Conditions: Metastatic Urothelial Carcinoma Bladder Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 37
Healthy volunteers: no

Brief summary:
This is an open label, non-randomized phase 2 study of the combination of pembrolizumab and cabozantinib to assess overall response rate (ORR), progression free survival at 6 months (PFS6), and overall survival (OS) in patients with metastatic urothelial carcinoma (UC) ineligible for cisplatin.

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: Cabozantinib intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: Cabozantinib is administered at 40 mg oral daily intervention 2: Pembrolizumab will be administered at a fixed dose of 200mg intravenously every 3 weeks.

Protocol document:
Prot_SAP_000.pdf: 
Short Title: Cabozantinib plus Pembrolizumab as First-Line Therapy for Cisplatin-Ineligible Advanced 
Urothelial Carcinoma (PemCab) 
Version Date:30MAR2022 
 
Page 1 of 82 
 
Cabozantinib plus Pembrolizumab as First-Line Therapy for Cisplatin-Ineligible 
Advanced Urothelial Carcinoma (PemCab) 
CTO ID # HCI-17-GU-10 – Lead Trial ID # HCI104688 – IRB # 104688 
Coordinating Center 
Huntsman Cancer Institute 
Principal Investigator 
Neeraj Agarwal, MD 
Huntsman Cancer Institute - University of Utah 
2000 Circle of Hope 
Salt Lake City, UT 84112 
Phone: 801-585-9682 
Email: Neeraj.Agarwal@hci.utah.edu 
Statistician(s) 
Kenneth M. Boucher, PhD  
Statistician 
Research Associate Professor, Internal Medicine 
Huntsman Cancer Institute - University of Utah 
2000 Circle of Hope Room 1710 
Email: Ken.Boucher@hci.utah.edu 
Medical Monitor 
Paul Shami, MD 
Coordinating Center Site 
Contact 
Please contact your assigned Clinical Site Monitor and 
the Clinical Trials Compliance Office 
2000 Circle of Hope 
Salt Lake City, UT 84112 
HCI-RCO@utah.edu  
 
Drug Manufacturer  
Exelixis 
Drug Manufacturer Protocol 
ID 
IST-071 
Investigational agent(s) 
Cabozantinib  
Commercial agent(s) 
Pembrolizumab 
IND Number 
139643 
NCT Number (CT.gov) 
03534804 
Historical Protocol Versions 
Version 1: 10JUL2018 
Version 2: 25SEP2018 


Short Title: Cabozantinib plus Pembrolizumab as First-Line Therapy for Cisplatin-Ineligible Advanced Urothelial 
Carcinoma (PemCab)  
Version Date: 30MAR2022 
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Version 3: 15MAY2019 
Version 4: 19SEP2019 
Version 5: 19FEB2020 
Version 6: 09JUL2020 
Version 7: 08NOV2021 
Version 8: 30MAR2022 
 
 


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Carcinoma (PemCab)  
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TABLE OF CONTENTS 
Page 
TABLE OF CONTENTS ................................................................................................................ 3 
LIST OF ABBREVIATIONS ......................................................................................................... 5 
PROTOCOL SIGNATURE ......................................................................................................... 9 
STUDY SUMMARY.................................................................................................................... 10 
1 
OBJECTIVES ....................................................................................................................... 12 
1.1 
Primary Objective and Endpoint .................................................................................... 12 
1.2 
Secondary Objectives and Endpoints ............................................................................. 12 
1.3 
Exploratory Objectives and Endpoints ........................................................................... 12 
2 
BACKGROUND .................................................................................................................. 12 
3 
DRUG INFORMATION ...................................................................................................... 15 
3.1 
Cabozantinib................................................................................................................... 15 
3.2 
Pembrolizumab............................................................................................................... 21 
4 
STUDY DESIGN.................................................................................................................. 23 
4.1 
Description ..................................................................................................................... 23 
4.2 
Number of Patients ......................................................................................................... 23 
4.3 
Number of Study Centers ............................................................................................... 23 
4.4 
Study Duration ............................................................................................................... 23 
4.5 
Conditions for Terminating the Study ............................................................................ 23 
5 
ELIGIBILITY CRITERIA.................................................................................................... 24 
5.1 
Pre-Screening Eligibility for Patients Scheduled for Urothelial Diagnostic Procedure 
(biopsy or surgery) .................................................................................................................... 24 
5.2 
Inclusion Criteria ............................................................................................................ 25 
5.3 
Exclusion Criteria ........................................................................................................... 27 
6 
TREATMENT PLAN ........................................................................................................... 32 
6.1 
Administration Schedule ................................................................................................ 32 
6.2 
Cabozantinib................................................................................................................... 32 
6.3 
Pembrolizumab (MK-3475) Treatment .......................................................................... 34 
6.4 
Dose Calculation ............................................................................................................ 36 
6.5 
Preparation of Infusion Solution .................................................................................... 36 
6.6 
Administration ................................................................................................................ 37 
6.7 
Accountability and Compliance ..................................................................................... 38 
6.8 
Concomitant Medications and Therapies ....................................................................... 39 
6.9 
Duration of Therapy ....................................................................................................... 44 
7 
TOXICITIES AND DOSEAGE MODIFICATION ............................................................. 45 
7.1 
Dose Modifications and Guidelines for Adverse Event Management for Cabozantinib 45 
7.2 
Dose modification and toxicity management guidelines for pembrolizumab................ 56 
7.3 
Contraception ................................................................................................................. 60 
7.4 
Supportive Care .............................................................................................................. 61 
8 
STUDY CALENDAR .......................................................................................................... 62 
9 
STUDY PROCEDURES ...................................................................................................... 64 
9.1 
Pre-Screening ................................................................................................................. 64 
9.2 
Screening ........................................................................................................................ 64 
9.3 
On-Treatment Evaluations ............................................................................................. 64 


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9.4 
End of Treatment Assessments (completed 28 days ± 14 days after completion of 
treatment ................................................................................................................................... 65 
9.5 
Follow-up Assessments .................................................................................................. 66 
10 CRITERIA FOR EVALUATION AND ENDPOINT .......................................................... 66 
10.1 
Efficacy ....................................................................................................................... 66 
10.2 
Safety .......................................................................................................................... 67 
11 STATISTICAL CONSIDERATIONS.................................................................................. 68 
11.1 
Primary objective ........................................................................................................ 68 
11.2 
Secondary Objectives and Endpoints ......................................................................... 68 
11.3 
Exploratory Objectives and Endpoints ....................................................................... 68 
12 REGISTRATION GUIDELINES ......................................................................................... 69 
13 DATA SUBMISSION SCHEDULE .................................................................................... 69 
14 SPECIAL INSTRUCTIONS ................................................................................................ 69 
14.1 
Correlative Studies ..................................................................................................... 69 
15 ETHICAL AND REGULATORY CONSIDERATIONS .................................................... 71 
15.1 
Informed consent ........................................................................................................ 71 
15.2 
Institutional Review .................................................................................................... 71 
15.3 
Data and Safety Monitoring Plan ............................................................................... 71 
15.4 
Adverse Events / Serious Adverse Events .................................................................. 72 
15.5 
SAE Reporting Requirements .................................................................................... 74 
15.6 
Reporting of Pregnancy .............................................................................................. 75 
15.7 
Medication Errors/Overdose ....................................................................................... 75 
15.8 
Protocol Amendments ................................................................................................ 75 
15.9 
Protocol Deviations .................................................................................................... 76 
15.10 
FDA Annual Reporting .............................................................................................. 76 
15.11 
Clinical Trials Data Bank ........................................................................................... 76 
15.12 
Record Keeping .......................................................................................................... 76 
16 PUBLICATIONS OF DATA ............................................................................................... 76 
17 BIBLIOGRAPHY ................................................................................................................. 77 
APPENDIX A - Cabozantinib Dosing Diary............................................................................ 81 
APPENDIX B- Stool Sample Collection Questionnaire .......................................................... 82 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation or 
Term1 
Definition/Explanation 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of variance 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AV 
Atrioventricular 
β-HCG 
Beta-human chorionic gonadotropin 
BID 
Twice daily 
BLQ 
Below limit of quantification 
BMI 
Body mass index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
Ca++ 
Calcium 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CHF 
Congestive heart failure 
CI 
Confidence interval 
Cl- 
Chloride 
CLcr 
Creatinine clearance 
Cmax 
Maximum observed concentration 
Cmin 
Trough observed concentration 
CNS 
Central nervous system 
CR 
Complete response 
CRF 
Case report form 
CT 
Computed tomography 


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Abbreviation or 
Term1 
Definition/Explanation 
CTCAE 
Common Toxicity Criteria for Adverse Events 
CV 
Coefficient of variation 
CYP 
Cytochrome P450 
D/C 
Discontinue 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
DLT 
Dose Limiting Toxicity 
ECG 
Electrocardiogram 
Eg 
Exempli gratia (for example) 
FACS 
Fluorescence Activated Cell Sorting  
FDA 
Food and Drug Administration 
FDG-PET 
Fluorodeoxyglucose (FDG)-positron emission tomography (PET) 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GGT 
Gamma glutamyl transferase 
GLP 
Good laboratory practice  
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCO3- 
Bicarbonate 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
hr 
Hour or hours 
IC50 
Half maximal inhibitory concentration 
i.e. 
Id est (that is) 
IEC 
Independent ethics committee 
INR 
International normalized ratio 


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Abbreviation or 
Term1 
Definition/Explanation 
IRB 
Institutional review board 
IU 
International unit 
IV 
Intravenous, intravenously 
LDH 
Lactate dehydrogenase 
LLQ 
Lower limit of quantitation 
MedRA 
Medical Dictionary for Drug Regulatory Activities 
MRI 
Magnetic resonance imaging 
MRSD 
Maximum recommended starting dose 
MTD 
Maximum tolerated dose  
NOAEL 
No-observed-adverse-effect level 
NOEL 
No-observed-effect-level 
PD 
Pharmacodynamic(s) 
PFS 
Progression Free Survival 
PK 
Pharmacokinetic(s) 
PO 
Per os (administered by mouth) 
PR 
Partial response 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QC 
Quality control 
RBC 
Red blood cell 
QD 
Once daily 
QTc 
QT interval corrected  
QTcF 
QT interval corrected using Fredericia equation 
SAE 
Serious adverse event 
SD 
Standard deviation or stable disease 
T1/2 
Terminal elimination half-life 
T3 
Triiodothyronine 


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Carcinoma (PemCab)  
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Abbreviation or 
Term1 
Definition/Explanation 
T4 
Thyroxine 
Tmax 
Time of maximum observed concentration 
TID 
Three times daily 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
ULQ 
Upper limit of quantitation 
UV 
Ultraviolet 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
WONCBP 
Women of nonchildbearing potential 
1 All of these abbreviations may or may not be used in protocol.  
 
 


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PROTOCOL SIGNATURE 
I confirm that I have read this protocol, and I will conduct the study as outlined herein and 
according to the ethical principles stated in the latest version of the Declaration of Helsinki, the 
applicable ICH guidelines for good clinical practice, and the applicable laws and regulations of the 
federal government. I will promptly submit the protocol to the IRB for review and approval. Once 
the protocol has been approved by the IRB, I understand that any modifications made during the 
study must first be approved by the IRB prior to implementation except when such modification 
is made to remove an immediate hazard to the subject. 
I will provide copies of the protocol and all pertinent information to all individuals responsible to 
me who assist in the conduct of this study. I will discuss this material with them to ensure that they 
are fully informed regarding the study treatment, the conduct of the study, and the obligations of 
confidentiality. 
This document is signed electronically through submission and approval by the Principal 
Investigator at Huntsman Cancer Institute in the University of Utah IRB Electronic Research 
Integrity and Compliance Administration (ERICA) system. For this reason, the Principal 
Investigator at Huntsman Cancer Institute will not have a hand-written signature on this signature 
page.  
Instructions to multi-site Principal Investigators at locations other than Huntsman Cancer Institute: 
SIGN and DATE this signature page and PRINT your name. Return the original, completed and 
signed, to the HCI Research Compliance Office. Retain a copy in the regulatory binder.  
 
 
 
____________________________________ 
_______________ 
Signature of Principal Investigator  
 
Date 
 
 
 
____________________________________ 
Principal Investigator Name (Print) 
 
 
 
____________________________________ 
Name of Institution 
 


Short Title: Cabozantinib plus Pembrolizumab as First-Line Therapy for Cisplatin-Ineligible Advanced Urothelial 
Carcinoma (PemCab)  
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STUDY SUMMARY 
Title 
Cabozantinib plus pembrolizumab as first-line therapy for 
cisplatin-ineligible advanced urothelial carcinoma 
Short Title 
CaboPembro UC 
Protocol Number 
IRB#104688 
IND 
IND#139643 
Phase 
Phase II 
Design 
Single-arm, nonrandomized phase II study to test efficacy of 
combination pembrolizumab and cabozantinib. 
Study Duration 
Accrual will take approximately 1-2 years with 1 year of 
treatment and 6 months follow up. Total study duration 3-4 
years.  
Study Centers 
This study will be conducted at the Huntsman Cancer Institute 
and up to two additional cancer centers. 
Objectives 
Primary Objective: Evaluate measurable disease overall 
response rate (ORR).  
Secondary Objectives: Evaluation of progression-free survival 
(PFS) at 6 months (PFS6), overall survival (OS), and 
evaluation of toxicities of the combination.  
Number of Subjects 
39 subjects will be enrolled to ensure 35 evaluable patients 
Diagnosis and Main 
Eligibility Criteria 
Cisplatin-ineligible urothelial carcinoma 
Key Inclusion Criteria: 
• Histologically proven transitional cell or urothelial 
carcinoma (UC).  
• Metastatic (any N+ or M1) or locally advanced, 
unresectable (T4bN0) disease. 
• Measurable disease is required as determined by RECIST 
v1.1. 
• Cisplatin-ineligibility based on ≥1 of the following:  
o Estimated CrCl of between ≥40 and <60 ml/min (CG 
formula) 
o ECOG PS≥2 
o Hearing loss 
o Baseline neuropathy 
o Patient refusal 
Key Exclusion Criteria: 
• Prior chemotherapy for metastatic/ advanced urothelial 
carcinoma.  
• Prior chemotherapy treatment for localized urothelial 
carcinoma that has been completed less than 6 months 
before registration. 


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• Small-cell or sarcomatoid component in histology. 
Study Product, Dose, 
Route, Regimen 
Pembrolizumab 200mg IV q 3 weeks with cabozantinib 
administered 40mg orally, with dose reductions to 20 mg daily. 
Subsequent dose reduction to 20 mg every other day to 
improve tolerability is allowed. 
Duration of 
administration 
Patients will receive therapy until treatment discontinuation 
criteria is met or until 12 months from start of therapy 
Reference therapy 
Study treatment will be compared to pembrolizumab as single 
agent.  
Statistical 
Methodology 
A 95% one-sided exact binomial confidence interval (Clopper-
Pearson) will be calculated for ORR. With 35 evaluable 
subjects the lower bound of the 95% confidence interval will 
extend no more than 26% from the observed proportion. If 
there are 17 or more objective responses in 35 patients the 
confidence interval will exclude 32%. Secondary analyses will 
include an association of risk group (based on performance 
status and visceral metastasis) with PFS. Stratified Kaplan-
Meier methodology will be used to associate risk group (based 
on performance status and visceral metastasis) with PFS. 
 
 
 


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1 OBJECTIVES 
1.1 
Primary Objective and Endpoint 
To evaluate measurable disease overall response rate (ORR).  
Endpoint: Subjects will be evaluated by CT scans at regular intervals for disease assessment 
by RECISTv1.1 criteria for the duration of treatment. 
1.2 
Secondary Objectives and Endpoints 
 To evaluate progression-free survival (PFS) at 6 months (PFS6). 
Endpoint: Subjects will be evaluated by CT scans at regular intervals for disease assessment 
by RECISTv1.1 criteria for the duration of treatment. 
 To evaluate Overall Survival (OS). 
Endpoint: Subjects will be evaluated using Kaplan-Meier estimation for survival for up to 6 
months after discontinuation of study treatment; patients surviving longer than 6 months will 
be censored. 
 To evaluate toxicities associate with the combination treatment. 
Endpoint: Adverse events will be collected beginning with study treatment and tabulated 
according to drug attribution. 
1.3 
Exploratory Objectives and Endpoints 
 To evaluate molecular markers for pharmacodynamic pathways associated with 
response. 
Endpoints: Blood, tissue, and stool samples will be collected at various time points to 
measure molecular markers to correlate with response to develop a panel predictive of 
response which will be validated in future studies. Once the model is determined, statistical 
methods will be determined. 
 To evaluate ORR and PFS6 using immune specific disease assessment criteria 
Endpoint: Subjects will be evaluated by CT scans at regular intervals for disease assessment 
by iRECIST criteria for the duration of treatment. 
2 BACKGROUND 
Currently the standard of care first-line therapy for urothelial carcinoma (UC) is cisplatin based 
chemotherapy. However, many patients diagnosed with UC are not eligible for cisplatin due to 
age, frailty or other comorbid conditions. In a retrospective analysis of 299 patients presenting in 
a community-based cancer center system with stage 4 disease, the regimens administered were 
cisplatin based in 107 patients (35.9%), carboplatin based in 81 (27.2%), and non-platinum based 
in 25 (8.4%).1 Notably, no chemotherapy was administered in 71 (23.8%) patients. Cisplatin 
administration was more common in patients aged ≤70 years (62/150 [41.3%]) as opposed to 
>70 years (45/148 [30.4%]) (P = 0.05).  


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In another retrospective study of 1031 patients aged ≥66 years presenting with advanced bladder 
cancer in the SEER-Medicare linked database, among patients receiving chemotherapy, 
carboplatin accounted for 50.6%, cisplatin for 39.7% and other agents for 9.8%.2 A relatively 
large proportion of patients did not receive chemotherapy in this Medicare database (48.4%), 
again highlighting the difficulties of administering aggressive chemotherapy in this population. 
The reasons for non-administration of cisplatin were not available in both of these studies, 
although it may be postulated that the presence of renal dysfunction, poor performance status, 
elderly age and comorbidities likely are responsible as these are frequent exclusion criteria for 
previously reported large phase III clinical trials of cisplatin based chemotherapy for UC. 
Carboplatin is often substituted for cisplatin in cisplatin-ineligible patients, but is associated with 
inferior response rates, especially CR rates, which suggests the lack of potential cures. In a meta-
analysis of randomized phase II trials, cisplatin-based chemotherapy was associated with a 
significantly higher likelihood of achieving a CR (relative risk {RR} = 3.54; 95% confidence 
interval {CI} 1.48-8.49; P = 0.005) and ORR (RR = 1.34; 95% CI 1.04-1.71; P = 0.02) compared 
to carboplatin-based chemotherapy.3 Clearly, other tolerable and high-effective therapies are 
needed for this population of patients with cisplatin-ineligible invasive urothelial carcinoma.  
In a previously reported study,4 prognostic markers for poor clinical outcomes associated with 
disease progression were studied. The authors demonstrated that expression of Met was 
positively associated with histologic grade, stage classification, tumor size, and nodular tumor 
growth (P <.05, respectively) in urothelial carcinoma. Factors that predicted disease progression 
were tumor stage, Met status, and TP53 accumulation (P <.05, respectively). Indicators for poor 
long-term survival were invasive cancer, multiple tumors, and Met overexpression (P =0.0006, 
0.01 and 0.04, respectively). The authors concluded that the c-met proto-oncogene plays a more 
important role in the progression of bladder carcinogenesis. Evaluation of Met expression could 
identify a subset of bladder cancer patients who may benefit from molecularly targeted therapy. 
In a recent report, a positive association of Axl or platelet-derived growth factor receptor-alpha 
(PDGFR-α) with c-Met expression was demonstrated through preclinical models of disease.5 The 
transactivation of c-Met on Axl or PDGFR-α in vitro was 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 RTKs 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). Thus, in addition to c-Met, the 
cross-talk with Axl and/or PDGFR-α also contributes to the progression of human bladder 
cancer. 
Finally, recent data6 suggest significant activity for Met inhibition in bladder cancer. PF-2341066 
(crizotinib), a small, orally available, highly specific Met-inhibitor was evaluated in an 
orthotopic xenograft model of bladder transitional cell carcinoma (TCC). Animals were treated 
with intra peritoneal PF-2341066 after positive detection of bladder tumor primary and/or 
metastatic disease. Fluorescence imaging (Xenogen IVIS) of mice was performed weekly. Mice 
were euthanized 4 weeks after the start of treatment and their tissues studied histologically. PF-
2341066 was found to reduce tumor burden to below detectable levels in both primary and 
metastatic sites in all mice treated. No noticeable side effects were detected in treated mice 
secondary to drug administration. Thus, this was the first study to test a small orally available 


