 
Instructions 
 
Date, Time and 
source of urine on 
tube 
 
  
  
Immune subsets 
and 
angiogenesis 
markers in 
tissue 
4-6 cores of fresh 
tumor biopsy 
8-18 weeks post 
treatment 
When scheduled email Jane 
Trepel (trepel@helix.nih.gov), 
Sunmin Lee 
(lees@pop.nci.gov), Mi-Jung 
(leemin@mail.nih.gov), and 
Maria Merino 
Tissue biopsies 
strictly on 
voluntary basis 
Xenobiotic 
Metabolism 
100 ul of plasma 
 
Nagireddy Putluri, Ph.D  
Associate Professor  
120D, Jewish Building 
One Baylor Plaza, Houston, 
TX, 77030 
Eppendorf tube 
 
 
 


Abbreviated Title: Ph 2 XL184 in urothelial CA 
 
CTEP Study #: 9236 
Version Date: 05/10/2019 
113 
 
16.7 APPENDIX G: MDASI QUALITY OF LIFE ASSESSMENT 
 
 
 


Abbreviated Title: Ph 2 XL184 in urothelial CA 
 
CTEP Study #: 9236 
Version Date: 05/10/2019 
114 
 
 
 

ICF_003.pdf: 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• Adult Patient or 
• Parent, for Minor Patient 
INSTITUTE: 
 
National Cancer Institute 
STUDY NUMBER: 
12-C-0205 
PRINCIPAL INVESTIGATOR: 
Andrea Apolo, M.D. 
STUDY TITLE:  
A Phase II Study of Cabozantinib (XL184) in Patients with Advanced/Metastatic Urothelial 
Carcinoma 
Continuing Review Approved by the IRB on 12/10/19 
Amendment Approved by the IRB on 06/28/19 (P) 
 
Date Posted to Web: 12/18/19 
Standard 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent (1) 
 
INTRODUCTION 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
First, we want you to know that: 
Taking part in NIH research is entirely voluntary.  
 
You may choose not to take part, or you may withdraw from the study at any time.  In 
either case, you will not lose any benefits to which you are otherwise entitled.  However, 
to receive care at the NIH, you must be taking part in a study or be under evaluation for 
study participation. 
You may receive no benefit from taking part.  The research may give us knowledge that 
may help people in the future. 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions).  If you 
have such beliefs, please discuss them with your NIH doctors or research team before you agree 
to the study. 
Now we will describe this research study.  Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with anyone at NIH, or with family, 
friends or your personal physician or other health professional.   
Why is this study being done?  
Cabozantinib is an agent that slows down the growth of blood vessels that feed tumors.  
Although it has been approved by the Food and Drug Administration to treat medullary thyroid 
cancer, it has not been approved for urothelial cancer and its use in this study is experimental.  
Early studies have also shown that prostate and ovarian tumors respond to cabozantinib.  This 
study is being done to determine whether and measure how much tumors in patients with 
progressive urothelial carcinoma that have received prior chemotherapy respond to cabozantinib.  
In addition, we will measure how long it takes for disease to progress and whether cabozantinib 
improves overall survival and what the side effects of cabozantinib are. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
12-C-0205 
CONTINUATION: page 2 of 19 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Why are you being asked to take part in this study? 
You are being asked to take part in this study because you have been diagnosed with metastatic 
urothelial carcinoma or another form of bladder cancer that has been treated with chemotherapy 
in the past but continues to worsen.    
How many people will take part in this study?  
About 71 people will take part in this study.   
How long will you be in the study? 
You will be in the study for as long you are receiving benefit from cabozantinib without 
experiencing any intolerable side effects. 
Description of Research Study 
What will happen if you take part in this research study?   
This study will be conducted primarily on an outpatient basis.  You will take 60 mg of 
cabozantinib by mouth once per day on each day of a 28 day cycle.  Cabozantinib should be 
taken on an empty stomach (no food should be eaten 2 hours before and 1 hour after taking 
cabozantinib).  If you miss a dose, do not make it up the next day.  Avoid eating or drinking 
grapefruit/juice or Seville orange while on this study. 
You will be given a pill diary and a blood pressure monitoring form as part of the study.  We ask 
that you record the times that you take cabozantinib each day in the pill diary. 
If you have a history of high blood pressure, you will also be asked to take your blood pressure at 
home once a week and record it on a blood pressure monitoring form. 
Please bring this (these) forms as well as all of your remaining study pills at each study visit. 
In addition, if you are taking a type of drug called a bisphosphonate (eg. alendronate, risedronate, 
pamidronate, etc.), we ask that you tell your doctor about any dental procedures that you have 
planned before you see the dentist.   
Before you begin the study: 
You will need to have the following exams, tests or procedures to find out if you can be in the 
study.  These exams, tests or procedures are part of regular cancer care and may be done even if 
you do not join the study.  If you have had some of them recently, they may not need to be 
repeated.  This will be up to the study team. These tests include:  
x A complete physical examination including your medical history 
x A 12-lead ECG (electrocardiogram)  
x Blood and urine tests  


