Phase II Clinical Trial Evaluating Cabozantinib and Pembrolizumab in Metastatic Pancreatic Cancer
Phase: PHASE2
Conditions: Pancreatic Cancer
Sponsor: Joseph Kim

Document Coversheet
Study Title: Phase II Clinical Trial Evaluating Cabozantinib and Pembrolizumab in Metastatic 
Pancreatic Cancer
Institution/Site: 
University of Kentucky
Document (Approval/Update) Date:
3/27/2023 
NCT Number:
NCT05052723
IRB Number 
70173
Coversheet created:
11/3/2025 

MCC Study ID: MCC-21-GI-117
Protocol Version, Version Date: Amendment 2, 27MAR2023
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COVER PAGE

 
MCC Protocol #: 
MCC-21-GI-117  
ClinicalTrials.gov Identifier:  NCT05052723 
 
TITLE:    Phase II Clinical Trial Evaluating Cabozantinib and Pembrolizumab in Second-Line  
                      Therapy for Metastatic Pancreatic Adenocarcinoma 
 
 
Short Title: Cabozantinib and Pembrolizumab in Metastatic Pancreas 
 
 
PROTOCOL FACE PAGE FOR 
MCC INTERVENTIONAL THERAPEUTIC PROTOCOL 
 
 
Funding Sources: Exelixis (drug and fees) & Merck (Pembro only)  
Alternate protocol identifiers: MISP-60103 
 
Investigational Agents (combination):  Cabozantinib [XL184, Cometriq; Exelixis] 
                                                                   Pembrolizumab [MK-3475, Keytruda; Merck] 
FDA IND Status: Study Exempt from IND Requirements per 21 CFR 312.2(b), received 8/29/2021. 
 
 
Protocol Type with Version # / Version Date:  Original Protocol / 12.April.2021 
                                                                               Revision 1 /  27.October.2021 
                                                                               Amendment 1 /  04.August.2022 
                                                                               Amendment 2 /  27.March.2023 
 
 
 
ROLE 
NAME 
DEPARTMENT/DIVISION 
Principal Investigator 
Joseph Kim, MD 
Department of Surgery 
Co-PI 
Reema Patel, MD 
Medical Oncology 
Co-I 
Jill Kolesar, PharmD 
Director, Precision Medicine Initiatives 
Statistician 
Heidi Weiss, PhD 
Professor and Director, Biostatistics and 
Bioinformatics Shared Resource Facility 
Central Radiology Expert Jinha Park, MD, PhD, 
FACR 
President, The Radiology Experts, Inc. 
 
Investigator-Initiated 
Trials Team 
Leigh Anne Faul, PhD 
Director, Investigator-Initiated Trials Office 
Akosua Adu, DrPH 
IITs Senior Project Manager 
Jennifer Land 
Senior Clinical Data Manager 
Teresa Roberts, RN 
Lead CRO Clinical Research Nurse 

MCC Study ID: MCC-21-GI-117 
Protocol Version, Version Date: Amendment 2, 27MAR2023
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Protocol Development History –
         Original Version to Current Version, w/ major Summary of Changes noted
Original Protocol
MCC protocol draft version dated 12APR2021 (Protocol file name 120220 from sponsor). 
5/7/2021 
PRMC Initial Full Review of the original protocol, pvd 12APR2021. 
     Resolution: Full approval.
7/9/2021 
Initial coverage analysis received from UKHC Central Research Support Office.
7/14/2021
IRB review of 12APR2021 protocol (initial review). 
     Resolution: Edits required from initial IRB review. IRB Approval was obtained on 09/02/2021 
         for the revised 12APR2022 protocol 
8/29/2021
FDA IND status determination. 
Revision 1 
10/27/2021 
Protocol was modified slightly in response to IRB critiques (clarifying 4-months is the window to 
report pregnancy after last dose); clarification that research samples for the correlatives will be 
collected under a biospecimen sample collection protocol.  
New protocol version date, 27OCT2021. This revised protocol also contains a new pill diary for 
Cabozantinib (new Appendix B); added clinicaltrials.gov identifier (cover page); clarifications re: 
urinalysis and aPTT tests (addresses questions re: Medicare coverage analysis). 
     Resolution: Revision 1 protocol approved by IRB (11/23/2021).  
12/22/2021
Open to Accrual
Amendment 1 
04AUG2022 
The protocol version date 27OCT2021 was modified to create Amendment 1, version dated 
04AUG2022. Protocol edits are as follows: clarify 3.2.26 exclusion re: cavitating pulmonary 
lesions; clarify 3.2.27 exclusion criterion, invading blood vessels and encasement; and, clarify 
window for ECOG PS as within 2 weeks (sections 3.1.4, 4.3.3). Other minor updates in this 
amendment: trial opening date date trial (added above); noted the IND exemption from the FDA
(page 1); text added to clarify language regarding emerging new first-line therapies (Schema); 
noted radiologist, affiliation address for imaging RECIST reads (Pg 1, 12.2.2, and 12.2.3). 
Amendment 2
27MAR2023
The 04AUG2022 protocol was revised to correct the reporting of concomitant medications (S11 
Study Calendar was clarified to align with Section 8.1). The Key Personnel (cover page) was 
updated. New protocol version date is 27MAR2023. 
Placeholder for future amendment
Placeholder for future amendment

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Protocol Version, Version Date: Amendment 2, 27MAR2023
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SCHEMA
NOTE: “1st line therapy” is defined as FOLFIRINOX and/or gemcitabine+abraxane, as well as
other treatment regimens that are approved for 1st line therapy of metastatic pancreatic
cancer during the course of this trial. 
*One cycle of therapy is Q3W administration of pembrolizumab (200 mg IV) and cabozantinib
(40 mg po daily). 
*Completion of pembrolizumab Q3W monotherapy consists of 35 treatments (approximately 2 
years).  Discontinuation of treatment may be considered for participants who have attained
a confirmed complete response (CR) and have been treated for at least 8 cycles (at least 
24 weeks), receiving at least 2 cycles of the combination including 2 doses of 
pembrolizumab and at least 80% of the planned doses of cabozantinib beyond the date
when the initial CR was declared.

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TABLE OF CONTENTS
1.
OBJECTIVES..........................................................................................................6
1.1
Primary Objective....................................................................................................6
1.2
Secondary Objectives...............................................................................................6
1.3
Exploratory / Correlative Objectives .......................................................................6
2.
BACKGROUND .....................................................................................................6
2.1
Pancreatic Cancer.....................................................................................................6
2.2
Cabozantinib ............................................................................................................7
2.3
Pembrolizumab ........................................................................................................8
2.4
Study Rationale and In Vivo Studies.......................................................................9
2.5
Correlative Studies Background ............................................................................11
2.6
Study Hypothesis ...................................................................................................13
3.
ELIGIBILITY........................................................................................................14
3.1
Inclusion Criteria ...................................................................................................14
3.2
Exclusion Criteria ..................................................................................................17
3.3
Inclusion of Women and Minorities ......................................................................20
4.
INVESTIGATOR REQUIREMENTS AND REGISTRATION 
PROCEDURES..............................................................................................................................21
4.1
Protocol Review and Monitoring Committee and Institutional Review 
Board......................................................................................................................21
4.2
Investigator and Research Associate Registration with MCC...............................21
4.3
Screening and Study Enrollment Guidelines.........................................................22
4.4
Eligibility Confirmation and Enrollment...............................................................23
5.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ............................24
5.1
Summary for Specimen Collection........................................................................24
5.2
Specimen Collection and Processing.....................................................................24
6.
TREATMENT PLAN............................................................................................25
6.1
Pembrolizumab/Cabozantinib Administration.......................................................25
6.2
General Concomitant Medication and Supportive Care Guidelines......................27
6.3
Compliance ............................................................................................................29
6.4
Duration of Therapy...............................................................................................29
6.5
Duration of Follow-Up ..........................................................................................30
7.
PHARMACEUTICAL INFORMATION..............................................................30
7.1
Drug Ordering and Accountability ........................................................................30
7.2
Cabozantinib ..........................................................................................................30
7.3
Pembrolizumab ......................................................................................................38
8.
DOSING DELAYS/DOSE MODIFICATIONS ...................................................40
8.1
Concomitant Medications/Vaccinations (allowed & prohibited) ..........................41
8.2
Prohibited or Restricted Medications or Therapy..................................................42
9.
STATISTICAL CONSIDERATIONS...................................................................43
9.1
Study Design/Endpoints.........................................................................................43

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9.2
Sample Size/Accrual Rate......................................................................................43
9.3
Stratification Factors..............................................................................................44
9.4
Analysis of Primary Endpoint................................................................................44
9.5
Secondary Endpoints .............................................................................................44
9.6
Interim Analysis.....................................................................................................44
9.7
Reporting and Exclusions ......................................................................................45
9.8
Clinical Trial Registration with NIH .....................................................................45
10.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ................45
10.1
Adverse Event Characteristics ...............................................................................46
10.2
MCC Expedited Adverse Event Reporting Guidelines .........................................53
10.3
Expedited Reporting to External Agencies............................................................55
10.4
Expedited Reporting to the Food and Drug Administration (FDA) ......................56
10.5
Expedited Reporting to Hospital Risk Management .............................................56
10.6
Routine Adverse Event Reporting .........................................................................56
10.7
Pregnancy...............................................................................................................56
10.8
Secondary Malignancy...........................................................................................57
10.9
Second Malignancy................................................................................................57
11.
STUDY CALENDAR ...........................................................................................58
12.
MEASUREMENT OF EFFECT............................................................................61
12.1
Antitumor Effect – Solid Tumors ..........................................................................61
12.2
Antitumor Effect – Immune-Related RECIST (iRECIST) Criteria.......................65
13.
STUDY APPROVAL, OVERSIGHT AND DATA REPORTING / 
REGULATORY REQUIREMENTS.............................................................................................72
13.1
Protocol Review and Monitoring Committee and Institutional Review 
Board Review.........................................................................................................72
13.2
Quality Assurance..................................................................................................72
13.3
Data and Safety Monitoring Committee................................................................73
13.4
Data Reporting.......................................................................................................73
13.5
Data Management ..................................................................................................74
13.6
Compliance with Laws and Regulations................................................................74
14.
REFERENCES ......................................................................................................75
Appendix A. ECOG Performance Status.......................................................................................81
Appendix B. Cabozantinib Med Log.............................................................................................82
Appendix C. Lab Manual: PDAC Organoid Cultures ...................................................................84
Appendix D. Lab Manual: Exosomal Lipids.................................................................................88
Appendix E. Management of Cabozantinib-related Adverse Events ............................................90
Appendix F. Management of Pembrolizumab-related Adverse Events.........................................95
Appendix G. Potential Drug Interactions with Cabozantinib......................................................100

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1.
OBJECTIVES
1.1
Primary Objective
To measure progression-free survival (PFS), defined as the time from the start of treatment 
(Cabozantinib + Pembrolizumab combination) until the first documentation of disease progression 
or death due to any cause, whichever occurs first.
1.2
Secondary Objectives
1.2.1
To identify the proportion of participants with adverse events.
1.2.2
To measure the proportion of patients with overall response to therapy [i.e., overall 
response rate (ORR): complete response (CR) + partial response (PR)] as determined by 
RECIST v1.10 via imaging conducted at 2 (+/- 1-2 weeks) months, 4 (+/- 1-2 weeks) 
months, and 6 (+/- 1-2 weeks) months and thereafter, imaging at q3 months or as clinically
indicated.
1.2.3
To measure the proportion of patients with CR or PR at 1-year post-treatment initiation.
1.2.4
To measure 1-year overall survival (defined as time from start of treatment until up to 1-
year post-treatment initiation or death from any cause). 
1.3
Exploratory / Correlative Objectives
Patient-derived organoids will be developed from archival tumor tissue (if available) and 
exosomal lipids will be extracted from plasma samples to predict clinical response to 
Cabozantinib and Pembrolizumab. In order to participate in the correlative studies, patients will 
be consented on a separate biospecimen collection protocol. This separate consent allows 
collection of research blood and utilization of archival tumor tissue from patients enrolled in 
this clinical trial. Participation in correlative studies (organoids and lipids) is optional. 
2.
BACKGROUND
2.1
Pancreatic Cancer
Pancreatic cancer will soon become one of the deadliest cancers worldwide and routine diagnosis 
at advanced stages of disease complicates the ability to treat this devastating disease.1 In fact, 60-
80% of patients with pancreatic cancer have advanced disease at the time of diagnosis. 
Furthermore, >90% of patients develop metastatic disease and nearly all patients during their 
course of treatment become refractory to standard cytotoxic regimens. 
2.1.1
Current Treatment 
Current first-line standard of care therapy for metastatic pancreatic cancer is FOLFIRINOX [5-FU
+ leucovorin (LV) + oxaliplatin + irinotecan] or Gem-Abraxane (gemcitabine + nab-Paclitaxel). 
Each of these regimens are also indicated in the second-line as is the NAPOLI regimen (5-FU +
LV + nanoliposomal irinotecan). 

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2.1.2
Immunotherapy in Pancreatic Cancer
Immune checkpoint inhibitors targeting the PD-1/PD-L1 axis have been successful against certain 
cancers but have shown marginal improvement for pancreatic cancer survival.2-4
2.2
Cabozantinib
Cabozantinib (XL184) is a potent inhibitor of multiple receptor tyrosine kinases (RTKs) known to play 
important roles in tumor cell proliferation and/or tumor neovascularization including MET, vascular 
endothelial growth factor receptor (VEGFR), AXL, and RET. Increased expression of MET and AXL 
has been implicated in the development of resistance to VEGFR inhibitors in preclinical models of 
several cancers (Shojaei et al 2010, Zhou et al 2016, Sennino et al 2012, Ciamporcero et al 2015). In 
addition, targets of Cabozantinib are implicated in promoting tumor-immune suppression including 
TYRO3, MER, and AXL [tumor-assisted macrophage (TAM) family kinases].
Cabozantinib capsules (140 mg) are approved in the US for the treatment of patients with progressive, 
metastatic medullary thyroid cancer (MTC). Cabozantinib tablets (60 mg) are approved in the US, 
Europe, and other regions for advanced renal cell carcinoma (different patient populations depending 
on region; Cabozantinib® US PI). Based on the results from a randomized placebo-controlled Phase 3 
study (CELESTIAL) in subjects who had received prior sorafenib, Cabozantinib tablets (60 mg) as a 
single agent have also been approved in the US, EU, and other regions for a hepato-cellular carcinoma 
indication.
Cabozantinib has also demonstrated encouraging clinical activity in other tumor indications: 
monotherapy in advanced urothelial carcinoma (Apolo et al [J Clin Oncol] 2016), in combination with 
ICIs in advanced urothelial carcinoma (Nadal et al 2018, Nadal et al 2017, Apolo et al [Ann Oncol] 
2016), monotherapy in castration-resistant prostate cancer (Smith et al 2013, Smith et al 2014, Basch 
et al 2015), monotherapy or in combination with erlotinib in advanced non-small cell lung cancer 
(NSCLC) (Schöffski et al 2017, Neal et al 2016), monotherapy in RET-rearranged NSCLC (Drilon et 
al 2016), monotherapy in advanced TNBC (Tolaney et al 2017), monotherapy in advanced OC 
(Matulonis et al 2016, Vergote et al 2017), monotherapy in advanced EC (Dhani et al 2017; Mandilaras 
et al 2017), monotherapy in advanced GC (Schöffski et al 2017), in combination with panitumumab in 
CRC (Strickler et al 2016), and monotherapy in radioactive-iodine refractory DTC (Brose et al 2018, 
Cabanillas et al 2014, Cabanillas et al 2017). Cabozantinib has also been shown to be safe when 
combined with pembrolizumab in a phase I study for patients with renal cell carcinoma (Keeler et al 
2019). More recently, a phase 3 randomized controlled trial for advanced renal cell cancer 
demonstrated the safety and efficacy of nivolumab combined with cabozantinib at 40 mg (Choueiri et 
al 2021). This cabozantinib dosage has been selected for the proposed pancreatic cancer clinical trial.
Preclinical studies (Kwilas et al 2014, Song et al 2015, Lu et al 2017) and clinical observations on 
circulating immune suppressive cells and immune effector cells (Apolo et al 2014) suggest that 
Cabozantinib promotes an immune-permissive environment through inhibition of immune-modulatory 
targets on immune cells. This might present an opportunity for synergistic effects from combination 
treatment with ICIs. The combination of Cabozantinib with ICIs may also provide a strategy to 
overcome resistance to ICI therapy. This is based on recent observations in clinical trials where re-
treatment with an ICI in combination with Cabozantinib or a VEGFR-TKI that has a target profile 
similar to Cabozantinib resulted in reversal of prior ICI resistance in advanced UC and NSCLC patients 
(Nadal et al 2018, Leal et al 2017). These results suggest that combining ICIs with Cabozantinib may 
result in a tumor microenvironment that is conducive to re-sensitization to ICI therapy after prior 
progression on an ICI.

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2.3
Pembrolizumab
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) 
with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting its 
interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-
L2).  Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor 
blocking activity for PD-1.  Pembrolizumab has an acceptable preclinical safety profile and is in 
clinical development as an intravenous (IV) immunotherapy for advanced malignancies. 
Keytruda® (pembrolizumab) is indicated for the treatment of patients across a number of 
indications because of its mechanism of action to bind the PD-1 receptor on the T cell.  
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, 2010].  Accumulating evidence shows a 
correlation between tumor-infiltrating lymphocytes 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 (T-regs) correlates with improved prognosis and long-term 
survival in solid malignancies, such as ovarian, colorectal, and pancreatic cancer; hepatocellular 
carcinoma; malignant melanoma; and renal cell carcinoma.  Tumor-infiltrating lymphocytes can 
be expanded ex vivo and reinfused, inducing durable objective tumor responses in cancers such as 
melanoma [Dudley et al., 2005; Hunder et al., 2008].
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 immunoglobulin (Ig) superfamily 
member related to cluster of differentiation 28 (CD28) and cytotoxic T-lymphocyte-associated 
protein 4 (CTLA-4) that has been shown to negatively regulate antigen receptor signaling upon 
engagement of its ligands (PD-L1 and/or PD-L2) [Greenwald et al., 2005; Okazaki et al., 2001].
The structure of murine PD-1 has been resolved [Zhang et al., 2004]. PD-1 and its family members 
are type I transmembrane glycoproteins containing an Ig-variable–type (IgV-type) domain 
responsible for ligand binding and a cytoplasmic tail 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, and an immunoreceptor tyrosine-based switch 
motif. Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, 
to the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, leading to the 
-
and zeta-chain-associated protein kinase (ZAP70), which are involved in the CD3 T-cell signaling 
cascade [Okazaki et al., 2001; Chemnitz et al., 2004; Sheppard et al., 2004; and Riley, 
2009]. The mechanism by which PD-1 down-modulates T-cell responses is similar to, but distinct 
from, that of CTLA-4, because both molecules regulate an overlapping set of signaling proteins 
[Parry et al., 2005; Francisco, 2010].  As a consequence, the PD-1/PD-L1 pathway is an attractive 
target for therapeutic intervention in pancreatic cancer. 
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W).  Based on the 
totality of data generated in the Keytruda development program, 200 mg Q3W is the appropriate 
dose of pembrolizumab for adults across all indications and regardless of tumor type.  As outlined 
below, this dose is justified by:

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Clinical data from 8 randomized studies in melanoma and NSCLC indications 
demonstrating flat dose- and exposure-efficacy relationships from 2 mg/kg Q3W to 10 
mg/kg Q2W, representing an approximate 5- to 7.5-fold exposure range.
Population PK analysis showing that both fixed dosing and weight-based dosing provides 
similar control of PK variability with considerable overlap in the distributions of exposures, 
supporting suitability of 200 mg Q3W
Clinical data showing meaningful improvement in benefit-risk including overall survival 
at 200 mg Q3W across multiple indications, and
Pharmacology data showing full target saturation in both systemic circulation (inferred 
from pharmacokinetic [PK] data) and tumor (inferred from physiologically-based PK 
[PBPK] analysis) at 200 mg Q3W
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled with 
melanoma and non-small cell lung cancer (NSCLC), covering different disease settings (treatment 
naïve, previously treated, PD-L1 enriched, and all-comers) and different treatment settings 
(monotherapy and in combination with chemotherapy).  Five studies compared 2 mg/kg Q3W versus 
10 mg/kg Q2W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and KN021), and 3 studies 
compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, KN001 Cohort F2 and KN006).  
All of these studies demonstrated flat dose- and exposure-response relationships across the doses 
studied representing an approximate 5- to 7.5-fold difference in exposure.  The 2 mg/kg (or 200 mg 
fixed-dose) Q3W provided similar responses to the highest doses studied.  Subsequently, flat dose-
exposure-response relationships were also observed in other tumor types including head and neck 
cancer, bladder cancer, gastric cancer and classical Hodgkin Lymphoma, confirming 200 mg Q3W as 
the appropriate dose independent of the tumor type.  These findings are consistent with the mechanism 
of action of pembrolizumab, which acts by interaction with immune cells, and not via direct binding 
to cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W.  First, PK data in 
KN001 evaluating target-mediated drug disposition (TMDD) conclusively demonstrated saturation of 
PD-1 in systemic circulation at doses much lower than 200 mg Q3W.  Second, a PBPK analysis was 
conducted to predict tumor PD-1 saturation over a wide range of tumor penetration and PD-1 
expression.  This evaluation concluded that pembrolizumab at 200 mg Q3W achieves full PD-1 
saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of body weight 
and other participant covariates on exposure, has shown that the fixed-dosing provides similar control 
of PK variability as weight based dosing, with considerable overlap in the distribution of exposures 
from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose.  Supported by these PK characteristics and 
given that fixed-dose has advantages of reduced dosing complexity and reduced potential of dosing 
errors, the 200 mg Q3W fixed-dose was selected for evaluation across all pembrolizumab protocols.
2.4
Study Rationale and In Vivo Studies
Our previous studies revealed autonomous PD-1 expression and functionality on pancreatic cancer 
cells, organoids, and mouse models devoid of immune cells (Fig. 1).5 Furthermore, we conducted 
a phospho-protein array which revealed activation of the oncogene MET by the PD-1/PD-L1 axis 
(Fig. 2). We then performed western blot assays and observed PD-1-dependent activation of MET 
(Fig. 3). These data suggested an avenue for directly targeting cancer cells by targeting both the 
immune checkpoint and MET pathways in combination. 