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Met-selective inhibitor in an orthotopic, HGF-driven model of human bladder cancer, supporting 
its potential use in patients with bladder cancer.  
In vitro biochemical and/or cellular assays have shown that cabozantinib inhibits the tyrosine 
kinase activity of RET, MET, VEGFR-1, -2 and -3, KIT, TRKB, FLT-3, AXL, and TIE-2. This 
suggests that cabozantinib may be effective in urothelial carcinoma. This concept is currently 
being studied in an ongoing clinical trial evaluating the efficacy of single agent cabozantinib 
(NCT01688999), with final results expected soon. Preliminary results suggest clinical activity 
with single agent cabozantinib with objective radiographic responses seen.  
Previously, immune-based treatments have demonstrated significant clinical benefit as single 
agent therapies in UC. To date, many different immunotherapies are approved with PD-1 
antagonists (pembrolizumab, nivolumab) and PD-L1 antagonists (atezolizumab, avelumab, 
durvalumab). In the second-line pembrolizumab trial for patients with UC (KEYNOTE-045)7, 
542 patients were randomized to pembrolizumab or the treating physician’s choice of 
chemotherapy (vinflunine, docetaxel or paclitaxel) with significant clinical benefit demonstrated 
in the pembrolizumab arm. The overall survival was improved at 10.3 months versus 7.4 months 
for pembrolizumab versus chemotherapy respectively (HR for death 0.73; 95% CI 0.59—0.91; P 
= 0.002). It was also better tolerated with decreased grade 3-5 adverse events (15.0% versus 
49.4% respectively). Pembrolizumab is now one standard-of-care option that is FDA approved 
for UC in the second-line setting. Similarly, durvalumab8, atezolizumab,9 and nivolumab10 have 
also demonstrated efficacy in the second-line setting, while pembrolizumab11 and atezolizumab12 
have demonstrated efficacy in the first-line setting. Immunotherapy for urothelial carcinoma is 
clearly effective, active therapy in urothelial carcinoma. However, the primary challenge with 
these therapies is the relatively low response rate. In the KEYNOTE-045 clinical trial of second-
line pembrolizumab for instance, there was a low 21.1% response rate for pembrolizumab 
compared to 11.4% with chemotherapy. Robust responses are frequently observed with 
immunotherapy, but unfortunately only a relatively few number of patients experience a 
response to this type of treatment.  
Using both cabozantinib plus pembrolizumab in cisplatin-ineligible UC is attractive as this may 
be a well-tolerated and synergistically active combination. VEGFR therapy appears to modulate 
the immune system, suggesting possible clinical benefit for this combination. In mouse models, 
axitinib (another multi-targeted kinase inhibitor similar to cabozantinib) demonstrated a 
significant increase in the number of tumor infiltrating lymphocytes and altered the 
microenvironment from a suppressive to a stimulatory environment relative to vehicle controls.13 
Another study analyzing archival tissue from patients with metastatic renal cell carcinoma 
demonstrated a positive relationship between tumor-infiltrating lymphocytes and VEGF gene 
expression (r = -0.18; P = 0.089), suggesting that the VEGF pathway partially regulates the 
immune effect in kidney cancer. This theory has been tested in a pilot clinical trial of ten 
patients.14 Patients were treated with 1 cycle of bevacizumab (a VEGF antagonist) prior to 
treatment with the combination of atezolizumab (a PD-L1 antagonist) and bevacizumab. Patients 
underwent biopsies at baseline, after the lead-in phase with bevacizumab and after two cycles of 
the combination therapy. The tumor tissue demonstrated an increase in gene signatures 
associated with Th1, CD8, and natural killer cell activity after treatment at all times in the study 
including after the bevacizumab-only period. This strongly suggests that the combination of 
VEGFR TKI and immunotherapy with PD-L1 therapy will be effective and safe in patients with 


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metastatic urothelial carcinoma. Perhaps most importantly, the combination of axitinib plus 
avelumab was recently reported in a phase IB clinical trial of 55 patients with metastatic renal 
cancer.15 This combination appears to be relatively well tolerated with an incidence of grade 3-5 
toxicities in 52% (axitinib related) and 20.0% (avelumab related) of patients. The confirmed 
overall response rate was 54.5% (95% CI 40.6—68.0) with 2 complete responses and 28 partial 
responses. Though this trial is in a different disease state than the proposed clinical trial, this 
combination of a VEGF targeted therapy plus a PD-1 antagonist appears to be safe and well 
tolerated, and potentially more active than single agent immunotherapy.  
We hypothesize that the combination of cabozantinib plus pembrolizumab will be safe in 
cisplatin-ineligible patients as a first-line treatment. Also we hypothesize that this combination 
will demonstrate significant additive or synergistic activity resulting in a 20% increase in 
response in this disease compared to historic benchmarks for progression-free survival. 
3 DRUG INFORMATION 
3.1 
Cabozantinib  
 Description 
Cabozantinib is the (S)-malate salt of cabozantinib, a kinase inhibitor. Cabozantinib (S)-
malate is described chemically as N-(4-(6, 7-dimethoxyquinolin-4-yloxy) phenyl)-N’-(4- 
fluorophenyl) cyclopropane-1, 1-dicarboxamide, (2S)-hydroxybutanedioate. The molecular 
formula is C28H24FN3O5·C4H6O5 and the molecular weight is 635.6 Daltons as malate salt. 
Cabozantinib (S)-malate salt is a white to off-white solid that is practically insoluble in 
aqueous media. 
Cabozantinib tablets are supplied as film-coated tablets containing 20 mg of cabozantinib, 
which is equivalent to 25 mg of cabozantinib (S)-malate. Cabozantinib also contains the 
following inactive ingredients: microcrystalline cellulose, lactose anhydrous, 
hydroxypropyl cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium 
stearate. 
The film coating contains hypromellose, titanium dioxide, triacetin, and iron oxide yellow. 
 Pharmacology 
Mechanism of Action 
In vitro biochemical and/or cellular assays have shown that cabozantinib inhibits the 
tyrosine kinase activity of MET, VEGFR-1, -2 and -3, AXL, RET, ROS1, TYRO3, MER, 
KIT, TRKB, FLT-3, and TIE-2. These receptor tyrosine kinases are involved in both 
normal cellular function and pathologic processes such as oncogenesis, metastasis, tumor 
angiogenesis, drug resistance, and maintenance of the tumor microenvironment. 
Cardiac Electrophysiology 
The effect of orally administered cabozantinib 140 mg on QTc interval was evaluated in a 
randomized, double-blinded, placebo-controlled study in patients with MTC. A mean 
increase in QTcF of 10 - 15 ms was observed at 4 weeks after initiating cabozantinib. A 
concentration-QTc relationship could not be definitively established. Changes in cardiac 


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wave form morphology or new rhythms were not observed. No cabozantinib-treated 
patients had a QTcF > 500 ms. Details can be found in the Investigator’s Brochure 
The effect of orally administered cabozantinib 140 mg qd on corrected QT interval (QTc) 
was evaluated in a placebo-controlled study in subjects with medullary thyroid cancer 
(evaluable subjects: cabozantinib arm, 209; placebo arm, 107). A mean increase in 
Fridericia’s correction of QT interval (QTcF) of 10 - 15 ms was observed 4 weeks after 
initiating cabozantinib treatment. A concentration-QTc relationship could not be 
definitively established. Changes in cardiac wave form morphology or new rhythms were 
not observed. No cabozantinib-treated subjects in this study had a QTcF > 500 ms. Review 
of the larger safety database (~5000 patients exposed to cabozantinib in clinical trials and 
in post-marketing experience) confirmed the absence of safety concerns associated with 
QT prolongation. There were no events of torsades de pointes reported. 
Clinical Pharmacokinetics 
Pharmacokinetics 
A population PK analysis was conducted in subjects with RCC who received repeated oral 
daily cabozantinib tablet dosing at 60 mg (with protocol-permitted dose reductions to 40 
mg and 20 mg) combined with healthy subjects who received a single oral cabozantinib 
tablet dose of 20, 40, or 60 mg. This analysis indicated that for a white male subject, the 
predicted terminal plasma half-life of cabozantinib was approximately 99 h; the terminal 
phase volume of distribution (Vz) was approximately 319 L; and the CL/F at steady-state 
was estimated to be approximately 2.2 L/h. Female gender and Asian race were significant 
covariates on CL/F, and while the attributes were statistically significant, they were not 
deemed clinically meaningful given the magnitude of the effects. 
Absorption and Distribution 
Following oral administration of cabozantinib, median time to peak cabozantinib plasma 
concentrations (Tmax) ranged from 2 to 5 hours post-dose. Repeat daily dosing of 
cabozantinib at 140 mg for 19 days resulted in 4- to 5-fold mean cabozantinib accumulation 
(based on AUC) compared to a single dose administration; steady state was achieved by 
Day 15. Cabozantinib is highly protein bound in human plasma (99.7%). A high-fat meal 
increased Cmax and AUC values by 41% and 57%, respectively relative to fasted 
conditions in healthy subjects administered a single 140 mg oral cabozantinib dose. 
Metabolism and Elimination 
Cabozantinib is a substrate of CYP3A4 in vitro. Inhibition of CYP3A4 reduced the 
formation of the XL184 N-oxide metabolite by >80%. Inhibition of CYP2C9 had a 
minimal effect on cabozantinib metabolite formation (i.e., a <20% reduction). Inhibition of 
CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP2E1 had no effect 
on cabozantinib metabolite formation. Within a 48-day collection period after a single dose 
of 14C- cabozantinib in healthy subjects, approximately 81% of the total administered 
radioactivity was recovered with 54% in feces and 27% in urine. 


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Specific Populations 
Renal Impairment 
Cabozantinib should be used with caution in subjects with mild or moderate renal 
impairment. No formal pharmacokinetic study of cabozantinib has been conducted in 
patients with renal impairment. The results of a population pharmacokinetic analysis 
suggested that mild to moderate renal impairment (creatinine clearance value <30 mL/min) 
does not have a clinically relevant effect on the clearance of cabozantinib. 
Hepatic Impairment  
Cabozantinib should be used with caution and dose reductions may be warranted in 
subjects with mild or moderate hepatic impairment, and clinical monitoring is 
recommended for these subjects. Cabozantinib is not recommended for use in subjects with 
severe hepatic impairment as safety and efficacy have not been established in this 
population 
The pharmacokinetics of cabozantinib has not been studied in patients with hepatic 
impairment.  
Pediatric population: This study will not enroll pediatric patients. 
Effects of Age, Gender and Race: A population PK analysis did not identify clinically 
relevant differences in clearance of cabozantinib between females and males or between 
Whites (89%) and non-Whites (11%). Cabozantinib pharmacokinetics was not affected by 
age (20-86 years). 
Drug Interactions 
CYP Enzyme Inhibition and Induction: cabozantinib is a noncompetitive inhibitor of 
CYP2C8 (Kiapp = 4.6 μM), a mixed-type inhibitor of both CYP2C9 (Kiapp = 10.4 μM) 
and CYP2C19 (Kiapp = 28.8 μM), and a weak competitive inhibitor of CYP3A4 (estimated 
Kiapp = 282 μM) in human liver microsomal (HLM) preparations. IC50 values >20 µM 
were observed for CYP1A2, CYP2D6, and CYP3A4 isozymes in both recombinant and 
HLM assay systems. Cabozantinib is an inducer of CYP1A1 mRNA in human hepatocyte 
incubations (i.e., 75-100% of CYP1A1 positive control _ naphthoflavone induction), but 
not of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP3A4 mRNA or isozyme-
associated enzyme activities. Cabozantinib at steady-state plasma concentrations (100 
mg/day daily for a minimum of 21 days) showed no effect on single-dose rosiglitazone (a 
CYP2C8 substrate) plasma exposure (Cmax and AUC) in patients with solid tumors.  
P-glycoprotein inhibition: cabozantinib is an inhibitor (IC50 = 7.0 µM), but not a substrate, 
of P-gp transport activities in a bi-directional assay system using MDCK-MDR1 cells. 
Therefore, cabozantinib may have the potential to increase plasma concentrations of co-
administered substrates of P-gp. Details can be found in the Investigator’s Brochure. 


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 Cabozantinib Nonclinical Toxicology 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
Studies examining the carcinogenic potential of cabozantinib have not been conducted. 
cabozantinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay and 
was not clastogenic in both the in vitro cytogenetic assay using human lymphocytes or in 
the in vivo mouse micronucleus assay. Based on nonclinical findings, male and female 
fertility may be impaired by treatment with cabozantinib. In a fertility study in which 
cabozantinib was administered to male and female rats at doses of 1, 2.5, and 5 mg/kg/day, 
male fertility was significantly compromised at doses equal to or greater than 2.5 
mg/kg/day (approximately equal to the human exposure by AUC at the recommended 
dose), with a decrease in sperm counts and reproductive organ weights. In females, fertility 
was significantly reduced at doses equal to or greater than 1 mg/kg/day (approximately 
50% of the human exposure by AUC at the recommended dose) with a significant decrease 
in the number of live embryos and a significant increase in pre- and post-implantation 
losses. Observations of effects on reproductive tract tissues in general toxicology studies 
were supportive of effects noted in the dedicated fertility study and included hypospermia 
and absence of corpora lutea in male and female dogs in a 6-month repeat dose study at 
exposures equal to 6% and 3%, respectively, the human exposure by AUC at the 
recommended dose. In addition, female rats administered 5 mg/kg/day for 14 days 
(approximately equal to the human exposure by AUC at the recommended dose) exhibited 
ovarian necrosis. Details can be found in the Investigator’s Brochure. 
 Clinical Experience 
Adverse Events 
The most frequent AEs experienced by ≥ 20% of subjects treated with cabozantinib in 
descending order of frequency were diarrhea, fatigue, decreased appetite, nausea, weight 
decreased, palmar plantar erythrodysesthesia syndrome (PPES), vomiting, constipation, 
hypertension, dysgeusia, dysphonia, asthenia, and dyspnea. For a full description of the 
safety profile of cabozantinib, refer to the most recent cabozantinib Investigator’s Brochure. 
Other medically important but less frequent AEs including arterial thrombotic AEs (e.g., 
transient ischemic attack [TIA], and myocardial infarction [MI]) and venous thrombotic AEs 
(e.g., deep vein thrombosis [DVT] and pulmonary embolism), severe hemorrhagic events, 
proteinuria, wound healing complications, gastrointestinal (GI) perforation, abscesses 
including intra-abdominal and pelvic abscess, GI and non-GI fistula formation, 
osteonecrosis, and reversible posterior leukoencephalopathy syndrome (RPLS). 
Adverse events associated with laboratory abnormalities experienced by ≥ 5% of subjects 
treated with cabozantinib in descending order of frequency were anemia, AST increased, 
ALT increased, hypothyroidism, hypokalemia, hypomagnesemia, thrombocytopenia, 
hypocalcemia, hypophosphatemia, lactate dehydrogenase (LDH) increased, lipase increased, 
neutropenia, hyponatremia, ALP increased, leukopenia, and hyperglycemia. 
Adverse events may occur within the first few weeks in the course of treatment with 
cabozantinib, as cabozantinib is expected to reach steady state exposure at approximately 2 
weeks following first dose. Events that generally have an early onset include hypocalcemia, 


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hypokalemia, thrombocytopenia, hypertension, PPES, abdominal pain, mucosal 
inflammation, constipation, diarrhea, and vomiting. Adverse events should be managed with 
supportive care at the earliest signs of toxicity. Dose reductions and treatment interruptions 
should be considered. Dose reductions are recommended for events that, if persistent, could 
become serious or intolerable. Please refer to section 7 for more specific details regarding 
Adverse Event descriptions and management. 
Clinical Activity 
Cabozantinib has demonstrated broad range of clinical anti-tumor activity in early Phase 1 
and Phase 2 studies in Medullary Thyroid Carcinoma (MTC) and several other tumor types. 
In a randomized discontinuation trial (RDT) XL184-203, the following disease control rates 
(DCR = complete response [CR] + partial response [PR] + stable disease [SD]) at Week 12 
were observed: non-small cell lung cancer (NSCLC), 38%; breast cancer, 48%; melanoma, 
46%; ovarian cancer, 53%; HCC, 66%; and CRPC, 66%. Observations of clinical activity 
have included decrease of soft tissue tumor lesions including visceral metastases, effects on 
metastatic lesions on bone scan (partial or complete bone scan resolution), reduction in serum 
markers of bone resorption and formation, reduction in circulating tumor cells (CTCs; 
subjects with prostate cancer), increases in hemoglobin, and improvements in bone pain and 
reductions in narcotic use in subjects with bone metastases. In the placebo-controlled Phase 3 
study XL184-301 in 330 MTC subjects, a significant increase in median PFS was seen in the 
cabozantinib arm compared with placebo (11.2 vs 4.0 months; hazard ratio [HR] =0.28; 95 
CIs: 0.19, 0.40) with durable response (median of 14.6 months). An unplanned 
administrative analysis of overall survival (OS) performed at the request of the FDA with a 
data cut-off of 15 June 2012 (75% of required deaths) showed a trend for improved duration 
of OS in the cabozantinib arm compared with placebo (26.0 months vs 20.3 months; HR = 
0.83; 95% CI: 0.60, 1.14).  
In the Phase 2 study XL184-203, cabozantinib demonstrated broad clinical activity in men 
with CRPC. During the RDT phase, the majority of CRPC subjects with bone metastases and 
elevated total alkaline phosphatase (t-ALP) levels at baseline showed reductions in t-ALP 16. 
These effects were independent of prior or concomitant bisphosphonate treatment. Subjects 
achieved a bone scan response (BSR) in both the 100 mg and 40 mg assigned NRE dose 
cohorts (73% and 45%, respectively). In addition, cabozantinib treatment has shown effects 
on bone metastases (by computed tomography [CT], or bone scan) in five tumor types, 
including CRPC, breast cancer, DTC (papillary), melanoma, and RCC. These effects include 
partial or complete bone scan resolution associated with reduction in circulating markers of 
bone resorption and formation, reduction in CTCs (CRPC), increases in hemoglobin, 
improvements in bone pain, and reductions in narcotic use. 
The preliminary analysis of an ongoing phase II study with cabozantinib in patients with 
heavily pretreated relapsed or refractory advanced UC revealed promising clinical activity 
(NCT01688999) 17, 18. Preliminarily, responses have been observed in 13% of 26 patients and 
associated with low peripheral blood regulatory T cells (Tregs). Moreover, cabozantinib 
decreased Tregs and increased PD-1 expression in Tregs, suggesting a potential role for 
combination or sequencing with immunotherapy. 


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CTEP Study: A Phase II Study of Cabozantinib (XL184) in Subjects with 
Advanced/Metastatic Urothelial Carcinoma 
A total of 67 eligible subjects with diagnoses of progressive metastatic carcinoma of the 
bladder, urethra, ureter, or renal pelvis were enrolled in three cohorts: Cohort 1 (n=50), 
metastatic UC; Cohort 2 (n=6), bone only metastatic UC; Cohort 3 (n=11), non-UC (rare 
histologies).26 Subjects were treated with 60 mg cabozantinib orally qd. 
In Cohort 1, ORR for 42 evaluable subjects was determined to be 19.1% with 7 PRs and 1 
CR. Median PFS for these subjects was 3.7 months (95% CI: 3.1, 6.5), and median OS was 
8.0 months (95% CI: 5.2, 10.3) with 27.2% of subjects still alive 12 months after starting 
study treatment. Median OS among responders (n=8) was 21.5 months (95% CI: 7.3, 36.0). 
The median PFS for evaluable subjects with bone-only disease (Cohort 2, n=5) was 5.3 
months (95% CI: 1.8, 8.3), and median OS was 9.3 months (95% CI: 3.6, 12.5). For 
evaluable subjects with non-urothelial rare histologies (Cohort 3, n=10), median PFS was 2.9 
months (95% CI: 1.8, 3.7), and median OS was 4.6 months (95% CI: 2.6, 8.0). 
Across all cohorts (n=67), the most frequently reported cabozantinib-related AEs were 
anemia (94%), PPES (83%), fatigue (69%), diarrhea (67%), AST increased (59%), platelet 
count decreased (58%), hypoalbuminemia (55%), hypophosphatemia (49%), creatinine 
increased (38%), nausea (36%), and hypothyroidism (40%); most of these AEs were Grade 1 
or 2. The most frequent Grade 3 AEs related to cabozantinib were fatigue (9%), hypertension 
(7%), hypophosphatemia (6%), AST increased (4%), platelet count decreased (4%), diarrhea 
(3%), abdominal pain (3%), hyponatremia (3%), lymphocyte count decreased (3%), and 
proteinuria (3%). Grade 4 AEs were reported for hypomagnesemia (3%) and lipase increased 
(1%); no Grade 3 events were reported for either of these terms. 
CTEP Study: A Phase I/Expansion Study of Cabozantinib plus Nivolumab Alone or With 
Ipilimumab in Subjects with Metastatic Urothelial Carcinoma and Other Genitourinary 
Tumors 
In an ongoing Phase 1 clinical trial in subjects with refractory metastatic UC and other 
genitourinary tumors, cabozantinib has been evaluated in combination with nivolumab, a 
monoclonal antibody to PD-1, and in combination with both nivolumab and ipilimumab, a 
monoclonal antibody to CTLA-4 (CaboNivo and CaboNivoIpi, respectively).27 Forty-three 
(43) of 48 subjects enrolled were assessed for tumor response at the time of analysis 
(CaboNivo 26 subjects; CaboNivoIpi: 17 subjects). The ORR was 38% in the CaboNivo 
cohort (8 PRs and 2 CRs) and 18% in the CaboNivoIpi cohort (2 PRs and 1 CR); among the 
16 evaluable metastatic UC subjects across both cohorts, the ORR was 38% (4 PRs and 2 
CRs). 
CaboNivo and CaboNivoIpi were well-tolerated among all enrolled subjects, and no DLTs 
were reported. Grade 3 AEs among subjects in the CaboNivo cohort irrespective of 
relationship to study treatment comprised neutropenia (n=5), hypophosphatemia (n=4), 
hypertension (n=3), dehydration, diarrhea, fatigue, lipase increased (each n=2), amylase 
increased, anemia, aseptic meningitis, hyperthyroidism, hyponatremia, proteinuria, 
thrombocytopenia, thromboembolic event, vomiting (each n=1); Grade 3 AEs among 
subjects in the CaboNivoIpi cohort comprised hypertension, hypophosphatemia (each n=3), 
fatigue, hyponatremia, lipase increased, nausea (each n=2), alanine aminotransferase 