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
12-C-0205 
CONTINUATION: page 3 of 19 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
x MRI or CT scan of your chest, abdomen and pelvis (This scan will be repeated if 
you have stopped taking the study drug and start again after more than 6 weeks) 
x Sodium fluoride-18 PET CT scan in the event that you have bone disease.  This is 
a special CT that uses a radioactive tracer (fluoride 18) to help us better see 
disease in your bones. (This scan will be repeated if you have stopped taking the 
study drug and start again after more than 6 weeks) 
A pregnancy test if you are female.  You will need to supply a complete list of your current 
medications to the study doctor.  This includes over-the-counter medications and herbal 
supplements.  Some medications may interact adversely with cabozantinib and it is important 
that your study doctor and prescribing physician be aware of any potential risks so that they can 
prescribe alternative medications as necessary.  If you do not already do so, please consider 
carrying a list of your medications at all times.  
During the study: 
If the exams, tests and procedures show that you can be in the study, and you choose to take part, 
then you will need the following tests and procedures: 
x Dental examination (if you have used or are using a type of medication called a 
bisphosphonate) – before you receive study drug 
You will need the following tests and procedures that are part of regular cancer care.  
x Blood tests  
x Pregnancy test if you are female – every 4 weeks 
You will also need these tests and procedures that are part of regular cancer care.   They are 
being done more often because you are in this study.   
x MRI or CT scan of the chest, abdomen, and pelvis - every 8 weeks  
x Sodium fluoride-18 PET CT scan in the event that you have or are suspected of 
having bone disease – every 8 weeks 
x Physical examination - every two weeks for the first 12 weeks, then every 4 
weeks 
x Blood tests to evaluate toxicities- every two weeks for the first 12 weeks, then 
every 4 weeks 
x Urinalysis – every two weeks for the first 12 weeks, then every 4 weeks 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
12-C-0205 
CONTINUATION: page 4 of 19 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
You will need these tests and procedures that are either being tested in this study or being done 
to see how the study is affecting your body.  
x 12-lead ECG 
x Research blood tests to study the effects of cabozantinib on markers in your 
blood. The research blood samples collected as part of this study are not expected 
to produce a significant decrease in the total amount of blood in your body. These 
tests will be done: 
- 
After you have enrolled but before you receive any study drug 
- 
Before you receive the study drug at each study visit and at the time of tumor 
biopsy.  (May be collected up to 5 days before.) 
- 
At the time your disease worsens  
- 
Some samples collected may be sent outside NIH for analysis 
x Research urine sample will be collected, at each clinic visit to study the effects of 
cabozantinib on markers in your urine.   
x Quality of life survey.  We will ask you to complete a survey before you take any 
study drug and at the beginning of cycle 3 of your treatment to help us determine 
the severity of any symptoms you might be experiencing. The survey will take 
about 5 – 10 minutes to complete. 
x Biopsy (required for study participation) 
- 
We will also require a sample of your tumor to study how cabozantinib might 
affect the immune cells within the tumor and the effects of this treatment on 
the blood vessels of your tumor.  If you have any tissue from a previous 
surgery or biopsy, we will ask you to provide it to us.  If adequate tumor tissue 
is not available, we will ask you to undergo a biopsy. 
x FDG PET/CT and optional FDG PET/MRI for research  
- 
PET stands for Positron Emission Tomography.  It is a technique that 
produces a 3-D image of functional processes in the body.  PET/CT is an 
imaging technology that fuses PET images and CT images into one image.  
FDG or Fluorine-18 2-fluoro-2-deoxy-D-glucose is a radioactive tracer similar 
to sugar that is used to allow us to see images of how your cells take up the 
tracer. You will be asked to undergo PET/CT at the following times:  before 
you have started taking the study drug, week 4 and week 8.  We will not be 
using the results of the PET/CT to make clinical decisions.  We will use these 
results only to determine how well they can track the progress of your disease. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
12-C-0205 
CONTINUATION: page 5 of 19 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
- 
On the day of your FDG-PET/CT scan, you will be first given an injection of 
a small amount of FDG into a vein in your arm or hand.  The amount of 
radiation is very small, no more than what you would have during a normal x-
ray.  It only stays in your body for few hours.  The FDG will travel to 
particular parts of your body.  It travels to places where glucose is used for 
energy.  It shows up cancer because the cancer cells use glucose in a different 
way from normal tissue.   
- 
The PET/CT scanner is a large machine with an opening of 27 to 30 inches in 
the middle.  It looks like a donut with a table in the middle.  Approximately 
30-90 minutes after the injection of FDG, you will be asked to go to the 
bathroom (urinate) and then lie on a partially enclosed scanning table.  The 
table will slide into the machine.  You will be asked to remain still during the 
scan.  You will hear buzzing or clicking sounds during the scan.  You will 
need to lie still for about 20-60 minutes before coming off of the scanning 
table.  If you feel any anxiety over being in enclosed spaces, let your study 