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Since PD-1 and MET are proteins targeted by current clinical drugs, Pembrolizumab and 
Cabozantinib, respectively, this novel multi-targeted combination is appropriate for human clinical 
trials. We observed synergistic killing from immune checkpoint inhibitors and Cabozantinib in 
pancreatic cancer cells and organoids (Figs. 4 and 5, below). Currently, human trials combining 
Cabozantinib with immune checkpoint inhibitors are being conducted in various cancer types, but 
none have investigated this combination in pancreatic cancer. Our goal is to administer this clinical 
combination with the goal to increase metastatic pancreatic cancer survival.

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2.5
Correlative Studies Background
Cancer immunotherapies represent an important and novel class of antitumor agents. However, 
the mechanism of action of these exciting new therapies, including novel combinations with anti-
MET, is not completely understood and much remains to be learned regarding how best to leverage 
these new drugs in treating patients. Thus, to aid future patients, it is important to investigate the 
determinants of response and resistance to cancer immunotherapy and other treatments 
administered, as well as determinants of adverse events (AEs) in the course of our clinical studies. 
These efforts may identify novel predictive or disease progression biomarkers and generate 
information that may better guide single-agent and combination therapy with immuno-oncology 
drugs. 
To accomplish these goals, we will examine plasma exosomal lipids and utilize patient-derived 
organoids (PDOs). Exosomes are extracellular vesicles released from cells that play a role in 

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intercellular signaling and transport of proteins, lipids, and nucleic acids. Exosomes are released 
from numerous cells in the body and have been detected in blood, bile, urine, cerebrospinal fluid, 
and tissues. Cancer cells produce elevated concentrations of exosomes compared to normal cells
(Muralidharan-Chari et al, 2010). Cancer-derived exosomes interact with the tumor 
microenvironment and impact cancer proliferation, metastasis, immune evasion (Muralidharan-
Chari et al 2010; Arscott et al, 2011; Costa-Silva et al, 2015; Gesierich et al, 2006; Upadhrasta et 
al, 2019; Zech et al, 2012) and drug resistance (Safaei et al, 2005; Yu et al, 2015). Our previous 
work revealed distinct lipid profiles in plasma exosomes from pancreatic cancer patients compared 
to healthy volunteers, thus highlighting the potential to use blood-based exosomal lipids as a 
biomarker for pancreatic cancer. Our group profiled exosomal lipids from 60 pancreatic cancer 
patients and 38 healthy volunteers. Our data showed that the exosomal lipid composition of 
pancreatic cancers was distinct from matched benign pancreatic tissues (Fig. 6A) and 
discriminated cancer from healthy controls (Figs. 6B and 6C). By using advanced multivariate 
statistical approaches to analyze plasma exosomal lipid profiles of different cohorts, we observed 
a high sensitivity and specificity to detect pancreatic cancer with a set of 20 lipid features (Figs. 7
and 8). These results demonstrated the potential for liquid biopsies to harbor exosomal lipids that 
are pancreatic cancer biomarkers that can be utilized to monitor responses to clinical therapies. 
PDOs are three-dimensional in vitro models used to study the biology of human cancers and their 
interactions with the cancer microenvironment. They function as miniature organs with cells that 
resemble the epithelium of origin by maintaining innate tissue cytoarchitecture, giving rise to 
distinct cell lineages, and undergoing self-renewal. Importantly, organoids possess all the genetic 
alterations present in the primary cancer tissues, making them precise genomic models of human 
cancers and have tremendous potential for predicting in vivo drug sensitivity (Boj et al, 2015; Gao 
et al, 2019; Tiriac et al, 2018). In prior studies, we observed that the results of drug testing in PDOs 
exactly mirrored the results from patient derived tumor xenografts, which is considered the gold 
standard cancer model. Since PDOs can be developed and drug tested rapidly, we propose to utilize 
this model to predict response to the proposed combination therapy. We will also determine if 
PDO prediction of therapy corresponds to data gathered from plasma exosome analysis. 

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To carry out these investigations, we will collect liquid biopsies from all patients prior to initiation 
of therapy and once monthly to determine if we can correlate clinical response to exosomal lipid 
levels. Methods for this analysis will follow prior investigations (Fan et al, 2018; Lane et al, 2009). 
We will collect tumor samples, when possible, for development of PDOs as previously described
(Gao et al, 2018; Tiriac et al, 2018). These organoids will be used to test sensitivity to the 
combination of Cabozantinib and Pembrolizumab to predict clinical response.
2.6
Study Hypothesis 
We hypothesize that Cabozantinib will synergize with Pembrolizumab to improve PFS in the 2nd
line setting for patients with metastatic pancreatic cancer.

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3.
ELIGIBILITY
3.1
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
3.1.1
Male/female participants who are at least 18 years of age on the day of signing informed 
consent with histologically confirmed diagnosis of pancreatic ductal adenocarcinoma, 
stage IV will be enrolled in this study.
3.1.2
Have measurable disease based on RECIST v1.1 (Response Evaluation Criteria in Solid 
Tumors). Lesions situated in a previously irradiated area are considered measurable if 
progression has been demonstrated in such lesions. 
3.1.3
Evidence of progression or intolerance to previous standard of care pancreatic cancer 
systemic or locoregional therapies. Patients may have received prior radiation therapy and 
chemotherapy >4 weeks from start of treatment. Patients may not have been on prior 
clinical trial with investigational drugs for this cancer. 
3.1.4
Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. 
Evaluation of ECOG is to be performed within 7-14 days prior to the first dose of study 
intervention. (see Appendix A).
3.1.5
Patients must have adequate organ function as defined below. Specimens must be collected 
within 14 days prior to the start of study intervention:
absolute neutrophil count
1,500/µL
platelets
100,000/µL
hemoglobin
9.0 g/dL
Criteria must be met 
without erythropoietin dependency and without 
packed red blood cell (pRBC) transfusion within last 
2 weeks.
total bilirubin
1.5 x ULN or direct bilirubin 
ULN for 
participants with total bilirubin levels >1.5 x ULN
AST(SGOT)/ALT(SGPT)
2.5 × ULN
5 × ULN for participants with liver
                                                          metastases)
International normalized ratio
(INR) or prothrombin time 
anticoagulant therapy as long as PT or aPTT is
(PT) and activated thrombo-
within the therapeutic range of intended use of
plastin time (aPTT)
anticoagulants                       
Serum Cr or measured or 
1.5 x ULN or calculated creatinine clearance 
     calculated creatinine clearance
30 mL/min (
using Cockcroft-Gault
(GFR can be used in place of
equation) for participants with Cr >1.5 x ULN
Cr or CrCl)                                                     
Urine protein/creatinine ratio        UPCR
1 mg/mg
113.2 mg/mmol)
3.1.6
Patients must have a negative hepatitis screening test. Patients with a history of hepatitis C 
virus (HCV) infection must have been treated and cured. For patients with HCV infection 

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15 
who are currently on treatment, they are eligible if they have an undetectable HCV viral 
load. 
3.1.7
Patients with treated brain metastases are eligible if follow-up brain imaging after central 
nervous system (CNS)-directed therapy shows no evidence of progression.   
3.1.8
Patients with a prior or concurrent malignancy whose natural history or treatment does not 
have the potential to interfere with the safety or efficacy assessment of the investigational 
regimen are eligible for this trial.  
3.1.9
A male participant must agree to use a contraception during the treatment period and for 4 
months after the last dose of study treatment and refrain from donating sperm during this 
period.  
Male participants with female partners of childbearing potential are eligible to participate 
if they agree to one of the following during the protocol defined time frame in section X:  
Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent 
Use a male condom plus partner use of a contraceptive method with a failure rate of 
<1% per year when having penile-vaginal intercourse with a woman of childbearing 
potential who is not currently pregnant. 
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of penile 
penetration. 
3.1.10 A female participant is eligible to participate if she is not pregnant, not breastfeeding, and 
at least one of the following conditions applies: 
a. Not a woman of childbearing potential (WOBCP) or 
b. A WOCBP who agrees to follow contraceptive guidance during the treatment period and 
for 4 months after the last dose of treatment. 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below) 
Women in the following categories are not considered WOCBP: 
Premenarchal
 Premenopausal female with 1 of the following: 
Documented hysterectomy
Documented bilateral salpingectomy
 Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
Postmenopausal female
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. 
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 

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12 months of amenorrhea, confirmation with two FSH measurements in the 
postmenopausal range is required. 
Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment.
Female participants of childbearing potential are eligible to participate if they agree to use 
a highly effective method of contraception that has a low user dependency consistently and 
correctly.  
Table 1. Highly Effective Contraceptive Methods That Have Low User Dependency
Highly Effective Methods That Have Low User Dependency 
Failure rate of <1% per year when used consistently and correctly.
Progestogen- only contraceptive implant a, b
Intrauterine hormone-releasing system (IUS) b
Intrauterine device (IUD)
Bilateral tubal occlusion
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner is the 
sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an 
additional highly effective method of contraception should be used. 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant. 
Notes:
Use should be consistent with local regulations regarding the use of contraceptive methods for 
participants of clinical studies.
a) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable contraceptive implants are limited to those which inhibit ovulation.
b) If hormonal contraception efficacy is potentially decreased due to interaction with study 
treatment, condoms must be used in addition to the hormonal contraception during the treatment 
period and for at least [X days, corresponding to time needed to eliminate study treatment plus 30 
days for study treatments with genotoxic potential] after the last dose of study treatment.  
3.1.11 The participant (or legally acceptable representative if applicable) has the ability to 
understand and the willingness to provide written informed consent for the trial. 
3.1.12 Able to swallow oral medication

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3.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply: 
3.2.1
Chemotherapy or other locoregional anti-tumoral therapies performed within 28 days of
study treatment initiation. 
3.2.2
Has received palliative radiation therapy within 2 weeks or any other radiation therapy 
within 4 weeks of start of study intervention. Systemic treatment with radionuclides 
within 6 weeks before first dose of study treatment. Participants must have recovered from 
all radiation-related toxicities, not require corticosteroids, and not have had radiation 
pneumonitis.  A 1-
radiotherapy) to non-CNS disease.
Subjects with clinically relevant ongoing 
complications from prior radiation therapy are not eligible.
3.2.3
Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., 
have residual toxicities > Grade 1), unless AEs are clinically non-significant and/or stable 
on supportive therapy. Participants must have recovered from all AEs due to previous 
3.2.4
Has received prior systemic anti-cancer therapy including investigational agents within 4 
weeks prior to allocation. Participants must have recovered from all AEs due to previous 
therapies to Grade 1 or baseline. Participants with Grade 2 neuropathy may be eligible. 
Participants with endocrine-related AEs Grade 
2 requiring treatment or hormone 
replacement may be eligible. If the participant received major surgery, the participant must 
have recovered adequately from the procedure and/or complications from the procedure 
and/or any complications from the surgery prior to starting study intervention.   
3.2.5
Has known active CNS metastases or carcinomatous meningitis. Participants with 
previously treated brain metastases may participate provided they are radiologically 
stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging (note 
that the repeat imaging should be performed during study screening), clinically stable and 
without requirement of steroid treatment for at least 14 days prior to first dose of study 
intervention. 
3.2.6
Has severe hypersensitivity ( Grade 3) to pembrolizumab or cabozantinib and/or any of 
their excipients. History of allergic reactions attributed to monoclonal antibodies (mAb), 
compounds of similar chemical or biologic composition to Cabozantinib
or 
Pembrolizumab.
3.2.7
Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose 
of study drug.  Administration of killed vaccines is allowed.
3.2.8
Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an 
agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, 
OX-40, CD137).
3.2.9
Prior treatment with Cabozantinib or other receptor for MET or dual MET/HGF 
monoclonal antibodies or MET/HGF tyrosine kinase inhibitors.

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3.2.10
Major surgery (e.g., laparoscopic nephrectomy, GI surgery, removal or biopsy of brain 
metastasis) within 2 weeks before first dose of study treatment. Minor surgeries within 10 
days before first dose of study treatment. Subjects must have complete wound healing 
from major surgery or minor surgery before first dose of study treatment. Subjects with 
clinically relevant ongoing complications from prior surgery are not eligible.
3.2.11 Gastrointestinal (GI) disorders including those associated with a high risk of perforation or 
fistula formation: 
i. The subject has evidence of tumor invading the GI tract, active peptic ulcer disease, 
inflammatory bowel disease (e.g., Crohn’s disease), diverticulitis, cholecystitis, 
symptomatic cholangitis or appendicitis, acute pancreatitis, acute obstruction of the 
pancreatic duct or common bile duct, or gastric outlet obstruction.
ii. Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess 
within 6 months before first dose of study treatment. 
iii. Note: Complete healing of an intra-abdominal abscess must be confirmed before first 
dose of study treatment.
3.2.12
Has a history of known additional malignancy that is progressing or has required active 
treatment within the past 3 years; or unless potentially curative treatment has been 
completed with no evidence of malignancy for 3 years. The time requirement does not 
apply to participants who underwent successful definitive resection of basal cell 
carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, in 
situ cervical cancer, or other in-situ cancers (e.g., breast carcinoma).
3.2.13 Has a diagnosis of immunodeficiency (autoimmune disease) or is receiving chronic 
systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any 
other form of immunosuppressive therapy within 7 days prior to first dose of study 
treatment.   
  Note: Inhaled, intranasal, intraarticular, and topical corticosteroids and mineralocorticoids 
are allowed. Transient short-term use of systemic corticosteroids for allergic conditions (e.g., 
contrast allergy) is also allowed. Replacement therapy (e.g., thyroxine, insulin, or physiologic 
corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered 
a form of systemic treatment and is allowed.
3.2.14 Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. 
with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment and is allowed. 
3.2.15 Clinically significant cardiovascular disease, for example cerebrovascular accidents (less 
than 6 months, CVA) /stroke, myocardial infarction (also less than 6 months), unstable 
angina pectoris, New York Heart Association class 3 or 4 congestive heart failure, or 
serious cardiac arrhythmia requiring medication. 
3.2.16 Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm Hg systolic 
or > 90mm Hg diastolic despite optimal antihypertensive treatment. 

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3.2.17 QT interval calculated by the Fridericia formula (QTcF) > 480 ms per electrocardiogram 
(ECG) within 14 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 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 
3.2.18 Concomitant anticoagulation with or plan to use oral anticoagulants (warfarin, direct 
thrombin and Factor Xa inhibitors) or platelet inhibitors (e.g., clopidogrel). Allowed 
anticoagulants are the following:
Prophylactic use of low-dose aspirin for cardio-protection (per local applicable 
guidelines) and low-dose low molecular weight heparins (LMWH).
Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors 
rivaroxaban, edoxaban, or apixaban in subjects without known brain metastases who are 
on a stable dose of the anticoagulant for at least 1 week before first dose of study 
treatment without clinically significant hemorrhagic complications from the 
anticoagulation regimen or the tumor.
3.2.19 Pregnant, breastfeeding, and/or lactating women. A WOCBP who has a positive urine 
pregnancy test within 72 hours prior to allocation will be excluded. If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be required. 
Female subjects are considered to be of childbearing potential unless one of the following 
criteria is met: permanent sterilization (hysterectomy, bilateral salpingectomy, or bilateral 
oophorectomy) or documented postmenopausal status (defined as 12 months of 
amenorrhea in a woman over 45 years-of-age in the absence of other biological or 
physiological causes. In addition, females under 55 years-of-age must have a serum follicle 
stimulating hormone (FSH) level > 40 mIU/mL to confirm menopause). 
3.2.20 Patients that are expecting to conceive or father children within the projected duration of 
the study, starting with the screening visit through 120 days after the last dose of trial 
treatment.
3.2.21 Patients with uncontrolled intercurrent illness.
3.2.22  Patients with known psychiatric illness or substance abuse disorders or other social 
situations that would interfere with cooperation with the requirements of the trial. 
3.2.23 Inability to swallow tablets.
3.2.24 Has had an allogenic tissue/solid organ transplant.
3.2.25 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 of study treatment.

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3.2.26 Cavitating pulmonary lesion(s) related to bacterial infections or pneumonia or known 
endotracheal or endobronchial disease manifestation. Note that cavitating pulmonary 
lesion(s) related to malignancy, with the exception of central lesions measuring 4 cm, are 
not excluded. 
3.2.27 Lesions invading or encasing major blood vessels, specifically the abdominal aorta and 
inferior vena cava. Encasement of local vascular structure(s) is not excluded. 
3.2.28 Other clinically significant disorders that would preclude safe study participation. 
a.
Serious non-healing wound/ulcer/bone fracture.  
b. Uncompensated/symptomatic hypothyroidism
3.2.29 Moderate to severe hepatic impairment (Child-Pugh B or C). 
3.2.30 Is currently participating in or has participated in a study of an investigational agent or has 
used an investigational device within 4 weeks prior to the first dose of study intervention. 
Participants who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks after the last dose of the previous investigational 
agent.  
3.2.31 Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids 
or has current pneumonitis/interstitial lung disease. 
3.2.32 Has an active infection requiring systemic therapy.
3.2.33 Has a known history of Human Immunodeficiency Virus (HIV) infection.  No HIV testing 
is required unless mandated by local health authority.  
3.2.34 Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] 
reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) 
infection.  
3.2.35 Has a known history of active TB (Bacillus Tuberculosis).   
3.2.36 Has a history or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the study, interfere with the subject’s participation for the 
full duration of the study, or is not in the best interest of the subject to participate, in the 
opinion of the treating investigator.   
3.3
Inclusion of Women and Minorities
Women and members of minority groups and their subpopulations will be included.   

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4.
INVESTIGATOR REQUIREMENTS AND REGISTRATION PROCEDURES
4.1
Protocol Review and Monitoring Committee and Institutional Review Board 
Before implementing this study, the protocol must be reviewed by the Markey Cancer Center’s 
Protocol Review and Monitoring Committee (PRMC). Additionally, the protocol, the proposed 
informed consent form and other information to subjects, must be reviewed by the University of 
Kentucky Institutional Review Board (IRB). A signed and dated UK IRB initial review approval 
memo must be maintained in the Markey Cancer Center Clinical Research Office (MCC CRO) 
regulatory binder. Any amendments to the protocol, other than administrative ones, must be 
reviewed and approved by the PRMC, and UK IRB. 
4.2
Investigator and Research Associate Registration with MCC
All investigators must be qualified by education, training and experience to assume responsibility 
for the proper conduct of human subject research.  Investigators are responsible for being able to 
provide evidence of such qualifications through up-to-date curriculum vitae and/or other relevant 
documentation and training per institutional, state and federal guidelines.  All investigators 
conducting MCC trials will register with the MCC Clinical Research Office and complete all 
requisite training and registrations per MCC SOPs.  
4.2.1
Delegation of Tasks Log (DTL)
All MCC studies require a Delegation Task Log which is maintained by the MCC Regulatory Unit 
of the Clinical Research Office. The DTL for this study has training requirements as follows: In 
order to be added to the DTL for a given study, each staff member must have appropriate training 
to conduct assigned duties including but not limited to protocol-specific training. The DTL log 
will identify the protocol version on which each staff member was trained when being added to a 
study. 
The Principal Investigator and Co-Investigator are responsible for monitoring the conduct and 
progress of the clinical trial, including the ongoing review of accrual, patient-specific clinical and 
laboratory data, and routine and serious adverse events; reporting of expedited adverse events; and 
accumulation of reported adverse events from other trials testing the same drug(s). The Principal 
Investigator and Statistician have access to the study data at all times through OnCore.  All 
decisions regarding dose modifications of HAI require consultation with the Principal Investigator. 