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increased, anorexia, colitis, rash (each n=1). Grade 4 AEs in the CaboNivo cohort comprised 
lipase increased (n=2) and thrombocytopenia (n=1); there was one Grade 4 AE of lipase 
increased in the CaboNivoIpi cohort. There were no Grade 5 AEs.  
More details regarding the efficacy of cabozantinib can be found in the Investigator’s 
Brochure. 
 Translational Medicine 
In preclinical studies, cabozantinib has shown potent anti-angiogenic, tumor growth 
inhibition, and tumor regression effects in vivo. In addition, cabozantinib blocked metastasis 
and improved overall survival in the transgenic RIP-Tag2 mouse model of pancreatic 
neuroendocrine cancer 19. In human prostate and breast xenograft models, cabozantinib 
blocked osteoblastic and osteolytic progression of tumors in bone. Cabozantinib inhibited 
progression of multiple prostate cancer cell lines in bone metastatic and soft tissue murine 
models of prostate cancer and exerted a dose-dependent biphasic effect on osteoblast activity 
and inhibitory effect on osteoclast production in vitro 20 Oral administration of cabozantinib 
resulted in blockade of MET phosphorylation in human lung tumor xenografts grown in nude 
mice, blockade of MET phosphorylation in livers of mice, and blockade of VEGFR2 
phosphorylation in mouse lung tissue. For both targets, the duration of action for 
cabozantinib was sustained, with > 50% inhibition observed for > 8 hours post-dose at a 
single dose level of 100 mg/kg 21 Anti-tumor effects of cabozantinib, were also examined in 
cultured HCC cells as well as in vivo models. In cultured HCC cells that are refractory to 
sorafenib and expressed p-MET (phosphorylated-MET), the cabozantinib inhibited the 
activity of MET and its downstream effectors, leading to G1 phase arrest with relatively 
more profound efficacy in p-MET-positive HCC xenografts 22. Details can be found in the 
Investigator’s Brochure. 
3.2 
Pembrolizumab 
Refer to the most recent Investigator’s Brochure (IB) for detailed background information on 
MK-3475 (Pembrolizumab). 
 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades. Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies. In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and 
long-term survival in many solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 which has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2). 
The structure of murine PD-1 has been resolved. PD-1 and family members are type I 


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transmembrane glycoproteins containing an Ig Variable-type (V-type) domain responsible 
for ligand binding and a cytoplasmic tail which is responsible for the binding of signaling 
molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-
based switch motif (ITSM). Following T-cell stimulation, PD-1 recruits the tyrosine 
phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70, which are 
involved in the CD3 T-cell signaling cascade. The mechanism by which PD-1 down 
modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both molecules 
regulate an overlapping set of signaling proteins. PD-1 was shown to be expressed on 
activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, Tregs and 
Natural Killer cells. Expression has also been shown during thymic development on CD4-
CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells. The 
ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a 
variety of cell types, including non-hematopoietic tissues as well as in various tumors. Both 
ligands are type I transmembrane receptors containing both IgV- and IgC-like domains in the 
extracellular region and contain short cytoplasmic regions with no known signaling motifs. 
Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell 
receptor. PD-L1 is expressed at low levels on various non-hematopoietic tissues, most 
notably on vascular endothelium, whereas PD-L2 protein is only detectably expressed on 
antigen-presenting cells found in lymphoid tissue or chronic inflammatory environments. 
PD-L2 is thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 
serves to dampen unwarranted T-cell function in peripheral tissues. Although healthy organs 
express little (if any) PD-L1, a variety of cancers were demonstrated to express abundant 
levels of this T-cell inhibitor. This suggests that the PD-1/PD-L1 pathway plays a critical role 
in tumor immune evasion and should be considered as an attractive target for therapeutic 
intervention. 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of 
the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its 
ligands, PD-L1 and PD-L2. KeytrudaTM (pembrolizumab) has recently been approved in the 
United Stated for the treatment of patients with unresectable or metastatic melanoma and 
disease progression following ipilumumab and, if BRAF V600 mutation positive, a BRAF 
inhibitor. 
 Preclinical and Clinical Trial Data 
Refer to the most recent Investigator’s Brochure for Preclinical and Clinical data. 
 Rationale for Dose Selection/Regimen/Modification 
PK data analysis of MK-3475 administered Q3W showed slow systemic clearance, limited 
volume of distribution, and a long half-life (refer to IB). Pharmacodynamic data (IL-2 release 
assay) suggested that peripheral target engagement is durable (>21 days). This early PK and 
pharmacodynamic data provides scientific rationale for testing a Q3W dosing schedule. This 
clinical trial uses the FDA approved dose and schedule for treatment of metastatic urothelial 
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4 STUDY DESIGN 
4.1 
Description 
This is an open label, non-randomized phase 2 study of the combination of pembrolizumab 
and cabozantinib to assess overall response rate (ORR), progression free survival at 6 months 
(PFS6), and overall survival (OS) in patients with metastatic urothelial carcinoma (UC) 
ineligible for cisplatin. Cabozantinib is administered at 40 mg oral daily. Pembrolizumab will 
be administered at a fixed dose of 200mg intravenously every 3 weeks for all patients. A 
safety analysis will be performed after the first 6 patients enroll and receive treatment. 
During this stage, the decision to continue enrollment will be made by the Data Safety and 
Monitoring Committee (DSMC). When all 6 subjects in the have been followed for at least 
21 days following first dose of pembrolizumab and cabozantinib, all available safety data 
will be considered in a decision to continue enrollment. Therapy continues until progression 
or intolerable toxicities. Study treatment may continue beyond initial radiographic or clinical 
disease progression as long as the patient is deriving clinical benefit from the treatment, as 
assessed by the investigator. Patients removed from therapy without evidence of progression 
will undergo radiological examination every 12 weeks or earlier if clinically warranted. 
4.2 
Number of Patients 
A total of up to 39 subjects will be enrolled with the objective of having a minimum of 35 
evaluable subjects for the primary objective. 
4.3 
Number of Study Centers 
This is a multisite study to be conducted at Huntsman Cancer Institute at the University of 
Utah, Salt Lake City, Utah. Up to two additional sites may be included. 
4.4 
Study Duration  
We anticipate up to 2 years to complete enrollment followed by 1 year of treatment and 5 
months follow up. Total duration of the trial will be 3-to-4 years. 
4.5 
Conditions for Terminating the Study 
At any time, the study may be terminated by the study sponsor or by Exelixis as described in 
the clinical trial agreement.  
 


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5 ELIGIBILITY CRITERIA 
5.1 
Pre-Screening Eligibility for Patients Scheduled for Urothelial Diagnostic 
Procedure (biopsy or surgery) 
This eligibility checklist is used to determine a subject’s eligibility for pre-screening 
correlative tissue collection. It must be filed in the subject’s research chart with the enrolling 
investigator’s signature.  
Patient No. ______________________ 
Patient’s Initials: (L, F, M) _________________ 
 Inclusion Criteria 
Yes/No (Response of “no” = patient ineligible) 
 _____ Male or female subject aged ≥ 18 years. 
 _____ Clinically, subject is a candidate for urothelial diagnostic procedure (fresh soft-
tissue biopsy or TURBT). 
 _____ Subject meets general medical criteria for consideration of treatment with 
immunotherapy using a checkpoint inhibitor. 
I certify that this patient meets all inclusion and exclusion criteria for enrollment onto 
the pre-screening portion of this study.  
______________________________ 
 
_________ 
_______ 
Investigator Signature   
 
 
Date  
Time 
 


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This eligibility checklist is used to determine patient eligibility and filed with enrolling 
physician’s signature in the patient research chart.  
Patient No. ______________________ 
Patient’s Initials: (L, F, M) _________________ 
5.2 
Inclusion Criteria 
Yes/No (Response of “no” = patient ineligible) 
 _____ Histologically proven transitional cell or urothelial carcinoma. 
 
 _____ Patients with locally advanced or metastatic urothelial carcinoma must meet 
one of the following:  
• Patients who are not eligible for cisplatin-containing chemotherapy AND 
whose tumors express PD-L1 (Combined Positive Score (CPS) ≥ 10 as 
determined by an FDA-approved test  
OR 
• Patients who are not eligible for any platinum-containing chemotherapy 
regardless of PD-L1 status. 
 _____ Metastatic (any N+ or M1) or locally advanced, unresectable (T4bN0) disease. 
 _____ Measurable disease is required as determined by RECIST v1.1. 
 _____ Performance Status ECOG 0-2 
 _____ Cisplatin-ineligibility based on ≥1 of the following:  
• Estimated creatinine clearance between ≥30 and <60 ml/min (Cockcroft-
Gault formula)  
• ECOG PS>1  
• Hearing loss 
• Baseline neuropathy > grade 1. 
• Patient refusal 
 _____ Be ≥ 18 years of age on day of signing informed consent. 
 


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 _____ Serum albumin ≥ 2.8 g/dl 
 _____ Alkaline phosphatase (ALP) ≤ 3 × upper limit of normal (ULN). ALP ≤ 5 × 
ULN with documented bone metastases. 
 _____ Negative serum or urine pregnancy test at screening for women of childbearing 
potential (see section 7.3). 
 _____ Highly effective contraception for both male and female subjects throughout 
the study and for at least 120 days after last pembrolizumab treatment administration 
if the risk of conception exists (section 7.3).  
 _____ Must have recovered from adverse effects of any prior surgery, radiotherapy or 
other antineoplastic therapy to grade ≤2. If not recovered to grade ≤ 2, these must be 
deemed to be irreversible adverse events related to prior surgery and /or radiation 
therapy (such as incontinence or sexual dysfunction) per investigator clinical 
judgment.  
 _____ Recovery to baseline or ≤ Grade 2 CTCAE v.5.0 from toxicities related to any 
prior treatments, unless AE(s) are clinically nonsignificant and/or stable on 
supportive therapy. Alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not 
constituting a safety risk based on investigator’s judgment are acceptable. 
 _____ Last dose of any radiation therapy > 2 weeks before first dose of study 
treatment. 
 _____ Able to provide informed consent and willing to sign an approved consent 
form that conforms to federal and institutional guidelines. 
 _____ Adequate organ function as defined as:  
 Hematologic: Absolute neutrophil count (ANC) ≥ 1.5 × 109/L (without 
granulocyte colony-stimulation factor support within 2 weeks of 
screening), platelet count ≥ 100 × 109/L (without platelet transfusion 
within 2 weeks of screening), hemoglobin ≥ 9 g/dL (may have been 
transfused), and white blood cell count (WBC) ≥ 2.5 × 109/L. 
 Hepatic: Total bilirubin level ≤ 1.5 × the upper limit of normal (ULN) (≤ 
3 × ULN for subjects with Gilbert’s disease / or unconjugated 
hyperbilirubenemia) and AST and ALT levels ≤ 2.5 × ULN or AST and 
ALT levels ≤ 3 × ULN for subjects with documented metastatic disease. 
Patient with a history of unconjugated hyperbilirubinemia with otherwise 
acceptable liver enzyme levels (as per above criteria) may have higher 
bilirubin levels.  
 Renal: Urine protein/creatinine ratio (UPCR) ≤ 2 mg/mg (≤ 113.2 
mg/mmol) and serum creatinine ≤ 2.0 × ULN or calculated creatinine 
clearance ≥ 30 mL/min (≥ 0.5 mL/sec) using the Cockcroft-Gault 


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equation: 
• Males: (140 – age) × weight [kg]/(serum creatinine [mg/dL] × 72) 
• Females: [(140 – age) × weight (kg)/(serum creatinine [mg/dL] × 72)] 
× 0.85 
5.3 
Exclusion Criteria 
Yes/No (Response of “yes” = patient ineligible) 
 _____ Prior chemotherapy for metastatic urothelial carcinoma. 
 Prior chemotherapy for localized urothelial carcinoma that has been completed less 
than 6 months before registration. 
 _____ Variant histologies other than urothelial carcinoma will not be allowed. 
Patients with a component of variant histologies will be allowed to enroll, if urothelial 
carcinoma is the predominant histology per investigator judgement. Patients with any 
component of small cell will be excluded. 
 _____ Has received prior treatment with cabozantinib. 
 _____ Receipt of any type of small molecule kinase inhibitor (including 
investigational kinase inhibitor) within 2 weeks before first dose of study treatment. 
 _____ Receipt of any type of cytotoxic, biologic, or other systemic anticancer therapy 
(including investigational) within 4 weeks before first dose of study treatment. 
 _____ Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent 
or other checkpoint inhibitors previously. 
 _____ Radiation therapy for bone metastasis ≤2 weeks, any other radiation therapy 
within 4 weeks before first dose of study treatment. Systemic treatment with 
radionuclides within 6 weeks before the first dose of study treatment. Subjects with 
clinically relevant ongoing complications from prior radiation therapy are not 
eligible. 
 _____ Has known active central nervous system (CNS) metastases and/or 
carcinomatous meningitis. Subjects with previously treated brain metastases may 
participate provided they are stable (without evidence of progression by imaging for 
at least 4 weeks prior to the first dose of trial treatment and any neurologic symptoms 
have returned to baseline), have no evidence of new or enlarging brain metastases, 
and are not using steroids for at least 7 days prior to trial treatment. This exception 
does not include carcinomatous meningitis which is excluded regardless of clinical 
stability. 
 ____ Concomitant anticoagulation with oral coagulants except for those specified 
below.   


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Allowed anticoagulants are the following: 
• Prophylactic use of low-dose aspirin for cardio protection (per local applicable 
guidelines) 
• Low-dose low molecular weight heparins (LMWH) 
• Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors 
rivaroxaban, edoxaban, or apixaban is allowed in subjects without known brain 
metastases who are on a stable dose of the anticoagulant for at least 1 week before 
the first dose of study treatment without clinically significant hemorrhagic 
complications from the anticoagulation regimen or the tumor.  
 _____ The subject has prothrombin time (PT)/INR or partial thromboplastin time 
(PTT) test ≥ 1.3 × ULN within 14 days before the first dose of study treatment. 
 _____ The subject has uncontrolled, significant intercurrent or recent illness 
including, but not limited to, the following conditions:  
• Cardiovascular disorders: 
o Ongoing congestive heart failure exacerbation or New York Heart 
Association Class 4, unstable angina pectoris, serious cardiac 
arrhythmias. 
o Uncontrolled hypertension defined as sustained blood pressure (BP) > 
150 mm Hg systolic or > 100 mm Hg diastolic despite optimal 
antihypertensive treatment. Uncontrolled hypertension needs to be 
determined based on persistently high blood pressure readings over 
more than 24 hours and should NOT be based on the blood pressure 
readings from one clinic visit. Blood pressure readings done at home or 
by primary care providers are acceptable. If a blood pressure reading on 
the day of screening is high, but there are documented acceptable (≤150 
mm Hg systolic and ≤100 mm Hg diastolic) blood pressure readings 
prior to or after the screening visit (with or without the use of anti-
hypertensive medications), patient will not be considered to have 
uncontrolled hypertension. 
o Stroke (including transient ischemic attack [TIA]), myocardial 
infarction (MI), or other ischemic event, or symptomatic 
thromboembolic event (e.g., deep venous thrombosis, pulmonary 
embolism) occuring less than or equal to 6 months before first dose of 
cabozantinib. [ Note: Subjects with a diagnosis of  deep vein 
thrombosis (DVT) or incidentally detected asymptomatic and sub-
segmental pulmonary embolism (PE) on routine scans are allowed if on 
a stable dose of anti-coagulation for at least 1 week before first dose of 
study treatment ] 
o Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 
teaspoon (2.5 ml) of red blood, or other history of significant bleeding 
(e.g., pulmonary hemorrhage) within 12 weeks before first dose. 
 


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• Gastrointestinal (GI) disorders including those associated with a high risk 
of perforation or fistula formation:  
o The subject has evidence of tumor invading the GI tract, active peptic 
ulcer disease, inflammatory bowel disease (e.g., Crohn’s disease), 
diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, 
acute pancreatitis, acute obstruction of the pancreatic duct or common 
bile duct, or gastric outlet obstruction. 
o Abdominal fistula, GI perforation, bowel obstruction, or intra-
abdominal abscess within 6 months before first dose.  
Note: Complete healing of an intra-abdominal abscess must be confirmed 
before first dose. 
• Cavitating pulmonary lesion(s) or known endotracheal or endobronchial 
disease manifestation. 
• Lesions invading or encasing any major blood vessels. 
• Other clinically significant disorders that would preclude safe study 
participation per investigator clinical judgement. 
o Serious non-healing wound/ulcer/bone fracture.  
o Uncompensated/symptomatic hypothyroidism. 
o Moderate to severe hepatic impairment (Child-Pugh B or C). 
 _____ Other severe acute or chronic medical conditions including immune colitis, 
inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric 
conditions including recent (within the past year) or active suicidal ideation or 
behavior; or laboratory abnormalities that may increase the risk associated with study 
participation or study treatment administration or may interfere with the interpretation 
of study results and, in the judgment of the investigator, would make the patient 
inappropriate for entry into this study. 
 _____ Major surgery (e.g., GI surgery, removal or biopsy of brain metastasis) within 
8 weeks before first dose of study treatment. Complete wound healing from major 
surgery must have occurred 1 month before first dose and from minor surgery (e.g., 
simple excision, tooth extraction) at least 10 days before first dose. Subjects with 
clinically relevant ongoing complications per investigator clinical judgement from 
prior surgery are not eligible. 
 ____ Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms per 
electrocardiogram (ECG) within 28 days before first dose of study treatment. 
Note: If a single ECG shows a QTcF with an absolute value > 500 ms, two 
additional ECGs at intervals of approximately 3 minutes must be performed after 
the initial ECG, and the average of these three consecutive results for QTcF will 
be used to determine eligibility.  


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 _____ Diagnosis of another malignancy within 2 years before first dose of study 
treatment, with the exception of those determined by the treating investigator to have 
a negligible risk of metastasis or death (such as adequately treated carcinoma in situ 
of the cervix, basal or squamous cell skin cancer, ductal carcinoma in situ treated 
surgically with curative intent, localized prostate cancer treated with curative intent 
and/or no intent for further treatment, or incidental prostate cancer). 
 _____ Current use of immunosuppressive medication, EXCEPT for the following: a. 
intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular 
injection); b. Systemic corticosteroids at physiologic doses ≤ 10 mg/day of 
prednisone or equivalent; c. Steroids as premedication for hypersensitivity reactions 
(e.g., CT scan premedication). 
 _____ Has active autoimmune disease currently requiring systemic treatment with 
high dose corticosteroids (dose more than physiologic replacement doses equivalent 
to prednisone 10 mg daily) or disease modifying immunosuppressive agents). 
Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, intranasal, inhaled, topical 
steroids, or local steroid injection) is not considered an exclusion.  
 _____ Active autoimmune disease that might deteriorate significantly when receiving 
an immuno-stimulatory agent per treating physician’s clinical judgment. Subjects 
with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not 
requiring immunosuppressive treatment are eligible. 
 _____ Prior organ transplantation including allogenic stem-cell transplantation. 
 _____ Has known history of (non-infectious) pneumonitis that required steroids or 
has current pneumonitis. 
 _____ Has an active infection currently requiring systemic (intravenous) antibiotic 
therapy.  
 _____ Has a known history of active TB (Bacillus Tuberculosis). 
 _____ Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV 
RNA [qualitative] is detected). 
 _____ Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 
antibodies). 
 _____ Active and inactive vaccinations within 4 weeks of the first dose of 
pembrolizumab is prohibited. 
 _____ Known prior severe hypersensitivity to investigational products or any 
component in its formulations, including known severe hypersensitivity reactions to 
monoclonal antibodies (NCI CTCAE v.5.0 Grade ≥ 3). 


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 _____ Is pregnant or breastfeeding, or expecting to conceive or father children within 
the projected duration of the trial, starting with the pre-screening or screening visit 
through 120 days after the last dose of trial treatment. 
 ______ Subjects taking prohibited medications as described in Section 6.8. A 
washout period of prohibited medications for a period of at least two weeks or as 
clinically indicated should occur prior to the start of treatment. 
 _____ Inability to swallow tablets or evidence of impaired intestinal absorption 
I certify that this patient meets all inclusion and exclusion criteria for enrollment onto 
this study.  
______________________________ 
 
_________ 
_______ 
Investigator Signature   
 
 
Date  
Time 
 
 


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6 TREATMENT PLAN 
Treatment should be administered on Day 1 of each cycle after all procedures and assessments 
have been completed as detailed on the Study Calendar (Section 8). Trial treatment may be 
administered up to 3 days before or after the scheduled Day 1 of each cycle. 
All trial treatments will be administered on an outpatient basis. 
6.1 
Administration Schedule 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks. Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible. 
However, given the variability of infusion pumps from site to site, a window of -5 minutes 
and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
Cabozantinib is administered at 40 mg oral daily (with dose reductions to 20 mg daily; a 
subsequent dose reduction to 20 mg every other day to improve tolerability is allowed). 
Therapy continues until progression or intolerable toxicities. Study treatment may continue 
beyond initial radiographic or clinical disease progression as long as the patient is deriving 
clinical benefit from the treatment, as assessed by the investigator. A safety analysis will be 
performed after the first 6 patients enroll and receive treatment. During this stage, the 
decision to continue enrollment will be made by the Data Safety and monitoring committee 
(DSMC), when all 6 subjects have been followed for at least 21 days following first dose of 
pembrolizumab and cabozantinib. All available safety data will be considered in a decision to 
continue enrollment. Patients removed from therapy without evidence of progression will 
undergo radiological examination every 12 weeks or earlier if clinically warranted.).  
6.2 
Cabozantinib  
At study sites, all study medication will be stored as described in the pharmacy manual and 
inventoried in accordance with applicable state and federal regulations. 
Clinical Supplies will be provided by Exelixis. 
 Investigational Treatment  
Chemical Name: Chemical Name: N-{4-[(6, 7-dimethoxyquinolin-4-yl) oxy] phenyl}-N’-(4-
fluorophenyl) cyclopropane-1, 1-dicarboxamide, (2S)-hydroxybutanedioate 
 
Cabozantinib Tablets  
Exelixis internal number: XL184 
Cabozantinib tablets are supplied as film-coated tablets containing cabozantinib malate 
equivalent to 20 mg of cabozantinib and contain microcrystalline cellulose, lactose anhydrous, 
hydoxypropyl cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate 
and Opadry® yellow. All tablet strengths are prepared from a common blend and are 
distinguished by shape. The 20 mg tablets are round in shape. The components of the tablets 
are listed in Table 6 1. 