doctor know.   
- 
The entire FDG-PET/CT scan procedure is expected to take about 2 hours. 
- 
After the FDG-PET/CT scan is completed, you will be given the option of 
undergoing an additional scan called FDG-PET/MRI.  You will not receive 
any additional injections of radioactivity and, because the MRI does not use 
ionizing radiation, there will be no additional radiation exposure.   An 
additional hour of scanning will be required to complete this optional study.   
You will be given the opportunity to undergo the optional FDG PET/MRI 
after your FDG-PET/CT.  
You will be provided with a wallet-sized information card (“Information on Possible Drug 
Interactions”) that names your study agent and outlines the specific risk of adverse interactions 
with other drugs or substances.  Should you require any new medications while on study, please 
consult with your study doctor if possible, and present the card to the prescriber (doctor, 
pharmacist, physician’s assistant, or nurse practitioner).  Please check with your 
doctor/prescriber or pharmacist before using any new over-the-counter medications or herbal 
supplements. 
Stopping Therapy 
Your participation in this study will continue until either you or your study team decides that this 
medication is not beneficial to you. If your disease completely disappears, the medication will be 
stopped (drug holiday). You will be monitored by scans every 12 weeks. If your disease comes 
back, you will have the option to resume treatment.  Your participation is voluntary; so you may 
stop receiving the study drugs at any time, but we ask that you speak to your study team before 
stopping. Your doctor may decide to permanently stop your therapy for the following reasons: 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
12-C-0205 
CONTINUATION: page 6 of 19 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
x 
if he/she believes that it is in your best interest 
x 
if your disease progresses during treatment 
x 
if you have side effects from the treatment that your doctor thinks are too 
severe 
x 
if new information shows that another treatment would be better for you 
x 
if you are unable to comply with the protocol requirements 
x 
if you are unable to tolerate the lowest dose of cabozantinib (20 mg once 
per day) 
x 
if your treatment has been delayed for more than 6 weeks and it is not 
clear that you have been benefiting from cabozantinib 
x 
if you are a woman and you become pregnant 
In this case, you will be informed of the reason therapy is being stopped. 
You can stop taking part in the study at any time. However, if you decide to stop taking part in 
the study, we would like you to talk to the study doctor and your regular doctor first. 
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to Exelixis, the manufacturer 
of the study drug, or their designated representatives. If you withdraw your consent and leave the 
trial, any samples of yours that have been obtained for the study and stored at the NCI can be 
destroyed upon request. However, any samples and data generated from the samples that have 
already been distributed to other researchers or placed in the research databases cannot be 
recalled and destroyed. 
When you are finished taking cabozantinib: 
30 – 37 days after you have stopped taking the study treatment (except when you stop treatment 
in order to take a drug holiday), we will telephone you to determine whether you have 
experienced any side effects. You will receive instructions on how to mail back any drug you 
have remaining at this time.  
If you have experienced any side effects that are still ongoing at the time of this call, the   study 
team may request that you continue follow-up and/or testing for this until it has resolved.  
After this phone call, someone on the study team will try to contact you or a member of your 
family every 2 months, give or take a week to see how you are doing and to find out if you have 
started any other anti-cancer therapy. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
12-C-0205 
CONTINUATION: page 7 of 19 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Birth Control 
You should not become pregnant or father a baby while on this study because the drugs in this 
study can affect an unborn baby.  It is important you understand that you need to use birth 
control before starting study treatment, during study treatment, and for 4 months after you finish 
study treatment.  If you think that you or your partner is pregnant, you should tell your study 
doctor or nurse at once.   
Effective forms of birth control include:  
• abstinence  
x intrauterine device (IUD) 
• hormonal [birth control pills, injections, or implants] 
• tubal ligation 
• vasectomy 
You should recognize that no method of birth control besides abstinence provides 100% 
protection from pregnancy.  
Women should not breastfeed a baby while on this study.   
Risks or Discomforts of Participation 
What side effects or risks can I expect from being in this study?  
If you choose to take part in this study, there is a risk that the XL184 (cabozantinib) may not be as good 
as the usual approach for your cancer or condition at shrinking or stabilizing your cancer. 
You also may have the following discomforts: 
x 
Spend more time in the hospital or doctor’s office. 
x 
Be asked sensitive or private questions about things you normally do not discuss. 
x 
May not be able to take part in future studies. 
The XL184 (cabozantinib) used in this study may affect how different parts of your body work such as 
your liver, kidneys, heart, and blood.  The study doctor will test your blood and will let you know if 
changes occur that may affect your health. 
There is also a risk that you could have side effects from the study drug(s)/study approach. 
 