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4.3
Screening and Study Enrollment Guidelines
4.3.1
Overview
Eligible patients will be identified by the principal investigator and co-investigators of this study. 
Potentially eligible patients will be recruited from medical and surgical oncology clinics at the 
University of Kentucky Markey Cancer Center, with oversight by the Principal Investigator. The 
consenting professional will explain in detail the study to the patient and will review the informed 
consent with the patient (Section 4.4). Broadly, patients will be made aware of the protocol, its 
specific aims and objectives, and the potential risks and benefits the patient may incur. A copy of 
the signed informed consent form is provided to the patient. Upon obtaining consent, study staff 
will register potentially eligible patients in the OnCore database. During the screening and 
enrollment process, registering individuals (study staff and PI) will be required to complete a 
protocol-specific Eligibility Checklist for each patient. The PI or treating physician signing the 
Eligibility Checklist is confirming whether or not the patient is eligible to enroll in the trial. Upon 
confirmation of eligibility, the patient will be enrolled into the study as participant (i.e., on-study 
date is entered in OnCore).  
4.3.2
Informed Consent
The goal of the informed consent process is to provide people with sufficient information so they can 
make informed choices about whether to begin or continue participation in clinical research.  The 
process involves a dynamic and continuing exchange of information between the research team and 
the participant throughout the research experience.  It includes discussion of the study's purpose, 
research procedures, risks and potential benefits, and the voluntary nature of participation.
The informed consent document provides a summary of the clinical study and the individual's rights 
as a research participant.  The document acts as a starting point for the necessary exchange of 
information between the investigator and potential research participant.  Also, research participants 
and their families may use the consent document as an information resource and reference throughout 
participation in the trial.  The informed consent document is often considered the foundation of the 
informed consent process; it does not, however, represent the entirety of the process.  Nor is the 
informed consent document a risk-management tool for the investigator and/or institution.
The investigator must explain to each subject (or legally authorized representative) the nature of the 
study, its purpose, the procedures involved, the expected duration, the potential risks and benefits 
involved and any discomfort it may entail. Each subject must be informed that participation in the 
study is voluntary and that he/she may withdraw from the study at any time and that withdrawal of 
consent will not affect his/her subsequent medical treatment or relationship with the treating physician.
This informed consent should be given by means of a standard written statement, written in non-
technical language. The subject should read and consider the statement before signing and dating it, 
and should be given a copy of the signed document. If the subject cannot read or sign the documents, 
oral presentation may be made or signature given by the subject’s legally appointed representative, if 
witnessed by a person not involved in the study, mentioning that the patient could not read or sign the 
documents. No patient can enter the study before his/her informed consent has been obtained.  The 
informed consent form is considered to be part of the protocol, and must be submitted by the 
investigator with the protocol at the time of IRB review.

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4.3.3
Screening and Enrollment Guidelines
Prior to any study-required tests, subjects must first provide written informed consent to participate 
in this study.  
Pre-treatment evaluation and their corresponding timeframes to screen for and verify eligibility
for study enrollment include the following: 
Medical History: within 4 weeks
Physical Exam, Vitals: within 2 weeks prior to treatment initiation
ECG: within 4 weeks 
Imaging to confirm disease at baseline: scans must be within 8 weeks
ECOG Performance Status: within 2 weeks
CBC w/ diff, platelets: within 2 weeks
CMP (Alk phos, total bilirubin, AST, ALT, and albumin): within 2 weeks
Urine protein/creatinine ratio (UPCR): within 2 weeks
Urine/serum pregnancy test: within 4 weeks 
TSH: at baseline 
Viral serologies (hepatitis, HIV): these will be checked to assess current or past infection 
and viral load as indicated
4.4
Eligibility Confirmation and Enrollment
The following information should be reviewed by the Clinical Research Nurse (CRN) / Clinical 
Research Associate (CRA) with the study physician per MCC SOPs to confirm eligibility:
Copy of required laboratory tests
Pathology reports and Imaging reports
Signed patient consent form
HIPAA authorization form
Physician dictations and Referring physician records (as available)
Eligibility Checklist
Once eligibility is confirmed, the CRN/CRA will complete subject enrollment to the study in the 
OnCore database. To complete the enrollment process, the CRN/CRA will complete the OnCore 
on-study form, which comprises the following: 
Assignment of a patient study number
diagnosis
date of diagnosis
histology
entry of the On-Study date
Patients will be instructed to complete medication logs for Cabozantinib (“pill diaries”) and 
return the logs on clinic visits for review by the study team. See Appendix B for a sample 
Cabozantinib Medication Log. 

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24 
5.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES
Patient-derived organoids and exosomal lipids will be developed and tested to predict response to 
Cabozantinib and Pembrolizumab. To participate in this study’s correlatives, enrolled trial 
participants will be asked to sign a separate consent in order for collection of blood/tumor tissue 
underlying analyses of exploratory endpoints (i.e., patient-derived organoids and exosomal lipids). 
Participation in the correlatives component is optional.   
5.1
Summary for Specimen Collection
Specimen
Archival Tumor Tissue (optional, if available) 
Archival Tumor Tissue to develop patient-derived organoids: 
Prospective biopsies are not required.
If pancreatic cancer tissues from the patients enrolled on this clinical trial are available
from prior biopsy and prior storage in Dr. Kim’s biobank, they will be used to develop 
patient-derived organoids.* 
Pre-treatment Baseline (optional blood draw)
Optional Blood Draw for Exosomal Lipids: 
              10 cc blood in lavender-top tube with EDTA. * 
Send specimens to 
Dr. Teresa Fan lab
Once Monthly during the 6-month study period (optional blood draws) 
Optional Blood Draws for Exosomal Lipids: 
           10 cc blood in lavender-top tube with EDTA. *  
Cycle 2 visit
Cycle 3 visit
Cycle 4 visit
Cycle 5 visit
Cycle 6 visit
Cycle 7 visit
Send specimens to
Dr. Teresa Fan lab
*The samples for correlatives analyses will be collected via another protocol for biospecimen 
sample collection. Thus, patients enrolled on this clinical trial will be asked to sign a separate
consent form for collection of blood and access to archival tumor tissue.  
5.2
Specimen Collection and Processing 
As noted above, patients enrolled on this clincal trial will also be asked to sign a separate
biospecimen consent, allowing collection of blood and access to archival tumor tissue (if available) 
that underlies the correlative studies of this trial. Appendix C describes procedures for establishing 
tumor organoid cultures from human pancreatic cancer specimens. Appendix D describes 
procedures for lipid exosomal analysis from plasma samples.  

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6.
TREATMENT PLAN
6.1
Pembrolizumab/Cabozantinib Administration
Reported adverse events and potential risks are described in Section 10.  Appropriate dose 
modifications are described in Section 7.  No investigational or commercial agents or therapies 
other than those described below may be administered with the intent to treat the patient's 
malignancy.
6.1.1
First Dose of the Combination Therapy
The first doses of Cabozantinib and Pembrolizumab (C1D1) will be administered at the clinic; 
Pembrolizumab is to be administered first. After the completion of IV administration of the first 
dose of Pembrolizumab in the clinic, the subject will wait for at least 1 hour before taking 
Cabozantinib. If the subject develops an infusion reaction, the oral administration of Cabozantinib 
will be delayed or interrupted until the subject has recovered and the investigator believes that it 
is safe to administer Cabozantinib. 
The subject will be fasted (with the exception of water) for at least 2 hours before receiving the 
initial dose of Cabozantinib in the clinic. The subject will receive the oral dose of Cabozantinib 
with a minimum of 8 oz. (240 mL) of water in the clinic and then the subject will continue to fast 
for 1 hour while under in-clinic observation to monitor for potential AEs.
6.1.2
Subsequent Daily Doses of Cabozantinib
Following the first dose of Cabozantinib, the subject should take subsequent Cabozantinib doses 
outside the clinic at approximately the same time every day, preferentially before going to bed, 
and should adhere to the fasting requirements described in this section. Subjects should fast (with 
the exception of water) for at least 2 hours after eating the evening meal before taking their dose. 
After the 2-hour fast and before going to bed, subjects are to take Cabozantinib with a full glass of 
water (minimum of 8 oz or 240 mL) with no more food intake for one hour post-dose. If the 
subject’s schedule requires taking Cabozantinib during the day, the subject is to be instructed to 
follow the same fasting recommendations.

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6.1.3
Treatment Regimen 
Table 2. Overview of Cabozantinib and Pembrolizumab Combination
Regimen Description
Agent
Premedications; Precautions
Dose
Route
Schedule
Cycle 
Length
Pembrolizumab
(MK-3475)
N/A
200 mg
IV 
infusion
Day 1, 
Q3 weeks
Q3 
weeks
Cabozantinib
(XL184)
1 hour before or 2 hours after 
meal; take dose with 8oz water 
(minimum).
Swallow tablets (do not crush 
or chew). 
Avoid grapefruit and Seville 
oranges during treatment.
40 mg
Oral
Daily
Notes: 
Cabozantinib: 
Subjects are to be instructed to not make up vomited doses and to maintain the planned dosing
schedule. Subjects are not to make up for missed doses if more than 12 hours have elapsed after
the time the subject would usually take Cabozantinib. In the event of missed doses, subjects are
not to take 2 doses to make up for the one the subject missed.
Participants will be provided a daily dosing diary with instructions to record Cabozantinib, in 
accordance with the SOP on compliance with oral medications per Markey Cancer Center 
Quality Assurance Office.  
-
The patient will be requested to maintain a medication diary of each dose of medication. 
The diary will be distributed on C1D1 and collected at the beginning of Cycle 2, etc.
-
The medication diary will be returned to clinic staff at the end of each 21-day course. 
-
The daily diary is not a CRF. The diary will serve as source documentation and be 
maintained with other subject clinical source documents. 
-
Study staff should carefully review the diary with the subject and to ensure it is 
complete and accurate before transcription to the subject’s CRFs.

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Pembrolizumab Infusion Requirements and Guidance 
First Infusion
Subsequent Infusions:
• No premedication is permitted.
• Vital signs (blood pressure, respiratory 
rate, pulse, and temperature) should be 
recorded within 60 min prior to the 
infusion. 
• Pembrolizumab should be infused over 30 
min (-5 min/+10 min). 
• If clinically indicated, vital signs should 
be recorded during the infusion at 15, 30, 
45, and 60 min (± 5 min for all time points) 
during the infusion and at 30 (± 10) min 
after the infusion. 
• Subjects should be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact their
physician 
• If the subject experienced an infusion-related 
reaction with any previous infusion, 
premedication with antihistamines, antipyretics, 
and/or analgesics may be administered for 
subsequent doses at the discretion of the 
investigator.
• Vital signs should be recorded within 60 min 
prior to the infusion. 
• Pembrolizumab should be infused over 30 (± 
15) min if the previous infusion was tolerated 
without an infusion-related reaction, or 60 (± 
15) min if the subject experienced an infusion-
related reaction with the previous infusion. 
• If the subject experienced an infusion-related 
reaction with the previous infusion or if 
clinically indicated, vital signs should be 
recorded during the infusion and at 30 (± 5) min 
after the infusion. 
6.2
General Concomitant Medication and Supportive Care Guidelines
The chemotherapy pharmacist will review all medications (concurrent use of other all other drugs, 
over the counter medications or alternative therapies) for interactions at the start of therapy and 
new medications will be reviewed if started. The study team should check a frequently-updated 
medical reference for a list of drugs to avoid or minimize use of.   
Rescue Medications & Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in the 
protocol.  Where appropriate, these guidelines include the use of oral or IV treatment with 
corticosteroids, as well as additional anti-inflammatory agents if symptoms do not improve with 
administration of corticosteroids.  Note that several courses of steroid tapering may be necessary 
as symptoms may worsen when the steroid dose is decreased.  For each disorder, attempts should 
be made to rule out other causes such as metastatic disease or bacterial or viral infection, which 
might require additional supportive care.  The treatment guidelines are intended to be applied when 
the Investigator determines the events to be related to pembrolizumab.  
If after the evaluation of the event, it is determined not to be related to pembrolizumab, the 
Investigator does not need to follow the treatment guidance.  It may be necessary to perform 
conditional procedures such as bronchoscopy, endoscopy, or skin photography as part of 
evaluation of the event.  

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Participant Discontinuation Criteria
Discontinuation of study intervention does not represent withdrawal from the study. 
As certain data on clinical events beyond study intervention discontinuation may be important to the 
study, they must be collected through the participant’s last scheduled follow-up, even if the participant 
has discontinued study intervention.  Therefore, all participants who discontinue study intervention 
prior to completion of the protocol-specified treatment period will still continue to be monitored in this 
study and participate in the study visits and procedures, unless the participant has withdrawn from the 
study.
Participants may discontinue study intervention at any time for any reason or be discontinued from the 
study intervention at the discretion of the investigator should any untoward effect occur.  In addition, 
a participant may be discontinued from study intervention by the investigator or the Sponsor if study 
intervention is inappropriate, the study plan is violated, or for administrative and/or other safety 
reasons.  
A participant must be discontinued from study treatment but continue to be monitored in the study 
for any of the following reasons:
The participant or participant’s legally acceptable representative requests to discontinue 
study treatment
After prolonged study intervention interruption that prohibits restarting study intervention 
if agreed upon with the Sponsors.
Confirmed radiographic disease progression
Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment
Any study intervention-related toxicity specified as a reason for permanent discontinuation 
as defined in the guidelines for dose modification due to AEs
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or sponsor, placed the participant at unnecessary risk from continued 
administration of study treatment.
The participant has a confirmed positive serum pregnancy test
Noncompliance with study treatment or procedure requirements
Recurrent Grade 2 pneumonitis
The participant is lost to follow-up
Completion of 17 treatments (approximately 1 year) with the combination of 
cabozantinib and pembrolizumab or an additional 18 treatments with pembrolizumab 
monotherapy (total 35 treatments)
Note: The number of treatments is calculated starting with the first dose. 
Note: Completion of pembrolizumab Q3W monotherapy consists of 35 treatments 
(approximately 2 years).  Discontinuation of treatment may be considered for participants
who have attained a confirmed complete response (CR) and have been treated for at least 8
cycles (at least 24 weeks), receiving at least 2 cycles of the combination including 2 doses 
of pembrolizumab and at least 80% of the planned doses of cabozantinib beyond the date
when the initial CR was declared.
Administrative reasons

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Participant withdrawal From Study
A participant must be withdrawn from the study if the participant or the participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specified details regarding procedures to be performed at the time of withdrawal from the study 
as well as specific details regarding withdrawal from future biomedical research are outlined in 
this protocol. 
6.3
Compliance 
Subject compliance with outpatient study treatment will be assessed using drug dispensing and 
return records, progress notes about dose reductions/interruptions, subject interview, and the 
subject daily diary (Cabozantinib). These data will not be directly recorded in the CRF; rather, the 
CRF will capture intervals of constant dose and reasons for changes in dose level (e.g., dose level 
changes, periods where no dose was taken, and the reason for a dose level change).
6.4
Duration of Therapy
In the absence of treatment delays due to adverse events, the combination Cabozantinib + 
Pembrolizumab therapy may continue for up to 17 cycles in total (1 year of treatment); and up to 
35 cycles (2 years of treatment) with pembrolizumab monotherapy. Pembrolizumab treatment is 
administered Q3W which is defined as 1 cycle. Treatment will continue until one of the following 
criteria applies:
Disease progression
Intercurrent illness that prevents further administration of treatment
Unacceptable adverse event(s)
Patient decides to withdraw from the study
General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator
Clinical progression
Patient non-compliance
Pregnancy
o
All women of childbearing potential should be instructed to contact the investigator 
immediately if they suspect they might be pregnant (e.g., missed or late menstrual 
period) at any time during study participation.
Termination of the study by sponsor
The drug manufacturer can no longer provide the study agent
The reason for protocol therapy discontinuation and/or study removal, and the corresponding 
date must be documented in the Case Report Form (CRF).
Note: Completion of pembrolizumab Q3W monotherapy consists of 35 treatments (approximately 2 
years).  Discontinuation of treatment may be considered for participants who have attained a confirmed 
complete response (CR) and have been treated for at least 8 cycles (at least 24 weeks), receiving at least 
2 cycles of the combination including 2 doses of pembrolizumab and at least 80% of the planned 
doses of cabozantinib beyond the date when the initial CR was declared.

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6.5
Duration of Follow-Up
Safety: 
Patients will be followed for safety of the Cabozantinib/Pembrolizumab combination therapy for 
100-days after the last dose of Pembrolizumab (or the combination). 
Patients removed from the study treatment for unacceptable adverse event(s) will be followed 
until resolution or stabilization of the adverse event.  
Survival: 
Patients will be followed for disease progression and survival status up to 1 year post-therapy 
initiation or until death, whichever occurs first.
7.
PHARMACEUTICAL INFORMATION
A list of the adverse events and potential risks associated with Cabozantinib (investigational) and 
Pembrolizumab (commercial) can be found in Section 10.1.
7.1
Drug Ordering and Accountability
7.1.1
Procurement of medications: 
Prescriptions for medications will be written by the site PI, treating physician, preferably the 
medical oncologist, using study-approved standardized Markey Cancer Center order sets.  The 
clinical research pharmacist of the MCC-CRO will review and approve these orders per published 
MCC polices. Drug accountability will be maintained on a Drug Accountability Report Form 
(DARF).
7.1.2
Storage & Drug Accountability: 
The clinical research pharmacist at MCC-CRO will ensure that all study drug is stored in a secured, 
limited access storage area, under recommended storage conditions in accordance with applicable 
labeling and regulatory requirements and as provided by the separate study drug accountability 
manual. Under no circumstances should the investigator or other site personnel supply study drug 
to other investigators, patients, or clinics. Adequate records documenting receipts, use, return, loss, 
or other disposition of study provided drugs must be kept. Drug accountability forms will be used,
per institutional policies. Unless otherwise authorized by the co-sponsors, at the end of the clinical 
trial all drug supplies unallocated or unused by MCC or study patients must be returned in 
accordance with sponsors’ instructions. 
7.2
Cabozantinib
7.2.1
Product Description and Administration
Exelixis (one of the two co-sponsors) will provide adequate supplies of Cabozantinib, which will 
be supplied as 40-mg yellow film-coated tablets and also as 20-mg yellow film-coated tablets. 
The components of the tablets are listed below.
40 mg Cabozantinib tablets are yellow film-coated, oval shaped with no 
score, and debossed with “XL” on one side and “60” on the other side.
20 mg CABOMETYX tablets are yellow film-coated, round with no 
score, and debossed with “XL” on one side and “20” on the other side.

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Table 3. Cabozantinib Tablet Components and Composition
Ingredient
Function
% w/wa
Cabozantinib Drug Substance (25% drug load as free base)
Active Ingredient
31.68
Microcrystalline Cellulose (Avicel® PH-102)
Filler
38.85
Lactose Anhydrous (60M) 
Filler
19.42
Hydroxypropyl Cellulose (EXF)
Binder
3.00
Croscarmellose Sodium (Ac-Di-Sol®) 
Disintegrant
6.00
Colloidal Silicon Dioxide 
Glidant
0.30
Magnesium Stearate
Lubricant
0.75
Opadry® yellow film coating which includes
HPMC 2910/hypromellose 6 cp, titanium dioxide, triacetin, 
and iron oxide yellow
Film Coating
4.00
a weight fraction, expressed in percentage; HPMC, Hydroxypropyl methylcellulose
Preparation, Storage and Stability 
Store at 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F).
Administration
Refer to the treatment section for specific administration instructions. Oral: 40 mg once daily, 
continue as long as benefiting clinically or until unacceptable toxicity (Choueiri 2021); do not 
exceed 60 mg daily.  Administer on an empty stomach (1 hour before or 2 hours after eating).
Note: The prescribing information (for Cometriq) describes when to give food with respect 
to Cabozantinib; no food should be consumed for at least 2 hours before or for at least 1 hour after 
the Cabozantinib dose. Swallow whole; do not crush tablets. Do not substitute Cabozantinib
tablets.
7.2.2
Adverse Events from Cabozantinib monotherapy
Consult the package insert and investigator brochure for the most current and complete 
information. 
The most frequent AEs experienced
descending order of frequency were diarrhea, fatigue, nausea, decreased appetite, vomiting, weight 
decreased, PPE, constipation, hypertension, dysgeusia, dysphonia, and asthenia. For a full 
description of the safety profile of Cabozantinib, refer to the Cabozantinib Investigator’s Brochure.
Other medically important but less frequent AEs including arterial thrombotic AEs (e.g., TIA, 
and MI) and venous thrombotic AEs (e.g., DVT and PE), severe hemorrhagic events, proteinuria, 
wound-healing complications, 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
with Cabozantinib in descending order of frequency were anemia, AST increased, ALT increased, 

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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, hypokalemia, 
thrombocytopenia, hypertension, PPE, abdominal pain, mucosal inflammation, constipation, 
diarrhea, and vomiting. Adverse events should be managed with supportive care at the earliest 
signs of toxicity. Dose reductions and treatment interruptions should be considered. Dose 
reductions are recommended for events that, if persistent, could become serious or intolerable.  
Cabozantinib should be discontinued for the following AEs: 
visceral perforation or fistula formation, severe hemorrhage, serious arterial thromboembolic 
events, nephrotic syndrome, hypertensive emergency, persistent uncontrolled hypertension despite 
optimal medical management, and RPLS.
Gastrointestinal Disorders
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 (Turnage et al, 2016) are present. Discontinue Cabozantinib 
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 Appendix D. 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.
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.