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Table 6.1: Cabozantinib Tablet Components and Composition 
Ingredient 
Function 
% w/w 
Cabozantinib malate (25% drug load as cabozantinib) 
Active Ingredient 
31.7 
Microcrystalline Cellulose (Avicel PH-102) 
Filler 
38.9 
Lactose Anhydrous (60M) 
Filler 
19.4 
Hydroxypropyl Cellulose (EXF) 
Binder 
3.0 
Croscarmellose Sodium (Ac-Di-Sol) 
Disenegrant 
6.0 
Colloidal Silicon Dioxide, 
Glidant 
0.3 
Magnesium Stearate 
Lubricant 
0.75 
Opadry Yellow Film Coating which includes: 
- 
HPMC 2910/Hypromellose 6 cp  
- 
Titanium dioxide  
- 
Triacetin  
- 
Iron Oxide Yellow 
Film Coating 
4.00 
 Dose, Schedule, and Route 
Subjects will receive cabozantinib orally at a (starting) dose of 40 mg once daily (with dose 
reductions to 20 mg daily, and subsequently 20 mg every other day to improve tolerability is 
allowed). The first dose will be given in clinic on day 1 of each cycle under supervision while 
the patient will take the rest of the medications at home. Patients will be provided with a 
dosing diary to keep track of medication taken (Appendix I).  
Cabozantinib must be taken on an empty stomach. Subjects must be instructed not to eat for at 
least 2 hours before and at least 1 hour after taking cabozantinib. Subjects should be instructed 
to take their cabozantinib dose at approximately the same time every day. If a subject misses a 
dose, the dose may be taken later only if it is within 12 hours of when the missed dose should 
have been taken. The missed dose should not be made up if it is within 12 hours of the next 
scheduled dose. Cabozantinib tablets should be swallowed whole with at least 8 ounces of 
water. The tablets should not be crushed. Grapefruit, grapefruit juice, seville oranges, and their 
products should be avoided by subjects taking cabozantinib. In all subjects, dose reductions 
and delays to manage toxicity are allowed under the guidelines in Section 7 below. 
 Accountability and Compliance 
Accountability and compliance should be handled per institutional policies for commercially 
available medications. Patients will be provided with a dosing dairy to track oral dosing of 
cabozantinib (Appendix I).  
All study drugs will be stored at the Huntsman Cancer Institute Investigational Pharmacy in 
accordance with Good Clinical Practice (GCP) and GMP requirements and the instructions 
given by the clinical supplies department of the sponsor, and will be inaccessible to 
unauthorized personnel. The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the inventory and disposition of the agent. 
An adequate record of receipt, distribution, and return of all study drugs must be kept in the 
form of a Drug Accountability Form. Subject compliance with the treatment and protocol 


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includes willingness to comply with all aspects of the protocol, and to have blood collected 
for all safety evaluations. At the discretion of the principal investigator, a subject may be 
discontinued from the trial for non-compliance with follow-up visits or study drug.  
Instructions on medication resupply and destruction will be made available to affected parties 
as applicable.  
At the conclusion of the study, and, as appropriate during the course of the study, the 
Investigator will return all used and unused study drug, packaging, drug labels, and a copy of 
the completed drug accountability ledger to Exelixis.  
 Post-Treatment Period 
Subjects will return to the study site approximately 28 days after their last dose of 
cabozantinib to complete end-of-study assessments. 
Laboratory and physical examinations will be performed. Remaining study treatment will be 
returned by the subject, 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 
visit, and for subjects with SAEs related to study treatment that occur after the time of this 
visit. 
6.3 
Pembrolizumab (MK-3475) Treatment  
 How Supplied, Stored, Packaged, and Labeled 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
Clinical Supplies will be provided as Standard of Care by the Huntsman Cancer Institute 
pharmacy. 
Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
 Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided. 


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 Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
 Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies, the 
amount dispensed to and returned by the subjects, and the amount remaining at the 
conclusion of the trial. 
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. It is the 
Investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, 
local, and institutional guidelines and procedures, and provided that appropriate records of 
disposal are kept. 
 Preparation and Administration 
Pembrolizumab (MK-3475) Solution for Infusion, 100 mg/ 4 mL vial: pembrolizumab 
(MK-3475) Solution for Infusion vials should be stored at refrigerated conditions (2 – 8 °C) 
and protected from light. 
Note: vials should be stored in the original box to ensure the drug product is protected from 
light. 
Pembrolizumab (MK-3475) infusion solutions should be prepared in 0.9% Sodium 
Chloride Injection, USP (normal saline) or regional equivalent or 5% Dextrose Injection, 
USP (5% dextrose) or regional equivalent and the final concentration of pembrolizumab 
(MK-3475) in the infusion solutions should be between 1 mg/mL and 10 mg/mL.  
Please note, the preferred diluent is 0.9% Sodium Chloride and 5% dextrose is only 
permissible if normal saline is not available. 
Local guidelines should be followed for collection of diluent information such as 
manufacturer, lot and expiry.  
Pembrolizumab (MK-3475) SHOULD NOT BE MIXED WITH OTHER DILUENTS.  
Pembrolizumab (MK-3475) solutions may be stored at room temperature for a cumulative 
time of up to 4 hours. This includes room temperature storage of admixture solutions in the 
IV bags and the duration of infusion 
In addition, IV bags may be stored under refrigeration at 2 °C to 8 °C (36 °F to 46 °F) for up 
to 20 hours. If refrigerated, allow the IV bags to come to room temperature prior to use.  


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Parenteral drug products should be inspected visually for particulate matter and discoloration 
prior to administration. Discard the drug product vial if extraneous particulate matter other 
than translucent to white proteinaceous particles is observed. 
Sites should follow their SOPs for drug transport and delivery, with all possible effort to 
minimize agitation of the drug product between the pharmacy and the clinic 
DO NOT USE PEMBROLIZUMAB (MK-3475) IF DISCOLORATION IS 
OBSERVED. 
DO NOT SHAKE OR FREEZE THE VIAL(S). 
DO NOT ADMINISTER THE PRODUCT AS AN (INTRAVENOUS (IV) PUSH OR 
BOLUS). 
DO NOT COMBINE, DILUTE OR ADMINISTER IT AS AN INFUSION WITH 
OTHER MEDICINAL PRODUCTS. 
Any departure from the guidance listed in this protocol, must be discussed with sponsor 
6.4 
Dose Calculation 
200 mg Fixed Dose 
• 2 vials (100 mg/4 mL) 
• 8 mL total  
6.5 
Preparation of Infusion Solution 
Aseptic technique must be strictly observed throughout the preparation procedure preferably 
in a biologic safety cabinet or hood since no anti-microbial preservative is present in the 
solutions.  
Equilibrate required number of pembrolizumab MK-3475 vials to room temperature. 
The preferred method of dose preparation is the volumetric method; gravimetric method is 
not permitted.  
Choose a suitable infusion bag size so that the following conditions are met: 
• Concentration of pembrolizumab MK-3475 is between 1 mg/mL and 10 mg/mL 
• The infusion volume to bag capacity ratio should not be less than 0.3. In other words, 
the bag must be filled to at least 30% of its capacity.  
Choose a suitable infusion bag material. The bag may be empty or it may contain normal 
saline. The following infusion bag materials are compatible with pembrolizumab (MK-
3475):  
• PVC plasticized with DEHP 
• Non-PVC (polyolefin) 
• EVA 
• PE lined polyolefin 


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Calculate the volume of pembrolizumab (MK-3475) and normal saline required to prepare 
the infusion (admixture) bag. 
Volume of pembrolizumab (MK-3475) (mL) = required dose amount (mg) / 25 (mg/mL). 
Volume of normal saline = total infusion volume – volume of pembrolizumab (MK-3475) 
from above. 
If a bag pre-filled with normal saline is being used, remove the excess volume of normal 
saline using a sterile syringe (Polypropylene, latex-free) attached to a suitable needle. Keep 
in consideration the excess bag fill volume as well as the volume of pembrolizumab (MK-
3475) to be added to the bag to prepare the infusion solution. This helps ensure that the 
concentration in the bag can be accurately calculated and falls within the acceptable range of 
1 mg/mL to 10 mg/mL. If the site would like to proceed without removing excess saline they 
must ensure that the concentration of MK-3475 would still fall within acceptable range. 
If an empty bag is being used, withdraw the necessary volume of normal saline from another 
appropriate bag and inject into the empty bag. Keep in consideration the volume of 
pembrolizumab (MK-3475) to be added to the bag to prepare the infusion solution. 
Withdraw the required volume of pembrolizumab (MK-3475) from the vial(s) (up to 4 mL 
from each vial) using a sterile syringe attached to a suitable needle. The vial(s) may need to 
be inverted to remove solution. 
Volume of pembrolizumab (MK-3475) (mL) = required dose amount (mg) / 25 (mg/mL). 
Note: If it is necessary to use several vials, it is advisable to withdraw from several vials into 
a suitable size single use syringe using a new needle for each vial.  
Add the required pembrolizumab (MK-3475) into the infusion IV bag containing normal 
saline and gently invert the bag 10-15 times to mix the solution. 
Pembrolizumab (MK-3475) solutions may be stored at room temperature for a cumulative 
time of up to 4 hours. This includes room temperature storage of admixture solutions in the 
IV bags and the duration of infusion.  
In addition, IV bags may be stored under refrigeration at 2 °C to 8 °C (36 °F to 46 °F) for up 
to 20 hours. If refrigerated, allow the IV bags to come to room temperature prior to use.  
DO NOT FREEZE THE PEMBROLIZUMAB (MK-3475) INFUSION SOLUTION. 
Discard any unused portion left in the vial as the product contains no preservative. 
6.6 
Administration 
Pembrolizumab (MK-3475) infusions should be administered in 30 minutes, with a window 
of -5 and +10 minutes, using an infusion pump. A central catheter is not required for 
infusion; however, if a subject has a central venous catheter in place, it is recommended that 
it be used for the infusion.  
The following infusion set materials are compatible with (pembrolizumab) MK-3475: 
o PVC Infusion set that is plasticized using DEHP 
o PVC and tri-(2-ethylhexyl) trimellitate (TOTM) infusion set 


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o Polyethylene lined PVC infusion set 
o PVC Infusion set that is plasticized using Di-2-ethylhexyl Terephthalate (DEHT) 
o Polyurethane set 
A sterile, non-pyrogenic, low-protein binding 0.2 to 5 µm in-line filter made of 
polyethersulfone (PES) must be used during administration to remove any adventitious 
particles. If the infusion set does not contain 0.2 to 5 µm in-line filter, it is recommended to 
use 0.2 to 5 µm add-on filter which may contain an extension line (Note: the materials of the 
extension line and filter should be as mentioned above). 
Attach the infusion line to the pump and prime the line, either with normal saline (at least 25 
mL) or with infusion solution as per local SOP, before starting the infusion. 
Infuse pembrolizumab (MK-3475) over approximately 30 minutes, with a window of -5 and 
+10 minutes, through a peripheral line or indwelling catheter. 
Ensure the entire contents of the bag are dosed and all remaining drug solution in the line is 
administered according to institutional guidelines for saline flushing. 
Document volume administered according to data entry guidelines. 
In case of infusion reactions, infusion rate may differ; refer to protocol section 7.2 for 
specific instructions.  
Whenever possible, the lowest infusion rate should be used that will allow completion of the 
infusion within the 30 minutes. 
Maximum rate of infusion should not exceed 6.7 mL/min. through a peripheral line or 
indwelling catheter. However, when it is necessary to infuse a larger volume (i.e., 250 mL), 
the flow rate may go as high as 10 mL/min (maximum) in order to keep the infusion within 
the window as defined above.  
DO NOT CO-ADMINISTER OTHER DRUGS THROUGH THE SAME INFUSION 
LINE. 
UNUSED INFUSION SOLUTION FOR INJECTION SHOULD NOT BE USED FOR 
ANOTHER INFUSION OF THE SAME SUBJECT OR DIFFERENT SUBJECT. 
6.7 
Accountability and Compliance 
The investigator is responsible for keeping accurate records of the clinical supplies, the 
amount dispensed to and returned by the subjects, and the amount remaining at the 
conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the investigator’s 
responsibility to arrange for disposal of all empty containers, provided that procedures for 
proper disposal have been established according to applicable federal, state, local, and 
institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 


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6.8 
Concomitant Medications and Therapies 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids. If changes occur during the trial period, documentation of drug dosage, frequency, 
route, and date may also be included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded. Concomitant 
medications administered up to 30 days after the last dose of trial treatment should be 
recorded in the appropriate CRF. 
 Other Medications 
All concomitant medications used by the subject (including prescription and over-the-counter 
medications, transfusions, vitamins, herbal remedies, and nutritional supplements) during the 
period from 28 days before the first dose of study treatment through 30 days after the date of 
the last dose of study treatment are to be recorded in the CRF. 
 Allowed Therapies  
• Granulocyte colony stimulating factors (G-CSF or GM-CSF) are allowed if used per 
clinical guidelines (e.g., American Society of Clinical Oncology [ASCO] or [European 
Society for Medical Oncology] ESMO guidelines). Not allowed within two weeks prior 
to screening. 
• Drugs used to control bone loss (e.g., bisphosphonates and denosumab) are allowed if 
started before screening activities but may not be initiated or exchanged during the course 
of the study and require Principal Investigator approval. 
• Transfusions and hormone replacement should be utilized as indicated by standard 
clinical practice. Treatments are prohibited within two weeks prior to screening. 
• Individualized anticoagulation therapy with heparin or direct factor Xa inhibitors 
rivaroxaban, edoxaban, or apixaban is allowed if it can be provided safely and effectively 
under the following circumstances:  
At the time of first dose of study treatment: 
o Low dose low molecular weight heparins (LMWH) for prophylactic use are allowed 
if clinically indicated and the benefit outweighs the risk per the investigator’s 
discretion.  
 Therapeutic doses of LMWH or the direct factor Xa inhibitors rivaroxaban, 
edoxaban, or apixaban at the time of the first dose of study treatment are allowed 
if the subject has no evidence of brain metastasis, has been on a stable dose of 
anticoagulant for at least 1 week, and has had no clinically significant 
hemorrhagic complications from the anticoagulatin regimen or the tumor. 
After first dose of study treatment:  


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 Low dose low molecular weight heparins (LMWH) for prophylactic use after first 
dose of study treatment are allowed if clinically indicated (e.g., for the treatment 
of deep venous thrombosis), and the benefit outweighs the risk per the 
investigator’s discretion. For management of thromboembolic complications 
while on study, refer to Section 7.  
 Thereapeutic doses of LMWH or the direct factor Xa oral inhibitors rivaroxaban, 
edoxaban, or apixaban are allowed if clinically indicated (e.g., for the treatment of 
DVT), and the benefit outweights the risk per the investigator’s discretion.  
Accepted clinical guidelines regarding appropriate management while receiving anticoagulation 
therapy with heparins must be followed. This includes, but is not limited to, subject education 
regarding potential adverse drug reactions, monitoring laboratory parameters, dose adjustments 
(e.g., due to kidney dysfunction). Caution is warranted in settings associated with an increased 
risk for bleeding such as gastrointestinal cancers, urothelial cancers, gastrointestinal mucosal 
abnormality (e.g., mucositis), renal or hepatic impairment, thrombocytopenia, arterial 
hypertension, or prior history of gastrointestinal bleed. For direct factor Xa inhibitors, the 
potential for drug-drug interaction with other concomitant medications, as well as 
gastrointestinal absorption, should be considered. Aspirin and other nonsteroidal anti-
inflammatory drugs (NSAIDs) should not be used concomitantly with heparin or factor Xa 
inhibitors due to the increased risk for bleeding complications. The risks and benefits of the use 
of anticoagulants should be reassessed on a regular basis. For more information regarding the use 
of anticoagulants, refer to the prescribing information of the anticoagulant and accepted clinical 
practice guidelines. 
• Potential drug interactions with cabozantinib are summarized in Section 6.8.5. 
 Prohibited or Restricted Therapy 
The following therapies are prohibited until study treatment has been permanently 
discontinued: 
• Any investigational agent or investigational medical device. 
• Oral anticoagulation with coumarin agents (e.g., warfarin), direct thrombin inhibitors 
(e.g., dabigatran), direct factor Xa inhibitor betrixaban, platelet inhibitors (e.g., 
clopidogrel), and chronic use of aspirin above low-dose levels for cardio protection per 
local applicable guidelines), until 4 weeks after cabozantinib has been permanently 
discontinued.  


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• Any nonprotocol systemic anticancer treatment (e.g., chemotherapy, immunotherapy, 
radionuclides, drugs or herbal products used specifically for the treatment of the cancer 
under investigation). 
The following therapies should be avoided until study treatment has been permanently 
discontinued or until otherwise specified: 
• Local anticancer treatment including palliative radiation, ablation, embolization, or 
surgery with impact on tumor lesions should not be performed on the RECIST v1.1 
measurable lesions. Initiation of local anticancer therapy (e.g., palliative radiation) will  
be considered as progression of disease. 
• Erythropoietic stimulating agents (e.g., epoetin alfa and darbepoetin alfa) should not be 
used based on a report of increased risk of tumor recurrence/progression associated with 
erythropoietin. 
• Concomitant medications that are known to prolong the QTc interval should be avoided 
in subjects who receive cabozantinib until they have permanently discontinued study 
treatment (refer to http://www.qtdrugs.org for a list of drugs which have the potential to 
prolong the QTc interval). 
• Chronic co-administration of cabozantinib with strong inducers of the CYP3A4 family 
(e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. 
John’s Wort) may significantly decrease cabozantinib concentrations and should be 
avoided. Selection of alternate concomitant medications with no or minimal CYP3A4 
enzyme induction potential is recommended.  
• Caution must be used when discontinuing treatment with a strong CYP3A4 inducer in a 
subject who has been concurrently receiving a stable dose of cabozantinib, as this could 
significantly increase the exposure to cabozantinib.  
• Co-administration of cabozantinib with strong inhibitors of the CYP3A4 family (e.g., 
boceprevir, conivaptan, posaconazole, ketoconazole, itraconazole, clarithromycin, 
atazanavir, indinavir, nefazodone, nelfinavir, saquinavir, ritonavir, lopinavir, telaprevir, 
telithromycin, and voriconazole) may increase cabozantinib concentrations and should be 
avoided. Grapefruit, star fruit, and Seville oranges, and their products may also increase 
plasma concentrations of cabozantinib and should be avoided. 
• Additional information on potential drug interactions with cabozantinib is provided in 
Section 6.8.5. 
 Potential Drug Interactions with Cabozantinib 
Cytochrome P450: Data from a clinical drug interaction study (Study XL184 008) show that 
clinically relevant steady state concentrations of cabozantinib appear to have no marked 
effect on the area under the plasma concentration-vs-time curve (AUC) of co administered 
rosiglitazone, a CYP2C8 substrate. Therefore, cabozantinib is not anticipated to markedly 
inhibit CYP2C8 in the clinic, and by inference, is not anticipated to markedly inhibit other 
CYP450 isozymes that have lower [I]/Ki values compared to CYP2C8 (i.e., CYP2C9, 
CYP2C19, CYP2D6, CYP1A2, and CYP3A4). In vitro data indicate that cabozantinib is 


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unlikely to induce cytochrome P450 enzymes, except for possible induction of CYP1A1 at 
high cabozantinib concentrations (30 μM).  
Cabozantinib is a CYP3A4 substrate and a weak substrate for CYP2C9 (but not a CYP2D6, 
CYP2C8, CYP2C19, CYP2B6, or CYP1A2 substrate), based on data from in vitro studies. 
Results from a clinical pharmacology study, XL184 006, showed that concurrent 
administration of cabozantinib with the strong CYP3A4 inducer, rifampin, resulted in an 
approximately 77% reduction in cabozantinib exposure (AUC values) after a single dose of 
cabozantinib in healthy volunteers. Chronic co-administration of cabozantinib with strong 
inducers of the CYP3A4 family (e.g., phenytoin, carbamazepine, rifampin, rifabutin, 
rifapentine, phenobarbital, and St. John’s Wort) may significantly decrease cabozantinib 
concentrations. The chronic use of strong CYP3A4 inducers should be avoided. Other drugs 
that induce CYP3A4 should be used with caution because these drugs have the potential to 
decrease exposure (AUC) to cabozantinib. Selection of alternate concomitant medications 
with no or minimal CYP3A4 enzyme induction potential is recommended.  
Results from a clinical pharmacology study, XL184 007, showed that concurrent 
administration of cabozantinib with the strong CYP3A4 inhibitor, ketoconazole, resulted in a 
38% increase in the cabozantinib exposure (AUC values) after a single dose of cabozantinib 
in healthy volunteers. Co-administration of cabozantinib with strong inhibitors of the 
CYP3A4 family (e.g., boceprevir, conivaptan, posaconazole, ketoconazole, itraconazole, 
clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, saquinavir, ritonavir, lopinavir, 
telaprevir, telithromycin, and voriconazole) may increase cabozantinib concentrations. 
Grapefruit, star fruit and Seville oranges, and their products may also increase plasma 
concentrations of cabozantinib and are prohibited. Strong CYP3A4 inhibitors should be 
avoided and other drugs that inhibit CYP3A4 should be used with caution because these 
drugs have the potential to increase exposure (AUC) to cabozantinib. Selection of alternate 
concomitant medications with no or minimal CYP3A4 enzyme inhibition potential is 
recommended.  
Please refer to the drug interaction tables at the following websites for lists of substrates, 
inducers, and inhibitors of selected CYP450 isozyme pathways: 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx OR http://www.fda.gov/Drugs/ 
DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm08049
9.htm).  
Protein Binding: Cabozantinib is highly bound (≥ 99.7%) to human plasma proteins. 
Therefore, highly protein bound drugs should be used with caution with cabozantinib 
because there is a potential displacement interaction that could increase free concentrations 
of cabozantinib and/or a co-administered highly protein bound drug (and a corresponding 
increase in pharmacologic effect). 
Other Interactions: Food may increase exposure levels of cabozantinib by 57%, fasting 
recommendations should be followed. In vitro data suggest that cabozantinib is unlikely to be 
a substrate for P-glycoprotein, but it does appear to have the potential to inhibit the P-
glycoprotein transport activity. Therefore, cabozantinib may have the potential to increase 
plasma concentrations of co-administered substrates of P-glycoprotein. Additional details 
related to these overall conclusions can be found in the Investigator’s Brochure. 