Here are important things to know about side effects: 
x 
The study doctors do not know who will or will not have side effects. 
x 
Some side effects may go away soon, some may last a long time, and some may never go away. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
12-C-0205 
CONTINUATION: page 8 of 19 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
x 
Some side effects may make it hard for you to have children. 
x 
Some side effects may be mild.  Other side effects may be very serious and even result in death. 
You can ask your study doctor questions about side effects at any time.  Here are important ways to make 
side effects less of a problem: 
x 
If you notice or feel anything different, tell your study doctor.  He or she can check to see if it is a 
side effect. 
x 
Your study doctor will work with you to treat your side effects. 
x 
Your study doctor may adjust the study drugs to try to reduce side effects. 
 
The tables below show the most common and the most serious side effects doctors know about.  Keep in 
mind that there might be other side effects doctors do not yet know about.  If important new side effects 
are found, the study doctor will discuss these with you.” 
 
Risks and side effects related to cabozantinib: 
COMMON, SOME MAY BE SERIOUS   
In 100 people receiving XL184 (cabozantinib), more than 20 and up to 100 may have: 
x 
Diarrhea, nausea, vomiting 
x 
Tiredness 
x 
Weight loss, loss of appetite 
x 
Changes in taste  
x 
Redness, pain or peeling of palms and soles 
x 
High blood pressure which may cause headaches, dizziness, blurred vision 
 
OCCASIONAL, SOME MAY BE SERIOUS   
In 100 people receiving XL184 (cabozantinib), from 4 to 20 may have: 
x 
Anemia which may require blood transfusion 
x 
Pain 
x 
Constipation, heartburn 
x 
Dry mouth, skin 
x 
Sores in the mouth which may cause difficulty swallowing 
x 
Swelling of arms, legs 
x 
Infection 
x 
Bruising, bleeding 
x 
Dehydration 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
12-C-0205 
CONTINUATION: page 9 of 19 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
x 
Muscle weakness 
x 
Dizziness, headache 
x 
Cough, shortness of breath 
x 
Internal bleeding which may cause black tarry stool, blood in vomit, coughing up blood, or 
blood in urine 
x 
Bleeding from multiple sites including the nose 
x 
Changes in voice 
x 
Hair loss, rash 
x 
Change in hair color 
x 
Blood clot which may cause swelling, pain, shortness of breath 
 
RARE, AND SERIOUS 
In 100 people receiving XL184 (cabozantinib), 3 or fewer may have: 
x 
A tear or hole in internal organs that may require surgery 
x 
Non-healing surgical site 
x 
Damage to the jawbone which may cause loss of teeth 
x 
Bleeding in the brain which may cause confusion 
x 
Stroke which may cause paralysis, weakness 
x 
Brain damage which may cause headache, seizure, blindness (also known as Reversible 
Posterior Leukoencephalopathy Syndrome) 
x 
Lung collapse 
 