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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. 
Discontinue Cabozantinib 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.
Cabozantinib should be discontinued in subjects with serious and life-threatening bleeding events 
or recent hemo
Thromboembolic events
Thromboembolic events are frequent in cancer subjects due to procoagulant changes induced by 
the malignancy or anticancer therapy. DVT and PE have been observed in clinical studies with 
Cabozantinib, including fatal events. Subjects who develop a PE and/or DVT should have study 
treatment interrupted until therapeutic anticoagulation is established. Treatment with Cabozantinib 
may be resumed in subjects with PE or DVT if it is determined that the event is uncomplicated 
and that the subject is deriving clinical benefit from Cabozantinib treatment and that 
anticoagulation does not place them at a significant risk that outweighs the benefit of resuming 
treatment per discretion of the investigator and according to individual protocols. Low molecular 
weight heparins are the preferred management for thrombotic events; oral anticoagulants (e.g., 
warfarin or other coumarin-related agents, direct thrombin or direct FXa inhibitors, or antiplatelet 
agents, or chronic use of aspirin above low dose levels for cardioprotection per local applicable 
guidelines) are not allowed except under the following circumstances: 
Allowed anticoagulants are the following:
a.
Prophylactic use of low-dose aspirin for cardio-protection (per local applicable 
guidelines) and low-dose low molecular weight heparins (LMWH).
b.
Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors 
rivaroxaban, edoxaban, or apixaban in subjects without known brain metastases 
who are on a stable dose of the anticoagulant for at least 1 week before first dose 
of study treatment without clinically significant hemorrhagic complications from 
the anticoagulation regimen or the tumor.
Arterial thrombotic events (e.g., TIA, MI) have been observed in studies with Cabozantinib. 
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
Appendix D 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 

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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.  Cabozantinib should be discontinued in subjects 
with hypertensive emergency. 
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 3 weeks prior to elective surgery. Do not 
administer cabozantinib for at least 2 weeks after major surgery and until complete wound healing.
Palmar-plantar erythrodysesthesia (PPE; also known as hand-foot syndrome), skin rash (including 
blister, erythematous rash, macular rash, skin exfoliation, dermatitis acneiform, and papular rash), 
pruritus, dry skin, erythema, pigmentary changes, and alopecia have been reported 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.
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 

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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.
Perform an oral examination prior to initiation of cabozantinib and periodically during 
cabozantinib treatment. Caution should be used in subjects receiving bisphosphonates and/or 
denosumab.
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. Withhold cabozantinib for development of ONJ until complete resolution.
Proteinuria
Proteinuria has been reported with Cabozantinib. Proteinuria should be monitored by measuring 
UPCR Appendix D provides treatment guidelines for proteinuria deemed related to Cabozantinib.
Cabozantinib should be 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). 
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.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported. RPLS should be 
considered in any subject presenting with seizures, headache, visual disturbances, confusion or 
altered mental function. Cabozantinib treatment should be discontinued in subjects with RPLS.
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.
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.

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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 medullary thyroid cancer (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 (approximately 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 > 500ms, two additional 
ECGs must be performed with intervals not less than 3-min apart within 30min after initial ECG.
If the average QTcF from the three ECGs is > 500 ms, the following actions must be taken: 
Interrupt Cabozantinib treatment
Immediately notify the Sponsor
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, discontinue these medications (http://www.qtdrugs.org)
 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 
ms.
QT prolongation can be unequivocally associated with an event other than Cabozantinib 
administration and is treatable/has been resolved
Sponsor has reviewed all available information and has agreed to the continuation of 
study treatment
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.
 Cabozantinib treatment must be permanently discontinued if either of the following applies: 
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

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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 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.
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. Monitor TSH with Pembro. 
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 as clinically indicated. 
Standard clinical practice guidelines should be used for management of electrolyte disorders and 
may include oral or IV 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.
Hepatocellular Toxicity
Elevations of aminotransferases (ALT and AST) and bilirubin have been observed during 
treatment with Cabozantinib. It is recommended that subjects with elevation of ALT, AST, and/or 
bilirubin have more frequent laboratory monitoring of these parameters. If possible, hepatotoxic 
concomitant medications should be discontinued in subjects who develop increased values of ALT, 
AST, or bilirubin, and other causes (e.g., cancer related, infection) should be evaluated.
Management guidelines for hepatotoxicity related to Cabozantinib treatment are in Appendix E. 
More frequent monitoring of transaminases should be considered and study treatment should be 
held until the etiology of the abnormalities is determined and these abnormalities are corrected or 
stabilize to clinically acceptable levels (e.g., baseline grade or lower). If hepatic toxicity resolved 
during a temporary hold and was deemed related to study treatment, then study treatment may be 
restarted at a reduced dose. Study treatment should be discontinued if hepatic dysfunction is not 
reversible despite temporary interruption of study treatment.

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7.2.3
Management of Adverse Reactions from Cabozantinib
Withhold CABOZANTINIB for NCI CTCAE Grade 4 adverse reactions, and for Grade 3 or 
intolerable Grade 2 adverse reactions that cannot be managed with a dose reduction or supportive 
care.
Upon resolution/improvement (i.e., return to baseline or resolution to Grade 1) of an adverse 
reaction, reduce the dose as follows:
If previously receiving 60 mg daily dose, resume treatment at 40 mg daily
If previously receiving 40 mg daily dose, resume treatment at 20 mg daily
If previously receiving 20 mg daily dose, resume at 20 mg if tolerated, otherwise, 
discontinue CABOZANTINIB
Permanently discontinue CABOZANTINIB for any of the following:
development of unmanageable fistula or GI perforation
severe hemorrhage
arterial thromboembolic event (e.g., myocardial infarction, cerebral infarction)
hypertensive crisis or severe hypertension despite optimal medical management
nephrotic syndrome
reversible posterior leukoencephalopathy syndrome
In Patients Concurrently Taking a Strong CYP3A4 Inhibitor: Reduce the daily CABOZANTINIB 
dose by 20 mg (for example, from 40 mg to 20 mg daily). Resume the dose that was used prior to 
initiating the CYP3A4 inhibitor 2 to 3 days after discontinuation of the strong inhibitor 
In Patients Concurrently Taking a Strong CYP3A4 Inducer: Increase the daily CABOZANTINIB 
dose by 20 mg (for example, from 40 mg to 60 mg daily or from 20 mg to 40 mg daily) as tolerated. 
Resume the dose that was used prior to initiating the CYP3A4 inducer 2 to 3 days after 
discontinuation of the strong inducer. The daily dose of CABOZANTINIB should not exceed 80 
mg. 
In Patients with Hepatic Impairment: Reduce the starting dose of CABOZANTINIB to 20 mg 
once daily in patients with mild or moderate hepatic impairment. CABOZANTINIB is not 
recommended for use in patients with severe hepatic impairment.
Nursing Guidelines 
Monitor vital signs prior to infusion, then every 15 minutes until 1 hour after infusion on first dose. 
All patients with a history of infusion reactions to this immunotherapy should be monitored every 
15 minutes until 1 hour after the end of the infusion. 
7.3
Pembrolizumab
Consult the package insert and investigator brochure for the most current and complete 
information. 
7.3.1
Product description: 
The recommended dose of KEYTRUDA in adults is 200 mg administered as an intravenous 
infusion over 30 minutes every 3 weeks until disease progression, unacceptable toxicity, or up to 
24 months in patients without disease progression.

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Investigational Product 
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.
Pembrolizumab will be provided by Merck as summarized in the table below. 
Table 4. Product Description
Product Name & Potency
Dosage Form
Pembrolizumab 100 mg/ 4mL
Solution for Injection
Packaging and Labeling Information
Supplies will be labeled in accordance with regulatory requirements.
Clinical Supplies Disclosure
This trial is open-label; therefore, the participant, 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.
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 received from 
Merck or designee, the amount dispensed to and returned by the participants 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.
7.3.2
Dose modification and toxicity management for immune-related Adverse Events 
associated with pembrolizumab and combination therapy
AEs associated with pembrolizumab exposure, including coadministration with additional 
compounds, 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/combination 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 study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab/combination treatment, administration of corticosteroids, and/or 
other supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology or 

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exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, or skin 
biopsy may be included as part of the evaluation. Based on the severity of irAEs, withhold or 
permanently discontinue pembrolizumab/combination treatment and administer corticosteroids. 
Attribution of Toxicity:
When study interventions are administered in combination, attribution of an adverse event to a 
single component is likely to be difficult. Therefore, while the investigator may attribute a toxicity 
event [to the combination,  to cabozantinib alone, or to pembrolizumab alone] for adverse events, 
both interventions must be held according to the criteria in section 8. 
Holding Study Interventions:
When study interventions are administered in combination, if the AE is considered immune-
related, both interventions should be held according to recommended dose modifications.
Restarting Study Interventions:
Participants may not have any dose modifications (no change in dose or schedule) of 
pembrolizumab in this study as described in Table 19.
If the toxicity does not resolve or the criteria for resuming treatment are not met, the participant 
must be discontinued from all study interventions.
If the toxicities do resolve and conditions are aligned with what is defined in [Table 19], the 
combination of cabozantinib and pembrolizumab may be restarted at the discretion of the 
investigator. In these cases where the toxicity is attributed to the combination or to 
cabozantinibi alone, re-initiation of pembrolizumab as a monotherapy may be considered at 
the principal investigator’s discretion.
7.3.3
Management of Adverse Reactions to Pembrolizumab dose holds or discontinuation
Dose modification (Section 8) and toxicity management guidelines for irAEs in Appendix F.
8.
DOSING DELAYS/DOSE MODIFICATIONS
Study participants will be monitored for AEs from the time of signing consent through 100-days 
after the date of the decision to permanently discontinue all study treatment (i.e., last dose). 
Participants will be instructed to notify their physician immediately for any occurring AE. 
The following should be taken into consideration in decisions regarding dose modifications 
(reductions and/or delays) for treatment-related side effects. 
Cabozantinib and Pembrolizumab have class-specific safety profiles based on their mechanism of 
action but may also cause AEs that overlap. For management of AEs that can be clearly attributed 
to Cabozantinib or Pembrolizumab, independent dose modification for either agent is allowed. 
Examples of VEGFR TKI associated AEs caused by Cabozantinib are hypertension 
and hand-foot syndrome. 
Examples of irAEs and common AEs caused by Pembrolizumab are fatigue, 

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musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, 
cough, dyspnea, constipation, pain, and abdominal pain. 
Examples of overlapping AEs are diarrhea and elevations in liver function tests. 
Table 5. Dose Modifications. 
Dose Level
Cabozantinib Dose 
Pembrolizumab Dose 
0 (starting dose) 
40 mg, oral, qd 
200mg, IV, Q3weeks
-1
20 mg, oral, qd
200mg, IV, Q3weeks
-2 
20 mg, oral, qod 
200mg, IV, Q3weeks
-3 
Discontinue Cabo 
200mg, IV, Q3weeks
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. Participants should be placed back on 
study therapy within 3 weeks of the scheduled interruption, unless otherwise discussed with the Sponsor. 
The reason for interruption should be documented in the patient's study record. 
8.1
Concomitant Medications/Vaccinations (allowed & prohibited)
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during 
the ongoing trial.  If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The final decision on any supportive therapy or vaccination rests 
with the investigator and/or the participant's primary physician. However, the decision to continue 
the participant on study intervention requires the mutual agreement of the investigator, the 
Sponsors (Exelixis & Merck), and the participant. 
Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a participant’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. 
Allowed anticoagulants are the following: prophylactic use of low-dose aspirin for cardio-
protection (per local applicable guidelines) and low-dose low molecular weight heparins 
(LMWH); and therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors 
rivaroxaban, edoxaban, or apixaban in subjects without known brain metastases who are on a 
stable dose of the anticoagulant for at least 1 week before first dose of study treatment without 
clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor. 
All concomitant medications received within 28 days prior to the first dose of trial intervention 
and up to 30 days after the last dose of trial intervention should be recorded.  If participants 
experience an SAE or ECI, concomitant medications administered 30 days after the last dose of 
trial intervention are to be recorded.

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8.2
Prohibited or Restricted Medications or Therapy
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial:
Concomitant medications that are known to prolong the QTc interval should be avoided in 
subjects who receive Cabozantinib until they have permanently discontinued Cabozantinib 
treatment (refer to http://www.qtdrugs.org for a list of drugs which have the potential to 
prolong the QTc interval.  
Anticoagulation with coumarin agents (e.g., warfarin), direct thrombin inhibitors (e.g., 
dabigatran), direct factor Xa inhibitor betrixaban, or platelet inhibitors (e.g., clopidogrel) 
are prohibited. 
Co-administration of Cabozantinib with strong inhibitors of the CYP3A4 family may 
increase Cabozantinib concentrations and should be avoided. See Appendix G.  
o
Strong CYP3A4 inhibitors: if possible, avoid concomitant use with Cabozantinib.  
Examples 
of 
strong 
CYP3A4 
inhibitors 
include: 
Boceprevir, 
clarithromycin, conivaptan, indinavir/ritonavir, itraconazole, ketoconazole, 
lopinavir/ritonavir, atazanavir, telaprevir, telithromycin, nefazodone, 
nelfinavir, posaconazole, ritonavir, saquinavir/ritonavir, and voriconazole. 
o
Grapefruit, grapefruit juice, star fruit and Seville oranges may also increase plasma 
concentrations of Cabozantinib and should also be avoided. 
o
Other drugs that inhibit CYP3A4 should be used with caution because these drugs 
have the potential to increase exposure (AUC) to Cabozantinib. 
o
Selection of alternate concomitant medications with no or minimal CYP3A4 
enzyme inhibition potential is recommended. 
o
When concomitant use of strong CYP3A4 inhibitors cannot be avoided, reduce 
Cabozantinib dose by 20 mg.  
o
Resume Cabozantinib at the dose that was used prior to initiating the strong 
CYP3A4 inhibitor 2 to 3 days after discontinuation of the strong inhibitor. 
Chronic co-administration of Cabozantinib with strong inducers of the CYP3A4 may 
significantly decrease Cabo concentrations and should be avoided. See Appendix F.
o
Strong CYP3A4 inducers: if possible, avoid concomitant use with Cabozantinib.  
Examples of strong CYP3A4 inducers include: Rifampin, phenytoin, 
carbamazepine, rifabutin, rifapentine, phenobarbital and St. John’s wort. 
o
Other drugs that induce CYP3A4 should be used with caution as these drugs have 
the potential to decrease exposure (AUC) to Cabozantinib.  
o
Selection of alternate concomitant medications with no or minimal CYP3A4 
enzyme induction potential is recommended for subjects receiving Cabozantinib. 
o
Caution must be used with 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 exposure to Cabozantinib.  
o
When concomitant use of strong CYP3A4 inducers cannot be avoided, increase 
Cabozantinib dose by 20 mg.  
o
Resume Cabozantinib at the dose used prior to initiating the strong CYP3A4 
inducer 2 to 3 days after discontinuation of the strong inducer.  
Do not exceed daily dose of 60 mg (Cabozantinib).  

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Antineoplastic systemic chemotherapy or biological therapy 
Immunotherapy not specified in this protocol
Chemotherapy not specified in this protocol
Investigational agents other than cabozantinib or pembrolizumab
Radiation therapy: Radiation therapy to a symptomatic solitary lesion or to the brain may 
be allowed at the investigator’s discretion.  
Live vaccines within 30 days prior to the first dose of study treatment and while 
participating in the study. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live 
attenuated vaccines and are not allowed. 
Systemic glucocorticoids for any purpose other than to modulate symptoms from an event 
of clinical interest of suspected immunologic etiology.  The use of physiologic doses of 
corticosteroids may be approved after consultation with the Sponsors.
Participants who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the study.  All 
treatments that the Investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the Investigator in keeping with the community standards of 
medical care.  
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during 
the ongoing study.  If there is a clinical indication for any medication or vaccination specifically 
prohibited during the study, discontinuation from study therapy or vaccination may be required.  
The final decision on any supportive therapy or vaccination rests with the investigator and/or the 
participant's primary physician.  However, the decision to continue the participant on study 
treatment requires the mutual agreement of the investigator, the Sponsor and the participant. 
However, the decision to continue the participant on study intervention requires the mutual 
agreement of the investigator, the Sponsors (Exelixis & Merck), and the participant.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
9.
STATISTICAL CONSIDERATIONS
9.1
Study Design/Endpoints
A single arm, Phase II trial will be performed using combination Cabozantinib and Pembrolizumab
in patients with refractory pancreatic cancer. The primary study endpoint is PFS compared to 
historical PFS.  
9.2
Sample Size/Accrual Rate
The historical median PFS for 2nd line metastatic pancreatic cancer will be assumed to be 2.0 
months. We hypothesize an improvement in PFS to 4.0 months for this combination regimen. 
A sample of 21 evaluable patients will provide 80% power to detect this hypothesized 
improvement in PFS with 80% power based on a one-sided log-rank test with 5% alpha and an 

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exponential distribution with an interim analysis plan (Section 9.6). Patient accrual is projected for 
24 months with an estimated enrollment of 1 patient per month and 6 months of follow-up after 
the last patient is enrolled in the trial. Assuming a 5% unevaluable or drop-out rate, a sample of 
23 patients will be enrolled in the Phase II trial. 
9.3
Stratification Factors
None.  
9.4
Analysis of Primary Endpoint 
PFS will be estimated using the Kaplan-Meier curve and median PFS and confidence interval 
will be calculated. The one sample log-rank test will be employed to test improvement in PFS 
with the combination regimen.  Exploratory analysis using the Cox regression model to assess 
PFS adjusted for a few key clinical parameters will be performed. An intent-to-treat analysis, 
wherein all patients who received study drug, will be the primary analysis of the PFS outcome.
Given that the timing of radiology scans is every Q8 weeks (+/- 1-2 weeks) or scans as clinically 
indicated, we will consider the analysis of PFS as interval censored data.  The SAS ICLIFETEST 
will be used for nonparametric survival analysis of interval-censored data while SAS LIFEREG 
can deal with parametric survival model with both interval and right censored data. 
The R package for interval censored data (icenReg) which can do nonparametric, parametric and 
semiparametric Cox models will also be implemented. 
9.5
Secondary Endpoints
All patients who received study drugs will be included in the safety analysis. The maximum grade 
of toxicity for each AE category of interest will be recorded for each patient and the summary 
results will be tabulated by categor
events on a patient-by-patient basis. Frequency and incidence tables of toxicity and AEs will be 
generated. 
Other time-to-event endpoints including OS will be estimated using survival analysis methods. 
Overall response rate and benefit response rate will be estimated along with the exact 95% 
binomial confidence intervals.
Bioinformatics methods for data processing and data analysis pipelines will be applied and 
exploratory comparisons of exosomal lipid and organoid cytotoxicity profiles with response and 
clinical outcomes will be performed using two sample t-test or linear models with control for false 
discovery rate (FDR). 
9.6
Interim Analysis
Interim analysis will be performed based on an optimal two-stage design for Phase II survival 
trials.  Specifically, an exponential distribution with an exact variance estimate of the one-sample 
log-rank test (OSLT) will be used for the two-stage design (Wu, 2015). Using the R function 
Optimal.rKJ, this two-stage design assuming an exponential distribution will enroll 14 patients at 
the first stage. At the time of interim analysis, each patient is followed for an event (disease 
progression or death) or is censored. If the first stage test statistic Z1 < 0.088, we stop the trial for 
futility. Otherwise the trial continues to the second stage until a total of 21 evaluable patients is 
enrolled on the study. The final analysis will be conducted when all patients have been enrolled. 

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If the second stage test statistic Z < 1.632, we don’t reject the null hypothesis and conclude no 
9.7
Reporting and Exclusions
9.7.1
Evaluation of Toxicity 
All patients who received study drug will be evaluable for toxicity and included in the safety 
analysis from the time of their first treatment with Cabozantinib and Pembrolizumab combination 
treatment.
9.7.2
Evaluation of Response 
An intent-to-treat analysis will be employed for assessment of clinical endpoints. All patients who 
met the eligibility criteria and received the study medication are included in the primary analysis. 
Thus, an incorrect treatment schedule or drug administration does not result in exclusion from the 
analysis of primary endpoint and the response rate.   
9.8
Clinical Trial Registration with NIH 
All clinical treatment trials have to be registered into clinicaltrials.gov before opening to accrual 
and trial results have to be published. The MCC-CRO Regulatory unit (mccreg@uky.edu) supports 
investigators in completing registration and renewal of their trials to NIH system in conjunction 
with a representative from UKHC. Results of this trial will be released on Clinicaltrials.gov within 
12 months after follow-up is completed (of final patient accrued). If the trial is stopped early, data 
will be posted within six months of the study’s termination.
10. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
The definitions of an AE or SAE, as well as the method of recording, evaluating, and assessing 
causality of AE and SAE and the procedures for completing and transmitting AE, SAE, and other 
reportable safety event reports are listed below.   
Adverse events, SAEs, and other reportable safety events will be reported by the participant (or, 
when appropriate, by a caregiver, surrogate, or the participant's legally authorized representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AEs, SAEs, and other reportable safety events 
for outcome. 
The investigator, who is a qualified physician, will assess events that meet the definition of an AE 
or SAE as well as other reportable safety events with respect to seriousness, intensity/toxicity and 
causality.

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10.1 Adverse Event Characteristics 
CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0 will be utilized for AE reporting. (http://ctep.cancer.gov/reporting/ctc.html) 
All appropriate treatment areas should have access to a copy of the CTCAE version 5.0.  
CTCAE version 5.0 can be downloaded from 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
Attribution of the AE: 
-
Definite – The AE is clearly related to the study treatment.
-
Probable – The AE is likely related to the study treatment.
-
Possible – The AE may be related to the study treatment.
-
Unlikely – The AE is doubtfully related to the study treatment.
-
Unrelated – The AE is clearly NOT related to the study treatment.
Adverse Event (AE) definition
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the study 
intervention. 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the 
use of a study intervention. 
NOTE: For purposes of AE definition, study intervention (also referred to as Merck product) 
includes any pharmaceutical product, biological product, vaccine, diagnostic agent, or 
protocol specified procedure whether investigational or marketed (including placebo, active 
comparator product, or run-in intervention), manufactured by, licensed by, provided by, or 
distributed by Merck for human use in this study. 
Events meeting the AE definition
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, ECG, radiological scans, vital signs measurements), including those 
that worsen from baseline, considered clinically significant in the medical and scientific 
judgment of the investigator. 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
New conditions detected or diagnosed after study intervention administration even though it
may have been present before the start of the study. 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention 
or a concomitant medication. 
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose without 
any associated clinical symptoms or abnormal laboratory results is reported using the 
terminology “accidental or intentional overdose without adverse effect.” 

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Events NOT meeting the AE definition
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to the 
procedure is the AE.
Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital).
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
Hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization 
for an elective procedure to treat a pre-existing condition that has not worsened is not an 
SAE. A pre-existing condition is a clinical condition that is diagnosed prior to the use of a 
Merck product and is documented in the participant’s medical history.
d. Results in persistent or significant disability/incapacity
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions.
This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental 
trauma (eg, sprained ankle) that may interfere with or prevent everyday life functions but do 
not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the participant or may 
require medical or surgical intervention to prevent 1 of the other outcomes listed in the above 
definition. These events should usually be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that 
do not result in hospitalization, or development of drug dependency or drug abuse.

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Additional events that require reporting in the same manner as SAE
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to Merck in the same time frame as SAEs to meet 
certain local requirements. Therefore, these events are considered serious by Merck for 
collection purposes.
o
Is a new cancer (that is not a condition of the study)
o
Is associated with an overdose of pembrolizumab
AE and SAE recording
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
The investigator will record all relevant AE/SAE information on the AE CRFs/worksheets 
at each examination.
There may be instances when copies of medical records for certain cases are requested by 
the Merck. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the Merck.
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. In such cases, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
1.
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) according to the NCI Common Terminology for Adverse Events 
(CTCAE), version 5. Any AE that changes CTCAE grade over the course of a given 
episode will have each change of grade recorded on the AE CRFs/worksheets.
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL).
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL.
Grade 4: Life threatening consequences; urgent intervention indicated.
Grade 5: Death related to AE.

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Assessment of causality
1.
Did Merck product cause the AE?
2.
The determination of the likelihood that Merck product caused the AE will be provided by 
an investigator who is a qualified physician. The investigator’s signed/dated initials on the 
source document or worksheet that supports the causality noted on the AE form, ensures that 
a medically qualified assessment of causality was done. This initialed document must be 
retained for the required regulatory time frame. The criteria below are intended as reference 
guidelines to assist the investigator in assessing the likelihood of a relationship between the 
test product and the AE based upon the available information.
3.
The following components are to be used to assess the relationship between Merck’s product 
and the AE; the greater the correlation with the components and their respective elements (in 
number and/or intensity), the more likely Merck product caused the AE:
Exposure: Is there evidence that the participant was actually exposed to Merck product such 
as: reliable history, acceptable compliance assessment (pill count, diary, etc.), expected 
pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course: Did the AE follow in a reasonable temporal sequence from administration of 
Merck product? Is the time of onset of the AE compatible with a drug-induced effect (applies 
to studies with investigational medicinal product)?
Likely Cause: Is the AE not reasonably explained by another etiology such as underlying 
disease, other drug(s)/vaccine(s), or other host or environmental factors.
Dechallenge: Was Merck product discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge.
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; 
(2) the AE resolved/improved despite continuation of the Merck product; (3) the study is a 
single-dose drug study; or (4) Merck product(s) is/are only used 1 time.)
Rechallenge: Was the participant re-exposed to Merck product in this study?
If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge.
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent 
disability, or (2) the study is a single-dose drug study; or (3) Merck product(s) is/are used 
only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND MAY 
HAVE BEEN CAUSED BY MERCK PRODUCT, OR IF RE-EXPOSURE TO MERCK’S 
PRODUCT 
POSES 
ADDITIONAL 
POTENTIAL 
SIGNIFICANT 
RISK 
TO 
THE 
PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE 
SPONSOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF 
REQUIRED, THE INIRB/IEC.

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4.
Consistency with study intervention profile: Is the clinical/pathological presentation of the 
AE consistent with previous knowledge regarding Merck product or drug class 
pharmacology or toxicology?
5.
The assessment of relationship will be reported on the case report forms/worksheets by an 
investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
6.
Use the following scale of criteria as guidance (not all criteria must be present to be indicative 
of Merck product relationship).
Yes, there is a reasonable possibility of Merck product relationship:
There is evidence of exposure to the Merck product. The temporal sequence of the AE 
onset relative to the administration of Merck product is reasonable. The AE is more likely 
explained by Merck product than by another cause.
No, there is not a reasonable possibility of Merck product relationship:
Participant did not receive the Merck product OR temporal sequence of the AE onset 
relative to administration of the Merck product is not reasonable OR the AE is more likely 
explained by another cause than the Merck product. (Also entered for a participant with 
overdose without an associated AE.)
7.
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
8.
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Merck. However, it is very important that 
the investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to Merck.
9.
The investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.
10.
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
11.
For studies in which multiple agents are administered as part of a combination regimen, the 
investigator may attribute each AE causality to the combination regimen or to a single agent 
of the combination. In general, causality attribution should be assigned to the combination 
regimen (ie, to all agents in the regimen). However, causality attribution may be assigned to 
a single agent if in the investigator’s opinion, there is sufficient data to support full attribution 
of the AE to the single agent.
Follow-up of AE and SAE
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated to elucidate the nature and/or 
causality of the AE or SAE as fully as possible. This may include additional laboratory 
tests or investigations, histopathological examinations, or consultation with other 
health care professionals. 
New or updated information will be recorded in the CRF. 

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The investigator will submit any updated SAE data to Merck within 2 business days 
but no longer than 3 calendar days of receipt of the information.
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Merck
SAE reports and any other relevant safety information are to be forwarded to the Merck Global Safety 
facsimile number:  +1-215-661-6229
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, European 
Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local regulators. 
Investigators will cross reference this submission according to local regulations to the Merck 
Investigational Compound Number (IND, CSA, etc.) at the time of submission.  Additionally, 
investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: Worldwide Product Safety; 
FAX 215-661-6229) at the time of submission to FDA.
Adverse events (AEs), SAEs, and other reportable safety events will be reported by the participant (or, 
when appropriate, by a caregiver, surrogate, or the participant’s legally authorized representative). The 
investigator and any designees are responsible for detecting, documenting, and reporting events that 
meet the definition of an AE or SAE as well as other reportable safety events. Investigators remain 
responsible for following up AEs, SAEs, and other reportable safety events for outcome. The 
investigator, who is a qualified physician, will assess events that meet the definition of an AE or SAE 
as well as other reportable safety events with respect to seriousness, intensity/toxicity and causality. 
The following list of AEs (Section 10.1) and the characteristics of an observed AE will determine 
whether the event requires expedited reporting to Overall PI and DSMC via the OnCore in addition
to routine reporting.
Time Period and Frequency for Collecting AE, SAE, and Other Reportable Safety Event 
Information
All AEs, SAEs, and other reportable safety events that occur after the consent form is signed but 
before intervention allocation/randomization must be reported by the investigator if the participant 
is receiving placebo run-in or other run-in treatment, if the event cause the participant to be 
excluded from the study, or is the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, or a procedure.
All AEs from the time of intervention allocation/randomization through 30 days following 
cessation of study intervention must be reported by the investigator.
All AEs meeting serious criteria, from the time of intervention allocation/randomization 
through 90 days following cessation of study intervention or 30 days following cessation 
of study intervention if the participant initiates new anticancer therapy, whichever is 
earlier, must be reported by the investigator.
All pregnancies and exposure during breastfeeding, from the time of intervention 
allocation/randomization through 120 days following cessation of study intervention, or 30 
days following cessation of study intervention if the participant initiates new anticancer 
therapy must be reported by the investigator.
Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified above must be reported immediately to Merck if the event is 
considered drug-related.

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Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events in 
former study participants. However, if the investigator learns of any SAE, including a death, at 
any time after a participant has been discharged from the study, and he/she considers the event to 
be reasonably related to the study intervention or study participation, the investigator must 
promptly notify Merck. 
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to Merck within the time frames as indicated in the Table below.
Table 6. Reportable safety events.
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through Protocol-
specified Follow-
up Period
Reporting Time Period:
After the Protocol-
specified Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to Merck:
Serious Adverse Event 
(SAE) including Cancer 
and Overdose
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 2 
business days 
but no longer 
than 3 
calendar days 
of learning of 
event
Pregnancy/Lactation 
Exposure
Report if:
- due to 
intervention
- causes exclusion
Report all
Previously reported – 
Follow to 
completion/termination; 
report outcome
Within 2 
business days 
but no longer 
than 3 
calendar days 
of learning of 
event
Event of Clinical 
Interest (require 
regulatory reporting)
Report if:
- due to 
intervention
- causes exclusion
Report 
- potential drug-
induced liver 
injury (DILI)
- require regulatory 
reporting
Not required
Within 2 
business days 
but no longer 
than 3 
calendar days 
of learning of 
event
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other reportable 
safety events. Open-ended and nonleading verbal questioning of the participant is the preferred 
method to inquire about AE occurrence. 
Follow-up of AE, SAE, and Other Reportable Safety Event Information 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events including 
pregnancy and exposure during breastfeeding, events of clinical interest (ECIs), cancer, and 

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overdose will be followed until resolution, stabilization, until the event is otherwise explained, or 
the participant is lost to follow-up. In addition, the investigator will make every attempt to follow 
all nonserious AEs that occur in randomized participants for outcome. 
Sponsor Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable country specific regulatory requirements, global laws and 
regulations.
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to the 
investigator or their designee) that occurs during the study are reportable to Merck.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome (health 
of infant) must also be reported.
Events of Clinical Interest (ECIs)
Selected nonserious and SAEs are also known as ECIs and must be reported to Merck. 
Events of clinical interest for this study include: 
1.
An overdose of pembrolizumab that is not associated with clinical symptoms or abnormal 
laboratory results. For purposes of this study, an overdose of pembrolizumab will be defined 
as any dose 
ic information is 
available on the treatment of overdose of pembrolizumab. In the event of overdose, the 
participant should be observed closely for signs of toxicity.  Appropriate supportive treatment 
should be provided if clinically indicated.  If an adverse event(s) is associated with (“results 
from”) the overdose of a Merck product, the adverse event(s) is reported as a serious adverse 
event, even if no other seriousness criteria are met.
2.
An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X 
the upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.* 
*Note: These criteria are based upon available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an additional 
evaluation for an underlying etiology. 
10.2 MCC Expedited Adverse Event Reporting Guidelines
Investigators within MCC will report SAEs directly to the MCC DSMC per the MCC DSMC SOP 
and the University of Kentucky IRB reporting policy, as specified in the table in below.  Use the 
MCC protocol number and the protocol-specific patient ID assigned during trial registration on all 
reports.

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10.2.1 MCC Required forms and reporting structure 
Study type
Expedited reporting to 
MCC
Expedited reporting to 
External Agency
Non-expedited AE
    Form
IRB
IIT by MCC 
investigator 
sponsored by 
industry
Grade 3 –Unexpected 
AE PLUS Possibly, 
Probably or Definitely 
Related 
ALL Grade 4 Unless 
expected AND listed 
in protocol as not 
requiring reporting.
ALL Grade 5 (fatal) 
Events
FDA:
Suspected AE that is 
serious and 
Unanticipated (not 
listed in IDB or 
consent)
OnCore and DSMC 
reporting only
Voluntary 
Medwatch 
3500 for 
Serious and 
unanticipated
OnCore for 
all AEs, 
including 
SAEs
Per 
SOPs
Note:  A death on study requires both routine and expedited reporting, regardless of 
causality.  Attribution to treatment or other cause must be provided.
Death due to progressive disease should be reported as Grade 5 “Disease progression” in the 
system organ class (SOC) “General disorders and administration site conditions.”  Evidence that 
the death was a manifestation of underlying disease (e.g., radiological changes suggesting tumor 
growth or progression: clinical deterioration associated with a disease process) should be 
submitted.  
10.2.2 Expedited Reporting guidelines for MCC IITs  
Investigators within MCC will report SAEs directly to the MCC DSMC per the MCC DSMC 
SOP and the University of Kentucky IRB reporting policy. 
Table 10.3.2 -- MCC Reportable AEs
Attribution
Gr. 2 & 3 AE
Gr. 2 & 3 AE
Gr. 4 AE
Gr. 4 AE
Gr. 5 AE
Expected
Unexpected
Expected
Unexpected
Expected or 
Unexpected
Unrelated
Unlikely
Not required
Not required
5 calendar days#
5 calendar days
24 hours*
Possible
Probable
Definite
Not required
5 calendar days
5 calendar days#
5 calendar days
24 hours*
NOTES: 
# If listed in protocol as expected and not requiring expedited reporting, event does not need to be reported.
* For participants enrolled and actively participating in the study or for AEs occurring within 30 days of the last 
Intervention/dose, the AE should be reported within 24 business hours of learning of the event.

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10.3 Expedited Reporting to External Agencies
The PI will comply with the policies of all external funding agencies (Exelixis, Merck) and the 
UK IRB regarding expedited reporting, as per the UK IRB’s Mandated Reporting to External 
Agencies SOP C4.0150. 
As soon as an Investigator becomes aware of an AE that meets the criteria for an SAE, the 
Investigator will document the SAE on an SAE Report Form or in an electronic database. SAEs, 
regardless of causal relationship, must be reported to Exelixis within one (1) business day of the 
Investigator’s knowledge of the event by submitting a completed SAE report form. The reports 
must be emailed to drugsafety@exelixis.com or faxed to 650-837-7392 with the below:
Required Information:
o
Identity of Investigator
o
Site name
o
Subject identifiers
o
Drug name and dosage 
o
Event description
o
Event terms (i.e., as recorded in the electronic database)
o
Investigator’s assessment of the relationship of the event to study treatment  
o
The reason why the event is considered to be serious
Recommended Information: 
o
Medications or therapeutic measures used to treat the event
o
Action taken with the study treatment because of the event
o
Outcome/resolution of the event
o
Any additional SAE information
Note – Medical records should not be sent to Exelixis unless requested.
The Investigator will perform adequate due diligence with regard to obtaining follow-up 
information on incomplete reports. All follow-up information must be sent to Exelixis within one 
(1) business day of the Investigator’s receipt of the new information.
SAEs that must be recorded on an SAE Reporting form include the following:
SAEs that occur after informed consent or study initiation and through 30 days after the 
date of the decision to permanently discontinue study treatment
SAEs assessed as related to study treatment or study procedures, even if the SAE occurs 
more than 30 days after the date of the decision to permanently discontinue study treatment.

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In all cases, the Investigator should continue to monitor the clinical situation and report all material 
facts relating to the progression or outcome of the SAE. Furthermore, the Investigator may be 
required to provide supplementary information as requested by Exelixis. 
When reporting SAEs, the following additional points will be noted: 
When the diagnosis of an SAE is known or suspected, the Investigator will report the 
diagnosis or syndrome as the primary SAE term, rather than as signs or symptoms. Signs 
and symptoms may then be described in the event description. 
Death will not be reported as an SAE, but as an outcome of a specific SAE, unless the event 
preceding the death is unknown. Terms of “Unexplained Death” or “Death from unknown 
origin” may be used when the cause is unknown. In these circumstances the cause of death 
must be investigated, and the diagnosis amended when the etiology has been identified. If 
an autopsy was performed, the autopsy report should be provided. 
10.4 Expedited Reporting to the Food and Drug Administration (FDA)
The PI, as study sponsor, will be responsible for all communications with the FDA. The PI will 
report to the FDA any serious adverse event that meets the FDA’s criteria for expedited reporting 
following the reporting requirements and timelines set by the FDA.  
10.5 Expedited Reporting to Hospital Risk Management 
Participating investigators will report to the UK Office of Risk Management any participant safety 
reports or sentinel events that require reporting according to institutional policy.  
10.6 Routine Adverse Event Reporting
All Adverse Events must be reported in routine study data submissions with the exception of those 
listed in Section 10.4.  AEs reported expeditiously to the Overall PI and DSMC via OnCore
must also be reported in routine study data submissions.
10.7 Pregnancy
Pregnancy is considered an unanticipated event and pregnancy as well as its outcome must be 
documented and reported to overall PI and DSMC and Office of Research Integrity, as well the 
FDA and sponsor in according to reporting requirements.  Any pregnancy occurring in a patient 
or patient’s partner from the time of consent to approximately 4 months  after the last dose of study 
drug must be reported and then followed for outcome.  Newborn infants should be followed until 
30 days old.  
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab, the 
participant will be immediately discontinued from study intervention. The site will contact the 
participant at least monthly and document the participant’s status until the pregnancy has been 
completed or terminated.  The outcome of the pregnancy will be reported to Merck within 2 
working days if the outcome is a serious adverse experience (e.g. death, abortion, congenital 
anomaly, or other disabling or life-threatening complication to the mother or newborn).  The study 

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Investigator will make every effort to obtain permission to follow the outcome of the pregnancy 
and report the condition of the fetus or newborn to Merck.  If a male participant impregnates his 
female partner, the study personnel at the site must be informed immediately and the pregnancy 
must be reported to Merck.
10.8    Secondary Malignancy
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., treatment 
with investigational agent/intervention, radiation or chemotherapy). A secondary malignancy is 
not considered a metastasis of the initial neoplasm.
All secondary malignancies that occur following treatment with an agent under an NCI IND/IDE 
must be reported to overall PI and DSMC and Office of Research Integrity, as well the FDA and 
sponsor in according to reporting requirements. Three options are available to describe the event: 
Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML]) 
Myelodysplastic syndrome (MDS) 
Treatment-related secondary malignancy 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol. 
10.9    Second Malignancy
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine AE reporting 
unless otherwise specified.

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11. STUDY CALENDAR
Baseline evaluations are to be conducted prior to start of protocol therapy as noted in the study calendar. 
In the event that the patient’s condition is deteriorating, laboratory evaluations should be repeated within 
48 hours prior to initiation of the next cycle of therapy. 
Pre-
enrollment
Planned Cabo/Pembro Treatment *
Cabozantinib daily concurrent w/ Pembrolizumab Q3 wks
         
Safety
(100-days
after
final dose)
1-year Post 
Treatment 
Initiation
   Assessment:
   Screening
Cycle 1
Cycles 2 - 8
Cycles 9 - 17
      Visit Windows
Day -30 to -1 
( ± 3 days)
( ± 3 days)
( ± 7 days)
( +14 days)
( +14 days)
     ---
Informed consent 
X
Demographics, 
medical history
Physical exam
X /  
-
X
X
Weight
X /  
-
X
X
Height
<
X
ECOG PS
X /  
-
X
X
Vital signs
X /  
X
X
-lead ECG
4 weeks
As clinically indicated.
As clinically indicated
As clinically indicated
   As clinically indicated
CBC w/ diff, platelets
all cycles. Record in the eCRF: ANC, plts, Hemoglobin
X
X
  CMP
         
only record results for the following   
in the eCRF: alk phos, total bilirubin, AST, ALT, albumin
X
X
Hepatitis screening
       X
PT/INR, aPTT
Urinalysis
X/ 
cycles
-
As clinically indicated
As clinically indicated
As clinically indicated
Urine chemistry 
(UPCR)
X
Q6 weeks at 
clinic visit
As clinically indicated
As clinically indicated
   As clinically indicated
Pregnancy test
X
TSH 
X
  Q6 weeks at 
clinic visit
-
X, optional
-
discretion per institutional standards. 
Imaging:
CT/MRI
C/A/P
weeks of
treatment 
initiation
CT of the chest, abdomen, and pelvis or CT of the chest with MRI of the abdomen and pelvis will be performed 
days) after first dose of Pembro/Cabo combination 
treatment for the first 6-months on-study or as clinically indicated. 
Upon completion of 6 months on study, these assessments will be performed every
-months post-treatment initiation. 
-months post-treatment initiation OR until radiographic disease 
criteria for response are first met.

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Correlative: 
Blood samples 
for Exosomal
Lipids
(optional)
See **
biospecimen sample collection protocol. 
            
-top tube w/ EDTA will be collected at t
Pre-treatment baseline: i.e., predose 
Cycle 2 clinic visit
Cycle 3 clinic visit
Cycle 4 clinic visit
Cycle 5 clinic visit
Cycle 6 clinic visit
collected once monthly for 6-months  (i.e., at clinic visit during Cycles 2 – 
Correlative:
Archival Tumor
(optional)
  *** If archival tissue is available, tumor tissue will be obtained via another protocol for 
biospecimen sample collection for correlative, patient-derived organoids. Patients enrolled on this 
trial will have to sign a separate consent for utilization of archival tissue.    
Con Meds
X 1
X 2
X 2
X 2
X 2
X 2
Adverse Events
X
X
X
X
X
Pembrolizumab 
(IV infusion)
X, q3 weeks
Could continue
Cabozantinib
(oral med)
given
in clinic to monitor 
safety.
D2-D
doses
are taken at home.
  
X, 
Daily dose taken at 
home C2-
Could continue
Cabozantinib dispensed to subjects every 
3 weeks.
Cabozantinib    
daily dosing diary
The patient will record the daily   amount 
of Cabozantinib taken in an oral 
medication log from 
-
to C
).
Tumor Assessment 
to determine 
PFS and ORR 
Imaging/scans will be assessed per RECIST and iRECIST and the results (PR, CR, etc.) will be 
not stopped early for futility.  
Survival Status
Interim analysis will be conducted 
enrolled 
and will be followed for an event 
(disease progression, death).
Survival S
-year post-
treatment initiation. 
Early Discontinuation 
X, (note reason for early DC of treatment and/or reason for removal from study participation)

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FOOTNOTES to Study Calendar: 
* Completion of pembrolizumab Q3W monotherapy consists of 35 treatments (approximately 2 years).  Discontinuation of
treatment may be considered for participants who have attained a confirmed complete response (CR) and have been
treated for at least  cycles (at least 24 weeks), receiving at least 2 cycles of the combination including 2 doses of 
beyond the date when the initial CR was
declared.
** Exosomal lipids correlative: Blood samples for exosomal lipids are optional, and will be obtained via another protocol for 
biospecimen sample collection. Patients enrolled on this trial will have to sign a separate consent for participation in the 
correlative studies. 
-top tube EDTA will be collected at pre-treatment and then, once monthly for 6-
months (i.e., at the clinic visit for Cycles 2 – 
*** Patient-derived organoids correlative:  Tumor tissue will be obtained via another protocol for collection of biospecimen 
samples. Patients enrolled on this trial will have to sign a separate consent for tissue collection (i.e., in order to participate in 
the correlative studies).  
ds at screening: 
. 
2: Con Meds after screening visit: CON meds should be recorded up to 30 days after the last dose of trial intervention should be 
recorded. If participants experience an SAE or ECI, concomitant medications administered 30 days after the last dose of trial 
intervention are to be recorded.  

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61 
12. MEASUREMENT OF EFFECT 
12.1 Antitumor Effect – Solid Tumors
For the purposes of this study, patients should be re-evaluated for response every 8 weeks during the first 
6-months, and thereafter, every 12 weeks up until 1-year post-treatment initiation or disease progression 
or death, whichever occurs first.   
Response and progression will be evaluated in this study using the new international criteria proposed by 
the revised Response Evaluation Criteria in Solid Tumors (RECIST, v1.1; Eisenhauer et al, 2009) and 
iRECIST guidelines (Seymour et al, 2017).  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are 
used in the RECIST criteria.
12.1.1 Definitions
Evaluable for Toxicity.  All patients will be evaluable for toxicity from the time of their first treatment 
with Pembrolizumab/Cabozantinib combination.  
Evaluable for Objective Response.  Only those patients who have measurable disease present at baseline, 
have received at least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for response.  These patients will have their response classified according to the definitions 
stated below.  (Note:  Patients who exhibit objective disease progression prior to the end of cycle 1 will 
also be considered evaluable.)
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline that are evaluable 
but do not meet the definitions of measurable disease, have received at least one cycle of therapy, and 
have had their disease re-evaluated will be considered evaluable for non-target disease.  The response 
assessment is based on the presence, absence, or unequivocal progression of the lesions.  
12.1.2 Disease Parameters
Measurable Disease.  Measurable lesions are defined as those that can be accurately measured in at least 
by chest x-
cm) with CT scan, MRI, or calipers by clinical exam.  All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters).
Malignant Lymph Nodes.  To be considered pathologically enlarged and measurable, a lymph node must 
in short axis when assessed by CT scan (CT scan slice thickness recommended to 
be no greater than 5 mm [0.5 cm]).  At baseline and in follow-up, only the short axis will be measured 
and followed. 
Non-Measurable Disease.  All other lesions (or sites of disease), including small lesions (longest diameter 
<10 mm [<1 cm]
short axis), are 
considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable.
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by definition, 
simple cysts. ‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-cystic lesions are 

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present in the same patient, these are preferred for selection as target lesions.
Target Lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and measured 
at baseline.  Target lesions should be selected on the basis of their size (lesions with the longest diameter), 
be representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements.  It may be the case that, on occasion, the largest lesion does not 
lend itself to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.  A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum diameters.  
If lymph nodes are to be included in the sum, then only the short axis is added into the sum.  The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease.
Non-Target Lesions.  All other lesions (or sites of disease) including any measurable lesions over and 
above the 5 target lesions should be identified as non-target lesions and should also be recorded at 
baseline.  Measurements of these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow-up.  
12.1.3 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All baseline 
evaluations should be performed as closely as possible to the beginning of treatment. The same method 
of assessment and the same technique should be used to characterize each identified and reported lesion 
at baseline and during follow-up. Imaging-based evaluation is preferred to evaluation by clinical 
examination unless the lesion(s) being followed cannot be imaged but are assessable by clinical exam.
Clinical Lesions.  Clinical lesions will only be considered measurable when they are superficial (e.g., 
diameter as assessed using calipers (e.g., 
skin nodules).  In the case of skin lesions, documentation by color photography, including a ruler to 
estimate the size of the lesion, is recommended. 
Conventional CT and MRI.  This guideline has defined measurability of lesions on CT scan based on the 
assumption that CT slice thickness is 5 mm (0.5 cm) or less.  If CT scans have slice thickness greater 
than 5 mm (0.5 cm), the minimum size for a measurable lesion should be twice the slice thickness.  MRI 
is also acceptable in certain situations (e.g. for body scans).   
12.1.4 Response Criteria
12.1.4.1
Evaluation of Target Lesions 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph nodes (whether 
target or non-target) must have reduction in short axis to <10 mm (<1 cm). 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target lesions, taking as 
reference the baseline sum diameters.
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target lesions, taking 
as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).  In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 
mm (0.5 cm).  (Note:  the appearance of one or more new lesions is also considered progressions). 

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Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the smallest sum diameters while on study.
12.1.4.2
Evaluation of Non-Target Lesions
Complete Response (CR):  Disappearance of all non-target lesions and normalization of tumor marker 
level.  All lymph nodes must be non-pathological in size (<10 mm [<1 cm] short axis).
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker 
level above the normal limits.
Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal progression of 
existing non-target lesions.  Unequivocal progression should not normally trump target lesion status.  It 
must be representative of overall disease status change, not a single lesion increase.
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed at a later 
time by the Principal Investigator and co-I. 
12.1.4.3
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements recorded 
since the treatment started).  The patient's best response assignment will depend on the achievement of 
both measurement and confirmation criteria (see table below). 
12.1.5 Duration of Response 
Duration of overall response:  The duration of overall response is measured from the time measurement 
criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). The duration of overall CR is measured from the time measurement 
criteria are first met for CR until the first date that progressive disease is objectively documented.
Duration of stable disease:  Stable disease is measured from the start of the treatment until the criteria for 
progression are met, taking as reference the smallest measurements recorded since the treatment started, 
including the baseline measurements.  

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12.1.6
Progression-Free Survival
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first. An intent-to-treat analysis, wherein all patients who received study drug, 
will be the primary analysis of the PFS outcome. 
Table 8. Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Overall Response when 
Confirmation is Required*
CR
CR
No
CR
4 wks. Confirmation** 
CR
Non-CR/Non-PD
No
PR
4 wks. Confirmation** 
CR
Not evaluated
No
PR
PR
Non-CR/      
Non-PD/          
not evaluated
No
PR
SD
Non-CR/      
Non-PD/          
not evaluated
No
SD
Documented at least once 4 wks. 
from baseline** 
PD
Any
Yes or No
PD
no prior SD, PR or CR 
Any
PD*** 
Yes or No
PD
Any
Any
Yes
PD
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be
accepted as disease progression.
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 

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Table 9. Patients with Non-Measurable Disease (i.e., Non-Target Disease)
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD*
Not all evaluated
No
not evaluated
Unequivocal PD 
Yes or No
PD
Any
Yes
PD
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease 
since SD is increasingly used as an endpoint for assessment of efficacy in 
some trials so to assign this category when no lesions can be measured is 
not advised 
12.2 Antitumor Effect – Immune-Related RECIST (iRECIST) Criteria
12.2.1 Definitions
Evaluable for Adverse Events.  All patients will be evaluable for adverse event evaluation from the time 
of their first treatment with Pembro/Cabo combination. 
Evaluable for Response.  All patients who have received at least one cycle of therapy and have their 
disease re-evaluated will be considered evaluable for response (exceptions will be those who exhibit 
objective disease progression prior to the end of Cycle 1 who will also be considered evaluable).  Patients 
on therapy for at least this period and who meet the other listed criteria will have their response classified 
according to the definitions set out below. 
Response and progression will be evaluated in this study using the revised international criteria (RECIST 
version 1.1, Eisenhauer et al, 2009) proposed by the RECIST Committee as well as the modified 
iRECIST guidelines (Seymour et al, 2017). Investigators should note the different requirements for 
confirmatory scans as well as follow-up for the two criteria. 

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12.2.2 Image Receipt and Processing 
Images will be reviewed by either a UK radiologist or sent to Dr. Jinha Park at The Radiology Experts, 
Inc.  De-identified images without any patient identifiers will be submitted to Dr. Park at The Radiology 
Experts, Inc (central radiology) by express mail for assessment of treatment response.  Submission can 
occur via upload of redacted images via compatible physical support (e.g., CD-ROM). 
Dr. Park will provide RECIST and iRECIST measurements within 24-48 hours after receipt. 
12.2.3 Site Performing Imaging Reads
De-identified images on physical support will be shipped from the University of 
Kentucky to: 
Jinha Park, MD, PhD 
5825 Lincoln Avenue, Suite D330 
Buena Park, CA 90620 
12.2.4 RECIST v1.1 Response and Evaluation Endpoints 
Measurable Disease.  Measurable tumor lesions (nodal, subcutaneous, lung parenchyma, solid organ 
metastases) are defined as those that can be accurately measured in at least one dimension (longest 
diameter to be record
X-ray and as
mm with CT scan or clinical 
examination.  Bone lesions are considered measurable only if assessed by CT scan and have an 
identifiable soft tissue component that meets these requirements (soft tissue component
mm by CT 
scan). Malignant lymph nodes must be 15 mm in the short axis to be considered measurable; only the 
short axis will be measured and followed.  All tumor measurements must be recorded in millimeters (or 
decimal fractions of centimeters).  Previously irradiated lesions are not considered measurable unless 
progression has been documented in the lesion. 
Non-Measurable Disease.  All other lesions (or sites of disease), including small lesions are considered 
non-measurable disease. Bone lesions without a measurable soft tissue component, leptomeningeal 
disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, 
lymphangitic involvement of lung or skin and abdominal masses followed by clinical examination are all 
non-measurable. Lesions in previously irradiated areas are non-measurable, unless progression has been 
demonstrated. 
Target Lesions.  When more than one measurable tumor lesion is present at baseline all lesions up to a 
maximum of 5 lesions total (and a maximum of 2 lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline.  Target lesions should 
be selected on the basis of their size (lesions with the longest diameter), be representative of all involved 
organs, and be those that lend themselves to reproducible repeated measurements. Note that pathological 
nodes must meet the criterion of a short axis of 
mm by CT scan and only the short axis of these nodes 
will contribute to the baseline sum.  All other pathological nodes (those with short axis 
but <15 
mm) should be considered non-target lesions. Nodes that have a short axis <10 mm are considered non-
pathological and should not be recorded or followed. At baseline, the sum of the target lesions (longest 
diameter of tumor lesions plus short axis of lymph nodes: overall maximum of 5) is to be recorded. 
After baseline, a value should be provided on the CRF for all identified target lesions for each assessment, 
even if very small. If extremely small and faint lesions cannot be accurately measured but are deemed 

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to be present, a default value of 5 mm may be used. If lesions are too small to measure and indeed are 
believed to be absent, a default value of 0 mm may be used.
Non-Target Lesions.  All non-measurable lesions (or sites of disease) plus any measurable lesions over 
and above those listed as target lesions are considered non-target lesions. Measurements are not required 
but these lesions should be noted at baseline and should be followed as "present" or "absent." 
12.2.5 Response Criteria   
All patients will have their best response from the start of study treatment until the end of treatment 
classified as outlined below: 
Complete Response (CR):  Disappearance of target and non-target lesions and normalization of tumor 
markers. Pathological lymph nodes must have short axis measures <10 mm (Note: continue to record 
the measurement even if <10 mm and considered CR).  Residual lesions (other than nodes <10 mm) 
thought to be non-malignant should be further investigated (by cytology specialized imaging or other 
techniques as appropriate for individual cases (Eisenhauer et al, 2009) before CR can be accepted. 
Confirmation of response is only required in non-randomized studies. 
Partial Response (PR):  At least a 30% decrease in the sum of measures (longest diameter for tumor
lesions and short axis measure for nodes) of target lesions, taking as reference the baseline sum of 
diameters. Non target lesions must be non-PD.  Confirmation of response is only required in non-
randomized studies. 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD taking as reference the smallest sum of diameters on study.
Progressive Disease (PD):  At least a 20% increase in the sum of diameters of measured lesions taking 
as references the smallest sum of diameters recorded on study (including baseline) AND an absolute 
increase of 5 mm. Appearance of new lesions will also constitute PD (including lesions in previously 
unassessed areas).  In exceptional circumstances, unequivocal progression of non-target disease may be 
accepted as evidence of disease progression, where the overall tumor burden has increased sufficiently 
to merit discontinuation of treatment or where the tumor burden appears to have increased by at least 
73% in volume. Modest increases in the size of one or more non-target lesions are NOT considered 
unequivocal progression.  If the evidence of PD is equivocal (target or non-target), treatment may 
continue until the next assessment, but if confirmed, the earlier date must be used. 
Table 10. Integration of target, non-target, and new lesions into response assessment
Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Response For This Category 
Also Requires
Target lesions ± non-target lesions  
CR
CR
No
CR
Normalization of tumor markers, 
tumor nodes <10 mm
CR
Non-CR/      
non-PD
No
PR
Normalization of tumor markers, 
tumor nodes <10 mm
CR
Not all 
evaluated
No
PR
  
PR
Non-PD/        
No
PR

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Table 10. Integration of target, non-target, and new lesions into response assessment
Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Response For This Category 
Also Requires
not all evaluated
SD
Non-PD/       
not all evaluated
No
SD
eeks 
from baseline
Not all 
evaluated
Non-PD
No
NE
  
PD
Any
Any
PD
Any
PD
Any
PD
Any
Any
Yes
PD
Non-target lesions ONLY 
No Target
CR
No
CR
Normalization of tumor markers, 
tumor nodes <10 mm
No Target
Non-CR/non-
PD
No
Non-CR/
non-PD
  
No Target
Not all 
evaluated
No
NE
  
No Target
Unequivocal 
PD
Any
PD
  
No Target
Any
Yes*
PD
Note: Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as "symptomatic 
deterioration." This is a reason for stopping therapy, but is NOT objective PD. Every effort should 
be made to document the objective progression even after discontinuation of treatment. 
*Investigators should record all new lesions.  If the new lesion is felt to be equivocal, treatment 
may be continued pending further assessments. 
12.2.6 iRECIST Response Assessment
Overall response will also be assessed using iRECIST.  Immunotherapeutics may result in infiltration of 
immune cells leading to transient increase in the size in malignant lesions, or undetectable lesions 
becoming detectable.  The criteria are identical to those of RECIST 1.1 in many respects but have been 
adapted to account for instances where an increase in tumor burden, or the appearance of new lesions, 
does not reflect true tumor progression.
Key differences are described below.  All responses defined using iRECIST criteria are designated with 
a prefix.  The iRECIST time-point and best overall responses will be recorded separately. 
Confirming progression:  Unlike RECIST 1.1, iRECIST requires the confirmation of progression and 
uses the terms iUPD (unconfirmed progression) and iCPD (confirmed progression) (Seymour et al, 
2017).  Confirmatory scans should be performed at least 4 weeks, but no longer than 8 weeks, after iUPD.
iCPD is confirmed if further increase in tumor burden, compared to the last assessment, is seen as 

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evidenced by one or more of the following: 
Continued increase in tumor burden (from iUPD) where RECIST 1.1 definitions of progression 
had been met (from nadir) in target, non-target disease, or new lesions. 
o
Progression in target disease worsens with an increase of at least 5 mm in the absolute 
value of the sum. 
o
Continued unequivocal progression in non-target disease with an increase in tumor 
burden. 
o
Increase in size of previously identified new lesion(s) (an increase of at least 5 mm in the 
absolute value of the sum of those considered to be target new lesions) or additional new 
lesions. 
RECIST 1.1 criteria are met in lesions types (target or non-target or new lesions) where 
progression was not previously identified, including the appearance of additional new lesions. 
If iUPD is not confirmed at the next assessment, then the appropriate response will be assigned (iUPD if 
the criteria are still met, but no worsening, or iSD, iPR, or iCR if those criteria are met compared to 
baseline).  The prior documentation of iUPD does not preclude assigning iCR, iPR, or iSD in subsequent 
time-point assessments or as best overall response (BOR) providing that iCPD is not documented at the 
next assessment after iUPD (Seymour et al, 2017, Table 2). 
New lesions:   
New lesions should be assessed and measured as they appear using RECIST 1.1 criteria (maximum of 5 
lesions, no more than 2 per site, at least 10 mm in long axis [or 15 mm in short axis for nodal lesions]), 
and recorded as New Lesions - Target (NLT) and New Lesion - Non-Target (NLNT) to allow clear 
differentiation from baseline target and non-target lesions.
New lesions may either meet the criteria of NLT or NLNT to drive iUPD (or iCPD). However, the 
measurements of target lesions should NOT be included in the sum of measures of original target lesions 
identified at baseline. Rather, these measurements will be collected on a separate table in the case record 
form.
PD is confirmed in the New Lesion category if the next imaging assessment, conducted at least 4 weeks 
(but not more than 8 weeks) after iUPD confirms further progression from iUPD with either an increase 
of at least 5 mm in the absolute value of the sum of NLT OR an increase (but not necessarily unequivocal 
increase) in the size of NLNT lesions OR the appearance of additional new lesions. 

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Table 11. Time-point (TP) iResponse
Target 
Lesions*
Non-Target 
Lesions*
New 
Lesions*
Time Point Response
No prior 
iUPD**
Prior iUPD**, ***
iCR
iCR
No
iCR
iCR
iCR
Non-iCR/  
Non- iUPD
No
iPR
iPR
iPR
Non-iCR/
Non- iUPD
No
iPR
iPR
iSD
Non-iCR/
Non- iUPD
No
iSD
iSD
iUPD with 
no change 
OR decrease 
from last TP
iUPD with no 
change OR 
decrease 
from last TP
Yes
NA
NLs confirms iCPD if NLs were 
previously identified and increase in size 
for NLNT) or number. If no change in 
NLs (size or number) from last TP, 
remains iUPD.
iSD
iUPD
No
iUPD
Remains iUPD unless iCPD confirmed 
based in further increase in size of NT 
disease (need not meet RECIST 1.1 
criteria for unequivocal PD).
iUPD
Non-iCR/
Non-iUPD
No
iUPD
Remains iUPD unless iCPD confirmed 
based on further increase in SOM of at 
least 5 mm, otherwise remains iUPD.
iUPD
iUPD
No
iUPD
Remains iUPD unless iCPD con-firmed 
based on further increase in:
previously identified T lesion iUPD 
NT lesion iUPD (prior assessment -
need not be unequivocal PD)
iUPD
iUPD
Yes
iUPD
Remains iUPD unless iCPD con-firmed 
based on further increase in:
mm and/or
previously identified NT lesion iUPD 
(need not be unequivocal) and/or
size or number of new lesions 
previously identified
Non-iUPD/
PD
Non-iUPD/
PD
Yes
iUPD
Remains iUPD unless iCPD confirmed 
based on increase in size or number of new 
lesions previously identified.
   * Using RECIST v1.1 principles. If no PSPD occurs, RECIST 1.1 and iRECIST categories for 
         CR, PR, and SD would be the same. 
  ** in any lesion category. 
*** previously identified in assessment immediately prior to this TP.

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All patients will have their iBOR from the start of study treatment until the end of treatment classified 
as outlined below. 
Table 12. iRECIST best overall response (iBOR)
TPR 1 
TPR 2 
TPR 3 
TPR 4 
TPR 5 
iBOR
iCR
iCR, iPR, 
iUPD, NE
iCR, iPR, 
iUPD, NE
iUPD
iCPD
iCR
iUPD
iPR, iSD, NE
iCR
iCR, iPR, iSD, 
iUPD, NE
iCR, iPR, iSD, 
iUPD, iCPD, NE
iCR
iUPD
iPR
iPR, iSD, 
iUPD, NE
iPR, iSD,iUPD, 
NE, iCPD
iPR, iSD, iUPD, 
NE, iCPD
iPR
iUPD
iSD, NE
PR
iPR, iSD, iUPD, 
NE
iPR, iSD, iUPD, 
iCPD, NE
iPR
iUPD
iSD
iSD,iUPD, 
NE
iSD, iUPD, 
iCPD, NE
iSD, iUPD, 
ICPD, NE
iSD
iUPD
iCPD
Anything
Anything
Anything
iCPD
iUPD
iUPD
iCPD
Anything
Anything
iCPD
iUPD
NE
NE
NE
NE
iUPD
Table assumes a randomized study where confirmation of CR or PR is not required.
NE = not evaluable that cycle.
Designation "I" for BOR can be used to indicate prior iUPD to aid in data interpretation. 
For patients with non-target disease only at baseline, only CR or non-CR/non-PD can be 
assigned at each TPR but is not shown in the table for ease of presentation. 
12.2.7 Response and Stable Disease Duration (RECIST 1.1 and iRECIST) 
Response duration will be measured from the time measurement criteria for CR/PR or iCR/iPR 
(whichever is first recorded) are first met until the first date that recurrent or PD is objectively 
documented, taking as reference the smallest measurements recorded on study (including baseline).  
Stable disease duration will be measured from the time of start of treatment until the criteria for 
progression are met, taking as reference the smallest sum on study (including baseline). 
12.2.8 Methods of Measurement
The same method of assessment and the same technique should be used to characterize each identified 
and reported lesion at baseline and during follow-up.  Assessments should be identified on a calendar 
schedule and should not be affected by delays in therapy.  While on study, all lesions recorded at baseline 
should have their actual measurements recorded at each subsequent evaluation, even when very small 
(e.g., 2 mm).  If it is the opinion of the radiologist that the lesion has likely disappeared, the measurement 
should be recorded as 0 mm. If the lesion is believed to be present and is faintly seen but too small to 
measure, a default value of 5 mm should be assigned.  For lesions which fragment/split add together the 
longest diameters of the fragmented portions; for lesions which coalesce, measure the maximal longest 
diameter for the "merged lesion."

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Clinical Lesions.  
mm as assessed using calipers (e.g., skin nodules).  For the case of skin lesions, documentation by color 
photography including a ruler to estimate the size of the lesion is recommended.  If feasible, imaging is 
preferred.
CT, MRI.  CT is the best currently available and reproducible method to measure lesions selected for
response assessment. This guideline has defined measurability of lesions on CT scan based on the 
assumption that CT slice thickness is 5 mm or less. When CT scans have slice thickness greater than 5 
mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable 
in certain situations (e.g., for body scans). Other specialized imaging or other techniques may also be 
appropriate for individual case (Eisenhauer et al, 2009).  For example, while PET scans are not considered 
adequate to measure lesions, PET-CT scans may be used providing that the measures are obtained from 
the CT scan and the CT scan is of identical diagnostic quality to a diagnostic CT (with IV and oral 
contrast).
13. STUDY APPROVAL, OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS
13.1 Protocol Review and Monitoring Committee and Institutional Review Board Review 
Before implementing this study, the protocol must be reviewed by the Markey Cancer Center’s 
Protocol Review and Monitoring Committee and the protocol, the proposed informed consent form 
and other information to subjects, must be reviewed by the University of Kentucky Institutional 
Review Board (IRB). A signed and dated UK IRB initial review approval memo must be 
maintained in the Markey Cancer Center Clinical Research Office (MCC CRO) regulatory binder. 
Any amendments to the protocol, other than administrative ones, must be reviewed and approved 
by the PRMC, study sponsor and the UK IRB.   
13.2 Quality Assurance  
The MCC places the highest priority on ensuring the safety of subjects participating in clinical 
trials and on the quality of data obtained from clinical and translation research.  The MCC Quality 
Assurance (QA) Office oversees the maintenance of quality standards in clinical cancer research 
through clinical data monitoring of Investigator-Initiated Trials (IITs) and routine audits.
13.2.1 Data Monitoring 
The MCC QA Office will collaborate with the PI, Biostatisticians and Lead OnCore® Data 
Management Specialist in creating a Clinical Data Monitoring Plan (CDMP) using a risk based 
approach. The CDMP will describe the scope, communication plan, and frequency of monitoring 
visits as well as describe query submissions and resolutions, action items and monitoring reports. 
The QA monitor assigned to the trial will perform the monitoring tasks in accordance with the 
protocol specified CDMP. The monitoring process will provide research staff and PI with the 
opportunity to evaluate the progress of the study, verify the accuracy and completeness of the case 
report forms, assure that all protocol requirements, including applicable regulations and 
investigator’s obligations are being fulfilled, and prompt resolution of any inconsistencies in the 
study records. 
13.2.2 Audit 
To ensure compliance with Good Clinical Practices and all applicable regulatory requirements, the 

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MCC Audit Committee will conduct a quality assurance audit. A minimum of 10% of patients 
enrolled in the study may be selected for review. The purpose of a MCC audit is to systematically 
and independently examine all study-related activities and documents to determine whether these 
activities were conducted, and data were recorded, analyzed, and accurately reported according to 
the protocol, Good Clinical Practice guidelines of the International Conference on Harmonization, 
and any applicable regulatory requirements.  
13.3 Data and Safety Monitoring Committee 
The MCC Data and Safety Monitoring Committee (DSMC) will oversee the conduct of this trial. 
The MCC DSMC performs routine real-time data monitoring and safety review of all trials, with 
a special focus upon investigator-initiated trials (IITs). The MCC DSMC will conduct review of 
the trial on a schedule determined the MCC Protocol Review & Monitoring Committee (PRMC). 
The MCC DSMC will monitor the following elements of the trial: adverse event analysis, serious 
adverse events, protocol deviations/violations, and accrual. In addition, when applicable will 
review QA audits and monitoring reports, previous reviews by the DSMC, suggested actions by 
other committees, such as the IRB, UK Risk Management Committee, and other parameters and 
outcomes as determined by the DSMC. If appropriate, the DSMC will designate and monitor 
corrective action(s) based on review outcome. The MCC DSMC has the authority to amend, 
temporarily suspend, or terminate the trial based upon patient safety or compliance matters.  
Adverse event lists, guidelines, and instructions for AE reporting can be found in Sections 7, 8, 
10 (& APPENDICES D AND E).
13.4 Data Reporting 
13.4.1 Method 
This study will require data submission and reporting via the OnCore Enterprise Research Clinical 
Trials Management System, which is the official database of the Markey Cancer Center.  
Instructions for submitting data is listed in study-specific guidance documents authored by a 
member of the MCC Data Management Team. These guidance documents may include any of the 
following, as appropriate for the scope of the study: eCRF Completion Guidelines, Data 
Management Specifications, Subject Console Guide, and Query Resolution Guide. These guidance 
documents will be approved and housed within OnCore to ensure access to approved versions to 
facilitate data submission. 
13.4.2 Responsibility for Data Submission 
This trial will be monitored by the MCC Data and Safety Monitoring Committee (DSMC) on a 
schedule determined by the Protocol Review and Monitoring Committee at the initial PRMC 
review.  Study staff are responsible for submitting study data and/or data forms to OnCore as per 
the Markey Cancer Center SOPs.  Study staff are responsible for compiling and submitting data 
for all participants and for providing the data to the Principal Investigator for review. 
   
13.4.3 Publications of data and protection of trade secrets  
The Principal Investigator holds the primary responsibility for publication of the study results; 
provided that the Principal Investigator will provide Exelixis with a copy of any proposed 
publication or release: (a) for abstracts, slide presentations or posters, at least five (5) business day 
prior to submission (in the case of abstracts) or first public presentation (in the case of slide 

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presentations and posters); and (b) at least thirty (30) days in advance of first submission and each 
subsequent submission in the case of manuscripts and also comply with any provisions regarding 
publication that are agreed to between the Principal Investigator’s institution (e.g., institution 
name.) and Exelixis, Inc. in the Clinical Trial Agreement related to this study.
13.5 Data Management 
Data management will be performed by cross-team members at MCC.  These team members will 
include representatives from the Data Management Team, Biostatistics and Bioinformatics SRF, 
and the Quality Assurance Office.  They will work closely with study staff to ensure timely and 
accurate data submission.  A protocol specific Data Management Plan (DMP) will be authored by 
a senior data manager in collaboration with the biostatistician and Principal Investigator with each 
expected to review and approve the finalization of the DMP.  In order to maintain best clinical 
practices in data management, the DMP may include, but not be limited to CRF/eCRF design, 
database build and design, database training, edit check/validation specifications, study database 
testing/release, data and paper workflow, report, metrics, query/discrepancy management, 
management of external (including lab) data, medical coding, SAE handling/reconciliation, data 
transfers and database lock. The protocol-specific DMP will additionally define the schedule at 
which data will be accessed by data management and study statistician to perform statistical 
programming for conduct of data quality, data control, data management, generation of interim 
reports and statistical analysis. Cross-team members will collaborate to establish procedures and 
timelines for quality control, audits, query resolution, annual reports, interim analysis and final 
data analysis. 
13.6 Compliance with Laws and Regulations
The study will be conducted in accordance with U.S. Food and Drug Administration (FDA) and 
International Conference on Harmonization (ICH) Guidelines for Good Clinical Practice (GCP), 
the Declaration of Helsinki, any applicable local health authority, and Institutional Review Board 
(IRB) requirements.  The PI will be responsible for obtaining continuing and not less than annual 
IRB re-approval throughout the duration of the study.  Copies of the Investigator’s annual report 
to the IRB and copies of the IRB continuance of approval must maintained by the MCC CRO.  
The PI is also responsible for notifying the Data and Safety Monitoring Committee of the MCCC 
and the UK IRB of any significant adverse events that are serious and/or unexpected, as per SOP’s 
of those entities. DSMC will review all adverse events of this IIT as per its SOP.

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Immunol Rev. 2010; 236: 219-42.

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Gao M, Lin M, Moffitt RA, et al. Direct therapeutic targeting of immune checkpoint PD-1 in 
pancreatic cancer. Br J Cancer. 2019; 120: 88-96. 
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PMC2848236 

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therapy in renal cell carcinoma. Oncogene. 2016; 35(21): 2687-97.

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APPENDIX A. ECOG PERFORMANCE STATUS
Table 13. ECOG Performance Status Scale
Grade
Descriptions
0
Normal activity.  Fully active, able to carry on all pre-disease performance 
without restriction.
1
Symptoms, but ambulatory.  Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., light 
housework, office work).
2
In bed <50% of the time.  Ambulatory and capable of all self-care, but unable 
to carry out any work activities.  Up and about more than 50% of waking 
hours.
3
In bed >50% of the time.  Capable of only limited self-care, confined to bed or 
chair more than 50% of waking hours.
4
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair.
5
Dead.

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APPENDIX B. CABOZANTINIB MED LOG
PATIENT’S MEDICATION LOG – PAGE 1 OF 2
Today’s Date _______________________      Agent ___Cabozantinib__            Cycle # ___________   
Patient Name __________________________ (initials acceptable).  Patient Study ID _________________
INSTRUCTIONS TO PATIENTS
Complete Medication Log. The med log form, 
2. You will take your prescribed dose of Cabozantinib once daily by mouth
, 
approximately 2 hours after your evening meal (or
before your evening meal).                                                
You will take either ____ 40 mg tablet daily OR  ____ 20 mg tablets daily.  
3. Doses should be taken at approximately the same time each day.  
4. Each dose must be swallowed. DO NOT chew or crush this medication.                                                 
Do not eat grapefruit or Seville oranges when taking Cabozantinib. 
5. If you vomit your daily Cabozantinib dose: Vomited doses should not be made up.  
6. If you forget to take your daily dose: y
have passed after the time you would usually take Cabozantinib.                                                                                     
If you miss a dose, DO NOT TAKE 2 doses at once to make up for the missed Cabozantinib dose.
On your medication log: Record the date, number of tablets you took, and what time you took them.  
If you have comments or notice any side effects, please record them in the Comments column.
Please return the forms to your physician when you attend your next appointment.
Day
Date
What time was 
Cabozantinib 
dose taken?
# of ___mg 
tablets
taken
Comments
2 
3 
4
5 
6 

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20
Your Physician's Office will complete this section below:
2. Date patient was removed from study: _________________________________
3. Patient's planned total daily dose: _____________________________________
4. Total number of pills taken this month: _________________________________
       Staff Signature: ___________________________________________________

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APPENDIX C. LAB MANUAL: PDAC ORGANOID CULTURES
Protocol for Establishing Human PDAC Organoid Cultures from a Tumor Specimen 
Notes: 
This protocol describes methods to establish tumor organoid cultures from human pancreatic 
cancer specimens. These specimens are obtained from endoscopic biopsies and surgical resections 
of pancreatic neoplasms and are usually delivered in a 5 mL or 15 mL tube, respectively, 
containing Human Wash Medium supplemented with GlutaMAX, HEPES, and Primocin. The 
specimens should be processed as soon as possible to prevent autolysis or degradation. Except for 
digestions, all procedures should be performed on ice. The protocol is written for generating 
organoids from tumor specimens, but the same procedure can be followed to generate organoids 
from adjacent normal tissue as long as the Human Complete Feeding Medium is supplemented 
All human experiments are approved by the IRB of UKY, and written informed consent from the 
donors for research use of tissue is obtained prior to acquisition of the specimen. All the procedures 
should be performed on ice (unless otherwise specified) under sterile conditions by using sterile 
tools and by operating in a biological hood. 
Reagents and Equipment: Human tumor (or 
adjacent normal) specimen 
Human Complete PDO Medium 
10.5 mM Rho Kinase Inhibitor (Y-27632) Stock 
10 mg/mL DNAse I stock 
AdDF Wash Medium containing 2.5%FBS 
Growth Factor Reduced Matrigel, 
Phenol Red Free on ice 
Human Digestion Medium 
ACK (Ammonium-Chloride-
Potassium) Lysing Buffer 
Ice bucket with ice 
Sterile scalpels 
Sterile 10 cm tissue culture dish 
Sterile forceps 
Sterile aspirator pipettes 
P2, P20, P200, P1000 pipettes and sterile tips 
Cryovials 
(For CAF isolation) 6 well culture dish 
15 and 50 mL conical tubes 
5 mL Protein LoBind Tubes 
Pre-warmed 24 well culture plates 
Sterile serological pipettes (5, 10, and 25 mL) 
Timer 
Small dewar with liquid nitrogen 
Mr. Frosty freezing container 
Pipet-Aid/Pipette controller 
37oC water bath 
-80oC freezer 
Tissue culture hood with aspirator 
Refrigerated 15/50 mL tube centrifuge 
Hot water flask pre-warmed to 37 oC 
Incubated rocker/rotator set to 37oC 
37oC tissue culture incubator 
Liquid nitrogen cryofreezer 
Recovery Cell Culture Freezing Medium 

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Procedure: 
1. At least 6 hours before organoid isolation, place a 24-well plate in a 37 oC tissue culture 
incubator. 
2. Thaw an aliquot of the Human Digestion Medium in the 37 oC water bath and bring 
temperature to 25-37 oC. 
mM Y-27632 to the 10 mL aliquot of Human 
4. Aliquot 3 mL of pre-warmed Human Digestion Medium supplemented with DNAse and Y-
27632 to a 5 mL protein LoBind tube.
5. Record all the information available for the specimen, including: nosography, hospital, sample 
identifier, date, and the names of the people processing the sample. 
6. Using sterile forceps, transfer the specimen to a sterile petri dish. 
7. Examine the tissue macroscopically, and record the size, shape and gross morphological 
characteristics. Since the handle of the scalpel contains centimeter markings, this can be used to 
measure the specimen. 
8. If adjacent normal tissue is visible on tumor specimen, carefully dissect this tissue away from 
the tumor tissue. 
9. If the specimen is large enough, take a central piece of tumor tissue and put into a 15ml tube 
with 10% formalin for fixation and histological staining. 
10. Mince the remaining specimen into small fragments (1 mm3 or less) using sterile scalpels. 
a. If there is fat present, try to dissect it away from the specimen. 
b. Note that pancreatic tumors are highly fibrotic, and therefore, the tissue is usually hard. 
11. Take a few pieces and place into a cryovial, labelled with the organoid ID, “p0” (indicating 
that vial contains primary tissue), the date, and your initials. Snap freeze cryovial in liquid 
nitrogen. 
12. Transfer remaining tissue to 5 mL protein LoBind tube containing the 3 mL Human 
Digestion Medium supplemented with DNAse and Y-27632. 
13. Place the tube in rotating incubator set to 37 oC with rapid rotation (35 rpm) for an initial 
digestion of 15 minutes. 
14. Using a P1000 pipette set to 1000 uL, prewet the tip by pipetting Human Wash Medium a 
few times, and then triturate the digested tumor 10 times. 
15. Allow the tube to sit for 1 minute so the larger tissue pieces can settle to the bottom. 
16. Transfer the supernatant in a separate LoBind tube, labeled “Fraction 1.” 
17. Add Human Wash Medium to Fraction 1 to fill tube to 5 mL total volume. 
18. Centrifuge Fraction 1 at 200 RCF for 5 minutes at 4 oC. 
19. Carefully remove the supernatant from Fraction 1 without disturbing the cell pellet. 

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20. Resuspend the Fraction 1 pellet in 2 mL AdDF Wash Medium and store on ice. 
21. Add 3 mL Human Digestion Medium supplemented with DNAse and Y-27632 to the 
remaining undigested tissue pieces leftover from the first digest. 
22. Repeat steps 13-21 to acquire “Fraction 2,” and (if there is sufficient undigested material to 
continue) 
23. Combine all fractions together in one 5 mL protein LoBind tube, and fill tube to 5 mL with 
AdDF Wash Medium. 
24. Add 5 mL AdDF Wash Medium to the remaining, undigested tissue fragments. 
25. Centrifuge the tube of combined fractions and the tube of undigested tissue fragments at 200 
RCF for 5 minutes at 4 oC. 
26. Place Human Complete Feeding Medium at 37 oC to warm. 
27. Carefully remove the supernatants from each tube without disturbing the pellets. 
28. In very rare cases, large numbers of red blood cells might be seen in the pellet of combined 
fractions, coloring entire pellet red. If this is the case, perform ACK Lysis of red blood cells as 
follows. If no or minimal numbers of red blood cells are present, proceed with the next step. 
a. Add 4 mL of room temperature ACK lysing buffer and let sit at room temperature for 1 to 
2 minutes. 
b. Invert and flick tube to resuspend the pellet and mix. Do not pipette up and down or cells 
will stick to the pipette. 
c. Centrifuge the tube at 200 RCF for 5 min at 4oC. 
d. Carefully aspirate the supernatant without disturbing the pellet. 
e. Resuspend cells in 1 mL Human Wash Medium and then fill tube to 5 mL with additional 
4 mL Human Wash Medium. 
f. Centrifuge the tube at 200 RCF for 5 min at 4oC. 
g. Carefully aspirate the supernatant without disturbing the pellet. 
29. Resuspend the pellet of combined fractions in Matrigel. The volume of Matrigel to use will 
depend on the size of the pellet. It is best to err on the side of resuspending the pellet in less 
Matrigel to keep the cells concentrated, rather than diluting the material too much. As a ballpark 
igel domes into a pre-warmed 24 well plates. To aid in dome solidification, 
plates can be placed on top of a hot water flask, while you are pipetting the domes. 
31. Place the plate into a 37 oC tissue culture incubator until RGF BME solidifies (~10 minutes). 
32. Resuspend the pelleted undigested tissue fragments in Recovery Cell Freezing Medium. (The 
volume to resuspend in depends on the volume of the pellet.) 
33. Aliquot the tissue fragments to cryovials. 
34. Place cryovials in a Mr. Frosty freezing container and freeze cells overnight at -80 oC. After 
24 hours, frozen cells can be moved to a liquid nitrogen freezer for long-term storage. 

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35. Add 10.5 mM Rho Kinase Inhibitor (Y-
the Human Complete Fee
generating adjacent normal organoids, the Human Complete Feeding Medium should also be 
-warmed Human Complete Feeding Medium supplemented with Rho 
Kinase Inhibitor (Y-27632) to each well of organoids. 
37. Return plates of organoids to tissue culture incubator. 
Optional: To isolate cancer associated fibroblasts: 
38. Separate a portion of digest to a new 15 mL conical tube. 
39. Centrifuge at 200 RCF for 5 min at 4 oC. 
40. Carefully remove the supernatant. 
41. Resuspend pellet in Human CAF Medium. 
42. Transfer to 1 well of a 6 well culture plate. 
43. Place in 37 oC tissue culture incubator. Note: At future passages, very short trypsin incubations 
will help dissociate fibroblasts while keeping cancer cells attached. This method may be used to 
enrich for fibroblasts. 

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APPENDIX D. LAB MANUAL: EXOSOMAL LIPIDS
Lipid Exosomal Analysis for Plasma 
*excerpts below from Fan et al, 2018 (PMID: 30292300)
Blood collection
Ten mL samples of blood will be drawn into a purple top vacutainer containing K2-EDTA (Becton-
Dickson), inverted twice to ensure dissolution of the EDTA, and kept on ice immediately after 
blood draw. The whole blood will be separated into packed red cells, buffy coat, and plasma within 
30 min of collection by centrifuging at 3500g for 15 min at 4 degrees C in a swing out rotor. All 
blood processing procedures were performed in a class II biosafety cabinet housed in a BSL 
category 2 laboratory. Plasma (0.7 mL) was aliquotted into 1.5 mL screw cap vials, flash frozen 
in liq. N2, and stored at -80 degrees C until exosomal isolation. These collection and processing 
procedures were designed to minimize variations in plasma and exosome quality.
Exosome preparation
Exosomes were isolated from plasma by differential ultracentrifugation adapted from Baranyai et 
al (2015) and Koga et al (2005). 0.7 mL cleared plasma were placed in 5 x 41mm polyallomer 
ultraclear ultracentrifuge tubes on ice, and centrifuged for 1 h at 70,000 g at 4 degrees C in a 
SWTi55 swing out rotor (Beckman). The supernatant was recentrifuged at 100,000 g for 1 h at 4 
degrees C, and the pellet was drained and resuspended in 0.7 mL cold PBS, and recentrifuged at 
100,000 g for 1 h at 4 degrees C. The washed exosomal pellets were resuspended in 100 µL 
nanopure water, vortexed for 30 s and transferred to a fresh microcentrifuge tube. The 
ultracentrifuge tube was washed with another 100 mL of nanopure water, vortexed for 30 s and the 
wash was transferred into same microcentrifuge tube, using the same pipet tip. The combined 
exosome suspensions were then lyophilized except for a small portion that was used for 
characterization by particle size distribution analysis (see below). These nanoparticles are 
operationally defined as exosomes.
Lipid extraction for exosomes
The lyophilized EXO preparations were extracted for lipidic metabolites using a solvent 
partitioning method with CH3CN:H2O:CHCl3 (2:1.5:1, v/v) as described previously [Fan et al
chapter, sample preparation for metabolomics investigation, 2012, https://doi.org/10.1007/978-1-
61779-618-0_11.]. The resulting lipid extracts were vacuum-dried in a vacuum centrifuge 
(Eppendorf), redissolved in 200 µL CHCl3:CH3OH (2:1) with 1mM butylated hydroxytoluene, 
which was further diluted 1:20 in isopropanol/CH3OH/CHCl3 (4:2:1) with 20mM ammonium 
formate for UHR-FTMS analysis.

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Microparticle characterization
A small fraction (<1%) of each exosome preparation was characterized by size distribution analysis 
using a Nanosight 300 (Malvern Instruments), which provided the distribution of the
Stokes' radius (mean 60-66 nm) and the number density of the particles. The method eliminates very 
small particles, and provides a strongly peaked, narrow distribution at the expected size for exosomes. 
UHR-FTMS analysis of exosomal lipids
High sample throughput ( 16 min total cycle time per sample, <7 min for MS1 portion) was achieved 
using the nanoelectrospray TriVersa NanoMate (Advion Biosciences, Ithaca, NY, USA) with 1.5 kV 
electrospray voltage and 0.4 psi head pressure. UHR-FTMS data were acquired from an Orbitrap 
Fusion Tribrid (Thermo Scientific, San Jose, CA, USA) set at a resolving power of 450,000 (at 200m/z) 
for MS1 full scans using 10 microscans per scan in the m/z range of 150-1,600, achieving sub ppm 
mass accuracy through <1200m/z in positive mode. AGC (Automatic Gain Control) target was set to 
1e5 and maximal injection time was set to 100 ms. During the MS1 run, the top 500 most intense 
monoisotopic precursor ions were isolated via quadrupole using 1m/z isolation window and HCD 
(Higher Energy Collisional Dissociation) set at 25% collision energy was performed in positive mode 
for data-dependent MS2 at a resolving power of 120,000 (at 200 m/z) to obtain fragments for acyl 
chain assignment and neutral loss of specific head groups. The AGC target was set to 5e4 with maximal 
injection time of 500 ms. MS2 does not distinguish the sn1 and sn2 acyl positions of glycerolipids, nor 
the position of unsaturations in acyl chains and acyl branching. 
Lipid assignment
The UHR-FTMS raw data were assigned by our (CESB) in-house software PREMISE (PRecalculated 
Exact Mass Isotopologue Search Engine) that compares UHR-FTMS m/z data against our metabolite 
m/z library (calculated with mass accuracy to the 5th decimal point) to discern all known lipid MF and 
their 13C isotopologues, including hypothetical lipids, while simultaneously taking into account all of 
the major adducts (here H+, Na+, K+, NH4+) (Lane et al, 2008, 2009). An in-house developed natural 
abundance (NA) correction algorithm (Carrerr et al, 2013; Moseley, 2010] was applied to 
simultaneously examine the distribution of naturally occurring 13C isotopologues of the unlabeled 
lipids to help verify the assigned molecular formulae, and to eliminate nonmonoisotopic
13C 
isotopologues from further analysis. For statistical classification, we used only high accuracy 
monoisotopic m/z values that mapped to lipid molecular formulae, and multiple adducts of each were 
tracked throughout to avoid redundancy. Below, such m/z values are referred to as “lipid features”, and 
neither molecular formulae nor lipid names were directly used. 
The number of assigned lipid features will be assessed for each sample. After combining all samples 
into a master file, the results of lipid features will be summarized and described. Prior to multivariate 
statistical analyses, MS1 peaks arising from solvent blanks and known contaminants will be assessed 
and potentially removed from the lipid feature lists. As absolute intensities vary from sample to sample, 
the lipid features must be normalized. This is equivalent to estimating the mole fraction of each lipid 
feature present, and therefore can be used for determining relative changes in composition. 

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APPENDIX E. MANAGEMENT OF CABOZANTINIB-RELATED ADVERSE EVENTS
Table 14. Management of Diarrhea Associated with Cabozantinib
Status
Management
Tolerable Grade 1-2 (duration
< 48 h)
Continue with study treatment and consider GI recommendations
Initiate treatment with an antidiarrheal agent (e.g., loperamide 4 mg followed 
by 2 mg after each episode of diarrhea [maximum: 16 mg loperamide perday])
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 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, 
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
For Grade 3-4 or complicated lower grade diarrhea considerhospitalization 
and IV hydration
Re-assess after 24 h
o
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 
secondline antidiarrheal or referral to gastroenterologist

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Table 15. Management of Hypertension Associated with Cabozantinib 
Event
Management
Subjects NOT receiving optimized anti-hypertensive therapy
> 140 mm Hg (systolic)a and < 160 
mm Hg
OR
> 90 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 
<140 mm Hg systolic or <90 mm Hg diastolic
If subject is symptomatic interrupt cabozantinib treatment
OR
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 < 140 mm Hg systolic or < 90 mm Hg diastolic, cabozantinib 
treatment should be dose reduced further or interrupted.
Cabozantinib treatment should be dose interrupted if upper limits of 
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 < 140 mm Hg systolic and 
< 90 mm Hg diastolic.
Hypertensive emergencyc
Discontinue cabozantinib treatment.
a Permitted dose levels are defined by individual protocols.
b 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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Table 16. Management of Palmar-plantar Erythrodysesthesia (PPE) associated with Cabozantinib
CTCAE v.4.0 Grade
Action To Be Taken
Grade 1
Cabozantinib treatment may be continued at the current dose if PPE is clinically 
insignificant and tolerable. Otherwise, Cabozantinib should be reduced to the next 
lower dose levela. Start urea 20% cream twice daily AND clobetasol 0.05% cream 
once daily. Reassess at least weekly; if PPE worsens at any time or does not
improve after 2 weeks, proceed to the intervention guidelines for Grade 2.
Grade 2
Cabozantinib treatment may be continued if PPE is tolerated. Cabozantinib should 
be dose reduced or interrupted if PPE 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 PPE 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 
eatment if 
PPE does not improve within 6 weeks.
CTCAE, Common Terminology Criteria for Adverse Events; NSAID, non-steroidal anti-inflammatory drug; PPE, palmar plantar 
erythrodysesthesia.
a Permitted dose levels are defined by individual protocols.

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Table 17. Management of Proteinuria Associated with Cabozantinib
Severity of Proteinuria 
(UPCR)
Management of Proteinuria
Non-UC:
For UC:
No change in Cabozantinib treatment or monitoring
Non-UC:
>
1 and < 3.5 mg/mg
(> 113.1 and < 395.9
mg/mmol)
For UC:
(> 2 and < 3.5 mg/mg
(> 226.2 and < 395.9
mg/mmol)
Consider confirming with a 24-h protein assessment within 7 days
No change in Cabozantinib
-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 
unless otherwise approved by sponsor.
If UPCR > 2 mg/mg, repeat UPCR monitoring within 7 days and once per 
week. If UPCR < 2 mg/mg on 2 consecutive readings, UPCR monitoring 
can revert to protocol-specific times. (Second reading is confirmatory and 
canbe done within 1 week of first reading.)
All Tumor Types:
mg/mmol)
Interrupt Cabozantinib treatment pending repeat UPCR monitoring 
within 7 days and/or 24-h urine protein.
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 UPCR until it remains < 2 mg/mg on two consecutive 
measurements. If UPCR monitoring is determined to be stable (< 20% 
change) for 1 month then continue with UPCR monitoring per protocol or as 
clinically indicated.
Nephrotic syndrome
Discontinue Cabozantinib treatment
UC, urothelial carcinoma; UPCR, urine protein/creatinine ratio.

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Table 18. Management of Hepatotoxicity Associated with Cabozantinib
Severity of Transaminase (ALT or AST) and 
total bilirubin Elevations
Management
If ALT or AST is within normal limits at baseline 
and increases to > ULN - 3.0 x ULN
OR
Total bilirubin increases to > ULN - 1.5 x ULN
Dose adjustment is usually not required.
Consider discontinuing concomitant hepatotoxic 
medications and adding supportive care asindicated.
If elevation of ALT or AST to > 3.0 - 5.0 x ULN 
OR
Total bilirubin increases to > 1.5 - 3.0 x ULN 
Interrupt Cabozantinib if lasting longer than 1 week.
Restart Cabozantinib after lab abnormalities have
same dose level prior to dose interruption or one dose 
level lower at the discretion of the Sponsor.
If ALT or AST 
OR
Total bilirubin increases to > 3.0 x ULN 
Interrupt Cabozantinib and consider more 
frequent monitoring of ALT, AST, and bilirubin.
Restart Cabozantinib at a reduced dose after lab 
baseline grade.
Discontinue if lab abnormalities cannot be reversed despite
interruption of Cabozantinib.
ALT or AST > 8 × 
ULN OR
ALT or AST > 3 × ULN in combination 
with total bilirubin > 2 × ULN without 
reasonable other explanation, consistent with 
DILI
Discontinue Cabozantinib unless these laboratory 
abnormalities have recovered to Grade 1 or baselinelevel 
after an interruption and the Sponsor has approved 
reinstitution of Cabozantinib.
ALT, alanine aminotransferase; AST, aspartate aminotransferase; CTCAE, Common Terminology Criteria for Adverse Events; 
DILI, drug-induced liver injury.
Note: The guidance for dose modifications for bilirubin abnormalities applies only to subjects without Gilbert’s Disease. Elevations 
of aminotransferases when hepatic metastases are present may not require dose modifications if there is less than a doubling in the 
aminotransferases from baseline 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 x ULN without other reasonable explanation, consistent with drug-induced liver injury (DILI).

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APPENDIX F. MANAGEMENT OF PEMBROLIZUMAB-RELATED ADVERSE EVENTS 
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 study 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. Dose 
modification and toxicity management guidelines for irAEs associated with pembrolizumab are 
provided in the table below.  
Table 19. Dose modification and toxicity management guidelines for immune-related AEs 
associated with pembrolizumab monotherapy and IO combinations. 
General instructions:
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other 
immunosuppressive treatment should begin if the irAEs are not controlled by corticosteroids. 
2.
Study intervention must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not 
mg/day within 12 weeks of the last study intervention treatment. 
3.
ntinue at least 4 weeks.
4.
If study intervention has been withheld, study intervention
Grade 1 after 
corticosteroid taper.
irAEs
Toxicity grade 
(CTCAE V5.0)
Action with 
pembrolizumab
Corticosteroid and/or 
other therapies 
Monitoring and follow-up 
Pneumonitis 
Grade 2
Withhold 
Administer 
corticosteroids 
(initial dose of 
1 - 2 mg/kg 
prednisone or 
equivalent) 
followed by taper
Add prophylactic 
antibiotics for 
opportunistic 
infections
Monitor participants for signs 
and symptoms of pneumonitis
Evaluate participants with 
suspected pneumonitis with 
radiographic imaging and initiate 
corticosteroid treatment
Grade 3 or 4, or 
recurrent Grade 2 
Permanently 
discontinue
Diarrhea / Colitis 
Grade 2 or 3
Withhold
Administer 
corticosteroids 
(initial dose of 
1 - 2 mg/kg 
prednisone or 
equivalent) 
followed by taper
Monitor participants for signs 
and symptoms of enterocolitis 
(ie, diarrhea, abdominal pain, 
blood or mucus in stool with or 
without fever) and of bowel 
perforation (ie, peritoneal signs 
and ileus)
diarrhea suspecting colitis should 
consider GI consultation and 
performing endoscopy to rule out 
colitis
Grade 4 or 
recurrent Grade 3
Permanently 
discontinue

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Participants 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
AST or ALT 
elevation or 
Increased 
Bilirubin
Grade 2 a
Withhold
Administer 
corticosteroids 
(initial dose of 
0.5 - 1 mg/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 b or 4 c
Permanently 
discontinue
Administer 
corticosteroids 
(initial dose of 
1 - 2 mg/kg 
prednisone or 
equivalent) 
followed by taper
Type 1 diabetes 
mellitus (T1DM) 
or Hyperglycemia
New onset T1DM 
or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold d
Initiate insulin 
replacement 
therapy for 
participants with 
T1DM
Administer anti-
hyperglycemic in 
participants with 
hyperglycemia
Monitor participants for 
hyperglycemia or other signs and 
symptoms of diabetes
Hypophysitis
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 
discontinue d
Hyperthyroidism 
Grade 2
Continue
Treat with non-
selective beta-
blockers (eg, 
propranolol) or 
thionamides as 
appropriate
Monitor for signs and symptoms 
of thyroid disorders
Grade 3 or 4
Withhold or 
permanently 
discontinue d
Hypothyroidism
Grade 2, 3, or 4
Continue
Initiate thyroid 
replacement 
hormones (eg, 
levothyroxine or 
liothyronine) per 
standard of care
Monitor for signs and symptoms 
of thyroid disorders

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Nephritis and 
renal dysfunction:
grading according 
to increased 
creatinine or acute 
kidney injury
Grade 2
Withhold
Administer 
corticosteroids 
(prednisone 
1 to 2 mg/kg or 
equivalent) 
followed by taper
Monitor changes of renal 
function
Grade 3 or 4
Permanently 
discontinue
Neurological 
Toxicities
Grade 2
Withhold
Based on severity 
of AE administer 
corticosteroids
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes
Grade 3 or 4
Permanently 
discontinue
Myocarditis
Grade 1
Withhold
Based on severity 
of AE administer 
corticosteroids
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes
Grade 2, 3, or 4
Permanently 
discontinue
Exfoliative 
Dermatologic 
Conditions
Suspected SJS, 
TEN, or DRESS
Withhold
Based on severity 
of AE administer 
corticosteroids
Ensure adequate evaluation to 
confirm etiology or exclude other 
causes
Confirmed SJS, 
TEN, or DRESS
Permanently 
discontinue
All Other 
immune-related 
AEs
Persistent Grade 2
Withhold
Based on severity 
of AE administer 
corticosteroids
Ensure adequate evaluation to 
confirm etiology or exclude other 
causes
Grade 3
Withhold or 
discontinue 
based on the 
event e. 
Recurrent Grade 3
or Grade 4 
Permanently 
discontinue
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for 
Adverse Events; DRESS=Drug Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; 
ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal 
Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a AST/ALT: >3.0 to 5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal; 
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x 
ULN if baseline normal; >3.0 - 10.0 x baseline if baseline abnormal
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; 
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating 
physician. If control achieved or 
, pembrolizumab may be resumed. 
e Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs (eg, vasculitis and 
sclerosing cholangitis).

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Dose modification and toxicity management of infusion-reactions related to pembrolizumab
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 the table below.
Table 20. 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 participant is deemed medically 
stable in the opinion of the investigator.
None
Grade 2
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated for 
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 participant 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 participant should be 
premedicated for the next scheduled dose.
Participants who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug intervention
Participant may be 
premedicated 1.5h (± 30 
minutes) prior to infusion of 
_____ 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 participant is deemed medically 
stable in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be used 
immediately.
No subsequent dosing

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Participant is permanently discontinued from 
further study drug intervention.
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 v5.0 (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 and/or unforeseen circumstances not related to study intervention. However, 
intervention is to be restarted within 3 weeks of the originally scheduled dose and within 42 days of 
the previously administered dose, unless otherwise discussed with the Sponsor. The reason for study 
intervention interruption is to be documented in the patient's study record. 

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APPENDIX G. POTENTIAL DRUG INTERACTIONS WITH CABOZANTINIB
The Investigator should evaluate concomitant medications prior to initiation for potential drug 
interactions with Cabozantinib through the CYP3A4 pathway.  
The table below shows examples of potential strong inhibitors and inducers of CYP3A4; this table 
below is not all-inclusive.  
Please refer to the FDA website for the most up-to-date lists of substrates, inducers and 
inhibitors of selected CYP450 isozyme pathways: http://www.fda.gov/Drugs/DevelopmentApproval 
Process/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm. 
Table 21. Drug interactions with cabozantinib 
Strong Inhibitors of CYP3A4
   Strong Inducers of CYP3A4
Conivaptan 
Diltiazem 
Grapefruit Juice 
Idelalisib 
Nefazodone 
Anti-virals 
Boceprevir 
Cobicistat 
Conivaptan  
Danoprevir  
Dasabuvir  
Elvitegravir 
Indinavir  
Lopinavir  
Nelfinavir 
Ombitasvir 
Paritaprevir 
Ritonavir  
Saquinavir  
Telaprevir 
Tipranavir 
Anti-Fungals  
Itraconazole 
Ketoconazole 
Posaconazole 
      Voriconazole 
Antibiotics
Clarithromycin 
Telithromycin 
Troleandomycin 
Carbamazepine 
Efavirenz 
Enzalutamide 
Erythromycin  
Mitotane 
Modafinil  
Nevirapine 
Oxcarbazepine 
Phenytoin  
Rifampin
St. John’s wort