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Administration of the proton pump inhibitor (PPI) esomeprazole resulted in no clinically-
relevant effect on cabozantinib plasma PK in healthy volunteers. Therefore, concomitant use 
of gastric pH modifying agents (i.e., PPIs, H2 receptor antagonists, and antacids) is not 
contraindicated in subjects administered cabozantinib. 
Additional details regarding potential drug interactions with cabozantinib can be found in the 
investigator brochure. 
Cabozantinib was shown to be a substrate of drug transporter MRP2 in an in vitro assay. 
Administration of MRP2 inhibitors to subjects may result in increases in cabozantinib plasma 
concentrations. 
Table 6.2: Clinically Significant Interactions Involving Drugs that Affect Cabozantinib 
Strong CYP3A4 Inhibitors 
Clinical Implications: • Concomitant use of cabozantinib with a strong CYP3A4 
inhibitor increased the exposure of cabozantinib 
compared to the use of cabozantinib alone  
• Increased cabozantinib exposure may increase the risk of 
exposure-related toxicity. 
Prevention or 
Management: 
Reduce the dosage of cabozantinib if concomitant use with 
strong CYP3A4 inhibitors cannot be avoided  
Examples: 
Boceprevir, clarithromycin, conivaptan, grapefruit juicea, 
indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, 
nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, 
telithromycin, and voriconazole 
Strong CYP3A4 Inducers 
Clinical Implications: 
• Concomitant use of cabozantinib with a strong 
CYP3A4 inducer decreased the exposure of 
cabozantinib compared to the use of cabozantinib alone  
• Decreased cabozantinib exposure may lead to reduced 
efficacy. 
Prevention or 
Management: 
Increase the dosage of cabozantinib if concomitant use 
with strong CYP3A4 inducers cannot be avoided  
Examples: 
Rifampin, phenytoin, carbamazepine, phenobarbital, 
rifabutin, rifapentine, and St. John’s Wortb 
a. The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-
dependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain 
preparation was used (e.g., high dose, double strength) or as a “moderate CYP3A inhibitor” when another 
preparation was used (e.g., low dose, single strength). 
b. The effect of St. John’s Wort varies widely and is preparation-dependent and is prohibited.  
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 


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6.9 
Duration of Therapy 
Subjects enrolled after Amendment 7 (version date 08NOV2021) will remain on study 
treatment for up to 12 months. After consultation with PI, subjects enrolled prior to 
Amendment 7 (version date 08NOV2021) who have demonstrated a response to study 
treatment may continue beyond 12 months of treatment, if there is demonstrated continued 
clinical benefit. 
Study treatment may continue beyond initial radiographic or clinical disease progression for 
up to 12 months as long as the patient is deriving clinical benefit from the treatment, as 
assessed by the investigator. 
Subjects must be withdrawn from the study treatment for the following reasons:  
• Subject withdraws consent from the study treatment and/or study procedures. A subject 
must be removed from the trial at his/her own request or at the request of his/her legally 
acceptable representative. At any time during the trial and without giving reasons, a 
subject may decline to participate further. The subject will not suffer any disadvantage as 
a result. 
• Radiographic disease progression by RECIST v1.1 (progression must be confirmed with 
follow up scan no less than 4 weeks and no more than 8 weeks after the first scan shows 
disease progression). Study treatment may continue beyond initial radiographic disease 
progression as long as the patient is deriving clinical benefit from the treatment, as 
assessed by the investigator.   
• Progressive disease (PD), without clinical benefit, as determined by the investigator. 
• Specific conditions described in the Management of Adverse Events Section 7. 
• An AE or intercurrent illness that in the opinion of the investigator warrants the subject’s 
withdrawal from study treatment. 
• Subject is lost to follow-up. 
• Necessity for treatment with other treatment prohibited by protocol. 
• Sexually active subjects who refuse to use medically accepted barrier methods of 
contraception (e.g., male condom, female condom) during the course of the study and for 
120 days after discontinuation of study treatment. 
• Women who become pregnant or are breastfeeding. 
• If the subject does not recover from his or her toxicities to tolerable Grade ≤ 2 within 6 
weeks, the subject will have study treatment discontinued unless there is unequivocal 
evidence that the subject is benefitting. In this situation, a subject may be able to restart 
therapy with a dose reduction upon resolution of the toxicity. 
• Request by regulatory agencies for termination of treatment of an individual subject or all 
subjects under the protocol. 
• Significant noncompliance with the protocol schedule in the opinion of the investigator. 


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• The starting dose of Cabozantinib study treatment will be 40 mg once daily (qd), (with 
dose reduction allowed for documented adverse events to 20 mg daily, and then to 20 mg 
every other day to improve tolerability.)  
 
Subjects may be withdrawn from the study for the following reasons:  
• The subject is non-compliant with study drug, trial procedures, or both; including the use 
of anti-cancer therapy not prescribed by the study protocol. 
• If, in the investigator's opinion, continuation of the trial would be harmful to the subject's 
well-being. 
• Development of an intercurrent illness or situation which would, in the judgment of the 
investigator, significantly affect assessments of clinical status and trial endpoints. 
• Deterioration of ECOG performance status to 4. 
7 TOXICITIES AND DOSEAGE MODIFICATION 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) 
Version 5.0 for adverse event and serious adverse event reporting. 
7.1 
Dose Modifications and Guidelines for Adverse Event Management for 
Cabozantinib 
Subjects will be monitored for AEs from the start of treatment through 30 days after the date 
of the last dose of cabozantinib treatment. Subjects will be instructed to notify their physician 
immediately at the onset of any AE. Causality assessment of AEs will be determined by the 
investigator. AE severity will be graded by the investigator in accordance with CTCAE v.5.0. 
The following should be taken into consideration in decisions regarding dose modifications 
(reductions or interruption): 
• As a general approach, all AEs should be managed with supportive care at the earliest 
signs of toxicity considered related to the study treatment. Should this be ineffective, 
dose interruptions and/or reductions should be considered to prevent worsening of 
toxicity. 
• The assigned starting dose for cabozantinib is 40 mg/day. Dose reductions are permitted 
per PI discretion (see Table 7.1). Dose re--escalation level (See 7.2) of cabozantinib is 
permitted. 
• Dose interruptions and/or reductions should be implemented for unacceptable toxicity. 
Doses may be modified at any time while on study. 
• Interruption of cabozantinib treatment for AEs may occur at any time per investigator 
discretion. If treatment is interrupted due to AEs for more than 6 weeks, all study 
treatment should be 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. 


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• Dose interruptions for reason(s) other than related AEs (e.g., surgical procedures) can be 
longer than 6 weeks per the discretion of the investigator. 
Table 7.1 
Assigned dose 
Dose Level Reduction 
40-mg cabozantinib oral, qd 
20-mg cabozantinib oral, qd. 
20-mg cabozantinib oral, qd 
20-mg cabozantinib oral, qad  
 
Table 7.2 
Assigned dose 
Dose Level Escalation 
20-mg cabozantinib, oral qad 
20-mg cabozantinib, oral qd 
20-mg cabozantinib, oral qd 
40-mg cabozantinib, oral qd 
Table 7.3: Dose Modifications of Cabozantinib for Treatment-Related AEs 
CTCAE v.5.0 Grade 
Recommended Guidelines for Managementa 
Grade 1 AEs 
Add supportive care as indicated. Continue cabozantinib treatment 
at the current dose level if AE is manageable and tolerable. 
Grade 2 AEs that are 
tolerable and are easily 
managed 
 
Grade 2 AEs that are 
intolerable and cannot be 
adequately managed  
Continue cabozantinib treatment at the current dose level with 
supportive care. 
 
At the discretion of the investigator, cabozantinib should be dose 
reduced or interrupted. 
Note: It is recommended that dose holds be as brief as possible.  
Grade 3 AEs (except 
clinically non-relevant 
laboratory abnormalities) 
Cabozantinib should be interrupted unless the toxicity can be easily 
managed with a dose reduction and optimal medical care.  
Note: It is recommended that dose holds be as brief as possible. 
Grade 4 AEs (except 
clinically non-relevant 
laboratory abnormalities) 
Subjects should have cabozantinib interrupted immediately.  
Permanently discontinue all study treatment unless the following 
criteria are met:  
• 
Subject is deriving clear clinical benefit as determined by 
the investigator 
• 
Toxicity can be managed with a dose reduction following 
recovery to Grade 1 (or baseline) and optimal medical care  
Note: The dose delay and modification criteria for specific medical conditions are provided in Section 7.1.1. 
For re-treatment criteria of study treatment after a dose hold see Section 7.1.1. 
a Study treatment dose adjustment is only needed if the toxicity was deemed related to cabozantinib 
treatment or had an unclear relationship to cabozantinib treatment. 
 Guidelines for Management of Potential Adverse Events for Cabozantinib 
Management of severe or intolerable adverse reactions may require temporary dose reduction 
and/or interruption for cabozantinib.  
All study treatment should be permanently discontinued for the following AEs: visceral 
perforation or fistula formation, severe hemorrhage, serious arterial thromboembolic events, 


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nephrotic syndrome, hypertensive emergency, persistent uncontrolled hypertension despite 
optimal medical management, and reversible posterior leukoencephalopathy syndrome 
(RPLS). 
Gastrointestinal perforation, GI fistula, and intra-abdominal and pelvic abscess: After 
starting treatment with cabozantinib, subjects should be monitored for early signs of GI 
perforation such as abdominal pain, nausea, emesis, constipation, and fever especially if 
known risk factors for developing GI perforation or fistula are present.  
Permanently discontinue all study treatment and initiate appropriate management in subjects 
who have been diagnosed with GI perforation or fistula. 
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. 
Guidelines for the evaluation and management of diarrhea are shown in Table 7.4. 
Administration of antidiarrheal/antimotility agents is recommended at the first sign of 
diarrhea as initial management. Some subjects may require concomitant treatment with more 
than one antidiarrheal agent. When therapy with antidiarrheal agents does not control the 
diarrhea to tolerable levels, cabozantinib should be temporarily interrupted or dose reduced. 
When the diarrhea is controlled, retreatment with cabozantinib may be acceptable per 
investigator decision. In addition, general supportive measures should be implemented such 
as continuous oral isotonic hydration, correction of fluid and electrolyte abnormalities, small 
frequent meals, and stopping lactose-containing products, high-fat meals, and alcohol. 
Recurrent or prolonged diarrhea can be associated with anal or perianal skin erosions which 
increase the risk for anal abscesses, fistulas, or proctitis. Good personal hygiene should be 
emphasized. Regular examinations of the perianal region should be performed whenever 
diarrhea has occurred during treatment with cabozantinib. Infections of the perianal region 
should be treated per local guidelines. 
Table 7.4:  
Management of Diarrhea Associated with Cabozantinib 
Status 
Management 
Tolerable Grade 1-2 
(duration < 48 h) 
• Continue with study treatment and consider dose reduction 
• Initiate treatment with an antidiarrheal agent (e.g., loperamide 4 mg followed by 
2 mg after each episode of diarrhea [maximum: 16 mg loperamide per day]) 
• Dietary modifications (e.g., small lactose-free meals, bananas, and rice) 
• Intake of isotonic fluids (1-1.5 L/day) 
• Re-assess after 24 hours: 
o Diarrhea resolving to baseline bowel habits: gradually add solid foods and 
permanently discontinue or decrease antidiarrheal treatment after 12 h 
diarrhea-free interval 
o Diarrhea not resolving: Continue/resume antidiarrheal treatment  
Intolerable Grade 2, 
Grade 2 > 48 h,  
or ≥ Grade 3 
• Interrupt study treatment 
• Ask subject to attend clinic 
• Rule out infection (e.g., stool sample for culture) 
o Administer antibiotics as needed (e.g., if fever or Grade 3-4 neutropenia 
persists > 24 h) 
• Administer fluids (1-1.5 L/day orally or IV, as appropriate) for hydration or to 
correct electrolyte abnormalities 


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• For Grade 3-4 or complicated lower grade diarrhea consider hospitalization and 
IV hydration 
• Re-assess after 24 h 
o Diarrhea resolving to baseline bowel habits or Grade ≤ 1: consider restarting 
study treatment at reduced dose 
o Diarrhea not resolving: Start and or continue antidiarrheal treatment (e.g., 
loperamide 4 mg followed by 2 mg after each episode of diarrhea 
[maximum: 16 mg loperamide per day]). Consider starting second line 
antidiarrheal or referral to gastroenterologist 
Nausea and vomiting: Antiemetic agents are recommended as clinically appropriate for 
treatment or prophylaxis of nausea and vomiting, along with supportive care. Dehydration 
and electrolyte abnormalities may be associated with vomiting and monitoring for and 
correction of fluid and electrolyte disturbances should be implemented. Antiemetic 
medications should be assessed for potential drug interactions (refer to Section 6.8.5). 
Non-Gastrointestinal Fistula: Complications from radiation therapy especially of the 
thoracic cavity including mediastinum have been identified as a possible predisposing risk 
factor for non-GI fistula formation in subjects undergoing treatment with VEGF pathway 
inhibitors.  
Permanently discontinue all study treatment and initiate appropriate management in subjects 
who have been diagnosed with a non GI fistula. 
Hemorrhage: Hemorrhagic events, including serious and sometimes fatal events, have been 
reported with cabozantinib. Subjects should be monitored for bleeding events with serial 
complete blood counts and physical examination while on study. The risk of hemorrhage in 
cabozantinib-treated subjects with brain metastases has not been thoroughly analyzed. 
Subjects enrolled with treated and stable brain metastases should be monitored with a high 
index of suspicion if symptoms that could be due to a CNS hemorrhage occur. 
All study treatment should be permanently discontinued in subjects with serious and life-
threatening bleeding events or recent hemoptysis (≥ 2.5 mL of red blood). 
Thromboembolic events: Thromboembolic events are frequent in cancer subjects due to 
procoagulant changes induced by the malignancy or anticancer therapy. DVT and pulmonary 
embolism have been observed in clinical studies with cabozantinib, including fatal events. 
Subjects who develop a pulmonary embolism and/or DVT should have study treatment 
interrupted until therapeutic anticoagulation is established. Treatment with cabozantinib may 
be resumed in subjects with pulmonary embolism or DVT if it is determined that the event is 
uncomplicated and that the subject is deriving clinical benefit from cabozantinib treatment 
and that the anticoagulation does not place them at a significant risk that outweighs the 
benefit of resuming treatment per discretion of the investigator and according to individual 
protocols. Therapeutic doses of LMWH or the direct factor Xa oral inhibitors rivoroxaban, 
edoxaban, or apixaban are allowed for the management of thrombotic events. Other oral 
anticoagulants including coumarin agents (e.g., warfarin), platelet inhibitors (e.g., 
clopidogrel), and chronic use of aspirin above low dose levels for cardio protection per local 
applicable guidelines are not allowed, until 4 weeks ater cabozantinib has been permanently 
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Arterial thrombotic events (e.g., TIA, MI) have been observed in studies with cabozantinib. 
Subjects should be evaluated for pre-existing risk factors for arterial thrombotic events such 
as diabetes mellitus, hyperlipidemia, hypertension, coronary artery disease, history of 
tobacco use, and cardiac and/or thromboembolic events that occurred prior to initiation of 
study treatment. Further treatment with cabozantinib should be discontinued in subjects who 
develop an acute MI, cerebral infarction, or any other clinically significant arterial 
thromboembolic complication. 
Hypertension: Table 7.5 provides treatment guidelines for hypertension deemed related to 
cabozantinib. Blood pressure should be monitored in a constant position visit to visit, either 
sitting or supine in a relaxed setting. Decisions to reduce or interrupt 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.  
All study treatment should be permanently discontinued in subjects with hypertensive 
emergency. 
Table 7.5: Management of Hypertension Associated with Cabozantinib 
Criteria for Dose Modifications 
Treatment/Cabozantinib Dose Modification 
Subjects NOT receiving optimized anti-hypertensive therapy 
> 150 mm Hg (systolic)a and < 160 mm 
Hg 
OR 
> 100 mm Hg (diastolic) and < 110 mm 
Hg 
 
• 
Optimize antihypertensive medications by adding new or 
additional antihypertensive medications and/or increase 
dose of existing medications. 
• 
Reduce cabozantinib treatment by one dose level if optimal 
antihypertensive therapy (usually to include 3 agents) does 
not result in BP <150 mm Hg systolic or <100 mm Hg 
diastolic 
• 
If subject is symptomatic interrupt cabozantinib treatment 
≥ 160 mm Hg (systolic) 
OR 
≥ 110 mm Hg (diastolic) 
• 
Reduce cabozantinib by one dose levelb or interrupt 
cabozantinib treatment per investigator discretion 
• 
Add new or additional anti-hypertensive medications and/or 
increase dose of existing medications and monitor subject 
closely for hypotension. If optimized antihypertensive 
therapy (usually to include 3 agents) does not result in BP < 
150 mm Hg systolic or < 100 mm Hg diastolic, cabozantinib 
treatment should be interrupted 
• 
Cabozantinib treatment should be dose interrupted if upper 
limits of systolic BP (≥ 160 mm Hg) are sustained and not 
adequately manageable or if systolic BP is > 180 mm Hg or 
diastolic BP > 110 mm Hg, or if subject is symptomatic 
• Re-start cabozantinib treatment at the most tolerable dose and 
re-escalate only if BP falls to and is sustained at < 150 mm 
Hg systolic and < 100 mm Hg diastolic 
Hypertensive emergencyc 
• 
Decide to initiate or adjust antihypertensive. Permanently 
discontinue all study treatment 
a The investigator may approve treatment at a lower threshold than systolic BP >150 or diastolic BP >100 based on their 
clinical judgment and assessment of the individual subject. 
b Permitted dose levels are defined by individual protocols and PI discretion. 
c Hypertensive emergency is defined as uncontrolled elevated BP with clinical evidence of progressive or impending 
end-organ damage (e.g., myocardial infarction/ischemia, intracranial hemorrhage, cerebral ischemia, pulmonary 
edema, encephalopathy, kidney damage). 


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Stomatitis and Mucositis: Preventive measures may include a comprehensive oral 
examination to identify and treat any potential risk for complications before study treatment 
is initiated. Appropriate correction of local factors should be instituted as indicated, such as 
modification of ill-fitting dentures and appropriate care of gingivitis. During treatment with 
cabozantinib, good oral hygiene and standard local treatments such as non-traumatic and 
non-irritating cleansing, and oral rinses (e.g., with a weak solution of salt and baking soda) 
should be maintained. Lips should be kept moisturized with lip balm. The use of lipstick, lip-
gloss, and Vaseline should be avoided. 
Local treatment should be instituted at the earliest onset of symptoms. Obtain bacterial/viral 
culture if oral infection is suspected and treat infection as clinically indicated.  
Skin and Subcutaneous Tissue Disorders: Wound healing and surgery: Cabozantinib has the 
potential to cause wound healing complications and wound dehiscence, which may even 
occur long after a wound has been considered healed. Therefore, surgical and traumatic 
wounds must not only be completely healed prior to starting cabozantinib treatment but must 
also be monitored for wound dehiscence, wound infection, and other signs of impaired 
wound healing while the subject is being treated with cabozantinib. If dehiscence occurs, 
cabozantinib treatment should not be restarted until complete healing has taken place.  
Treatment with cabozantinib should be stopped at least 28 days prior to scheduled surgery. 
The decision to resume treatment with cabozantinib after surgery should be based on clinical 
judgment of adequate wound healing. 
Palmar-plantar erythrodysesthesia syndrome (PPES; 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 with cabozantinib. All subjects on study should be advised on 
prophylactic measures including the use of emollients, 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. 
Early manifestations include tingling, numbness, mild hyperkeratosis, and 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. 
Analgesics may be required for pain control. 
Aggressive management of symptoms is recommended, including early dermatology referral. 
Treatment recommendations in response to PPES are summarized in Table 7.6. 
Table 7.6: Management of Hand-Foot Syndrome (PPES) Associated with Cabozantinib 
CTCAE v.5.0 Grade  
Action To Be Taken  
Grade 1 
Cabozantinib treatment may be continued at the current dose if PPES is clinically 
insignificant and tolerable. Otherwise, cabozantinib should be reduced to the next 
lower dose level.a Start urea 20% cream twice daily AND clobetasol 0.05% 
cream once daily. Reassess at least weekly; if PPES worsens at any time or does 
not improve after 2 weeks, proceed to the intervention guidelines for Grade 2. 