Procedure Risks 
In addition to risks posed by the cabozantinib, you may be exposed to the following 
risks/discomforts: 
Blood drawing:  Local pain, bruising, bleeding, blood clot formation, and, in rare instances, an 
infection might occur at the site where blood is drawn.  There is also the possibility of dizziness 
or fainting while your blood is being drawn.   
ECG: The ECG (electrocardiogram) is a procedure that requires you to lie still for a few minutes 
while adhesive pads are attached to your chest to record the activity of your heart.  The ECG 
leads may cause slight discomfort during their placement on and removal from your skin.   
Biopsy:  Your tumor tissue will be analyzed for the presence of a protein called c-met. Tissue 
may be analyzed from a previous biopsy or a new tissue biopsy will be obtained prior to starting 
therapy.  If we have enough tissue, we may also test this sample for white blood cells, blood 
vessels along other factors that affect tumor growth or factors that are expected to respond to the 
study drug.  Furthermore, we may test any remaining sample for gene changes (see 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
12-C-0205 
CONTINUATION: page 10 of 19 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Optional Biopsy for a description). This procedure usually causes only brief discomfort at the 
site from which the biopsy is taken. Rarely, infection or bleeding may occur at the needle site.   
Radiation Risks:   
This research study involves exposure to radiation from 3 whole body PET/CT scans of 10mCi 
F-18 FDG.  This radiation exposure is not required for your medical care and is for research 
purposes only. The amount of radiation you will receive in this study is 3.2 rem which is below 
the guideline of 5 rem per year allowed for adult research subjects by the NIH Radiation Safety 
Committee.  The average person in the United States receives a radiation exposure of 0.3 rem per 
year from natural sources, such as the sun, outer space, and the earth's air and soil.  If you would 
like more information about radiation, please ask the investigator for a copy of the pamphlet, An 
Introduction to Radiation for NIH Research Subjects. 
While there is no direct evidence that the amount of exposure received from participating in this 
study is harmful, there is indirect evidence it may not be completely safe.  There may be a very 
slight increase in the risk of cancer.  
Please tell your doctor if you have had any radiation exposure in the past year, either from other 
research studies or from medical tests or care, so we can make sure that you will not receive too 
much radiation. Radiation exposure includes x-rays taken in radiology departments, cardiac 
catheterization, and fluoroscopy as well as nuclear medicine scans in which radioactive materials 
were injected into your body.  
If you are pregnant you will not be permitted to participate in this research study. If you are 
breast feeding and the protocol involves injection of radioactive material you will not be 
permitted to participate.  It is best to avoid radiation exposure to unborn or nursing infants since 
they are more sensitive to radiation than adults. 
Potential Benefits of Participation 
Are there benefits to taking part in this study?  
Taking part in this study may or may not make your health better.  While doctors hope 
cabozantinib will be more useful against cancer compared to the usual treatment, there is no 
proof of this yet. We do know that the information from this study will help doctors learn more 
about drugs as a treatment for cancer.  This information could help future cancer patients. 
Alternative Approaches or Treatments 
What other choices do I have if I do not take part in this study?  
Instead of being in this study, you have these options: 
x Getting treatment or care for your cancer without being in a study 
x Taking part in another study 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
12-C-0205 
CONTINUATION: page 11 of 19 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
x Getting comfort care, also called palliative care.  This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer.  It does not treat 
the cancer directly.  Instead, it tries to improve how you feel.  Comfort care tries to keep 
you as active and comfortable as possible. 
Please talk to your doctor about these and other options. 
Research Subject’s Rights 
What are the costs of taking part in this study?  
If you choose to take part in the study, the following will apply, in keeping with the NIH policy: 
x 
The study agent, cabozantinib, will be provided by the NCI.  You will 
receive study treatment at no charge to you. This may include surgery, 
medicines, laboratory testing, x-rays or scans done at the Clinical Center, 
National Institutes of Health (NIH), or arranged for you by the research 
team to be done outside the Clinical Center, NIH if the study related 
treatment is not available at the NIH.  
x 
There are limited funds available to cover the cost of some tests and 
procedures performed outside the Clinical Center, NIH.  You may have 
to pay for these costs if they are not covered by your insurance company. 
x 
Medicines that are not part of the study treatment will not be provided or 
paid for by the Clinical Center, NIH. 
x 
Once you have completed taking part in the study, medical care will no 
longer be provided by the Clinical Center, NIH. 
Even though it probably won’t happen, it is possible that the manufacturer may not continue to 
provide the cabozantinib to the NCI for some reason.  If this would occur, other possible options 
are: 
x 
You might be able to get cabozantinib from the manufacturer or your 
pharmacy but you or your insurance company may have to pay for it. 
x 
If there is no cabozantinib available at all, no one will be able to get more 
and the study would close. 
If a problem with getting cabozantinib occurs, your study doctor will talk to you about these 
options.  
Will my medical information be kept private?  
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Your personal information may be 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
12-C-0205 
CONTINUATION: page 12 of 19 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
given out if required by law.  If information from this study is published or presented at scientific 
meetings, your name and other personal information will not be used.  
Organizations that may look at and/or copy your medical records for research, quality assurance, 
and data analysis include: 
x The pharmaceutical collaborator that makes cabozantinib  
x The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), involved in keeping research safe for people 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you. At most, the Web 
site will include a summary of study results.  You can search this Web site at any time. 
Conflict of Interest 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.   This process is detailed in a Protocol Review Guide. You may ask your research 
team for a copy of the Protocol Review Guide or for more information.  Members of the research 
team who do not work for NIH are expected to follow these guidelines but they do not need to 
report their personal finances to the NIH. 
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest.  
The National Institutes of Health and the research team for this study are using a drug developed 
by Exelixis through a joint study with your researchers and the company.   The company also 
provides financial support for this study. 
Optional Biopsy 
We would like to collect samples of your tumor after you have been using cabozantinib for 8 to 
18 weeks.  We will take no more than 4 – 6 pieces of tissue from each tumor site.  The samples 
will be used to study blood vessel development and the types of white blood cells in your tumor 
along with other factors that affect tumor growth or factors that are expected to respond to the 
study drug.  Leftover tissue will be used to study gene changes in your tumor that could be used 
to develop new ways of diagnosing and treating cancer.  Genes are segment of DNA (also called 
deoxyribonucleic acid) that provide instructions for making a particular protein.  DNA are the 
molecules inside cells that carry genetic information and pass it from one generation of cells to 
the next – like an instruction manual.  The manual used only an alphabet consisting of four 
letters, called bases.  Normal tissue contains the DNA (instructions) that you were born with, 
DNA in tumor cells has changed – or mutated – and we think that change in the DNA is what 
causes tumors to form and to grow.  DNA changes in your tumor tissue are not passed on from 
generation to generation and have usually been acquired over the course of your lifetime. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
12-C-0205 
CONTINUATION: page 13 of 19 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
The biopsy procedure usually causes only brief discomfort at the site from which the biopsy is 
taken.  Rarely, infection or bleeding may occur at the needle site. 
Optional Saliva Sample 
We would like to collect a saliva sample from you after you have enrolled on the study.  The 
sample (~ ½ tsp) of saliva may be taken at any after you have enrolled, but we will most likely 
collect it before you have taken any study drug.  This sample will be used to compare the genetic 
material in your tumor tissue with genetic material in normal tissue (saliva) to determine if there 
have been any changes in the molecules that make up your DNA or if the order of the molecules 
is different.  This will be done by determining which bases or “letters” appear in your DNA and 
the order in which they appear.  This technique is called sequencing.  
Once we obtain the saliva sample, the investigators take all your personal information off those 
samples and label them with a study code number.  Only the investigators on this study know 
who the sample came from.  The key linking your personal information with the code number is 
kept in a secure computer data base, with access only to the 2-3 research staff who will be 
discussing this study with you.  Once the sample has been labeled with a code, it is sent to an 
NIH laboratory for storage and testing.  No one testing your samples will be able to link the 
results to you personally.  Specimens obtained during your participation in this study may be sent 
for testing to investigators outside of NCI or the NIH.  All samples will be coded to protect your 
privacy and no personal information will be included.  Other investigators on this study will have 
access to limited clinical and biologic information such as age, gender and disease status. 
Any genomic data generated from your samples will be uploaded to a controlled-access shared 
database such as dbGaP.  This means that only researchers who apply for and get permission to 
use the information for a specific research project will be able to access the information.  Your 
genomic data and health information will not be labeled with your name or other information 
that could be used to identify you.  Researchers approved to access information in the database 
have agreed not to attempt to identify you. 
Your summary genomic data is being placed in an unrestricted database, so researchers will be 
able to access summary information about all the participants included in the study (including 
you), or summary information combined from multiple studies, without applying for permission. 
The risk of anyone identifying you with this information is very low. 
Such databases may be useful beyond the aims of this particular study, especially as various 
diseases turn out to have mechanisms in common.  The value of these data can increase when 
they are shared with the broader research community.  While no traditionally identifying 
information will be shared, it is possible that you or a family member may be identified as 
outlined below in the section on the release of genetic information. 
The saliva is collected exclusively for research purposes and will not benefit you.  It might help 
other people in the future. You will be given the opportunity to decide whether you want to 
participate at the time of the procedure.  


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
12-C-0205 
CONTINUATION: page 14 of 19 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Though there is no risk associated with the collection of the saliva sample, there are privacy risks 
involved in genetic studies on normal tissues due to the fact that you may be identified by your 
DNA sequences.  There is also the possibility that we may discover something about your health 
that causes you distress.  You will be given the option to learn about certain types of findings 
later on in this consent.  The risks are discussed below: 
1. Unanticipated medical information: During the course of this investigation, it is possible 
(although not likely) that we will obtain unanticipated information about your health or 
genetic background.   
2. Release of genetic information:   
x While the controlled-access databases developed for this project will not contain 
information that is traditionally used to identify you, such as your name, address, 
telephone number, or social security number, people may develop ways in the future that 
would allow someone to link your genetic or medical information in our databases back 
to you. For example, someone could compare information in our databases with 
information from you (or a blood relative) in another database and be able to identify you 
(or your blood relative). It also is possible that there could be violations to the security of 
the computer systems used to store the codes linking your genetic and medical 
information to you. 
x Since some genetic variations can help to predict the future health problems of you and 
your relatives, this information might be of interest to health providers, life insurance 
companies, and others. Patterns of genetic variation also can be used by law enforcement 
agencies to identify a person or his/her blood relatives. Therefore, your genetic 
information potentially could be used in ways that could cause you or your family 
distress, such as by revealing that you (or a blood relative) may carry a genetic disease or 
be at risk for other health problems. 
x There also may be other privacy risks that we have not foreseen. 
There are state and federal laws that protect against genetic discrimination. There is also a 
federal law called the Genetic Information Nondiscrimination Act (GINA). In general, this 
law makes it illegal for health insurance companies, group health plans, and most employers 
to discriminate against you based on your genetic information. However, it does not protect 
you against discrimination by companies that sell life insurance, disability insurance, or long-
term care insurance. GINA also does not apply to members of the United States military, to 
veterans obtaining health care through the Veteran’s Administration or the Indian Health 
Service. Lastly, GINA does not forbid insurance medical underwriting based on your current 
health status. 
Certificate of Confidentiality  
To help us protect your privacy, we have obtained a Certificate of Confidentiality. The 
researchers can use this Certificate to legally refuse to disclose information that may identify you 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
12-C-0205 
CONTINUATION: page 15 of 19 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
in any federal, state, or local civil, criminal, administrative, legislative, or other proceedings, for 
example, if there is a court subpoena. The researchers will use the Certificate to resist any 
demands for information that would identify you, except as explained below. 
You should also know that there are several circumstances in which the Certificate does not 
provide coverage. These include when information:  
x will be used for auditing or program evaluation internally by the NIH; or  
x must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA).  
x is necessary for your medical treatment and you have consented to this disclosure;  
x is for other research.  
In addition, identifiable, sensitive information protected by this Certificate cannot be admissible 
as evidence or used for any purpose in any action, suit, or proceeding without your consent.  
You should understand that a Certificate of Confidentiality does not prevent you or a member of 
your family from voluntarily releasing information about yourself or your involvement in this 
research. If an insurer, employer, or other person obtains your written consent to receive research 
information, then the researchers will not use the Certificate to withhold that information. 
The Certificate of Confidentiality will not protect against the required reporting by hospital staff 
of information on suspected child abuse, reportable communicable diseases, and/or possible 
threat of harm to self or others. We will also share information as described in item 1 on page 18. 
Returning of Genetic Results 
The sample you provide for genome sequencing will be analyzed at our laboratories. Our plan is 
to sequence most of your genetic material. This analysis will take months or years to complete. 
This is because genome sequencing is difficult to do. It is also because we have much to learn 
about the DNA we will be sequencing and the genetic variants we find.  
Gene changes will be identified that are not related to this research study.  These are known as 
“incidental medical findings”.  
These include  
• Changes in genes that are related to diseases other than cancer  
• Changes in genes that are not known to cause any disease. These are known as 
normal variations.  
• Changes in genes that are new and of uncertain clinical importance. This means that 
we do not know if they could cause or contribute to a disease or if they are normal 
variations.  