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Grade 2  
Cabozantinib treatment may be continued if PPES is tolerated. Cabozantinib 
should be dose reduced or interrupted if PPES is intolerable. Continue urea 20% 
cream twice daily AND high potency steroid cream (e.g., clobetasol 0.05%) once 
daily and add analgesics (e.g., NSAIDs/gamma-aminobutyric acid agonists) for 
pain control if needed. Reassess at least weekly; if PPES worsens or affects 
self-care, proceed to the intervention guidelines for Grade 3. 
Grade 3 
Interrupt cabozantinib treatment until severity decreases to Grade 1 or 0. 
Continue treatment of skin reaction with high potency steroid cream (e.g., 
clobetasol 0.05%) twice daily AND analgesics. Resume study drug at a reduced 
dose if PPES recovers to Grade ≤ 1. Permanently discontinue subject from study 
treatment if PPES does not improve within 6 weeks. 
CTCAE, Common Terminology Criteria for Adverse Events; NSAID, non-steroidal anti-inflammatory drug; 
PPES, palmar plantar erythrodysesthesia syndrome. 
a Permitted dose levels are defined by individual protocols. 
Osteonecrosis: Osteonecrosis has been reported in subjects treated with cabozantinib. 
Additional risk factors include use of bisphosphonates and denosumab, chemotherapy and 
anti-angiogenic drugs, use of corticosteroids, local radiotherapy, and dental or orofacial 
surgery procedures.  
Osteonecrosis of the jaw (ONJ) can manifest as jaw pain, osteomyelitis, osteitis, bone 
erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. 
Persistent pain or slow healing of the mouth or jaw after dental surgery may also be 
manifestations of osteonecrosis. 
Advise subjects regarding oral hygiene practice and to quickly report symptoms to 
investigator. Caution should be used in subjects receiving bisphosphonates. 
Invasive dental procedures should be avoided. In cases where dental procedures are 
unavoidable, treatment with cabozantinib should be interrupted for at least 4 weeks prior to 
the procedure and resumed after complete wound healing has occurred. Bone healing may 
often require a protracted time. 
Proteinuria: Proteinuria has been reported with cabozantinib. Proteinuria should be 
monitored by measuring UPCR. Table 7.7 provides treatment guidelines for proteinuria 
deemed related to cabozantinib.  
All study treatment should be permanently discontinued in subjects who develop nephrotic 
syndrome (proteinuria > 3.5 grams per day in combination with low blood protein levels, 
high cholesterol levels, high triglyceride levels, and edema).  
Table 7.7: Management of Proteinuria Associated with Cabozantinib 
Severity of Proteinuria 
(UPCR) 
Management of Proteinuria 
≤ 1 mg/mg 
(≤ 113.1 mg/mmol) 
• 
No change in cabozantinib treatment or monitoring 


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> 1 and < 3.5 mg/mg 
(> 113.1 and < 395.9 
mg/mmol) 
 
 
• 
Consider confirming with a 24-h protein assessment within 7 days 
• 
No change in cabozantinib treatment required if UPCR ≤ 2 mg/mg or 
urine protein ≤ 2 g/24 h on 24-h urine collection. 
• 
Dose reduce or interrupt cabozantinib treatment if UPCR > 2 mg/mg on 
repeat UPCR testing or urine protein > 2 g/24 h on 24-h urine collection. 
Continue cabozantinib on a reduced dose if UPCR decreases to < 2 
mg/mg. Consider interrupting cabozantinib treatment if UPCR remains > 
2 mg/mg despite a dose reduction until UPCR decreases to < 2 mg/mg. 
Restart cabozantinib treatment at a reduced dose after a dose 
interruption. 
• 
Repeat UPCR within 7 days and once per week. If UPCR < 1 mg/mg on 
2 consecutive readings, UPCR monitoring can revert to protocol-specific 
times. (Second reading is confirmatory and can be done within 1 week 
of first reading.) If UPCR remains > 1 mg/mg and < 2 mg/mg for 1 
month or is determined to be stable (< 20% change) for 1 month, check 
urine protein/creatinine per protocol or as clinically indicated. 
≥ 3.5 mg/mg 
(≥ 395.9 mg/mmol) 
• 
Interrupt cabozantinib treatment pending repeat UPCR within 7 days 
and/or 24-h urine protein.  
• 
If ≥ 3.5 mg/mg on repeat UPCR, continue to interrupt cabozantinib 
treatment and check UPCR every 7 days. If UPCR decreases to < 2 
mg/mg, restart cabozantinib treatment at a reduced dose and monitoring 
of urine protein/creatinine should continue weekly until the UPCR 
decreases to < 1 mg/mg. If UPCR remains > 1 mg/mg and < 2 mg/mg 
for 1 month or is determined to be stable (< 20% change) for 1 month, 
check urine protein/creatinine per protocol or as clinically indicated. 
Nephrotic syndrome 
• 
Permanently discontinue all study treatment 
RCC, renal cell carcinoma; UC, urothelial carcinoma; UPCR, urine protein/creatinine ratio. 
Nervous System Disorders: Cabozantinib appears to represent minimal risk of adverse 
neurological effects based on nonclinical Good Laboratory Practice (GLP)-compliant 
toxicology studies. Dysphonia, dysgeusia, headache, dizziness, confusional state, convulsion, 
depression, memory impairment, hypoesthesia, peripheral neuropathy, insomnia, ataxia, and 
encephalopathy have been observed in clinical studies with cabozantinib. The development 
of any new or progressive, unexplained neurological symptoms should be assessed for 
underlying causes. 
RPLS has been reported. RPLS should be considered in any subject presenting with seizures, 
headache, visual disturbances, confusion or altered mental function. All study treatment 
should be permanently discontinued in subjects with RPLS. 
Hepatocellular Toxicity: Investigators should monitor for DILI diligently and report any 
potential events.  
Elevation of aminotransferases (ALT and AST) and bilirubin have been observed during 
treatment with cabozantinib. It is recommended that subjects with elevations of ALT, AST, 
and/or bilirubin have more frequent laboratory monitoring of these parameters. If possible, 


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hepatotoxic concomitant medications should be discontinued in subjects who develop 
increased values of ALT, AST, or bilirubin, and other potential causes for these increases 
(e.g., cancer-related infection) should be evaluated. Management guidance for hepatoxocity 
related to cabozantinib is provided in Table 7.8.  
 
Table 7.8: Management of Liver Function Laboratory Abnormalities Related to Cabozantinib 
 
Severity of ALT, AST, Total Bilirubin Elevations by 
CTCAE v.5.0  
 
Treatment Dose Modification  
Grade 1  
 
• Dose adjustment is usually not required.  
• Consider discontinuing concomitant hepatotoxic 
medications and add supportive care as indicated.  
 
Grade 2  
 
• Interrupt study treatment if lasting longer than 1 week 
and consider more frequent monitoring of ALT, AST, 
and bilirubin.  
• Restart study treatment after lab abnormalities have 
resolved to at least CTCAE Grade ≤ 1 or baseline.  
 
Grade ≥ 3  
 
• Interrupt study treatment and consider more frequent 
monitoring of ALT, AST, and bilirubin.  
• Restart study treatment at a reduced dose after lab 
abnormalities have resolved to at least CTCAE Grade 
≤ 1 or baseline.  
• Discontinue if lab abnormalities cannot be reversed 
despite interruption of study treatment.  
• Discontinue if drug-related ALT or AST>3 X ULN in 
combination with total bilirubin >2 X ULN without 
other reasonable explanation, consistent with drug-
induced liver injury (DILI). 
 
ALT, alanine aminotransferase; AST, aspartate aminotransferase; CTCAE v.5.0, Common Terminology Criteria for Adverse 
Events version 4 
Elevations of aminotransferases when hepatic metastases are present may not require dose 
modifications if there are no progressive changes in the aminotransferases (less than a 
doubling) and if there are no progressive elevations in serum bilirubin concentration or 
coagulation factors.  
The following condition requires discontinuation of cabozantinib:  
Drug-related ALT or AST >3 × ULN in combination with total bilirubin >2 × ULN without 
other reasonable explanation, consistent with drug-induced liver injury (DILI).  
Infections and Infestations: Infections are commonly observed in cancer subjects. 
Predisposing risk factor include a decreased immune status (e.g., after myelosuppressive 
anticancer therapies, splenectomy), destructive growth of the underlying malignancy 


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including bone marrow infiltration with suppression of normal hematopoiesis, as well as the 
presence of IV devices.  
Infections and abscesses should be treated with appropriate local care and systemic therapy. 
Cabozantinib should be interrupted until adequate healing has taken place. 
Blood and Lymphatic System Disorders: Hematological toxicities (i.e., neutropenia and 
thrombocytopenia) and associated complications have been observed after administration of 
cabozantinib and may be managed with dose interruptions and/or dose reductions. Subjects 
with hematologic toxicities may require additional or more frequent laboratory tests 
according to institutional guidelines. 
Dose reductions or dose interruptions for hematological toxicities are not mandated but can 
be applied as clinically indicated. Supportive care for thrombocytopenia or anemia, such as 
transfusions, may be managed according to institutional guidelines. The use of colony-
stimulating growth factors should be considered. Febrile neutropenia or evidence of infection 
associated with neutropenia must be assessed immediately and treated appropriately and in a 
timely manner according to institutional guidelines. 
Fatigue: Common causes of fatigue, such as anemia, deconditioning, emotional distress 
(depression and/or anxiety), poor nutrition, dehydration, sleep disturbance, and 
hypothyroidism should be ruled out and treated according to standard of care. 
Pharmacological management should be considered after disease specific morbidities have 
been excluded when not prohibited.  
Weight Loss: Anorexia and weight loss should be managed according to local standard of 
care including nutritional support. Pharmacologic therapy should be considered for appetite 
enhancement when not prohibited by a particular protocol. 
Corrected QT Prolongation: The effect of orally administered cabozantinib 140 mg qd on 
QTc interval was evaluated in a placebo-controlled study in subjects with MTC. A mean 
increase in QTcF of 10-15 ms was observed after 4 weeks after initiating cabozantinib 
treatment. A concentration-QTc relationship could not be definitively established. Changes in 
cardiac wave form morphology or new rhythms were not observed. No cabozantinib-treated 
subjects in this study had a QTcF > 500 ms. Review of the larger safety database (~5000 
subjects exposed to cabozantinib in clinical trials and in post-marketing experience) 
confirmed the absence of safety concerns associated with QT prolongation. There were no 
events of torsades de pointes reported. 
Concomitant treatment with strong cytochrome P450 (CYP) 3A4 inhibitors, which may 
increase cabozantinib plasma concentrations, should be avoided.  
If at any time on study there is an increase in QTcF to an absolute value > 500 ms, two 
additional ECGs must be performed with intervals not less than 3 min apart within 30 min 
after the initial ECG. 
If the average QTcF from the three ECGs is > 500 ms, the following actions must be taken: 
• Interrupt cabozantinib treatment. 


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• Hospitalize symptomatic subjects (e.g., with palpitations, dizziness, syncope, 
orthostatic hypotension, a significant ventricular arrhythmia on ECG) for a thorough 
cardiology evaluation and management. 
• Consider cardiology consultation for asymptomatic subjects for evaluation and 
management. 
• Check electrolytes, especially magnesium, potassium, and calcium; correct 
abnormalities as clinically indicated. 
• Check concomitant medications for any medication that may have contributed to QT 
prolongation, and if possible, permanently discontinue these medications 
(http://www.qtdrugs.org). 
• Repeat ECG triplicates hourly until the average QTcF is ≤ 500 msec, or otherwise 
determined by consultation with a cardiologist or appropriate expert. 
Subjects with QTc prolongation and symptoms must be monitored closely until the QTc 
elevation and symptoms have resolved. Cabozantinib treatment may be restarted at a reduced 
dose level if all of the following conditions are met: 
• Symptoms are determined to be unrelated to the QT interval prolongation. 
• The QTcF value > 500 ms is not confirmed.  
• Cabozantinib treatment has been interrupted through a minimum of 1 week following 
the return of the QTcF to ≤ 500 ms. 
• QT prolongation can be unequivocally associated with an event other than 
cabozantinib.  
• Cardiac evaluation confirms that symptoms are the consequence of QT interval 
prolongation. 
• Recurrence of QTcF prolongation after reinitiation of study treatment at a reduced 
dose. 
• Administration and is treatable/has been resolved.  
Following reinitiation of study treatment, ECGs must be repeated weekly for 2 weeks, then 
every 2 weeks for 1 month, then according to the protocol-defined time points. 
All study treatment must be permanently discontinued if either of the following applies: 
Electrolyte Disorders: Serum electrolyte disorders including hyponatremia, hypokalemia, 
hypomagnesemia, and hypophosphatemia have been reported during treatment with 
cabozantinib, and serum electrolyte levels should be monitored frequently while receiving 
cabozantinib. Clinically relevant electrolyte disorders should be managed according to the 
dose modification guidelines. Standard clinical practice guidelines should be used for 
management of electrolyte disorders and may include oral or intravenous replacement.  
Endocrine Disorders: Treatment-emergent elevation of thyroid-stimulating hormone (TSH) 
has been observed with cabozantinib treatment. Currently available data are insufficient to 
determine the mechanism of thyroid function test alterations and its clinical relevance. 
Management of thyroid dysfunction (e.g., symptomatic hypothyroidism) should follow 
accepted clinical practice guidelines. 


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Angioedema: Angioedema should be managed according to standard practice. The subject 
should be observed until symptoms resolve, with particular attention to maintaining an open 
airway. 
7.2 
Dose modification and toxicity management guidelines for pembrolizumab 
Dose modification and toxicity management for immune-related AEs associated with 
Pembrolizumab 
AEs associated with pembrolizumab exposure may represent an immunologic etiology. 
These immune-related AEs (irAEs) may occur shortly after the first dose or several months 
after the last dose of pembrolizumab treatment and may affect more than one body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications. Based on existing clinical trial data, most irAEs were reversible and could be 
managed with interruptions of pembrolizumab, administration of corticosteroids and/or other 
supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology or 
exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin 
biopsy may be included as part of the evaluation. Based on the severity of irAEs, withhold or 
permanently discontinue pembrolizumab and administer corticosteroids. Dose modification 
and toxicity management guidelines for irAEs associated with pembrolizumab are provided 
in Table 7.9. 
Table 7.9: Dose modification and toxicity management guidelines for immune-related 
AEs associated with Pembrolizumab. 
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper 
over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE 
has been reduced to Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be 
permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids 
cannot be reduced to ≤ 10 mg prednisone or equivalent per day within 12 weeks.  
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral 
steroid. Other immunosuppressive treatment should be initiated if irAEs cannot be controlled by 
corticosteroids. 
Immune-
related 
AEs 
Toxicity 
grade or 
conditio
ns 
(CTCA
E v.5.0) 
Action 
taken to 
pembrolizu
mab 
irAE management 
with corticosteroid 
and/or other 
therapies  
Monitor and follow-up  
Pneumoniti
s  
Grade 2 
Withhold  
• Administer 
corticosteroids 
(initial dose of 1-
2mg/kg prednisone 
or equivalent) 
followed by taper 
 
• 
Monitor subjects for signs and 
symptoms of pneumonitis 
• 
Evaluate subjects with suspected 
pneumonitis with radiographic 
imaging and initiate corticosteroid 
treatment 
• 
Add prophylactic antibiotics for 
opportunistic infections 
Grade 3 
or 4, or 
recurrent 
grade 2 
Permanently 
discontinue 


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Diarrhea / 
colitis  
Grade 2 
or 3 
Withhold 
• Administer 
corticosteroids 
(initial dose of 1-
2mg/kg prednisone 
or equivalent) 
followed by taper 
 
• 
Monitor subjects for signs and 
symptoms of enterocolitis (i.e., 
diarrhea, abdominal pain, blood or 
mucus in stool with or without 
fever) and of bowel perforation (i.e., 
peritoneal signs and ileus). 
• 
Subjects with ≥ Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing 
endoscopy to rule out colitis.  
• 
Subjects with diarrhea/colitis should 
be advised to drink liberal quantities 
of clear fluids. If sufficient oral fluid 
intake is not feasible, fluid and 
electrolytes should be substituted via 
IV infusion. 
Grade 4 
Permanently 
discontinue 
AST / ALT 
elevation or 
Increased 
Bilirubin 
Grade 2 
Withhold 
• Administer 
corticosteroids 
(initial dose of 0.5- 
1mg/kg prednisone 
or equivalent) 
followed by taper 
• 
Monitor with liver function tests 
(consider weekly or more frequently 
until liver enzyme value returned to 
baseline or is stable 
Grade 3 
or 4  
Permanently 
discontinue 
• Administer 
corticosteroids 
(initial dose of 1-
2mg/kg prednisone 
or equivalent) 
followed by taper 
Type 1 
diabetes 
mellitus 
(T1DM) or 
Hyperglyce
mia 
 
Newly 
onset 
T1DM 
or  
Grade 3 
or 4 
hypergly
cemia 
associate
d with 
evidence 
of β-cell 
failure 
Withhold 
• Initiate insulin 
replacement 
therapy for subjects 
with T1DM  
• Administer anti-
hyperglycemic in 
subjects with 
hyperglycemia  
 
• 
Monitor subjects for hyperglycemia 
or other signs and symptoms of 
diabetes. 
Hypophysit
is 
Grade 2 
Withhold 
• Administer 
corticosteroids and 
initiate hormonal 
replacements as 
clinically 
indicated.  
 
• 
Monitor for signs and symptoms of 
hypophysitis (including 
hypopituitarism and adrenal 
insufficiency)  
Grade 3 
or 4  
Withhold or 
permanently 
discontinue1  
Hyperthyro
idism  
Grade 2 
Continue  
• Treat with non-
selective beta-
blockers (e.g. 
propranolol) or 
thionamides as 
appropriate  
• 
Monitor for signs and symptoms of 
thyroid disorders.  
 
Grade 3 
or 4  
Withhold or  
Permanently 
discontinue1 


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Hypothyroi
dism 
Grade 2-
4 
Continue  
• Initiate thyroid 
replacement 
hormones (e.g. 
levothyroxine or 
liothyroinine) per 
standard of care 
• 
Monitor for signs and symptoms of 
thyroid disorders.  
 
Serum 
Creatinine 
Increased 
Grade 2 
Withhold  
• Administer 
corticosteroids 
(prednisone 1-
2mg/kg or 
equivalent) 
followed by taper. 
• 
Monitor changes of renal function 
 
Grade 3 
or 4  
Permanently 
discontinue 
All Other 
immune-
related AEs 
Grade 3, 
or 
intolerab
le/ 
persisten
t Grade 
2 
Withhold 
• Based on severity 
of AE administer 
corticosteroids  
• 
Ensure adequate evaluation to 
confirm etiology or exclude other 
causes 
 
Grade 4 
or 
recurrent 
Grade 3  
Permanently 
discontinue 
NOTES:  
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating 
physician.  
2. For subjects with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is 
required, pembrolizumab may be resumed when AE resolves to ≤ Grade 2 and is controlled with 
hormonal replacement therapy or achieved metabolic control (in case of T1DM) 
Pembrolizumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 7.10.  
Table 7.10: Pembrolizumab Infusion Reaction Dose modification and Treatment 
Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at Subsequent 
Dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs 
as medically indicated until the 
subject is deemed medically stable 
in the opinion of the investigator. 
None 


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Grade 2 
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., 
antihistamines, NSAIDs, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs 
Stop Infusion. 
Additional appropriate medical 
therapy may include but is not 
limited to: 
IV fluids 
 Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs 
as medically indicated until the 
subject is deemed medically stable 
in the opinion of the investigator. 
If symptoms resolve within 1 hour 
of stopping drug infusion, the 
infusion may be restarted at 50% 
of the original infusion rate (e.g., 
from 100 mL/hr to 50 mL/hr). 
Otherwise dosing will be held 
until symptoms resolve and the 
subject should be premedicated for 
the next scheduled dose. 
Subjects who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued from 
further study drug treatment 
Subject may be premedicated 1.5h (± 
30 minutes) prior to infusion of 
pembrolizumab with: 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
Acetaminophen 500-1000 mg po (or 
equivalent dose of analgesic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; hospitalization 
indicated for other clinical 
sequelae (e.g., renal 
impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical 
therapy may include but is not 
limited to: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Increase monitoring of vital signs 
as medically indicated until the 
subject is deemed medically stable 
in the opinion of the investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, 
epinephrine should be used 
immediately. 
Subject is permanently 
discontinued from further study 
drug treatment. 
No subsequent dosing 


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Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period 
of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v.5.0 (CTCAE) at 
http://ctep.cancer.gov 
Other allowed dose interruption for pembrolizumab  
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. Subjects should be 
placed back on study therapy within 3 weeks of the scheduled interruption, unless otherwise 
discussed with the study sponsor (principal investigator). The reason for interruption should 
be documented in the patient's study record. Patients with a planned interruption may 
continue on the study with monotherapy of the other agent. Patients may also continue on the 
study with a planned permanent discontinuation of one of the study medications.  
7.3 
Contraception 
Pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.  
For this trial, male subjects will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).  
Female subjects will be considered of non-reproductive potential if they are either:  
(1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) level 
in the postmenopausal range may be used to confirm a post-menopausal state in women not 
using hormonal contraception or hormonal replacement therapy. In the absence of 12 months 
of amenorrhea, a single FSH measurement is insufficient.);  
OR  
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening;  
OR  
(3) has a congenital or acquired condition that prevents childbearing. 
Female and male subjects of reproductive potential must agree to avoid becoming pregnant 
or impregnating a partner, respectively, while receiving study drug and for 120 days after the 
last dose of study drug by complying with one of the following: 
(1) practice abstinence† from heterosexual activity;  
OR  
(2) use (or have their partner use) acceptable contraception during heterosexual activity.  
Acceptable methods of contraception are‡: 
Single method (one of the following is acceptable): 
• Intrauterine device (IUD) 


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• Vasectomy of a female subject’s male partner  
• Contraceptive rod implanted into the skin 
Combination method (requires use of two of the following): 
• Diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
• Cervical cap with spermicide (nulliparous women only)   
• Contraceptive sponge (nulliparous women only)  
• Male condom or female condom (cannot be used together) 
• Hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-
only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous 
contraceptive injection 
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual lifestyle and 
if considered acceptable by local regulatory agencies and ERCs/IRBs. Periodic abstinence 
(e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are 
not acceptable methods of contraception.  
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it 
does not qualify as an acceptable method of contraception for subjects participating at sites in 
this country/region. 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in 
the study subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the 
initiation of study medication for oral contraception) throughout the study period up to 120 
days after the last dose of trial therapy. If there is any question that a subject of childbearing 
potential will not reliably comply with the requirements for contraception, that subject should 
not be entered into the study. 
7.4 
Supportive Care 
All supportive measures consistent with optimal patient care will be given throughout the 
study. 
 


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8 STUDY CALENDAR 
1 cycle = 3 weeks ± 3 days 
Examination 
Pre-
screening23 
Screening1 
C1, 5, 9… 
Day 12 
C2, 6, 10… 
Day 1 
C3, 7, 11… 
Day 1 
C4, 8, 12… 
Day1 
End of 
Treatment20 
Follow-up21 
Informed consent 
X 
X 
  
  
  
  
  
  
Medical history 
 
X 
  
  
  
  
  
  
Eligibility criteria 
X 
X 
  
  
  
  
  
  
Vital signs, weight 
 
X 
X 
X 
X 
X 
X 
  
Height 
 
X 
  
  
  
  
  
  
Physical examination3 
 
X 
X 
X 
X 
X 
X 
  
ECOG performance status 
 
X 
X 
X 
X 
X 
X 
  
Viral Hepatitis Screening4 
 
X 
  
  
  
  
  
  
Smoking History 
 
X 
  
  
  
  
  
  
Hematology5 
 
X 
X 
X 
X 
X 
X 
  
Chemistry6 
 
X 
X 
X 
X 
X 
X 
  
LDH, Lipase, Lipid Panel, GGT7 
 
X 
 
 
 
X 
X 
  
BNP22 
 
X 
 
 
 
X 
X 
 
Urinalysis8 
 
X 
X 
X  
X  
X 
X 
  
Coagulation9 
 
X 
  
  
  
X 
X  
  
Thyroid Function Test10 
 
X 
  
  
  
X 
X  
  
Pregnancy test11 
 
X 
  
 X 
  
X 
  
  
ECG12 
 
X 
 
  
  
X 
  
  
Concomitant Medications 
 
X 
  
Adverse Event Assessment 
 
  
X 
  
CT Scans (c, a, p)13 
 
X 
  
  
  
X13 
X 
X21 
Bone Scans14 
 
X 
X 
  
  
 
X 
X  
Optional Tissue for Correlative Studies15 
X 
(X)15 
  
  
 
X 
 
  
Optional Blood for Correlative Studies16 
 
 
X 
X 
X 
X  
X 
  
Optional Stool for Correlative Studies17 
 
 
X 
X 
X 
X  
X 
  
Optional Stool Questionnaire to 
accompany Optional Stool sample 
collection for Correlative Studies17 
 
 
X 
X 
X 
X  
X 
 
Cabozantinib18 
 
  
X 
X 
X 
X 
  
  
Pembrolizumab19 
 
  
X 
X 
X 
X 
  
  
Survival Follow Up 
 
 
 
 
 
 
 
X21 


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1. 
Screening procedures must be completed within 28 days prior to C1D1 ALL Pre-study/Screening procedures should be completed within 4 weeks of study 
enrollment - with the exception of laboratory tests which need to be completed within 14 days prior to study treatment. 
2. 
Labs on C1D1 do not need to be repeated if conducted within 14 days of start of treatment 
3. 
Physical Exam including oral examination 
4. 
Hepatitis screening will be performed at screening if clinically indicated.  
5. 
Hematology includes CBC with differential and platelets (must be completed within 2 weeks prior to study enrollment). 
6. 
Chemistry includes Albumin, Alkaline Phosphatase, Aspartate Aminotransferase, Alanine Aminotransferase, Total Bilirubin, Calcium, Carbon Dioxide, Creatinine, 
Chloride, Glucose, Potassium, Protein, Sodium, Urea Nitrogen, phosphorus and magnesium (must be completed within 14 days prior to study enrollment at 
screening) 
7. 
Additional Labs: Lactate Dehydrogenase, Lipase, Lipid Panel, Gamma Glutamyl Transferase, and should be collected at baseline and at every 4th cycle. 
8. 
Urinalysis including urine protein/creatinine ratio on day 1 of each cycle. Both spot protein/creatinine and the 24 protein/creatinine evaluations are acceptable. 
9. 
Coagulation labs to be collected: PT/INR, APTT. Coagulation panel will only be required at EOT if patients are on active anticoagulant therapy and require 
monitoring. 
10. Free T4, Free T3 and TSH must be performed at baseline ant at least every 4th cycle during treatment  
11. Pregnancy test (serum or urine- if urine is positive it must be confirmed with serum test) must be done at screening for all women of childbearing potential and every 
even cycle (2,4,6 …etc.) during treatment (must be completed within 72hr prior to study enrollment) 
12. ECG should be collected at screening (see section 9 for QTcF eligibility details at screening) and at every 4th cycle.  
13. CT scans of chest, abdomen and pelvis will be repeated every 4th cycle during treatment within 1 week prior to the corresponding cycle (e.g., prior to cycle 5, 9, 13... 
etc.). However, if the study treatment is delayed, scans can be delayed to correspond to the treatment schedule, and this will not be a deviation. CT scans will be done 
at the end of treatment visit only if patient has come off for reasons other than progression. Use of contrast according to institutional practice is recommended but not 
required.  
14. Bone Scans if clinically indicated for evaluation of bone metastatic disease 
15. For participants who opt in to the optional tissue collection, tissue may be collected at pre-screening from an urothelial carcinoma diagnostic procedure (soft tissue 
biopsy or TURBT) or during screening from a soft tissue biopsy (only for patients who do not sign the pre-screening ICF). Subjects are also offered the option of a 
fresh soft-tissue biopsy or TURBT again prior to treatment at cycle 4 or after. See Section 14 for details.  
16. For participants who opt in to the optional blood collection, blood may be collected on C1D1, C2D1, C4D1, C7D1, C13D1, and at end of treatment. See Section 14 
for details. 
17. For participants who opt in to the optional stool collection, stool may be collected and stool questionnaire administered within 3 days prior to treatment on C1D1, 
C2D1, C4D1, C7D1, C13D1, and at end of treatment. See Section 14 for details. 
18. Cabozantinib at dose specified in dose escalation and specified in section 6.2. Subjects will complete dosing diary for each cycle (Appendix I) 
19. Pembrolizumab 200 mg IV q3weeks  
20. End of treatment visit should occur within 28 (±14) days after subject completes study treatment 
21. Follow up visits: Patients will be followed via telephone contact or medical record review for survival 6 months after completing study treatment. Patients removed 
from therapy without evidence of progression will undergo radiological examination every 12 (±1) weeks or earlier, if clinically warranted. 
22. B type Natriuretic Peptide should be collected 
23. Pre-screening ICF and eligibility review must be completed with 4 weeks prior to urothelial carcinoma diagnostic procedure (soft tissue biopsy or TURBT).  


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9 STUDY PROCEDURES 
9.1 
Pre-Screening 
Pre-screening informed consent 
Pre-screening eligibility review 
Optional tissue collection (at the time of the standard of care urothelial carcinoma 
diagnostic procedure) within 4 weeks of study registration 
9.2 
Screening 
Informed Consent 
Physical exam 
Vital Signs (incl. height/weight) 
Review of medical history/baseline symptoms/smoking history/concomitant 
medications 
ECOG Performance status 
Labs: 
 
• CBC w/diff 
• CMP – Albumin, Alkaline Phosphatase, Aspartate Aminotransferase, Alanine 
Aminotransferase, Total Bilirubin, Calcium, Carbon Dioxide, Creatinine, 
Chloride, Glucose, Potassium, Protein, Sodium, Urea Nitrogen, phosphorous 
and magnesium.  
• Additional Labs: LDH, Lipase, Lipid Panel, Gamma Glutamyl Transferase, B-
type Natriuretic peptide 
• Coagulation – PT/INR, APTT 
• Thyroid function – TSH, Free T4, Free T3 
• Serum pregnancy test (for women of childbearing potential) 
• Urinalysis including urine protein creatinine ratio  
• Viral Hepatitis Screening (if clinically indicated) 
ECG: If a single ECG shows a QTcF with an absolute value > 500 ms, two additional 
ECGs at intervals of approximately 3 min must be performed within 30 min after the 
initial ECG, and the average of these three consecutive results for QTcF will be used 
to determine eligibility. 
CT scans of chest/abdomen/pelvis 
Bone Scans if clinically indicated 
Optional Tissue Collection for correlatives see section 14 
9.3 
On-Treatment Evaluations 
Physical Exam – at each cycle 


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ECOG Performance Status – at each cycle 
Vital Signs (Incl. weight) – at each cycle 
Labs: (do not need to be repeated if screening labs performed within 14 days of 
C1D1) 
• CBC w/diff – at each cycle 
• CMP – Albumin, Alkaline Phosphatase, Aspartate Aminotransferase, Alanine 
Aminotransferase, Total Bilirubin, Calcium, Carbon Dioxide, Creatinine, 
Chloride, Glucose, Potassium, Protein, Sodium, Urea Nitrogen, phosphorous 
and magnesium. – at each cycle 
• Additional Labs: LDH, Lipase, Lipid Panel, Gamma Glutamyl Transferase, 
N-type Natriuretic peptide – at every fourth cycle (4, 8, 12…) 
• Coagulation – PT/INR, APTT – at every fourth cycle (4, 8, 12…) 
• Thyroid function – TSH, Free T4, Free T3 – at every fourth cycle (4, 8, 12…) 
• Serum pregnancy test (for women of childbearing potential) at every even 
cycle (2, 4, 6…)  
• Urinalysis including urine protein creatinine ratio – at every cycle  
ECG – at every fourth cycle (4, 8, 12…) 
Safety assessment - Monitoring and recording all adverse events and serious adverse 
events using the CTCAE version 5.0 – at each cycle 
Review of concomitant medications – at each cycle 
CT scans of the chest/abdomen/pelvis and response assessment by RECIST v1.1 to be 
repeated every 4th cycle. However, if the study treatment is delayed, scans can be 
delayed to correspond to the treatment schedule, and this will not be a deviation.  
Bone Scans if clinically indicated 
Optional Tissue Collection for correlatives at cycle 4, or after, see section 14 
Optional Blood and Stool Collection and administration of Stool Questionnaire for 
correlatives – at C1D1, C2D1, C4D1, C7D1, C13D1 see section 14 
Treatment with 200mg pembrolizumab per section 6.3 
Treatment with appropriate dose of cabozantinib – review of patient dosing diary per 
section 6.2  
9.4 
End of Treatment Assessments (completed 28 days ± 14 days after 
completion of treatment 
Physical exam 
Vital Signs  
Concomitant medication collection 
ECOG Performance status 


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Labs: 
 
• CBC w/diff 
• CMP – Albumin, Alkaline Phosphatase, Aspartate Aminotransferase, Alanine 
Aminotransferase, Total Bilirubin, Calcium, Carbon Dioxide, Creatinine, 
Chloride, Glucose, Potassium, Protein, Sodium, Urea Nitrogen. Phosphorus 
and magnesium  
• Additional Labs: LDH, Lipase, Lipid Panel, Gamma Glutamyl Transferase, B-
type Natriuretic peptide 
• Thyroid function – TSH, Free T4, Free T3 
• PT/INR, aPTT if patients are on active anticoagulant therapy and require 
monitoring 
• B-type Natriuretic peptide 
• Urinalysis including urine protein creatinine ratio  
Optional Blood and Stool Collection and administration of Stool Questionnaire for 
correlatives see section 14 
Adverse event collection for 30 days 
CT scans of the chest/abdomen/pelvis and response assessment by RECIST v1.1 to be 
performed at the end of treatment visit only if patient has come off for reasons other 
than progression  
9.5 
Follow-up Assessments 
Patients will be followed for 6 months after cessation of study treatment for survival.  
Patients removed from therapy without evidence of progression will undergo 
radiological examination every 12 weeks or earlier, if clinically warranted. 
Patients will be followed for SAEs for 90 days after the cessation of treatment 
10 CRITERIA FOR EVALUATION AND ENDPOINT 
10.1 
Efficacy 
The primary objective is ORR with a secondary objective of PFS6. Evaluable 
subjects will be all patients who complete at least one set of disease assessment scans 
after starting protocol treatment. Patients who discontinue therapy due to clinical 
progression will also be considered evaluable even if they do not have a set of disease 
assessment scans. 
Patients who discontinue treatment prior to one disease assessment evaluation will be 
deemed unevaluable and need to be replaced except if the patient was determined to 
have clinical progression as the reason for discontinuation of therapy. Disease 
assessments will be measured by CT or MRI scan. All evaluations and treatment 
decisions will be based on RECIST v1.1 criteria.28, 29 The iRECIST criteria30 will be 
used as an exploratory measurement of efficacy which may be performed 
retrospectively.  


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 RECIST v1.1  
Responses for Phase II patients must be confirmed as follows: 
• Partial or complete responses (PR or CR, respectively) must be confirmed by 
repeat imaging performed 4 to 6 weeks after the first assessment showing 
PR/CR. 
• Stable disease (SD), measurements must have met the SD criteria at least once 
after study entry at a minimum interval of 9 weeks.  
• Patients with progressive disease (PD) who are receiving clinical benefit in 
the opinion of the investigator will be allowed to continue on treatment after 
the first evidence of PD. Repeat imaging to confirm PD should be performed 
according to the schedule of events (9 weeks after the scan showing first 
evidence of progression) or sooner at the discretion of the investigator but at 
least 4 weeks after the first evidence of progression.  
• Patients who are experiencing unequivocal RECIST v1.1 disease progression 
or who are not receiving clinical benefit in the opinion of the investigator will 
not require repeat imaging. 
 Evaluation of Best Overall Response 
The best overall response is the best response observed until progression/recurrence 
and is determined as indicated in the table below: 
Target Lesions Non-Target 
Lesions 
 
Evaluation of New 
Lesions 
Best Overall 
Response 
CR 
CR 
No 
CR 
CR 
SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
10.2 
Safety 
Routine safety and tolerability will be evaluated from the results of reported signs and 
symptoms, scheduled physical examinations, vital sign measurements, and clinical 
laboratory test results. More frequent safety evaluations may be performed if 
clinically indicated or at the discretion of the investigator. All patients who receive at 
least one dose of any of the two agents are evaluable for safety. 
Physical Examination 
Complete and symptom-directed physical examinations will be performed by a 
licensed physician (or physician’s assistant or nurse practitioner). 
Vital Signs 


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Vital signs (blood pressure, respiratory rate, pulse rate and temperature) will be 
obtained.  
Safety Laboratory Determinations 
Laboratory evaluations will be performed as noted in the flow chart.  
11 STATISTICAL CONSIDERATIONS 
11.1 
Primary objective 
This is a non-randomized phase II trial designed to evaluate the combination of 
pembrolizumab plus cabozantinib. Prior clinical trials of first-line gemcitabine-
carboplatin in cisplatin-ineligible patients have been performed. One study identified 
an objective response rate of 36%, with a median progression-free survival of only 
4.8 months in 56 treated patients.23 A second study of 60 patients noted an objective 
response rate of 38.4%, with a median progression-free survival of 7.6 months. 24 It 
has also been reported a 26% ORR in patient treated with pembrolizumab with 
locally advanced or metastatic urothelial cancer25. ORR will be analyzed 
descriptively. The proportion of objective responses will be reported and a 95% one-
sided exact binomial confidence interval (Clopper-Pearson) will be calculated for 
ORR. With 35 evaluable subjects the lower bound of the 95% confidence interval will 
extend no more than 26% from the observed proportion. If there are 17 or more 
objective responses in 35 patients the confidence interval will exclude 32%. Adding 
another 10% for unevaluable patients that may be enrolled, a total of up to 39 patients 
will be enrolled.  
11.2 
Secondary Objectives and Endpoints 
The secondary objectives are to evaluate progression free survival at 6 months and 
overall survival of pembrolizumab + cabozantinib in subjects with UC. Kaplan-Meier 
methods and associated confidence intervals will be used to analyze PFS and OS. 
Subjects will be evaluated for survival for 6 months or until death after discontinuation 
of study treatment. The proportion of subjects who exhibit an objective response will 
be reported along with an exact binomial confidence interval. As an additional 
secondary analysis, stratified Kaplan-Meier methodology will be used to associate risk 
group (based on performance status and visceral metastasis) with PFS. 
11.3 
Exploratory Objectives and Endpoints 
We are planning to evaluate molecular markers of tissue in tissues to correlate with 
response to drug treatment and blood markers to evaluate pharmacodynamic markers 
of drug mechanisms. However, the specific biomarker tests and assays have not yet 
been finalized. Once a decision has been made, a statistical plan will be written and 
an amendment to the protocol will be made. 


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12 REGISTRATION GUIDELINES 
Patients must meet all of the eligibility requirements listed in Section 5 prior to 
registration.  
Study related screening procedures can only begin once the patient has signed a 
consent form. Patients must not begin protocol treatment prior to registration. 
Treatment should start within five working days after registration. 
To register eligible patients on study, complete a Clinical Trials Office Patient Registration 
Form and submit to: CTORegistrations@hci.utah.edu.  
13 DATA SUBMISSION SCHEDULE 
The Case Report Forms (CRFs) are a set of (electronic or paper) forms for each patient 
that provides a record of the data generated according to the protocol. CRF’s should be 
created prior to the study being initiated and updated (if applicable) when amendments to 
the protocol are IRB approved. Data capture should be restricted to endpoints and 
relevant patient information required for planned manuscripts. These forms will be 
completed on an on-going basis during the study. The medical records will be source of 
verification of the data. During the study, the CRFs will be monitored for completeness, 
accuracy, legibility and attention to detail by a member of the Research Compliance 
Office. The CRFs will be completed by the Investigator or a member of the study team as 
listed on the Delegation of Duties Log. The data will be reviewed no less than annually 
by the Data and Safety Monitoring Committee. The Investigator will allow the Data and 
Safety Monitoring Committee or Research Compliance Office personnel access to the 
patient source documents, clinical supplies dispensing and storage area, and study 
documentation for the above-mentioned purpose. The Investigator further agrees to assist 
the site visitors in their activities.  
14 SPECIAL INSTRUCTIONS  
14.1 
Correlative Studies 
Correlative studies may include but are not limited to analysis that identify the 
mechanisms of response and resistance to immunotherapy, at the cellular and 
molecular levels. 
 Collection of Tumor Tissue 
Participants who opt in to the optional tissue collection, tissue may be collected at 
pre-screening from an urothelial carcinoma diagnostic procedure (soft tissue biopsy 
or TURBT) or during screening from a soft tissue biopsy (only for patients who do 
not sign the pre-screening ICF). Subjects are also offered the option of a fresh soft-
tissue biopsy or TURBT again prior to treatment at cycle 4 or after. Up to ten sections 
will be collected during the TURBT and up to six cores will be obtained at the time of 
soft tissue biopsy. These tissues will be used to establish a biomarker panel predictive 
of treatment efficacy which will be validated in future clinical trials. 