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
12-C-0205 
CONTINUATION: page 16 of 19 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Most of the results that are important to your health and/or the health of your relatives fall in the 
first category – genetic variants that are known to cause or contribute to disease. If we find one 
or more of these genetic variants in your sample, it could be that:  
x The genetic variant has already caused you to have signs and symptoms of a disorder;  
x The genetic variant may cause you to have signs and symptoms of a disorder in the 
future;  
x The genetic variant may be important to the health of your offspring and/or other family 
members.  
If you decide below that you would like to know about incidental findings, we will only give you 
results about specific abnormal genetic variants that we think are important to your health and/or 
the health of your relatives.  As we expect to have the genetic analyses done within 5 years, in 
general we will only contact you within the first five years after you have signed this consent.  If 
we find a genetic variant that has health implications for you or members of your family, we will 
contact you so that we can obtain an additional blood sample and repeat the test for that specific 
genetic variant in a clinical laboratory.  In general, would only tell you about the results of tests 
that have been confirmed in a clinical laboratory.  However, if you are deceased at the time that a 
result that is important to the health of your relatives is discovered, we would like to contact your 
legal next of kin about the result even though it has not been confirmed in a clinical laboratory. 
This will allow others in your family the chance to undergo testing for important results in a 
clinical lab.  
Once the results are available, if you or your next of kin would like to receive your results we 
will offer to have you (or your next of kin) come to NIH (at our expense) to have genetic 
education and counseling to explain this result.  
If you do not want to come to NIH, we will help you (or your next of kin) find a local genetic 
healthcare provider who can explain the result (at your or your next of kin’s expense). 
If we find gene changes that are not known to be important at this time, we will not share that 
information with you or your next of kin. As this is a rapidly changing field, it is possible that 
genetic variants that are not known to be important at this time may be shown to be important at 
a later date. If you are receiving care from another physician who thinks that this testing may be 
of use in your care and treatment, you may contact us at any time and we will share the results 
with your physician.  
 
Please let us know your preference by circling and initialing your choices in the following 
statements: 
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 
12-C-0205 
CONTINUATION: page 17 of 19 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
I agree to be recontacted if genetic changes with potential health implications are discovered.   
(You will be given a choice to learn or not to learn about genetic changes that we find.) 
Yes              No               Initials_________ 
I agree that my next of kin should be recontacted if genetic changes with potential health 
implications for my family members are discovered after I am deceased.  (Your next of kin will 
be given a choice to learn or not to learn about genetic changes that we find.) 
Yes              No               Initials_________ 
Please note that for us to recontact you, you will have to keep us up to date with a current 
address and phone number. 
Use of Specimens and Data for Future Research 
To advance science, it is helpful for researchers to share information they get from studying 
human samples.  They do this by putting it into one or more scientific databases, where it is 
stored along with information from other studies. A researcher who wants to study the 
information must apply to the database and be approved.  Researchers use specimens and data 
stored in scientific databases to advance science and learn about health and disease. 
We plan to keep some of your specimens and data that we collect and use them for future 
research and share them with other researchers. We will not contact you to ask about each of 
these future uses.  These specimens and data will be stripped of identifiers such as name, address 
or account number, so that may be used for future research on any topic and shared broadly for 
research purposes.  Your specimens and data will be used for research purposes only and will not 
benefit you.  It is also possible that the stored specimens and data may never be used.  Results of 
research done on your specimens and data will not be available to you or your doctor.  It might 
help people who have cancer and other diseases in the future.   
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data.  Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers.  
 
 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY: 
•  Adult Patient or    •  Parent, for Minor Patient 
STUDY NUMBER: 
12-C-0205 
CONTINUATION: page 18 of 19 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY  
(Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
OTHER PERTINENT INFORMATION 
1. 
Confidentiality.  When results of an NIH research study are reported in medical journals 
or at scientific meetings, the people who take part are not named and identified.  In most cases, 
the NIH will not release any information about your research involvement without your written 
permission.  However, if you sign a release of information form, for example, for an insurance 
company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance 
company to sell you insurance. 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you 
should know that the Act allows release of some information from your medical record without 
your permission, for example, if it is required by the Food and Drug Administration (FDA), 
members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations. 
2. 
Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-
term medical care for any injury resulting from your participation in research here.  In general, 
no long-term medical care or financial compensation for research-related injuries will be 
provided by the National Institutes of Health, the Clinical Center, or the Federal Government.  
However, you have the right to pursue legal remedy if you believe that your injury justifies such 
action. 
3. 
Payments.  The amount of payment to research volunteers is guided by the National 
Institutes of Health policies.  In general, patients are not paid for taking part in research studies at 
the National Institutes of Health.  Reimbursement of travel and subsistence will be offered 
consistent with NIH guidelines. 
4. 
Problems or Questions.  If you have any problems or questions about this study, or 
about your rights as a research participant, or about any research-related injury, contact the 
Principal Investigator, Andrea Apolo, M.D., Building 10, Room 12N226, Telephone:  301-480-
0536. You may also call the Clinical Center Patient Representative at 301-496-2626. If you have 
any questions about the use of your specimens and data for future research studies, you may also 
contact the Office of the Clinical Director, Telephone: 240-760-6070. 
5. 
Consent Document.  Please keep a copy of this document in case you want to read it 
again. 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY: 
•  Adult Patient or    •  Parent, for Minor Patient 
STUDY NUMBER: 
12-C-0205 
CONTINUATION: page 19 of 19 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY  
(Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby consent to 
take part in this study. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby give 
permission for my child to take part in this 
study.   
(Attach NIH 2514-2, Minor’s Assent, if 
applicable.) 
 
  
  
 
 
 
Signature of Adult Patient/ 
Legal Representative 
Date 
Signature of Parent(s)/ Guardian Date 
 
 
Print Name 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to 
participate in the study. 
 
  
  
 
Signature of Parent(s)/Guardian 
Date 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM DECEMBER 10, 2019 THROUGH JANUARY 7, 2021.   
 
 
 
 
 
 
 
 
Signature of Investigator 
Date 
Signature of Witness 
Date 
 
 
Print Name 
 
 
Print Name