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Testing may include, but is not limited to: 
• 
Multiomics platforms 
• 
Immunohistochemistry 
• 
Flow cytometry  
• 
Ex vivo treatment to predict treatment efficacy 
Instructions for processing and analysis will be detailed in the lab manual. 
 Collection of Blood for Correlative Analysis 
Participants who opt in to the optional blood collection, up to 36mL of blood may be 
collected on C1D1, C2D1, C4D1, C7D1, C13D1, and at end of treatment.  
These samples will be used to test for biomarkers of disease response and prediction 
of treatment effect. Testing may include, but is not limited to:  
• C-reactive protein (CRP)  
• Neutrophil to Lymphocyte ratio  
• Hemoglobin  
• Cytokine/chemokine/interferon assays 
• Flow cytometry 
• Mass cytometry  
• T-cell kinetics  
• Genome analysis  
Specimen collection and processing instructions can be found in the lab manual. 
 Collection of Stool Samples for Correlative Analysis 
Collection of stool samples and administration of Stool Questionnaire may occur 
prior to treatment on cycles 1, 2, 4, 7, 13, and at the end of treatment. Stool collection 
kits will be given to subjects at the clinic visit preceding the collection time point and 
they will be instructed to collect the sample within 3 days prior to the time points 
noted above and answer the questionnaire provided in the stool kit (Appendix B).  
These samples will be used to determine a predictive microbiome signature 
associated with therapeutic response. 
Testing may include, but is not limited to: 
• 
16S ribosomal RNA sequencing  
• 
Cultivation of microbes 
• 
Shotgun metagenomics 
Specimen collection and storage instructions can be found in the lab manual and the 
patient stool collection instructions. 


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15 ETHICAL AND REGULATORY CONSIDERATIONS 
15.1 
Informed consent  
Informed consent will be obtained from all research participants prior to performing 
any study procedures using the most recent IRB approved version.  
15.2 
Institutional Review 
Before study initiation, the investigator must have written and dated approval/favorable 
opinion from the IRB/IEC for the protocol, consent form, subject recruitment materials 
(e.g., advertisements), and any other applicable patient-facing documents. The 
investigator should also provide the IRB/IEC with a copy of the Investigator Brochure 
or product labeling information. 
The investigator or designee should provide the IRB/IEC with reports, updates and 
other information (e.g., expedited safety reports, amendments, and administrative 
letters) according to regulatory requirements or institution procedures.  
 
15.3 
 Data and Safety Monitoring Plan 
A Data and Safety Monitoring Committee (DSMC) is established at Huntsman 
Cancer Institute (HCI) to ensure the well-being of patients enrolled on Investigator 
Initiated Trials that do not have an outside monitoring review. The roles and 
responsibilities of the DSMC are set forth in the NCI-approved Data and Safety 
Monitoring (DSM) plan. The activities of the committee include reviewing adverse 
events (including SAEs), deviations, important medical events, significant revisions 
or amendments to the protocol, and approving cohort/dose escalations. If the DSMC 
and/or the PI have concerns about unexpected safety issues, the study will be stopped 
and will not be resumed until the issues are resolved. The DSMC also reviews and 
approves audit reports generated by the Research Compliance Office. 
This is a Phase II, multicenter, study classified as high risk per the NCI-approved 
DSM plan.  
Each high risk study may be assigned a physician member of the DSMC as medical 
monitor, or in rare cases, an external medical monitor. The medical monitor will be 
notified of all serious adverse events (SAEs). Approval of the medical monitor is 
required for all dose escalations. SAEs occurring in patients treated at HCI or its 
affiliates will also be reviewed by the full DSMC monthly. The full committee will 
also review all toxicities for patients on treatment and within 30 days of their last 
treatment on a quarterly basis.  
Each high-risk study will be assigned a dedicated research compliance officer who 
will monitor the trial. High-risk trials will be monitored by RCO personnel after the 
first patient is enrolled and every three months thereafter during active enrollment. 
The RCO monitor will review the study status and summarize enrollment, toxicities, 
SAEs, dose escalation, statistical endpoints (e.g., stopping rules), deviations, etc. for 
the full DSMC membership at the regularly scheduled meetings. Amendments that 


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increase risk, change dosing, or impact study objectives will be reviewed by the 
DSMC and approved by the PRMC and IRB. High-risk trials will be formally 
reviewed by the DSMC after the first patient is enrolled and then quarterly thereafter.  
An initial audit of high-risk studies will be conducted by the RCO approximately one 
year after enrollment begins and annually thereafter. Audits of high-risk studies may 
be conducted more frequently as requested by the DSMC, IRB, PRMC, RCO 
management, or the PI. 
A safety analysis will be performed after the first 6 patients enroll and receive 
treatment. During this stage, the decision to continue enrollment will be made by the 
Data Safety and monitoring committee (DSMC). When all 6 subjects in the have been 
followed for at least 21 days following first dose of pembrolizumab and cabozantinib, 
all available safety data will be considered in a decision to continue enrollment. 
15.4 
Adverse Events / Serious Adverse Events 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse 
Events) Version 5.0 for AE and SAE reporting.  
 Adverse Events (AE) 
An adverse event is the appearance or worsening of any undesirable sign, symptom, 
or medical condition occurring after starting the study drug even if the event is not 
considered to be related to study drug. For the purposes of this study, the terms 
toxicity and adverse event are used interchangeably. Medical conditions/diseases 
present before starting study drug are only considered adverse events if they worsen 
after starting study drug. Abnormal laboratory values or test results constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically 
significant, or require therapy. 
The collection of adverse events will begin after the signature of the consent form and 
end 30 days post the last dose of study treatment.  
Information about all adverse events, whether volunteered by the subject, discovered 
by investigator questioning, or detected through physical examination, laboratory test 
or other means, will be collected and recorded and followed as appropriate. 
Adverse events should be evaluated to determine: 
1. The severity grade based on CTCAE v.5.0 (grade 1-5) 
2. Its relationship to the study drug(s) (definite, probable, possible, unlikely, not 
related). 
3. Its duration (start and end dates or if continuing at final exam) 
4. Action taken (no action taken; study drug dosage adjusted/temporarily 
interrupted; study drug permanently discontinued due to this adverse event; 
concomitant medication taken; non-drug therapy given; 
hospitalization/prolonged hospitalization) 
5. Whether it constitutes an SAE 


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All adverse events will be treated appropriately. Such treatment may include changes 
in study drug treatment as listed in the dose modification section of this protocol (see 
section 7 for guidance). Once an adverse event is detected, it should be followed until 
its resolution, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study drug, the 
interventions required to treat it, and the outcome. 
Information about common side effects already known about the investigational drugs 
is described in the Drug Information (section 3) and (the most recent Investigator 
Brochures). This information will be included in the patient informed consent and 
will be discussed with the patient during the study as needed. 
All adverse events will be immediately recorded in the patient research chart.  
 Serious Adverse Event (SAE) 
Information about all serious adverse events will be collected and recorded. A serious 
adverse event is an undesirable sign, symptom or medical condition which: 
• Is fatal or life-threatening 
• Results in persistent or significant disability/incapacity 
• Is medically significant, i.e., defined as an event that jeopardizes the patient or 
may require medical or surgical intervention to prevent one of the outcomes listed 
above 
• Causes congenital anomaly or birth defect 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
unless hospitalization is for: 
o Routine treatment or monitoring of the studied indication, not associated with 
any deterioration in condition (procedures such as central line placements, 
paracentesis, pain control) 
o Elective or pre-planned treatment for a pre-existing condition that is unrelated 
to the indication under study and has not worsened since the start of study 
drug 
o Treatment on an emergency outpatient basis for an event not fulfilling any of 
the definitions of a SAE given above and not resulting in hospital admission 
o Social reasons and respite care in the absence of any deterioration in the 
patient’s general condition 
Serious adverse event collection will begin after the signature of the consent form and 
end 90 days after the last dose of study treatment or until new cancer treatment is 
initiated, if sooner.  
Any death from any cause while a patient is receiving treatment on this protocol or up 
to 30 days after the last dose of protocol treatment, or any death which occurs more 
than 30 days after protocol treatment has ended but which is felt to be treatment 
related, must be reported. 


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Toxicities which fall within the definitions listed above must be reported as an SAE 
regardless if they are felt to be treatment related or not. Toxicities unrelated to treatment 
that do NOT fall within the definitions above, must simply be documented as AEs in 
the patient research chart.  
15.5 
SAE Reporting Requirements 
SAEs must be reported to the DSMC, the FDA, the IRB, and Exelixis according to the 
requirements described below: 
A MedWatch 3500A form must be completed and submitted to  HCI-RCO@utah.edu 
as soon as possible, but no later than 1 working day of first knowledge or notification 
of event. Medwatch 3500A form can be downloaded from the FDA website. 
DSMC Notifications: 
An HCI Research Compliance Officer (RCO) will process and submit the MedWatch 
form to the proper DSMC member as necessary for this study.  
The RCO will summarize and present all reported SAEs according to the Data and 
Safety Monitoring Plan at the monthly DSMC meeting. 
FDA Notifications: 
Adverse events occurring during the course of a clinical study that meet the following 
criteria will be promptly reported to the FDA: 
• Serious 
• Unexpected 
• Definitely, Probably or Possibly Related to the investigational drug 
Fatal or life-threatening events that meet the criteria above will be reported within 7 
calendar days after first knowledge of the event by the investigator; followed by as 
complete a report as possible within 8 additional calendar days. 
• All other events that meet the criteria above will be reported within 15 
calendar days after first knowledge of the event by the investigator. 
• The RCO will review the MedWatch report for completeness, accuracy and 
applicability to the regulatory reporting requirements. 
• The RCO will ensure the complete, accurate and timely reporting of the event 
to the FDA. 
• The Regulatory Coordinator will submit the report as an amendment to the 
IND application. 
• All other adverse events and safety information not requiring expedited 
reporting that occur or are collected during the course of the study will be 
summarized and reported to the FDA through the IND Annual Report. 


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IRB Notification: 
Events meeting the University of Utah IRB or local IRB reporting requirements will be 
submitted per local guidelines. 
Drug Manufacturer Notifications: 
All SAEs that are assessed by the PI as related to drug or study procedure and all 
pregnancy/lactation reports regardless of outcome must be sent to Exelixis within one 
(1) business day of the PI’s knowledge of the event. The reports must be sent to 
drugsafety@exelixis.com or fax 650-837-7392. Upon Exelixis request, the PI will 
query for follow-up information. 
15.6 
Reporting of Pregnancy  
Although pregnancy is not considered an adverse event, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject, 
including the pregnancy of a male subjects’ female partner as an SAE. Pregnancies or 
lactation that occurs during the course of the trial or with 30 days of completing the 
trial or starting another new anticancer therapy, whichever is earlier, must be reported 
to the DSMC, IRB, FDA, and the sponsor as applicable. All subjects and female 
partners who become pregnant must be followed to the completion/termination of the 
pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, fetal 
death, intrauterine death, miscarriage and stillbirth must be reported as serious events.  
15.7 
Medication Errors/Overdose 
Any overdose, or study drug administration error that results in an AE, even if it does 
not meet the definition of serious, requires reporting within one (1) business day to 
Exelixis. 
15.8 
Protocol Amendments 
Protocol modifications (including protocol amendments) may be made and will be 
prepared, reviewed, and approved by representatives of the investigator. Protocol 
modifications or amendments must be reviewed and approved by Exelixis prior to 
implementation. Any amendments or administrative changes to an IRB approved 
protocol will not be initiated without submission of an amendment for IRB review 
and approval.  
These requirements for approval will in no way prevent any immediate action 
from being taken by the investigator in the interests of preserving the safety of 
all patients included in the trial.  
Any amendments to the protocol that significantly affect the safety of subjects, 
scope of the investigation, or the scientific quality of the study are required to 
submit the amendment for FDA review. 


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15.9 
Protocol Deviations 
A protocol deviation (or violation) is any departure from the defined procedures and 
treatment plans as outlined in the protocol version submitted and previously approved 
by the IRB. Protocol deviations have the potential to place participants at risk and can 
also undermine the scientific integrity of the study thus jeopardizing the justification 
for the research. Protocol deviations are unplanned and unintentional events.  
Because some protocol deviations pose no conceivable threat to participant safety or 
scientific integrity, reporting is left to the discretion of the PI within the context of the 
guidelines below. The IRB requires the prompt reporting of protocol deviations 
which are: 
• Exceptions to eligibility criteria. 
• Intended to eliminate apparent immediate hazard to a research participant or  
• Harmful (caused harm to participants or others, or place them at increased risk 
of harm - including physical, psychological, economic, or social harm), or  
• Possible serious or continued noncompliance  
15.10 FDA Annual Reporting  
An annual progress report will be submitted to the FDA within 60 days of the 
anniversary of the date that the IND went into effect. (21 CFR 312.33).  
15.11 Clinical Trials Data Bank  
The study will be registered on http://clinicaltrials.gov and the NCI CTRP (Clinical 
Trials Reporting Program) by the Clinical Trials Office. 
15.12 Record Keeping 
Per 21 CFR 312.57, Investigator records shall be maintained for a period of 2 years 
following the date a marketing application is approved; or, if no application is filed or 
the application is not approved, until 2 years after the investigation is discontinued 
and the FDA is notified. Additional monitoring of the study documentation and 
record keeping can be monitored by Exelixis according to the clinical trial agreement.  
16 PUBLICATIONS OF DATA 
The Principal Investigator holds the primary responsibility for publication of the study 
results; provided that the PI will provide Exelixis with a copy of any proposed 
publication or release in accordance with the clinical trial agreement.  
 
 


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SS, Quinn DI, Durán I, Shaffer DR, Eigl BJ, Grivas PD, Yu EY, Li S, Kadel EE 3rd, 
Boyd Z, Bourgon R, Hegde PS, Mariathasan S, Thåström A, Abidoye OO, Fine GD, 
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16. Gerullis H, Eimer C, Ecke TH, Georgas E, Arndt C, Otto T. Combined treatment with 
pazopanib and vinflunine in patients with advanced urothelial carcinoma refractory 
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18. Apolo AB TY, Lee M-J, et al. Effect of cabozantinib on immunosuppressive subsets 
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19. Yeh CY, Shin SM, Yeh HH, et al. Transcriptional activation of the Axl and PDGFR-
alpha by c-Met through a ras- and Src-independent mechanism in human bladder 
cancer. BMC Cancer. 11:139 
20. Comperat E, Roupret M, Chartier-Kastler E, et al. Prognostic value of MET, RON 
and histoprognostic factors for urothelial carcinoma in the upper urinary tract. J Urol. 
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21. Choueiri TK, Ross RW, Jacobus S, et al. Double-blind, randomized trial of docetaxel 
plus vandetanib versus docetaxel plus placebo in platinum-pretreated metastatic 
urothelial cancer. J Clin Oncol. 2012 Feb 10: 30:507-12 
22. Sorbellini M GA, Srivastava G, et al. Effect of the orally available MET inhibitor PF-
2341066 on tumor burden and metastasis in an orthotopic xenograft model of bladder 
cancer. J Clin Oncol 29: 2011 (suppl 7; abstr 263) 
23. Linardou H1, Aravantinos G, Efstathiou E, Kalofonos C, Anagnostopoulos A, 
Deliveliotis C, Bafaloukos D, Athanasios Dimopoulos M, Bamias A; Phase II study 
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as first-line treatment in elderly patients and those unfit for cisplatin-based 
chemotherapy with advanced bladder carcinoma: Phase II study of the Hellenic Co-
operative Oncology Group. Urology. 2004 Sep;64(3):479-84. 
24. De Santis M, Wiechno PJ, Bellmunt J, Lucas C, Su WC, Albiges L, Lin CC, Senkus-
Konefka E, Flechon A, Mourey L, Necchi A, Loidl WC, Retz MM, Vaissière N, 
Culine S. Vinflunine-gemcitabine versus vinflunine-carboplatin as first-line 
chemotherapy in cisplatin-unfit patients with advanced urothelial carcinoma: results 
of an international randomized phase II trial (JASINT1). Ann Oncol. 2016 
Mar;27(3):449-54. doi: 10.1093/annonc/mdv609. Epub 2015 Dec 16. 
25. Plimack ER, Bellmunt J, Gupta S, Berger R, Chow LQ, Juco J, Lunceford J, Saraf S, 
Perini RF, O'Donnell PH. Safety and activity of pembrolizumab in patients with 
locally advanced or metastatic urothelial cancer (KEYNOTE-012): a non-
randomised, open-label, phase 1b study. Lancet Oncol. 2017 Feb;18(2):212-220. doi: 
10.1016/S1470-2045(17)30007-4. Epub 2017 Jan 10. 
26. R. Nadal, H.L. Parnes, D.C. Francis, L.M. Cordes, M. Berninger, R. Costello, L. 
Folio, M. Linderberg, L. Machado, S.M. Steinberg, J.J. Wright, Y.M. Ning, D.P. 
Bottaro, W.L. Dahut, A.B. Apolo. A phase II study of cabozantinib in patients (pts) 
with relapsed/refractory metastatic urothelial carcinoma (mUC). Annals of Oncology 
(2016) 27 (6): 266-295. 10.1093/annonc/mdw373 
27. Rosa Maria Nadal, Amir Mortazavi, Mark Stein, Sumanta K. Pal, Nicole N. 
Davarpanah, Howard L. Parnes, Yang-Min Ning, Lisa M. Cordes, Mohammadhadi H. 
Bagheri, Liza Lindenberg, Ryan Thompson, Seth M. Steinberg, Tina Moore, Tiffany 
Lancaster, Milisyaris Velez, Esther Mena, Rene Costello, Donald Bottaro, William L. 
Dahut, Andrea B. Apolo. Results of phase I plus expansion cohorts of cabozantinib 
(Cabo) plus nivolumab (Nivo) and CaboNivo plus ipilimumab (Ipi) in patients (pts) 
with with metastatic urothelial carcinoma (mUC) and other genitourinary (GU) 
malignancies. J Clin Oncol 36, 2018 (suppl 6S; abstr 515). 
28. Eisenhauer E.A., Therasse P., Bogaerts J., Schwartz L.H., Sargent D., Ford R., 
Dancey J., Arbuck S., Gwyther S., Mooney M., Rubinstein L., Shankar, L. Dodd, L. 
Kaplan, R. Lacombe D., Verweij J. New response evaluation criteria in solid 
tumours: Revised RECIST guideline (version 1.1) European Journal of Cancer 2009, 
45(2), 228-247. 
29. Schwartz L. H., Litière S., de Vries E., Forde R., Gwyther S., Mandrekar S., 
Shankarh, L. Bogaerts, J., Chen, A., Dancey J., Hayes W., Hodi S., Hoekstral, O. S., 
Huang E. P., Lin N., Liu Y., Therasse P., Wolchok J. D., Seymour L. RECIST 1.1—


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Update and clarification: From the RECIST committee. European Journal of Cancer 
2016, 62, 132-137 
30. Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz L H, Mandrekar S, Lin N U, 
Litière S, Dancey J, Chen A, Hodi F S, Therasse P, Hoekstra O S, Shankar L K, 
Wolchok J D, Ballinger M, Caramella C, de Vries E G E, RECIST working group. 
iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. 
The Lancet 18(3), e143-e152 (2017). 
 


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APPENDIX A - Cabozantinib Dosing Diary 
Patient Instructions: 
1) Take the number of pills prescribed to you by your study doctor each day with an 8oz glass of water at 
approximately the same time each day.  
2) If a pill is forgotten, it may be taken as soon as you remember on the same day with a return to normal 
scheduling the following day.  
3) Do not take 2 doses of Cabozantinib on the same day to try and make up for a missed dose.  
4) Complete one line of the diary each day and write the total number of pills taken each day. If a dose is 
missed, indicate “dose not taken”, in the comments briefly explain why, especially noting whether this 
is a dose reduction to every other day administration. 
5) Please bring this diary as well as all empty containers and any unused supplies to your next clinic visit.  
Day 
Date 
Time 
Number of 
Pills Taken 
Comments 
Day 1 
 
 
 
 
Day 2 
 
 
 
 
Day 3 
 
 
 
 
Day 4 
 
 
 
 
Day 5 
 
 
 
 
Day 6 
 
 
 
 
Day 7 
 
 
 
 
Day 8 
 
 
 
 
Day 9 
 
 
 
 
Day 10 
 
 
 
 
Day 11 
 
 
 
 
Day 12 
 
 
 
 
Day 13 
 
 
 
 
Day 14 
 
 
 
 
Day 15 
 
 
 
 
Day 16 
 
 
 
 
Day 17 
 
 
 
 
Day 18 
 
 
 
 
Day 19 
 
 
 
 
Day 20 
 
 
 
 
Day 21 
 
 
 
 
Day 22 
 
 
 
 
Day 23 
 
 
 
 
Day 24 
 
 
 
 
Day 25 
 
 
 
 
Day 26 
 
 
 
 
Day 27 
 
 
 
 
Day 28 
 
 
 
 
 
 
Patient Signature _____________________________________________ Date______________________ 


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APPENDIX B- Stool Sample Collection Questionnaire 
 
 
Stool Collection Questionnaire 
Date Collected: 
Time Collected: 
Dietary Questionnaire 
In the last week: 
How often did you consume red meat? 
Never ☐  Once ☐  2 – 5 times ☐  Daily ☐ 
How often did you consume desserts, sweets, soda, or juice? 
Never ☐  Once ☐  2 – 5 times ☐  Daily ☐ 
How often did you consume high fiber foods? 
Fresh vegetables? Never ☐  Once ☐  2 – 5 times ☐  Daily ☐ 
Whole grains*? Never ☐  Once ☐  2 – 5 times ☐  Daily ☐ 
Fresh Fruit? Never ☐  Once ☐  2 – 5 times ☐  Daily ☐ 
*Examples include oatmeal, quinoa, brown/wild rice, barley, whole-wheat products. 
For the use of the Huntsman Cancer Institute, study coordinator 
Time-point: 
Study ID: 
Study Name: