A Phase 2 Trial of Cabozantinib and Pembrolizumab in the First-Line Treatment of Advanced Hepatocellular Carcinoma
Phase: PHASE2
Conditions: Advanced Hepatocellular Carcinoma, BCLC Stage B Hepatocellular Carcinoma, BCLC Stage C Hepatocellular Carcinoma
Sponsor: University of Washington

 
RG1007034 
 
 
 
FRED HUTCHINSON CANCER CENTER UNIVERSITY 
OF WASHINGTON SCHOOL OF MEDICINE 
 
Current version: December 13, 2021 
 
 
Title of Protocol: 
A Phase 2 trial of cabozantinib and pembrolizumab in the first‐line treatment of advanced 
hepatocellular carcinoma 
 
Investigators List: 
Principal Investigator 
Professional Title 
Phone Number 
Gentry King, MD 
Assistant Member, FHCRC, Assistant Professor, UW 
(206) 606‐2494 
Investigator 
Professional Title 
Phone Number 
E. Gabriela Chiorean, MD 
Member, FHCRC, Professor, UW 
(206) 606‐6248 
Stacey Cohen, MD 
Assistant Member, FHCRC, Assistant Professor, UW 
(206) 606‐6658 
Andrew Coveler, MD 
Associate Member, FHCRC, Associate Professor, UW 
(206) 606‐7509 
William Harris, MD 
Associate Member, FHCRC, Associate Professor, UW 
(206) 606‐6856 
Veena Shankaran, MD 
Associate Member, FHCRC, Associate Professor, UW 
(206) 667‐7844 
David Zhen, MD 
Assistant Member, FHCRC, Assistant Professor, UW 
(206) 606‐1733 
 
 
 
Lindsay Hannan, MD 
Assistant Member, FHCRC, Assistant Professor, UW 
(206) 667‐4998 
Biostatistician: 
Ted Gooley, PhD 
Full Member, FHCRC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of 107 
Exelixis (drug and funding) and Merck (drug) 
Supported by: 
IRO received 07/12/22
FHCRC IRB Approval  
8/3/2022 
Document Released Date

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A Phase 2 trial of cabozantinib and pembrolizumab in the first‐line treatment of advanced 
hepatocellular carcinoma 
 
PROJECT SYNOPSIS 
 
Title 
A Phase 2 trial of cabozantinib and pembrolizumab in the first‐line treatment 
of advanced hepatocellular carcinoma 
Version date 
August 11, 2021 
Study center 
University of Washington/Fred Hutchinson Cancer Center 
Number of subjects 
29 patients 
Study duration 
Accrual period: 24 months; follow‐up period: 12 months 
Background and 
rationale 
Hepatocellular carcinoma (HCC) is the 3rd leading cause of cancer‐related 
mortality globally. Prognosis is poor for patients with advanced disease 
despite the recent approval of several new agents. The immune system plays a 
critical role in the pathogenesis of HCC. Increased regulatory T cells, decreased 
CD8+ and CD4+ tumor‐infiltrating lymphocytes, and high PD‐1/PD‐L1 
expression are associated with poorer outcomes. This is supported by the 
efficacy of PD‐1 inhibitors currently approved in the second‐line treatment of 
HCC, after progression on VEGFR tyrosine kinase inhibitors. 
Promising early results were noted for combinations of immune checkpoint 
inhibitors and VEGF/VEGFR blockade, which may activate synergistic or inhibit 
resistance pathways. Lenvatinib and pembrolizumab led to an ORR of 42%, 
while bevacizumab and atezolizumab led to an ORR of 61% in the first‐line 
treatment of advanced HCC. Furthermore, the role of cMET signaling is 
increasingly recognized in HCC. Cabozantinib is a multikinase inhibitor against 
cMET, VEGFR1‐3 and AXL. The Phase 3 CELESTIAL trial demonstrated a 
significant improvement in OS with cabozantinib compared to placebo in 
patients post‐sorafenib (HR 0.76, 95% CI 0.63‐0.92, p=0.0049), leading to FDA 
approval for patients with advanced HCC previously treated with sorafenib. 
Evidence also supports the immunomodulatory effects of cMET and the TAM 
receptors including AXL via enhancement of PD‐L1/PD‐L2 expression and 
regulation of immune effector and regulatory cells, thus supporting a 
combination strategy with cabozantinib and immunotherapy. 
There is a strong rationale for the combined inhibition of c‐MET/VEGFR and 
PD‐1 in HCC. This Phase 2 clinical trial will evaluate the efficacy of cabozantinib 
and pembrolizumab in the first‐line treatment of patients with advanced HCC. 
Design 
Non‐randomized Phase 2 trial (Simon’s optimal two‐stage design) 
Objectives 
Primary objective 
• 
To determine the objective response rate (ORR) of the combination of 

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cabozantinib and pembrolizumab in the first‐line treatment of 
advanced HCC based on RECIST v1.1. 
Secondary objectives 
• 
To assess the disease control rate (DCR) by RECIST v1.1, ORR and DCR 
by iRECIST, progression‐free survival (PFS) by RECIST v1.1, and overall 
survival (OS). 
• 
To assess the safety of the combination of cabozantinib and 
pembrolizumab based on NCI CTCAE v5. 
Exploratory objectives 
• 
To explore the predictive biomarkers for cabozantinib and 
pembrolizumab in HCC in blood and archival tissue or pre‐treatment 
fresh tumor biopsy (if applicable). 
Inclusion and 
exclusion criteria 
Inclusion criteria 
1. At least 18 years of age. 
2. Must have a histologically confirmed diagnosis of HCC or a non‐invasive 
diagnosis of HCC as per the American Association for the Study of Liver 
Diseases (AASLD) criteria. 
a. If available, archival tissue must be submitted. 
b. Mixed HCC‐cholangiocarcinoma is not allowed. 
3. Patient has BCLC stage C disease, or BCLC stage B disease that is not 
amenable to locoregional therapy or refractory to locoregional therapy, and 
not amenable to curative treatment. 
a. Previous locoregional therapy is allowed (e.g. surgical resection, 
external beam radiation, catheter‐based therapy), and patients must 
have evidence of disease progression from locoregional therapy. 
4. Must have measurable disease by RECIST v1.1. 
a. Lesions that were previously radiated or ablated cannot be target 
lesions unless there was subsequent radiographic progression at those 
sites. 
5. No prior systemic therapy for HCC. Prior chemotherapy given locally into 
the liver (e.g. TACE) is allowed. 
6. Must have Child‐Pugh class A hepatic function within 7 days prior to first 
dose of study intervention (Appendix 6). 
7. ECOG performance status 0‐1 (Appendix 5). 
8. Life expectancy of at least 12 weeks. 
9. Recovery to baseline or ≤ Grade 1 toxicities (CTCAE v5) related to any prior 
treatments, unless adverse events (AEs) are clinically nonsignificant and/or 
stable on supportive therapy. 
10. Adequate organ and marrow function, based upon meeting all of the 
following laboratory criteria within 14 days before first dose of study 
treatment: 
a. Absolute neutrophil count (ANC) ≥ 1500/mm3 without granulocyte 
colony‐stimulating factor support. 
b. Platelets ≥ 60,000/mm3 without transfusion within 14 days. 

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c. Hemoglobin ≥ 9 g/dL (≥ 90 g/L) without transfusion or EPO dependency 
within 14 days. 
d. Alanine aminotransferase (ALT) and aspartate aminotransferase 
(AST) ≤ 5 × upper limit of normal (ULN). 
e. Total bilirubin ≤ 2 mg/dL OR direct bilirubin ≤ ULN for participants with 
total bilirubin levels >2 mg/dL. 
f. 
Serum albumin ≥ 2.8 g/dl (≥ 28 g/L) without albumin infusion. 
g. Prothrombin time (PT)/INR or partial thromboplastin time (PTT) test 
≤ 1.5 × ULN. 
h. Serum creatinine ≤ 1.5 × ULN or calculated creatinine clearance 
≥ 40 mL/min using the Cockcroft‐Gault equation (Appendix 7). 
i. 
Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol) or 
24h urine protein ≤ 1g. 
j. 
Hemoglobin A1c (HbA1c) ≤ 8% within 28 days before randomization or 
fasting serum glucose ≤ 160 mg/dL. 
11. Patients with positive hepatitis B surface antigen (HBsAg) and/or HBV viral 
load >100 IU/mL at the time of enrollment are eligible to enroll on study if 
they meet the following criteria: 
a. Anti‐HBV therapy as per institutional practice must be given at least 4 
weeks and HBV viral load must be <100 IU/mL prior to initiating study 
treatment. Patients on active HBV therapy with viral loads <100 IU/mL 
should remain on the same therapy throughout study treatment. 
b. Note: Patients with positive anti‐hepatitis B core antibody (HBcAb), 
negative HBsAg, and negative or positive anti‐hepatitis B surface 
antibody, and who have an HBV viral load <100 IU/mL do not require 
anti‐viral prophylaxis. 
12. Patients with past or ongoing hepatitis C infection (HCV) are eligible to 
enroll on study, with or without prior anti‐viral treatment, as long as the 
other eligibility criteria are met. Treated patients must have completed 
their anti‐viral treatment at least 1 month prior to initiating study 
treatment. 
13. Sexually active fertile subjects and their partners must agree to use 
effective methods of contraception (see Appendix 8) during the course of 
the study and for at least 4 months after the last dose cabozantinib. They 
must also refrain from donating sperm during this time period. 
14. Female subjects of childbearing potential must not be pregnant at screening 
and not breastfeeding. Females of childbearing potential are defined as 
premenopausal females capable of becoming pregnant (i.e. females who 
have had any evidence of menses in the past 12 months, with the exception 
of those who had prior hysterectomy). 
a. Women who have been amenorrheic for 12 or more months are still 
considered to be of childbearing potential if the amenorrhea is possibly 
due to prior chemotherapy, antiestrogens, low body weight, ovarian 
suppression or other reasons. 
15. Capable of understanding and complying with the protocol requirements 
and must provide written informed consent/assent for the study. 
Exclusion criteria 

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1. Prior treatment with any systemic therapy for HCC, including anti‐VEGF 
therapy or any systemic investigational agent. 
a. If the patient previously received systemic treatment for reasons other 
than HCC: small molecule kinase inhibitors are not allowed within 2 
weeks and cytotoxic/biologic agents are not allowed within 4 weeks of 
study treatment. 
2. Prior 
exposure 
to 
immune 
checkpoint 
inhibitors 
or 
other 
immunotherapeutic agents. 
3. Currently participating in or has participated in a study of an investigational 
agent or device within 4 weeks prior to the first dose of study treatment. 
4. Major surgery within 6 weeks or minor surgery (e.g. dental extraction) 
within 10 days prior to first dose of study treatment. 
a. Complete wound healing from major surgery must have occurred at 
least 1 month before first dose and from minor surgery (e.g. simple 
excision, tooth extraction) at least 7 days before first dose. Subjects 
with clinically relevant ongoing complications from prior surgery are not 
eligible. 
5. Local liver‐directed therapy within 4 weeks of initiating study treatment. 
6. Palliative radiation for the purpose of symptomatic relief to non‐liver and 
non‐CNS disease within 2 weeks of starting treatment. Other radiation 
treatments within 4 weeks of starting treatment. 
a. Patients must have recovered from all radiation‐related toxicities, not 
require corticosteroids, and have not had radiation pneumonitis. 
7. Prior liver or other allogenic tissue/organ transplantation. 
8. History of primary immunodeficiency. 
9. Active autoimmune or inflammatory disease that has required systemic 
treatment in the past 2 years (i.e. with use of disease‐modifying agents, 
corticosteroids or immunosuppressive drugs). This includes, but is not 
limited to, inflammatory bowel disease, celiac disease, systemic lupus 
erythematosus, rheumatoid arthritis, myasthenia gravis, Graves’ disease, 
etc. 
a. The following autoimmune conditions are allowed: vitiligo or alopecia; 
hypothyroidism 
on 
stable 
hormone 
replacement 
therapy; 
psoriasis/eczema not requiring systemic treatment. 
b. Replacement therapy (e.g. thyroxine, insulin, or physiologic 
corticosteroid 
replacement 
therapy for 
adrenal 
or 
pituitary 
insufficiency) is not considered a form of systemic treatment and is 
allowed. 
10. Chronic use of systemic steroid (in dosing exceeding 10 mg daily of 
prednisone equivalent) or immunosuppressive therapy or use within 14 
days prior to enrollment. 
a. The following treatments are allowed: intranasal, inhaled, topical or 
local steroid injections; systemic corticosteroids at physiologic doses 
equivalent to no more than prednisone 10 mg/day; steroids as 
premedication for contrast dye allergy. 
11. History of (non‐infectious) pneumonitis/interstitial lung disease that 
required steroids or has current pneumonitis/interstitial lung disease. 
12. History of hepatic encephalopathy or treatment to prevent or control 

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encephalopathy within the past 12 months. Subjects on lactulose and/or 
rifaximin to control hepatic encephalopathy are not allowed. 
13. Esophageal or gastric variceal bleeding within the past 6 months. All 
subjects will be screened for esophageal varices unless performed in the 
last 6 months before study treatment. If varices are present, they should be 
treated according to institutional standards before starting study 
treatment. 
14. Uncontrolled ascites, clinically significant or symptomatic ascites requiring 
paracenteses or increasing doses of diuretics within the past 3 months. 
a. Patients who are on stable diuretic doses for at least 3 months are 
eligible if they meet other eligibility criteria. 
b. Asymptomatic ascites detected on imaging are allowed. 
15. Has known history or any evidence of CNS metastases and/or 
carcinomatous meningitis. Subjects with previously treated brain 
metastases may participate provided they are asymptomatic and 
radiologically stable (i.e. without progression for at least 4 weeks by repeat 
imaging (which must be performed during study screening), clinically stable, 
and without the need steroids for at least 4 weeks prior to first dose of study 
treatment). 
16. Concomitant anticoagulation with oral anticoagulants (e.g. warfarin, direct 
thrombin and Factor Xa inhibitors) or platelet inhibitors (e.g. clopidogrel). 
Allowed anticoagulants are the following: 
a. Low‐dose aspirin for cardioprotection (per local applicable guidelines) 
is permitted. 
b. Low molecular weight heparin (LMWH) is permitted. 
c. Anticoagulation with therapeutic doses of LMWH is allowed in subjects 
without known brain metastases who are on a stable dose of LMWH for 
at least 4 weeks before first dose of study treatment, and who have had 
no clinically significant hemorrhagic complications from the 
anticoagulation regimen or the tumor. 
17. The subject has uncontrolled, significant intercurrent or recent illness 
including, but not limited to, the following conditions: 
a. Cardiovascular disorders: 
i. 
Congestive heart failure New York Heart Association Class 3 or 4, 
unstable angina pectoris, serious cardiac arrhythmias with risk of 
hemodynamic instability within 12 months before the first dose 
of study treatment. 
ii. 
Uncontrolled hypertension defined as sustained blood pressure 
(BP) > 150 mm Hg systolic or > 95 mm Hg diastolic despite optimal 
antihypertensive treatment, and/or change in antihypertensive 
medications within 1 week before starting treatment. Note: 
eligibility of a subject receiving 4 or more antihypertensive 
medications prior to study entry will require approval from the PI. 
iii. 
Stroke (including transient ischemic attack [TIA]), myocardial 
infarction 
(MI), 
or 
other 
ischemic 
event, 
or 
arterial 
thromboembolic within 12 months before the first dose. 
iv. 
Asymptomatic venous thromboembolic event (e.g. deep venous 

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thrombosis, pulmonary embolism) is allowed if the patient has 
been stable on anticoagulation with LMWH for at least 4 weeks. 
b. 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), 
GI 
malabsorption, 
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. 
Note: Complete healing of an intra‐abdominal abscess must be 
confirmed before first dose. 
c. Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 
teaspoon (2.5 ml) of red blood, other history of significant bleeding (e.g. 
pulmonary hemorrhage) within 12 weeks before first dose, or known 
thrombotic disorder. 
d. Cavitating 
pulmonary 
lesion(s) 
or 
known 
endotracheal 
or 
endobronchial disease manifestation. 
e. Lesions invading any major blood vessels, including inferior vena cava 
or cardiac involvement of HCC based on imaging. 
Note: Main and branch portal vein and hepatic vein invasion is allowed. 
f. 
Ongoing active infection requiring antibiotics. Antibiotics must be 
completed at least 7 days before initiating study treatment. 
g. Known active tuberculosis. 
h. Serious non‐healing wound, ulcer, or bone fracture. 
18. Patients with proteinuria >1+ on urine dipstick testing will undergo 24‐hour 
urine collection for quantitative assessment of proteinuria. Participants 
with urine protein ≥1 g/24 hours will be ineligible. 
19. Corrected QT interval calculated by the Fridericia formula (QTcF) > 480 ms 
per electrocardiogram (EKG) within 28 days before first dose of study 
treatment. 
a. Note: If a single EKG shows a QTcF with an absolute value > 500 ms, two 
additional EKGs at intervals of approximately 3 min must be performed 
within 30 min after the initial EKG, and the average of these three 
consecutive results for QTcF will be used to determine eligibility. 
20. Inability to swallow tablets or any other condition that might interfere with 
oral absorption of medications. 
21. Previously identified allergy or hypersensitivity to study drugs and/or any of 
their excipients. 
22. Ongoing secondary malignancy that is progressing and/or has required 
active treatment within the past year. Adjuvant treatment for resected 
breast cancer is allowed. 
a. Subjects with basal cell carcinoma of the skin, squamous cell carcinoma 
or the skin, prostate cancer, or carcinoma in situ (e.g. breast carcinoma, 
cervical cancer in situ) that have undergone potentially curative therapy 
are allowed. 

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23. Has a known history of HIV infection. Note: HIV testing is not mandated for 
screening. 
24. Co‐infection with HBV (HBsAg (+) and /or detectable HBV DNA) and HCV 
(anti‐HCV Ab (+) and detectable HCV RNA) at study entry. 
25. Co‐infection with HBV and HDV at study entry. 
26. Live vaccine or live attenuated vaccine within 30 days prior to first dose of 
study treatment. Administration of killed vaccines is allowed. 
27. Pregnant or lactating females. 
28. Known psychiatric illness, substance abuse disorder, or other condition that 
would interfere with the ability to comply with the requirements of the 
study. 
29. Has 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. 
Study treatments 
All enrolled patients will receive cabozantinib 40mg PO daily continuously and 
pembrolizumab 200mg IV every 3 weeks, in 3‐week cycles. Dose modifications 
of cabozantinib and/or pembrolizumab may be made for adverse events (AEs) 
(guidelines provided in protocol). Immune‐related AEs will be treated per 
published guidelines. If one agent needs to be discontinued due to treatment‐ 
related toxicity, patients may continue to receive treatment with the other 
agent. 
Treatment will continue until disease progression, intolerance, or patient 
withdrawal. Treatment beyond progression will be allowed if pre‐specified 
criteria are met (Section 12.1). 
Study assessments 
Toxicity assessments (history, physical exam, labs) will occur weekly during 
cycle 1, then every 3 weeks on day 1 of each subsequent cycle. AEs will be 
graded by NCI CTCAE v5. 
Disease assessments will be performed by multiphasic contrast CT or MRI of 
abdomen/pelvis, as well as CT chest with or without contrast at baseline 
(within one month of enrollment) and every 9 weeks on treatment. Tumor 
response will be determined by RECIST v1.1 and iRECIST. The tumor marker 
alpha‐fetoprotein (AFP) will also be measured at baseline and every 9 weeks if 
abnormal at baseline. 
If patients discontinue treatment due to intolerable or unacceptable toxicity, 
they will be followed for progression and for survival at least every 4 months 
up to 3 years. 
Statistical plan and 
sample size 
calculation 
This Phase 2 trial uses Simon’s optimal two‐stage design. The null hypothesis 
that the true ORR by RECIST v1.1 is 20% will be tested against a one‐sided 
alternative that the assumed‐true ORR with the tested combination is 38%. In 
the first stage, 13 patients will be accrued. If there are 2 or fewer patients with 

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response (an observed ORR of 15% or less), the study will be suspended for 
lack of sufficient efficacy. Otherwise, 16 additional patients will be accrued for 
a total of 29 patients. The null hypothesis (ORR 20%) will be rejected if 9 or 
more patients have a tumor response out of 29 patients (an observed ORR of 
at least 31%). This design yields a type I error rate of 0.10 and power of 80% 
when the true ORR is 38%. 
Anticipated 
findings 
It is anticipated that the combination of cabozantinib and pembrolizumab will 
significantly improve the ORR of patients with advanced HCC in the first‐line 
treatment setting. 

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TABLE OF CONTENTS 
1.0 
INTRODUCTION ............................................................................................................................... 15 
1.1 
Overview of hepatocellular carcinoma ....................................................................................... 15 
1.2 
Systemic therapy in advanced HCC ............................................................................................. 15 
1.2.1 
Approved targeted multikinase inhibitors .......................................................................... 15 
1.2.2 
MET inhibition and cabozantinib ........................................................................................ 15 
1.2.3 
Immuno‐modulation by the PD‐1 pathway ........................................................................ 16 
1.2.4 
Immune checkpoint inhibition in HCC. ................................................................................ 16 
1.2.5 
Combination therapy with immune checkpoint inhibitors in HCC ..................................... 17 
1.3 
Rationale for combining cabozantinib and pembrolizumab in HCC ............................................ 18 
1.4 
Study drug information ............................................................................................................... 18 
1.4.1 
Cabozantinib drug profile .................................................................................................... 18 
1.4.2 
Pembrolizumab drug profile ............................................................................................... 21 
1.5 
Rationale for dose selection ........................................................................................................ 22 
1.5.1 
Rationale for cabozantinib dose selection .......................................................................... 22 
1.5.2 
Rationale for pembrolizumab dose selection ..................................................................... 23 
2.0 
TRIAL DESIGN .................................................................................................................................. 23 
3.0 
STUDY OBJECTIVES .......................................................................................................................... 24 
3.1 
Primary objectives ....................................................................................................................... 24 
3.2 
Secondary objectives .................................................................................................................. 24 
3.3 
Exploratory objectives ................................................................................................................. 24 
4.0 
STUDY ENDPOINTS .......................................................................................................................... 25 
4.1 
Primary endpoint ........................................................................................................................ 25 
4.2 
Secondary endpoints................................................................................................................... 25 
4.3 
Exploratory endpoints ................................................................................................................. 25 
5.0 
SUBJECT SELECTION ........................................................................................................................ 25 
5.1 
Inclusion criteria .......................................................................................................................... 25 
5.2 
Exclusion criteria ......................................................................................................................... 27 
5.3 
Re‐screening ................................................................................................................................ 29 
6.0 
PRE‐TREATMENT PROCEDURES ...................................................................................................... 29 
6.1 
Informed consent ........................................................................................................................ 30 

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6.2 
Screening ..................................................................................................................................... 30 
6.3 
Subject registration ..................................................................................................................... 30 
7.0 
TREATMENT PLAN ........................................................................................................................... 31 
7.1 
Cabozantinib administration ....................................................................................................... 31 
7.2 
Pembrolizumab administration ................................................................................................... 31 
7.3 
Duration of therapy ..................................................................................................................... 32 
7.4 
Treatment compliance ................................................................................................................ 32 
8.0 
CONCOMITANT MEDICATIONS AND THERAPIES ............................................................................ 32 
8.1. 
Allowed therapy .......................................................................................................................... 32 
8.2 
Recording concomitant therapy ................................................................................................. 33 
8.3 
Palliative radiation ...................................................................................................................... 33 
8.4 
Prohibited or restricted therapy ................................................................................................. 34 
9.0 
TOXICITIES AND DOSING MODIFICATIONS ..................................................................................... 35 
9.1 
Assessment of adverse events .................................................................................................... 35 
9.2 
General guidelines about toxicity assessment and management in combination therapy ........ 35 
9.3 
Information on cabozantinib toxicity .......................................................................................... 36 
9.3.1 
Gastrointestinal disorders ................................................................................................... 37 
9.3.2 
Non‐gastrointestinal fistula. ................................................................................................ 37 
9.3.3 
Hemorrhage ........................................................................................................................ 37 
9.3.4 
Thromboembolic events ..................................................................................................... 38 
9.3.5 
Hypertension ....................................................................................................................... 38 
9.3.6 
Stomatitis and mucositis ..................................................................................................... 39 
9.3.7 
Skin and Subcutaneous Tissue Disorders ............................................................................ 40 
9.3.8 
Osteonecrosis ...................................................................................................................... 41 
9.3.9 
Proteinuria .......................................................................................................................... 41 
9.3.10 
Nervous system disorders ................................................................................................... 42 
9.3.11 
Hepatocellular toxicity ........................................................................................................ 42 
9.3.12 
Infections and infestations .................................................................................................. 43 
9.3.13 
Blood and lymphatic system disorders ............................................................................... 43 
9.3.14 
Fatigue ................................................................................................................................. 43 
9.3.15 
Weight loss .......................................................................................................................... 43 
9.3.16 
QTc prolongation ................................................................................................................. 44 

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9.3.17 
Electrolyte disorders ........................................................................................................... 45 
9.3.18 
Endocrine disorders ............................................................................................................ 45 
9.3.19 
Angioedema ........................................................................................................................ 45 
9.4 
Dose levels of cabozantinib ......................................................................................................... 45 
9.5 
Guidance on dose modification of cabozantinib and pembrolizumab for non‐immune and 
immune toxicities .................................................................................................................................... 45 
9.5.1 
Non‐immune toxicities ........................................................................................................ 46 
9.5.2 
Diarrhea (immune and non‐immune) ................................................................................. 47 
9.5.3 
Liver toxicity ........................................................................................................................ 49 
9.5.4 
Skin toxicity other than PPES ............................................................................................... 52 
9.5.5 
Other immune‐related toxicities ......................................................................................... 53 
9.5.6 
Pembrolizumab‐related infusion reaction .......................................................................... 56 
9.6 
Adverse events not related to study drugs.................................................................................. 57 
10.0 
STUDY CALENDAR ........................................................................................................................... 58 
11.0 
STUDY ASSESSMENTS ...................................................................................................................... 61 
11.1 
Baseline/screening evaluations. .............................................................................................. 61 
11.2 
On study evaluations ............................................................................................................... 62 
11.3 
Assessment of safety parameters at baseline and duringstudy treatment ............................ 63 
11.4 
Evaluations at treatment discontinuation (at 30 days [+ 7 days] following last dose of 
cabozantinib or pembrolizumab) ............................................................................................................ 64 
11.5 
Post‐study follow‐up ............................................................................................................... 65 
12.0 
CRITERIA FOR TREATMENT DISCONTINUATION .............................................................................. 65 
12.1 
Treatment beyond progression. .................................................................................................. 67 
13.0 
GUIDELINES FOR DISEASE EVALUATION .......................................................................................... 68 
13.1 
Tumor assessment by RECIST v1.1 (primary endpoint) ............................................................... 68 
13.1.1 
Definitions for measurable disease and target lesions ....................................................... 68 
13.1.2 
Definitions of response ....................................................................................................... 69 
13.1.3 
Evaluation of overall response ............................................................................................ 70 
13.1.4 
Definitions for response evaluations ................................................................................... 70 
13.2 
Tumor assessment by iRECIST (secondary endpoints) ................................................................ 71 
13.2.1 
Similarities and differences between iRECIST andRECIST v1.1 ........................................... 71 
13.2.2 
Timepoint response using iRECIST ....................................................................................... 72 

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13.3 
Methods of measurement ...................................................................................................... 73 
14.0 
DRUG INFORMATION ...................................................................................................................... 74 
14.1 
Cabozantinib ........................................................................................................................... 74 
14.1.1 
Composition and formulation ............................................................................................. 74 
14.1.2 
Storage and handling .......................................................................................................... 74 
14.1.3 
Administration .................................................................................................................... 74 
14.1.4 
Treatment accountability .................................................................................................... 75 
14.2 
Pembrolizumab ........................................................................................................................... 75 
14.2.1 
Formulation and preparation .............................................................................................. 75 
14.2.2 
Storage and handling .......................................................................................................... 75 
14.3.3 
Treatment accountability .................................................................................................... 75 
15.0 
BIOLOGICAL CORRELATIVE STUDIES ............................................................................................... 76 
15.1 
Tissue collection ...................................................................................................................... 76 
15.2 
Immunohistochemistry (IHC) .................................................................................................. 76 
15.3 
RNA sequencing ...................................................................................................................... 76 
15.4 
Flow cytometry and cytokine assays. .......................................................................................... 77 
16.0 
ADVERSE EVENT ASSESSMENT AND REPORTING ............................................................................ 77 
16.1 
Definitions ............................................................................................................................... 77 
16.2 
Attribution to study treatment ................................................................................................... 78 
16.3 
Parameters of assessment for AEs and SAEs ............................................................................... 79 
16.4 
Monitoring and recording AEs .................................................................................................... 80 
16.4.1 
Responsibility for adverse event monitoring ...................................................................... 80 
16.4.2 
Time frame for AE monitoring ............................................................................................. 80 
16.4.3 
Laboratory data ................................................................................................................... 80 
16.4.4 
Recording AEs ...................................................................................................................... 80 
16.5 
Requirements for reporting AEs .................................................................................................. 81 
16.5.1 
SAE reporting....................................................................................................................... 81 
16.5.2 
Reporting of pregnancy and lactation ................................................................................. 81 
16.5.3 
Reporting of pembrolizumab overdose .............................................................................. 82 
16.5.4 
Events of clinical interest .................................................................................................... 82 
16.5.5 
Regulatory reporting ........................................................................................................... 82 
17.0 
STATISTICAL CONSIDERATIONS ....................................................................................................... 83 

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17.1 
Sample size calculation ........................................................................................................... 83 
17.2 
Statistical methods .................................................................................................................. 83 
18.0 
DATA AND SAFETY MONITORING PLAN .......................................................................................... 84 
18.1 
Trial monitoring ....................................................................................................................... 84 
18.2 
Data and safety reviews .......................................................................................................... 84 
19.0 
STUDY DOCUMENTATION AND RECORD‐KEEPING ......................................................................... 85 
19.1 
Investigator’s files and retention of documents ..................................................................... 85 
19.2 
Source documents and background data ................................................................................... 85 
19.3 
Audits and inspections ................................................................................................................ 85 
19.4 
Case report forms ........................................................................................................................ 85 
20.0 
PROTOCOL MODIFICATIONS ........................................................................................................... 86 
21.0 
TERMINATION OF STUDY ................................................................................................................ 86 
22.0 
ETHICAL ASPECTS ............................................................................................................................ 86 
22.1 
Local regulations ......................................................................................................................... 86 
22.2 
Institutional review board/ethics committee ............................................................................. 86 
22.3 
Confidentiality of trial documents and subject regions .............................................................. 87 
23.0 
PUBLICATION OF DATA ................................................................................................................... 87 
24.0 
APPENDICES .................................................................................................................................... 87 
Appendix 1: Abbreviations and definitions ............................................................................................. 87 
Appendix 2. Cabozantinib Drug Diary ..................................................................................................... 91 
Appendix 3: Clinical laboratory tests....................................................................................................... 93 
Appendix 4: Strong inducers and inhibitors of CYP3A ............................................................................ 94 
Appendix 5: ECOG performance status scale .......................................................................................... 94 
Appendix 6: Child‐Pugh score calculation for cirrhosis mortality ........................................................... 94 
Appendix 7: Cockcroft‐Gault equation for determining creatinine clearance (CrCl) .............................. 95 
Appendix 8: Highly effective methods of contraception ........................................................................ 96 
25.0 
REFERENCES .................................................................................................................................. 100 

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1.0 
INTRODUCTION 
 
 
1.1 
Overview of hepatocellular carcinoma 
 
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy, and is the 5th most 
common cancer (estimated 841,080 incident cases in 2018 worldwide) and the 3rd leading cause of cancer‐ 
related mortality globally (estimated 781,631 deaths in 2018 worldwide).1,2 Men are 3.5 times more likely 
than women to develop HCC. The rate of HCC has risen significantly in the US in the last decade with an 
annual increase in incidence of 3.64% based on analysis of the SEER data from 2000‐2012.3 Moreover, this 
trend is projected to continue into the next decade with aging of the baby boomers. It is estimated that 
the incidence rate (per 100,000 person‐years) of HCC in adults will increase from 13.5 in 2013 to 17.0 in 
2020 and 21.2 in 2030.3 
 
Common etiologic factors for HCC include hepatitis B virus (HBV), hepatitis C virus (HCV), alcohol, 
metabolic disorders (e.g. obesity, non‐alcoholic fatty liver disease, diabetes), and smoking.4 HBV is the 
most important etiology of HCC worldwide and accounts for >50% of cases, mainly in HBV‐endemic parts 
of southeast Asia and Africa.5 In the US, HCV, alcohol, and increasingly metabolic disorders are the primary 
risk factors for HCC.6 
 
HCC is associated with poor prognosis. The 5‐year overall survival (OS) of patients with primary liver 
malignancy is estimated to be 18%.7 The median OS of patients with advanced HCC remains limited (~18 
months) despite recent developments in systemic therapy.8 Thus, there is an ongoing need to develop 
novel therapeutic strategies in this disease. 
 
 
1.2 
Systemic therapy in advanced HCC 
 
1.2.1 
Approved targeted multikinase inhibitors 
 
Sorafenib has specificity for RAF, VEGFR1‐3 and PDGFRb, and was the first agent to significantly improve 
OS compared to placebo in patients with advanced HCC as demonstrated by the Phase 3 SHARP trial, 
serving as a standard treatment since 2007.9 Recently, several similar multikinase inhibitors with targets 
including VEGFR, PDGFR, FGFR and other receptors have been approved. In the REFLECT trial, lenvatinib 
was non‐inferior to sorafenib with respect to OS and is now an additional first‐line therapy option.10 The 
data also demonstrated that achieving an objective response was an independent predictive factor for 
increased OS.11 
 
In the RESORCE trial, regorafenib significantly improved OS compared to placebo (10.6 vs. 7.8 months; HR 
0.63, 95% CI 0.50‐0.79, p<0.0001) in advanced HCC patients who progressed on and tolerated prior 
sorafenib.12 Anti‐tumor activity of these multikinase inhibitors comes from their anti‐angiogenic, anti‐ 
proliferative, and pro‐apoptotic effects. 
 
1.2.2 
MET inhibition and cabozantinib 
 
The importance of the MET receptor signaling pathway, which is activated by its ligand HGF, is increasingly 
recognized in HCC. MET overexpression is observed in a large subset of HCC tumors and is associated with 
poorer survival.13,14 MET activation and signaling mediates the epithelial‐to‐mesenchymal transition, 

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invasion, and tumor metastasis.15 In fact, the anti‐tumor activity of MET inhibition in HCC has been well 
established in both preclinical and early clinical studies.16,17 Particularly, MET activation is believed to be 
one of the mechanisms of resistance to anti‐VEGF therapy, providing the rationale for concurrently 
inhibiting VEGFR and MET.18,19 
 
Cabozantinib is a multikinase inhibitor with its primary activity against MET, VEGFR1‐3 and AXL.20 The 
Phase 3 CELESTIAL trial randomized (2:1) patients with advanced HCC who previously progressed on 
sorafenib to cabozantinb 60mg orally daily vs. placebo. Cabozantinib demonstrated a significant 
improvement in OS (10.2 vs. 8.0 months, HR 0.76 (95% CI 0.63‐0.92), p=0.005) and in PFS (5.2 vs. 1.9 
months, HR 0.44 (95% CI 0.36‐0.52), p<0.001) compared to placebo. The objective response rate (ORR) 
was 4% vs. < 1% (p=0.009).21 In this trial, 68% of patients experienced a grade 3 or 4 AE (vs. 37% in patients 
receiving placebo). In the cabozantinib arm, dose reduction was required in 62% of patients, while 16% of 
patients discontinued treatment due to toxicity. Moreover, the median daily dose of cabozantinib 
received was 35.8 mg daily. 
 
Based on results of the CELESTIAL trial, cabozantinib was FDA approved for the treatment of advanced 
HCC post‐sorafenib in January 2019. 
 
1.2.3 
Immuno‐modulation by the PD‐1 pathway 
 
The programmed cell death 1 (PD‐1) receptor is essential in the control of the immune system. It is 
expressed on surface of activated lymphocytes including CD4+ and CD8+ T cells, B cells, T regulatory cells, 
and natural killer cells. The ligands for PD‐1 are PD‐L1 and PD‐L2, which are expressed or induced in various 
cell types. Binding of PD‐L1 or PD‐L2 to PD‐1 inhibits T cell activation, therefore modulating immune 
responses to prevent autoimmune reactions. PD‐L1 expression can be found in the vascular endothelium 
and other non‐hematopoietic tissues, while PD‐L2 is mainly expressed on antigen‐presenting cells.22,23 
 
PD‐L1 expression occurs at low levels in normal tissues. However, many cancers express high levels of PD‐ 
L1 in order to inhibit T cell activation and anti‐tumor immune responses.24 Thus, immune checkpoint 
inhibition of the PD‐1 pathway is one therapeutic strategy to prevent suppression of T cell responses 
against tumor cells. 
 
1.2.4 
Immune checkpoint inhibition in HCC 
 
The immune system plays a critical role in the pathogenesis of HCC.25 The cirrhotic liver is marked by an 
immunosuppressive state.26 Increased T regulatory cells, decreased CD8+ or CD4+ T cells, and high PD‐ 
L1/PD‐L2 expression are associated with disease progression and poorer outcomes.27‐33 
 
Immune checkpoint inhibition has been shown to be an active therapeutic strategy in this disease. In the 
Phase 1/2 trial CheckMate 040 of nivolumab in patients with advanced HCC with or without prior 
sorafenib, the ORR by modified RECIST (mRECIST) was 20% (95% CI 15‐26) in the dose‐expansion phase, 
while the 6‐ and 9‐month OS was 83% (95% CI 78‐88) and 74% (95% CI 67‐79), respectively.34 Response 
was observed independent of PD‐L1 expression and HCC etiology. Likewise, in the Phase 2 trial KEYNOTE‐ 
224, patients with advanced HCC who progressed on sorafenib were treated with pembrolizumab and 
demonstrated an ORR of 17% (95% CI 11‐26) and a disease control rate (DCR) of 62% (95% CI 52‐71) by 
mRECIST.35 Both nivolumab and pembrolizumab were safe and tolerable; the rate of grade 3 or 4 
treatment‐related adverse events (TRAEs) was 25% with both agents. Efficacy and toxicity were both 
independent of viral infection status. 34,35 Subgroup analyses suggested greater response in tumors with 

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PD‐L1 overexpression by the combined positive score, although further validation studies are needed. 
Interestingly, the randomized Phase 3 trial KEYNOTE‐240 of pembrolizumab vs. best supportive care in 
patients with advanced HCC previously treated with sorafenib did not meet its primary endpoints of OS 
and PFS.36 However, the study had a stringent pre‐specified p‐value cutoff of 0.0174 for statistical 
significance, and there was a clear trend towards improved OS with pembrolizumab compared to best 
supportive care (median OS 13.9 vs. 10.6 months, HR 0.781 (95% CI 0.611‐0.988), p=0.0238). Subsequent 
therapies received by the two groups also likely affected the results. Similar to prior experience, the ORR 
with pembrolizumab was 18.3% (95% CI 14.0‐23.4).36 
 
Moreover, PD‐1 inhibition has been evaluated in the first‐line treatment setting in HCC patients in the 
CheckMate 459 trial of nivolumab vs. sorafenib. The trial did not meet its primary endpoint of OS, with a 
median OS of 16.4 vs. 14.7 months (HR 0.85 (95% CI 0.72‐1.02), p=0.0752). ORR was 15% vs. 7%. 
Subsequent therapies received might have affected the OS, as 38% and 46% of patients in the nivolumab 
and sorafenib arms, respectively, received subsequent treatments.37 
 
Nivolumab and pembrolizumab are currently approved for the second‐line treatment of advanced HCC. 
Other immune checkpoint inhibitors currently in development in HCC include anti‐PD‐L1 (e.g. durvalumab, 
atezolizumab) and anti‐CTLA4 (e.g. tremelimumab) agents. 
 
1.2.5 
Combination therapy with immune checkpoint inhibitors in HCC 
 
The ORR associated with nivolumab and pembrolizumab monotherapy in refractory HCC was 20% and 
17%, respectively.34,35 Thus, there is a need to improve on these outcomes and maximize the efficacy of 
immune checkpoint inhibitors. Combination approaches have been explored and yielded promising early 
results. 
 
There is now growing evidence for the combination of VEGF/VEGFR‐targeting agents and PD‐1/PD‐L1 
inhibition, which may lead to increased effector T cell infiltration into tumors.38 
 
The combination of lenvatinib and pembrolizumab was evaluated in a Phase 1b trial of HCC patients in the 
first‐line treatment setting. There were 6 patients in the DLT evaluation phase (Part 1) and 24 patients in 
the expansion phase (Part 2). This study demonstrated an ORR of 42% (95%CI 23‐63) by mRECIST criteria 
(complete response (CR) 4%, partial response (PR) 39%).38 The median progression‐free survival (PFS) was 
9.69 (95%CI 5.55‐NE) months. The rate of grade 3‐4 treatment‐emergent adverse events (TEAEs) was 60%, 
and the rate of serious adverse events (SAEs) was 27%, including 3 deaths (out of 30 patients). The most 
common TEAEs were: decreased appetite (53%), hypertension (53%), diarrhea (43%), fatigue (40%), 
dysphonia (30%), proteinuria (30%), AST elevation (27%), weight loss (27%), hypothyroidism (20%), 
nausea (20%), and palmar‐plantar erythrodyesthesia syndrome (PPES) (20%). The most common grade 3 
TEAEs were: hypertension (17%), AST elevation (17%), decreased WBC (13%), hyponatremia (10%). 60% 
of patients required dose interruption of lenvatinib or pembrolizumab due to a TEAE, and 60% of patients 
had a dose reduction of lenvatinib. The rate of discontinuation of lenvatinib or pembrolizumab was 17%.38 
 
Furthermore, a Phase 1b trial of atezolizumab and bevacizumab was conducted in solid tumors, in which 
Arms A and F enrolled treatment‐naïve patients with unresectable HCC. Arm F was a randomized cohort 
of atezolizumab/bevacizumab vs. atezolizumab.39 The combination regimen demonstrated a significant 
improvement in the primary endpoint of PFS compared to atezolizumab monotherapy (median PFS 5.6 vs. 
3.4 months; HR 0.55, 80% CI 0.40‐0.74, p=0.0108). TRAEs occurred in 68% in the atezo/bev group (grade 
3 TRAEs, 20%) and 41% in the atezo group (grade 3 TRAEs, 5%). In Arm A, 104 patients with 

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treatment‐naïve unresectable HCC received atezolizumab/bevacizumab; its primary endpoint of ORR was 
36% (76% of responses were ongoing at the time of data cutoff). There were 88% TRAEs, and 39% grade 
3‐4 TRAEs (most commonly hypertension). 
 
While these were early phase studies with small numbers of patients, their results provided strong support 
for combining VEGF blockade with immune checkpoint inhibitors for increased efficacy in HCC. The 
combination of atezolizumab plus bevacizumab previously received FDA breakthrough designation for 
development in HCC.40 In fact, the Phase 3 randomized trial of atezolizumab/bevacizumab vs. sorafenib 
(IMbrave 150) for the first‐line treatment of unresectable HCC met its primary endpoint of OS and PFS 
(press release October 21, 2019).41 
 
Other similar immunotherapy combination Phase 3 trials in treatment‐naïve advanced HCC patients are 
currently ongoing: lenvatinib/pembrolizumab vs. lenvatinib (LEEP‐002) (NCT03713593), and 
cabozantinib/atezolizumab vs. sorafenib vs. cabozantinib (COSMIC‐312) (NCT03755791). 
 
 
1.3 
Rationale for combining cabozantinib and pembrolizumab in HCC 
 
Both cabozantinib and pembrolizumab have clinical activity as monotherapy in advanced refractory HCC, 
and there is significant benefit in combining VEGFR and PD‐1 inhibition in the first‐line treatment setting, 
as discussed above. In addition, MET has been shown to play an immunosuppressive role by interacting 
with immune checkpoint pathways. For instance, MET mediates immune suppression by upregulating PD‐ 
L1 expression, while PD‐L1 and PD‐L2 have been associated with increased levels of MET and VEGF.42,43 
Co‐expression of MET and PD‐L1/PD‐L2 was observed in squamous cell carcinomas of the lung and 
esophagus.44,45 Similarly, the TAM family of receptors including AXL have been demonstrated to suppress 
the immune system. Cabozantinib has specificity against AXL and has been shown to modulate the tumor 
microenvironment, as well as immune suppressor and effector cells.46‐49 
 
There is a strong rationale for combining inhibition of MET, AXL/TAM receptors, VEGFR and PD‐1 in HCC 
through the combination of cabozantinb and pembrolizumab, which will be explored in this non‐ 
randomized Phase 2 trial in the first‐line treatment of patients with advanced HCC. 
 
 
1.4 
Study drug information 
 
1.4.1 
Cabozantinib drug profile 
 
Please refer to the Investigator’s Brochure for complete information on cabozantinib. 
 
1.4.1.1 Target specificity 
 
Cabozantinib (XL184) is a multikinase targeted agent with specificity against several receptor tyrosine 
kinases. The main targets are MET (IC50 8 nM), VEGFR2/KDR (IC50 2 nM), and RET (IC50 85 nM), but it 
also inhibits KIT (IC50 5 nM), FLT3 (IC50 11 nM), and AXL (IC50 42 nM). Based on cellular and in vivo activity 
assays, cabozantinib exhibits comparable anti‐tumor activity against MET and VEGFR2, with lesser activity 
against RET, KIT, AXL and FLT3. 

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1.4.1.2 Preclinical data 
 
Preclinical studies demonstrated that cabozantinib given orally effectively blocked the phosphorylation of 
MET and VEGFR2 in tumor xenograft models, and the duration of inhibition was over 8 hours at 100 
mg/kg.50 In vivo changes in tumor vasculature and apoptosis were observed in xenografts treated with 
cabozantinib. Moreover, cabozantinib induced significant tumor growth inhibition or regression in 
xenograft models across various tumor types, including medullary thyroid cancer, breast cancer, lung 
cancer, and glioblastoma.50 In a MET‐overexpressed HCC xenograft model, cabozantinib prolonged the 
survival of mice compared to vehicle.51 There is also evidence that cabozantinib has specific anti‐tumor 
activity in bone metastatic lesions.50,52 
 
1.4.1.3 Pharmacokinetics (PK) 
 
A population PK analysis of cabozantinib at 60 mg daily (dose reduction allowed) in patients with renal cell 
carcinoma showed it had the following characteristics: terminal half‐life 99 h, terminal volume of 
distribution (V/F) ~319 L, clearance at steady state 2.2 L/h. Clearance was independent of age and sex. 
Cabozantinb is mostly protein‐bound in circulation. 
 
Cytochrome P450 and potential interactions with cabozantinib 
 
Data from a clinical drug interaction study (Study XL184‐008) showed that clinically relevant steady‐state 
concentrations of cabozantinib appear to have no marked effect on the area under the plasma 
concentration‐vs‐time curve (AUC) of co‐administered rosiglitazone, a CYP2C8 substrate. Therefore, 
cabozantinib is not anticipated to markedly inhibit CYP2C8 in the clinic, and by inference, is not anticipated 
to markedly inhibit other CYP450 isozymes that have lower [I]/Ki values compared to CYP2C8 (i.e. CYP2C9, 
CYP2C19, CYP2D6, CYP1A2, and CYP3A4). In vitro data indicate that cabozantinib is unlikely to induce 
cytochrome P450 enzymes, except for possible induction of CYP1A1 at high cabozantinib concentrations 
(30 μM). 
 
Based on in vitro studies, cabozantinib is a CYP3A4 substrate and a weak CYP2C9 substrate (but not a 
CYP2D6, CYP2C8, CYP2C19, CYP2B6, or CYP1A2 substrate). Results from a clinical pharmacology study 
(XL184‐006) showed that concurrent administration of cabozantinib with the strong CYP3A4 inducer, 
rifampin, resulted in an approximately 77% reduction in cabozantinib exposure (AUC values) after a single 
dose of cabozantinib in healthy volunteers. Chronic co‐administration of cabozantinib with strong 
inducers of the CYP3A4 family (see Appendix 4) may significantly decrease cabozantinib concentrations. 
The chronic use of these strong CYP3A4 inducers should be avoided. Other drugs that induce CYP3A4 
should be also used with caution due to the potential decreased exposure (AUC) to cabozantinib. Selection 
of alternate concomitant medications with no or minimal CYP3A4 enzyme induction potential is 
recommended if possible. 
 
In addition, results from a clinical pharmacology study (XL184‐007) showed that concurrent administration 
of cabozantinib with the strong CYP3A4 inhibitor, ketoconazole, resulted in a 38% increase in the 
cabozantinib exposure (AUC values) after a single dose of cabozantinib in healthy volunteers. Co‐ 
administration of cabozantinib with strong inhibitors of the CYP3A4 family (see Appendix 4) may increase 
cabozantinib concentrations. Grapefruit, star fruit and Seville oranges may also increase plasma 
concentrations of cabozantinib and should be avoided. Strong CYP3A4 inhibitors should be avoided and 
other drugs with inhibitory effects on CYP3A4 should be used with caution because these drugs have the 

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potential to increase exposure (AUC) to cabozantinib. Selection of alternate concomitant medications 
with no or minimal CYP3A4 enzyme inhibition potential is recommended if possible. 
 
Protein‐binding 
 
Cabozantinib is highly bound (≥ 99.7%) to human plasma proteins. Therefore, highly protein‐bound drugs 
should be used with caution with cabozantinib because there is a potential displacement interaction that 
could increase free concentrations of cabozantinib and/or of the co‐administered highly protein‐bound 
drug (and a corresponding increase in pharmacologic effect). 
 
Other interactions 
 
Food may increase exposure levels of cabozantinib by 57%. Therefore, fasting recommendations should 
be followed. 
 
In vitro data suggest that cabozantinib is unlikely to be a substrate for P‐glycoprotein, but it does appear 
to have the potential to inhibit the P‐glycoprotein transport activity. Therefore, cabozantinib may have 
the potential to increase plasma concentrations of co‐administered substrates of P‐glycoprotein. 
Cabozantinib was shown to be a substrate of drug transporter MRP2 in an in vitro assay. Administration 
of MRP2 inhibitors to subjects may result in increases in cabozantinib plasma concentrations. 
 
Administration of the proton pump inhibitor (PPI) esomeprazole resulted in no clinically relevant effect on 
cabozantinib plasma PK in healthy volunteers. Therefore, concomitant use of gastric pH modifying agents 
(e.g. PPIs, H2 receptor antagonists, and antacids) is not contraindicated in subjects administered 
cabozantinib. 
 
Additional details regarding potential drug interactions with cabozantinib can be found in the 
Investigator’s Brochure. 
 
1.4.1.4 Clinical safety in clinical trials of cabozantinib 
 
Cabozantinib has been studied across multiple malignancies, including HCC, medullary thyroid, prostate, 
breast and non‐small cell lung cancers, renal cell carcinoma, melanoma, and glioblastoma multiforme.50 
The capsule formulation has been approved in the US for refractory metastatic medullary thyroid cancer, 
and the tablet formulation has been approved for advanced renal cell carcinoma and HCC. 
 
Please see the Investigator’s Brochure for the most updated safety information on cabozantinib. Per 
Investigator Brochure v13, safety data are available from 2611 subjects who have been dosed with 
cabozantinib (2453 subjects in single agent cabozantinib studies [2410 subjects in a pooled analysis and 
43 subjects in a Japanese study] and 158 subjects in combination studies of cabozantinib with other 
agents). 
 
In prior studies, the most frequent AEs experienced by ≥ 20% of subjects treated with cabozantinib in 
descending order of frequency were: diarrhea, fatigue, decreased appetite, nausea, weight decreased, 
PPES, vomiting, constipation, hypertension, dysgeusia, dysphonia, asthenia, and dyspnea. For a full 
description of the safety profile of cabozantinib, refer to the cabozantinib Investigator’s Brochure. 

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Other medically important but less frequent AEs included: arterial thrombotic AEs (eg, transient ischemic 
attack [TIA], and myocardial infarction [MI]) and venous thrombotic AEs (e.g. deep vein thrombosis [DVT] 
and pulmonary embolism), severe hemorrhagic events, proteinuria, wound healing complications, 
gastrointestinal (GI) perforation, abscesses including intra‐abdominal and pelvic abscess, GI and non‐GI 
fistula formation, osteonecrosis, and reversible posterior leukoencephalopathy syndrome(RPLS). 
 
AEs associated with laboratory abnormalities experienced by ≥ 5% of subjects treated with cabozantinib 
in descending order of frequency were: anemia, AST increased, ALT increased, hypothyroidism, 
hypokalemia, hypomagnesemia, thrombocytopenia, hypocalcemia, hypophosphatemia, lactate 
dehydrogenase (LDH) increased, lipase increased, neutropenia, hyponatremia, ALP increased, leukopenia, 
and hyperglycemia. 
 
AEs may occur within the first few weeks in the course of treatment with cabozantinib, as the drug is 
expected to reach steady state exposure at approximately 2 weeks following the first dose. Events that 
generally have an early onset include hypocalcemia, hypokalemia, thrombocytopenia, hypertension, PPES, 
abdominal pain, mucosal inflammation, constipation, diarrhea, and vomiting. AEs should be managed with 
supportive care at the earliest signs of toxicity. Dose reductions and treatment interruptions/delays 
should be considered. Dose reductions are recommended for events that, if persistent, could become 
serious or intolerable (see Section 9.0). 
 
1.4.1.5 Safety of cabozantinib in HCC patients 
 
The safety profile of cabozantinib in HCC patients was characterized in a Phase 2 randomized 
discontinuation study and in a Phase 3 clinical trial.21,53 CELESTIAL was a Phase 3 randomized trial of 
cabozantinib (n=470) vs. placebo (n=237) in patients with HCC and Child‐Pugh class A5 liver function 
previously treated with sorafenib. The starting dose of cabozantinib was 60 mg daily, and 62% of patients 
required dose reductions with a median time to first dose reduction of 38 days. The median average daily 
dose administered was 35.8 mg daily. 
 
In the CELESTIAL trial, TEAEs occurred in 99% of patients, with grade 3‐4 AEs in 68% of patients and SAEs 
in 50% of patients. The most common TEAEs in >=20% of patients were: diarrhea (54%), decreased 
appetite (48%), PPES (46%), fatigue (45%), nausea (31%), hypertension (29%), vomiting (26%), AST 
increased (22%), and asthenia (22%). The most common grade 3‐4 TEAEs in >=5% of patients were: PPES 
(17%), hypertension (16%), AST elevation (12%), diarrhea (10%), fatigue (10%), asthenia (7%), decreased 
appetite (6%), ALT elevation (5%).21 16% of patients discontinued cabozantinib due to TRAEs, most 
commonly for PPES, fatigue, reduced appetite, diarrhea, and nausea. 
 
In the study, grade 5 TRAEs were reported in 6 patients in the cabozantinib group, including liver failure, 
bronchoesophageal fistula, portal vein thrombosis, upper GI hemorrhage, pulmonary embolism, and 
hepatorenal syndrome.21 
 
1.4.2 
Pembrolizumab drug profile 
 
Please refer to the Investigator’s Brochure for complete information on pembrolizumab. 
 
1.4.2.1 Preclinical and clinical trial data 

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Pembrolizumab is a potent and highly selective humanized immunoglobulin G4 (IgG4) monoclonal 
antibody (mAb) with high specificity of binding to the PD‐1 receptor, thus inhibiting its interaction with 
PD‐L1 and PD‐L2. Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor 
blocking activity for PD1. Pembrolizumab has been in clinical development in multiple advanced 
malignancies and has an acceptable safety profile. 
 
Keytruda™ (pembrolizumab) has been approved for advanced or metastatic melanoma, non‐small cell 
lung cancer, head and neck squamous carcinoma, classical Hodgkin lymphoma, urothelial carcinoma, MSI‐ 
H or dMMR solid tumors, PD‐L1‐expressing gastric or gastroesophageal cancer, PD‐L1‐expressing cervical 
cancer, primary mediastinal large B‐cell lymphoma, and Merkel cell carcinoma. Moreover, it was approved 
on November 9, 2018 for patients with advanced HCC previously treated withsorafenib. 
 
Please refer to the Investigator’s Brochure and the US Prescribing Information on pembrolizumab for more 
information. 
 
1.4.2.2 Safety of pembrolizumab in HCC patients 
 
The KEYNOTE‐224 trial was a Phase 2 non‐randomized trial of pembrolizumab in patients with HCC and 
Child‐Pugh class A hepatic function (n=104).35 Pembrolizumab was safe and tolerable in this population. 
TRAEs occurred in 73% of patients, with grade 3‐4 TRAEs in 25% and SAEs in 15% of patients. The most 
common TRAES in >=10% of patients were: fatigue (21%), AST elevation (14%), pruritis (12%), diarrhea 
(11%), and rash (10%). The most common grade 3‐4 TRAEs were: AST elevation (7%), ALT elevation (4%), 
and fatigue (4%). 17% of patients had a dose interruption due to a TRAE, most commonly AST elevation 
(4%), ALT elevation (3%), hypothyroidism (2%), and rash (2%). Five out of 104 patients discontinued 
pembrolizumab due to a TRAE, including adrenal insufficiency, increased AST, increased ALT, increased 
bilirubin, and cholestatic jaundice. One death due to ulcerative esophagitis was thought to be possibly 
related to pembrolizumab. Immune‐related AEs (irAEs) were reported in 15% of the study population, 
most commonly hypothyroidism (8%) and adrenal insufficiency (3%). The rate of immune‐mediated 
hepatitis was 3%; no flares or recurrence of HBV or HCV were observed. Four out of 104 patients had a 
grade 3 irAE: adrenal insufficiency (n=2), skin toxicity (n=1), and Type 1 diabetes mellitus (n=1). 
 
In the Phase 3 trial KEYNOTE‐240 of pembrolizumab vs. best supportive care, TRAEs occurred in 61% and 
49% of patients, respectively. In the pembrolizumab arm, the rate of grade 3‐4 TRAEs was 19%, while 7.2% 
of patients had a grade 3 immune‐mediated AE, leading to treatment discontinuation in 7%. The most 
common TRAEs were: pruritis (13%), fatigue (10%), AST elevation (9%), diarrhea (8%), and rash (8%). The 
most common grade 3‐4 TRAEs were: AST (5%) and ALT (4%) elevations. Hypo‐ (5%) and hyperthyroidism 
(3%) were the most common immune‐mediated AEs, mostly grade 1‐2, followed by severe skin reaction 
(3%), pneumonitis (2%), hepatitis (2%).36 
 
Please refer to the pembrolizumab Investigator’s Brochure for the complete drug safety and toxicity 
profile in other tumor types. 
 
 
1.5 
Rationale for dose selection 
 
1.5.1 
Rationale for cabozantinib dose selection 
 
Cabozantinib will be initiated at 40 mg orally once daily continuously. In the CELESTIAL trial, 62% of 

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patients treated with cabozantinib 60 mg required a dose reduction due to toxicities, and the median 
average daily dose was 35.8 mg.21 Ongoing trials of nivolumab and cabozantinib for triple negative breast 
cancer and renal cell carcinoma currently use a starting dose of 40 mg.54‐56 In fact, the 40 mg dose is 
recommended by Exelixis in trials of combination therapy with immune checkpointinhibitors. 
 
1.5.2 
Rationale for pembrolizumab dose selection 
 
The planned fixed dose of pembrolizumab for this study in combination with cabozantinib is 200 mg IV 
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: 
 
• 
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 (refer to IB, Section 5.2.2) 
• 
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 
 
Recently, the efficacy and safety of pembrolizumab 200 mg IV q3w in combination with the multikinase 
inhibitor lenvatinib has been evaluated in an investigational multicenter, multi‐indication, open‐label 
Phase 1b/1 clinical study38 and a Phase 3 study is ongoing. 
 
 
 
2.0 
TRIAL DESIGN 
 
This is a non‐randomized Phase 2 trial using the Simon’s optimal two‐stage design. In the first stage, 13 
eligible patients will enroll. If there are 2 or fewer patients with response (CR or PR), the study will be 
suspended for lack of sufficient efficacy. Otherwise, 16 additional patients will be accrued for a total of 29 
patients. An accrual period of 24 months and follow‐up period of 12 months are anticipated. More than 
29 patients may be screened and/or enrolled depending on screen fails and dropouts before starting 
treatment. 

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3.0 
STUDY OBJECTIVES 
 
 
3.1 
Primary objectives 
 
• 
To determine the objective response rate (ORR) of the combination of cabozantinib and 
pembrolizumab in the first‐line treatment of advanced HCC based on RECIST v1.1. 
 
 
3.2 
Secondary objectives 
 
• 
To assess the disease control rate (DCR) by RECIST v1.1, ORR and DCR by iRECIST, progression‐free 
survival (PFS) by RECIST v1.1, and overall survival (OS). 
• 
To assess the safety of the combination treatment with cabozantinib and pembrolizumab basedon 
NCI CTCAE v5. 
 
 
3.3 
Exploratory objectives 
 
• 
To explore the predictive biomarkers for cabozantinib and pembrolizumab in HCC using archival tissue 
or pre‐treatment fresh tumor biopsy (if available) and pre‐treatment peripheral blood. 

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4.0 
STUDY ENDPOINTS 
 
 
4.1 
Primary endpoint 
 
• 
Objective response (complete or partial response) per RECIST v1.1 (by blinded central review). 
 
4.2 
Secondary endpoints 
 
• 
Objective response (complete or partial response) per iRECIST (blinded central review). 
• 
Disease control (complete + partial response + stable disease) per RECIST v1.1 andiRECIST. 
• 
Progression‐free survival (PFS) is defined as time from study registration to radiographic progression 
per RECIST v1.1 (blinded central assessment), clinical progression, or death of anycause. 
• 
Overall survival (OS) is defined as time from study registration to death of any cause. 
• 
Safety will be evaluated by assessing AEs according to NCI CTCAE v5. 
 
4.3 
Exploratory endpoints 
 
Exploratory biomarkers will be assessed using archival tumor tissue or pre‐treatment fresh tumor biopsy 
(if available) and peripheral blood and correlated with tumor response. Tumor tissue will be assessed by 
multiplex immunohistochemistry (IHC) assay for intratumoral immune cell subsets and distribution, RNA 
sequencing (NanoString) for immune gene expression, and T cell receptor (TCR) clonality. The expression 
levels of biomarkers including c‐MET, PD‐L1 and PD‐L2 in tumor cells and cells of the tumor 
microenvironment will also be assessed by IHC. Blood‐based biomarkers will be explored, including 
circulating T cell subsets and cytokines. 
 
 
5.0 
SUBJECT SELECTION 
 
To be eligible for the study, the subject must meet all of the inclusion criteria and none of the exclusion 
criteria. 
 
5.1 
Inclusion criteria 
 
1. At least 18 years of age. 
2. Must have a histologically confirmed diagnosis of HCC or a non‐invasive diagnosis of HCC as perthe 
American Association for the Study of Liver Diseases (AASLD) criteria. 
c. If available, archival tissue must be submitted. 
d. Mixed HCC‐cholangiocarcinoma is not allowed. 
3. Patient has BCLC stage C disease, or BCLC stage B disease that is not amenable to locoregional therapy 
or refractory to locoregional therapy, and not amenable to curative treatment. 
a. Previous locoregional therapy is allowed (e.g. surgical resection, external beam radiation, 
catheter‐based therapy), and patients must have evidence of disease progression from 
locoregional therapy. 
4. Must have measurable disease by RECIST v1.1. 
a. Lesions that were previously radiated or ablated cannot be target lesions unless there 
was subsequent radiographic progression at those sites. 

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5. No prior systemic therapy for HCC. Prior chemotherapy given locally into the liver (e.g. TACE) is 
allowed. 
6. Must have Child‐Pugh class A hepatic function within 7 days prior to first dose of study intervention 
(Appendix 6). 
7. ECOG performance status 0‐1 (Appendix 5). 
8. Life expectancy of at least 12 weeks. 
9. Recovery to baseline or ≤ Grade 1 toxicities (CTCAE v5) related to any prior treatments, unless adverse 
events (AEs) are clinically nonsignificant and/or stable on supportive therapy. 
10. Adequate organ and marrow function, based upon meeting all of the following laboratory criteria 
within 14 days before first dose of study treatment: 
a. Absolute neutrophil count (ANC) ≥ 1500/mm3 without granulocyte colony‐stimulating factor 
support. 
b. Platelets ≥ 60,000/mm3 without transfusion within 14 days. 
c. Hemoglobin ≥ 9 g/dL (≥ 90 g/L) without transfusion or EPO dependency within 14 days. 
d. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5 × upper limit of normal 
(ULN). 
e. Total bilirubin ≤ 2 mg/dL OR direct bilirubin ≤ ULN for participants with total bilirubin levels >2 
mg/dL. 
f. 
Serum albumin ≥ 2.8 g/dl (≥ 28 g/L) without albumin infusion. 
g. Prothrombin time (PT)/INR or partial thromboplastin time (PTT) test ≤ 1.5 × ULN. 
h. Serum creatinine ≤ 1.5 × ULN or calculated creatinine clearance ≥ 40 mL/min using the Cockcroft‐ 
Gault equation (Appendix 7). 
i. 
Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol) or 24h urine protein ≤1g. 
j. 
Hemoglobin A1c (HbA1c) ≤ 8% within 28 days before randomization or fasting serum glucose ≤ 
160 mg/dL. 
11. Patients with positive hepatitis B surface antigen (HBsAg) and/or HBV viral load >100 IU/mL at the 
time of enrollment are eligible to enroll on study if they meet the followingcriteria: 
a. Anti‐HBV therapy as per institutional practice must be given at least 4 weeks and HBV viral load 
must be <100 IU/mL prior to initiating study treatment. Patients on active HBV therapy with viral 
loads <100 IU/mL should remain on the same therapy throughout study treatment. 
b. Note: Patients with positive anti‐hepatitis B core antibody (HBcAb), negative HBsAg, and negative 
or positive anti‐hepatitis B surface antibody, and who have an HBV viral load <100 IU/mL do not 
require anti‐viral prophylaxis. 
12. Patients with past or ongoing hepatitis C infection (HCV) are eligible to enroll on study, with or without 
prior anti‐viral treatment, as long as the other eligibility criteria are met. Treated patients must have 
completed their anti‐viral treatment at least 1 month prior to initiating studytreatment. 
13. Sexually active fertile subjects and their partners must agree to use effective methods of 
contraception (see Appendix 8) during the course of the study and for at least 4 months after the last 
dose cabozantinib. They must also refrain from donating sperm during this time period. 
14. Female subjects of childbearing potential must not be pregnant at screening and not breastfeeding. 
Females of childbearing potential are defined as premenopausal females capable of becoming 
pregnant (i.e. females who have had any evidence of menses in the past 12 months, with the 
exception of those who had prior hysterectomy). 
a. Women who have been amenorrheic for 12 or more months are still considered to be of 
childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, 
low body weight, ovarian suppression or other reasons. 
15. Capable of understanding and complying with the protocol requirements and must provide written 
informed consent/assent for the study. 

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5.2 
Exclusion criteria 
 
1. Prior treatment with any systemic therapy for HCC, including anti‐VEGF therapy or any systemic 
investigational agent. 
a. If the patient previously received systemic treatment for reasons other than HCC: small molecule 
kinase inhibitors are not allowed within 2 weeks and cytotoxic/biologic agents are not allowed 
within 4 weeks of study treatment. 
2. Prior exposure to immune checkpoint inhibitors or other immunotherapeutic agents. 
3. Currently participating in or has participated in a study of an investigational agent or device within 4 
weeks prior to the first dose of study treatment. 
4. Major surgery within 6 weeks or minor surgery (e.g. dental extraction) within 10 days prior to first 
dose of study treatment. 
a. Complete wound healing from major surgery must have occurred at least 1 month before first 
dose and from minor surgery (e.g. simple excision, tooth extraction) at least 7 days before first 
dose. Subjects with clinically relevant ongoing complications from prior surgery are noteligible. 
5. Local liver‐directed therapy within 4 weeks of initiating study treatment. 
6. Palliative radiation for the purpose of symptomatic relief to non‐liver and non‐CNS disease within 2 
weeks of starting treatment. Other radiation treatments within 4 weeks of starting treatment. 
a. Patients must have recovered from all radiation‐related toxicities, not require corticosteroids, and 
have not had radiation pneumonitis. 
7. Prior liver or other allogenic tissue/organ transplantation. 
8. History of primary immunodeficiency. 
9. Active autoimmune or inflammatory disease that has required systemic treatment in the past 2 years 
(i.e. with use of disease‐modifying agents, corticosteroids or immunosuppressive drugs). This includes, 
but is not limited to, inflammatory bowel disease, celiac disease, systemic lupus erythematosus, 
rheumatoid arthritis, myasthenia gravis, Graves’ disease, etc. 
a. The following autoimmune conditions are allowed: vitiligo or alopecia; hypothyroidism on stable 
hormone replacement therapy; psoriasis/eczema not requiring systemic treatment. 
b. Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy 
for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is 
allowed. 
10. Chronic use of systemic steroid (in dosing exceeding 10 mg daily of prednisone equivalent) or 
immunosuppressive therapy or use within 14 days prior to enrollment. 
a. The following treatments are allowed: intranasal, inhaled, topical or local steroid injections; 
systemic corticosteroids at physiologic doses equivalent to no more than prednisone 10 mg/day; 
steroids as premedication for contrast dye allergy. 
11. History of (non‐infectious) pneumonitis/interstitial lung disease that required steroids or has current 
pneumonitis/interstitial lung disease. 
12. History of hepatic encephalopathy or treatment to prevent or control encephalopathy within the past 
12 months. Subjects on lactulose and/or rifaximin to control hepatic encephalopathy are not allowed. 
13. Esophageal or gastric variceal bleeding within the past 6 months. All subjects will be screened for 
esophageal varices unless performed in the last 6 months before study treatment. If varices are 
present, they should be treated according to institutional standards before starting studytreatment. 

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14. Uncontrolled ascites, clinically significant or symptomatic ascites requiring paracenteses or increasing 
doses of diuretics within the past 3 months. 
a. Patients who are on stable diuretic doses for at least 3 months are eligible if they meet other 
eligibility criteria. 
b. Asymptomatic ascites detected on imaging are allowed. 
15. Has known history or any evidence of CNS metastases and/or carcinomatous meningitis. Subjects with 
previously treated brain metastases may participate provided they are asymptomatic and 
radiologically stable (i.e. without progression for at least 4 weeks by repeat imaging (which must be 
performed during study screening), clinically stable, and without the need steroids for at least 4 weeks 
prior to first dose of study treatment). 
16. Concomitant anticoagulation with oral anticoagulants (e.g. warfarin, direct thrombin and Factor Xa 
inhibitors) or platelet inhibitors (e.g. clopidogrel). Allowed anticoagulants are thefollowing: 
a. Low‐dose aspirin for cardioprotection (per local applicable guidelines) is permitted. 
b. Low molecular weight heparin (LMWH) is permitted. 
c. Anticoagulation with therapeutic doses of LMWH is allowed in subjects without known brain 
metastases who are on a stable dose of LMWH for at least 4 weeks before first dose of study 
treatment, and who have had no clinically significant hemorrhagic complications from the 
anticoagulation regimen or the tumor. 
17. The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, 
the following conditions: 
a. Cardiovascular disorders: 
i. Congestive heart failure New York Heart Association Class 3 or 4, unstable angina pectoris, 
serious cardiac arrhythmias with risk of hemodynamic instability within 12 months before the 
first dose of study treatment. 
ii. Uncontrolled hypertension defined as sustained blood pressure (BP) > 150 mm Hg systolicor 
> 95 mm Hg diastolic despite optimal antihypertensive treatment, and/or change in 
antihypertensive medications within 1 week before starting treatment. Note: eligibility of a 
subject receiving 4 or more antihypertensive medications prior to study entry will require 
approval from the PI. 
iii. Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or other ischemic 
event, or arterial thromboembolic within 12 months before the firstdose. 
iv. Asymptomatic venous thromboembolic event (e.g. deep venous thrombosis, pulmonary 
embolism) is allowed if the patient has been stable on anticoagulation with LMWH for at least 
4 weeks. 
b. 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), GI malabsorption, 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. 
Note: Complete healing of an intra‐abdominal abscess must be confirmed before first dose. 
c. Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5 ml) of red 
blood, other history of significant bleeding (e.g. pulmonary hemorrhage) within 12 weeks before 
first dose, or known thrombotic disorder. 
d. Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease manifestation. 

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f.e. Lesions invading any major blood vessels, including inferior vena cava or cardiac 
involvement of HCC based on imaging. 
Note: Main and branch portal vein and hepatic vein invasion is allowed. 
g.f. Ongoing active infection requiring antibiotics. Antibiotics must be completed at least7 days 
before initiating study treatment. 
h.g. Known active tuberculosis. 
i.h. Serious non‐healing wound, ulcer, or bone fracture. 
18. Patients with proteinuria >1+ on urine dipstick testing will undergo 24‐hour urine collection for 
quantitative assessment of proteinuria. Participants with urine protein ≥1 g/24 hours will be ineligible. 
19. Corrected QT interval calculated by the Fridericia formula (QTcF) > 480 ms per electrocardiogram 
(EKG) within 28 days before first dose of study treatment. 
a. Note: If a single EKG shows a QTcF with an absolute value > 500 ms, two additional EKGs at 
intervals of approximately 3 min must be performed within 30 min after the initial EKG, and the 
average of these three consecutive results for QTcF will be used to determineeligibility. 
20. Inability to swallow tablets or any other condition that might interfere with oral absorption of 
medications. 
21. Previously identified allergy or hypersensitivity to study drugs and/or any of their excipients. 
22. Ongoing secondary malignancy that is progressing and/or has required active treatment within the 
past year. Adjuvant treatment for resected breast cancer is allowed. 
a. Subjects with basal cell carcinoma of the skin, squamous cell carcinoma or the skin, prostate 
cancer, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone 
potentially curative therapy are allowed. 
23. Has a known history of HIV infection. Note: HIV testing is not mandated forscreening. 
24. Co‐infection with HBV (HBsAg (+) and /or detectable HBV DNA) and HCV (anti‐HCV Ab (+) and 
detectable HCV RNA) at study entry. 
25. Co‐infection with HBV and HDV at study entry. 
26. Live vaccine or live attenuated vaccine within 30 days prior to first dose of study treatment. 
Administration of killed vaccines is allowed. 
27. Pregnant or lactating females. 
28. Known psychiatric illness, substance abuse disorder, or other condition that would interfere with the 
ability to comply with the requirements of the study. 
29. Has 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. 
 
5.3 
Re‐screening 
 
Patients who failed initial screening due to a reversible cause (e.g. biliary obstruction, infection) may have 
an opportunity to re‐screen after discussion with the Study PI. 
 
6.0 
PRE‐TREATMENT PROCEDURES 
 
This study will be initiated only after the protocol, informed consent form, and any other required 
documents have been reviewed and approved by the responsible IRB according to applicable regulations. 
The same applies for the implementation of changes introduced by amendments to the protocol or 
consent form, except where such changes are necessary to prevent apparent immediate hazards to the 
research participant(s) or others. 

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Potential patients will be identified in the GI Oncology outpatient clinics at Fred Hutchinson Cancer Center 
(FHCC) and through referrals from outside physicians or the Liver Tumor Clinic at the University of 
Washington Medical Center (UWMC). Patients who are potentially eligible for this trial will undergo the 
informed consent process and be screened for eligibility utilizing the Eligibility Criteria (Section 5.0). 
 
 
6.1 
Informed consent 
 
Prior to participation in the study, written informed consent and HIPAA authorization must be obtained 
by the investigator (or person designated by the investigator) from each subject in accordance with 
regulatory, legal, and institutional requirements. The protocol will be discussed thoroughly with the 
subject, and all known risks will be described. The procedures and alternative forms of therapy will be 
presented as objectively as possible and the risks and hazards of the study explained. The subject will be 
informed of the planned use, level of confidentiality, and potential disclosure of study data. 
 
Consent will be obtained using forms approved by the Institutional Review Board (IRB) of the FHCRC/UW 
Cancer Consortium, which will be kept in the medical record. In the case where the subject is unable to 
read, an impartial witness should be present during the entire informed consent discussion. After the 
subject has orally consented to participation in the trial, the witness’s signature on the form will attest 
that the information in the consent form was accurately explained and understood. A summary of the 
consent discussion will be recorded in the patient’s medical chart. A signed copy of the informed consent 
will be given to each subject. 
 
If new safety information results in significant changes in the risk/benefit assessment, the consent form 
should be reviewed and updated as necessary. All subjects (including those already being treated) should 
be informed of the new information, should be given a copy of the revised form, and should give their 
consent to continue in the study. 
 
 
6.2 
Screening 
 
Written informed consent must be obtained before initiation of any clinical screening procedure that is 
performed solely for the purpose of determining eligibility for this study. Evaluations performed as part 
of routine care before informed consent can be considered as screening evaluations if done within the 
defined screening period. 
 
Study eligibility is based on meeting all of the study inclusion criteria and none of the exclusion criteria at 
screening and on Study Day 1 before study treatment administration. 
 
 
6.3 
Subject registration 
 
Once screening procedures are completed and eligibility is confirmed, the study subject will be registered 
and entered into the Clinical Trial Management System (CTMS) at the Fred Hutchinson Cancer Center. All 
patients must be registered and be assigned a unique study number prior to starting protocol therapy. 
Treatment initiation must occur within 5 working days of registration. 
 
If a patient is consented to the trial but is not registered or is withdrawn prior to initiation of protocol 
treatment, the reason for screen failure and/or withdrawal will be documented. However, no clinical trial 
data will be collected beyond the basic demographic data contained on the eligibility checklist. A 
registration log with dated entries for each patient registered will be kept. 

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7.0 
TREATMENT PLAN 
 
All enrolled patients will be treated with cabozantinib and pembrolizumab in 3‐week treatment cycles. 
 
 
7.1 
Cabozantinib administration 
 
Cabozantinib must be taken on an empty stomach. Subjects must be instructed not to eat for at least 2 
hours before and at least 1 hour after taking cabozantinib. Subjects should be instructed to take their 
cabozantinib dose at approximately the same time every day. If a subject misses a dose, the dose may be 
taken later only if it is within 12 hours of when the missed dose should have been taken. The missed dose 
should not be made up if it is within 12 hours of the next scheduled dose. 
 
Cabozantinib tablets should be swallowed whole with at least 8 ounces of water. The tablets should not 
be crushed. Grapefruit, grapefruit juice, Seville oranges and their products should be avoided by subjects 
taking cabozantinib. 
 
All patients will be given the Cabozantinib Drug Diary (Appendix 2) to record the date and time of each 
dose of cabozantinib taken. 
 
 
7.2 
Pembrolizumab administration 
 
Pembrolizumab will be administered at 200 mg intravenously over 30 minutes on Day 1 of each 3‐week 
cycle (+/‐ 2 days). Every effort should be made to target infusion timing to be as close to 30 minutes as 
possible. However, a window between ‐5 minutes and +10 minutes is permitted (i.e. infusion time is 30 
minutes ‐5 min/+10 min). Pembrolizumab should be infused before cabozantinib when the study drugs 
are given on the same day. The Pharmacy Manual contains specific instructions for the preparation of 
pembrolizumab and administration of infusion solution. 
 
Pembrolizumab may be administered up to 2 days before or after the scheduled day of dosing due to 
administrative reasons. Dosing interruptions/delays are permitted in the case of medical/surgical events 
or logistical reasons (i.e. elective surgery, unrelated medical events, patient vacation, holidays) not related 
to pembrolizumab‐induced toxicity. Patients should resume pembrolizumab therapy within 3 weeks of 
the scheduled interruption (for reasons other than toxicity), unless approved by the Study PI. The reason 
for interruption/delay should be documented in the patient's study record. 

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7.3 
Duration of therapy 
 
Patients will begin cabozantinib and pembrolizumab concurrently. Patients may continue study therapy 
until unequivocal disease progression, unacceptable drug‐related toxicity, or subject withdrawal. If one 
drug needs to be permanently discontinued due to toxicity, the other agent may be continued. Interval 
dosing interruption/delay of either or both agents is allowed for AEs (see Section 9.0). 
 
Treatment beyond progression with cabozantinib and/or pembrolizumab (depending on patient 
tolerance) will be allowed based on meeting pre‐specified criteria and after discussion with the study PI 
(see Section 12.1). 
 
Patients may be treated up to a maximum of two years from the time of treatment initiation. 
 
 
7.4 
Treatment compliance 
 
Patients will complete the Cabozantinib Drug Diary (Appendix 2) that helps with tracking of drug doses 
taken and confirming treatment compliance. Patient compliance with cabozantinib will be assessed at 
each visit. Compliance will also be confirmed by counting returned capsules. 
 
Patients who are significantly noncompliant will be discontinued from the study. A patient will be 
considered significantly noncompliant if he or she misses 7 or more consecutive days of cabozantinib, or 
more than 25% cumulative days of cabozantinib during the study for reasons other than toxicity, or if the 
patient takes more than the prescribed amount of medication. Cabozantinib dose suspensions or delays 
due to toxicity do not count in compliance assessment. 
 
8.0 
CONCOMITANT MEDICATIONS AND THERAPIES 
 
 
8.1. 
Allowed therapy 
 
During study participation, symptomatic or supportive treatment of tumor‐associated symptoms (e.g. 
pain, nausea) and side effects of treatment is encouraged if appropriate as per the treating investigator. 
 
Specifically, the following concomitant therapies are permitted, if clinically indicated: 
 
• 
Antiemetics and antidiarrheal (for non‐immune diarrhea) medications. 
• 
Opioid analgesics. 
• 
Granulocyte colony‐stimulating factors (G‐CSF) used as per clinical guidelines (e.g. ASCO or ESMO 
guidelines). 
• 
Bisphosphonates can be used for bone metastases or hypercalcemia if the benefit outweighs the risk 
per the investigator’s discretion. 
o Note: Osteonecrosis of the jaw has been reported with the use of bisphosphonates as well as 
with cabozantinib. Patients must be informed of this risk and be monitored frequently for 

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potentially overlapping toxicities. They should be advised regarding oral hygiene practice and 
to quickly report symptoms to the investigator. Oral examinations are recommended prior to 
starting bisphosphonates. See Section 9.3.8. 
• 
Transfusions and hormone replacement as indicated by standard clinical practice. 
• 
Individualized anticoagulation therapy with heparin is allowed if it can be provided safely and 
effectively under the following circumstances: 
o Low dose heparins for prophylactic use are allowed if clinically indicated and the benefit 
outweighs the risk per the investigator’s discretion. 
o Therapeutic doses of LMWH at the time of the first dose of study treatment are allowed if the 
subject has no evidence of brain metastasis, has been on a stable dose of LMWH for at least 4 
weeks, and has had no complications from a thromboembolic event or the anticoagulation 
regimen. 
o Therapeutic doses of LMWH after first dose of study treatment are allowed if clinically 
indicated (e.g. for the treatment of DVT), and the benefit outweighs the risk per the 
investigator’s discretion. For management of thromboembolic complications while on study, 
see Section 9.3.4. 
o Standard clinical management of anticoagulation therapy with heparins must be followed. This 
includes, but is not limited to, subject education regarding potential adverse drug reactions, 
monitoring laboratory parameters, dose adjustments (e.g. due to kidney dysfunction). 
o For restrictions on oral anticoagulants, see Section8.4. 
• 
Premedication is allowed for pembrolizumab‐related infusion reactions (Section 9.5.6). 
 
Patients cannot receive systemic glucocorticoids for any purpose other than to modulate symptoms from 
an AE that is suspected to have an immunologic etiology. The use of physiologic doses of corticosteroids 
may be approved after consultation with the Principal Investigator. Exception: steroids may be used for 
premedication prior to imaging. 
 
Potential drug interactions with cabozantinib are summarized in Section 1.4.3. 
 
 
8.2 
Recording concomitant therapy 
 
Concomitant medications administered within 28 days before the first dose of study treatment and during 
the treatment phase until the study discontinuation visit should be recorded, as well as medications 
administered for SAEs occurring after 30 days after the last dose of trial treatment, as defined in Section 
16.1. 
 
All premedications, supportive medications, and other concomitant therapy (including all prescription, 
over‐the‐counter (OTC), herbal supplements, and IV medications and fluids) that are taken between study 
consent and the end‐of‐study visit after treatment discontinuation should be recorded in the case report 
form (CRF), with the start and end of treatment dates, total daily dose, dosage unit, and the reason for 
use. If changes occur during the trial period, documentation of drug dosage, frequency, route, and date 
may also be included on the CRF. 
 
 
8.3 
Palliative radiation 
 
Limited data are available with cabozantinb and pembrolizumab and radiotherapy. Thus, palliative 
radiation should only be undertaken if medically necessary and indicated. 

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If radiation is undertaken, only palliative radiation to symptomatic bone metastases and limited to non‐ 
target lesions is allowed. Moreover, study treatment with both cabozantinib and pembrolizumab will be 
held at least 1 week before and resumed at least 1 week after radiation with complete recovery from 
acute toxicities of radiotherapy. The start and end dates of radiation, as well as the suspension and 
resumption dates of cabozantinib and pembrolizumab must be recorded in the CRF. 
 
 
8.4 
Prohibited or restricted therapy 
 
The following therapies are prohibited from the time of screening until study treatment has been 
permanently discontinued: 
 
• 
Any investigational agent or investigational medical device. 
• 
Oral anticoagulants (e.g. warfarin or other coumarin‐related agents, direct thrombin or direct FXa 
inhibitors, antiplatelet agents such as clopidogrel, or chronic use of aspirin above low dose levels for 
cardioprotection per local applicable guidelines). 
• 
Any non‐protocol systemic anticancer treatment (e.g. chemotherapy, immunotherapy, radionuclides, 
drugs or herbal products used specifically for the treatment of the cancer under investigation). 
• 
Local anticancer treatment including palliative radiation, ablation, embolization, or surgery on target 
lesions used for response monitoring by RECIST v1.1. 
o Note: radiation therapy to a symptomatic solitary lesion or to the brain that is not a target lesion 
may be allowed at the investigator’s discretion. 
• 
Anti‐HCV therapy. 
• 
Live vaccines or live attenuated within 30 days prior to the first dose of study treatment and while 
participating in the study. Administration of killed vaccines is 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 Principal Investigator. 
 
Subjects 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. 
 
The following therapies should be avoided until study treatment has been permanently discontinued or 
until otherwise specified: 
 
• 
Erythropoietic stimulating agents (e.g. epoetin alfa and darbepoetin alfa) should not be used based 
on a report of increased risk of tumor recurrence/progression associated with erythropoietin (Wright 
et al 2007). 
• 
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 QTcinterval). 
• 
Chronic co‐administration of cabozantinib with strong inducers of the CYP3A4 family (Appendix 4) 

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may significantly decrease cabozantinib concentrations and should be avoided. Selection of alternate 
concomitant medications with no or minimal CYP3A4 enzyme induction potential is recommended if 
possible. 
• 
Caution must be used when discontinuing treatment with a strong CYP3A4 inducer in a subject who 
has been concurrently receiving a stable dose of cabozantinib, as this could significantly increase the 
exposure to cabozantinib. 
• 
Co‐administration of cabozantinib with strong inhibitors of the CYP3A4 family (Appendix 4) may 
increase cabozantinib concentrations and should be avoided. Grapefruit, star fruit, and Seville oranges 
may also increase plasma concentrations of cabozantinib and should be avoided. Selection of 
alternate concomitant medications with no or minimal CYP3A4 enzyme inhibition potential is 
recommended if possible. 
 
Additional information on potential drug interactions with cabozantinib is provided in Section 1.4.3. 
There are no prohibited therapies during the Post‐Treatment Follow‐up Phase. 
The risks of solid organ transplantation following treatment with PD‐1 inhibitor therapy have not been 
extensively studied. The time frame for safe or appropriate liver transplantation after the last dose of 
pembrolizumab is unknown. Therefore, it is recommended not to perform liver transplantation within at 
least 120 days (5 half‐lives) of stopping pembrolizumab. The risks and benefits of transplant should be 
discussed with the participant by the treating investigator. 
 
 
9.0 
TOXICITIES AND DOSING MODIFICATIONS 
 
 
9.1 
Assessment of adverse events 
 
The patient’s pre‐existing conditions will be recorded, including signs and symptoms of the disease. 
Subjects will be monitored for AEs from the time of informed consent through their last follow‐up visit (30 
days after the date of the last dose of cabozantinib or pembrolizumab treatment, whichever occurs last). 
Subjects will be instructed to notify the investigator immediately at the onset of any AE experienced. 
Moreover, AEs will be assessed at scheduled study visits or non‐study clinic visits. In addition, any SAE 
attributed to treatment occurring after the last follow‐up visit will also be recorded. 
 
All AEs and changes in pre‐existing conditions will be documented, whether related or unrelated to study 
treatment. Seriousness, severity grade, and relationship to study treatment or protocol procedure will be 
determined by the investigator and reported on the CRF. The NCI CTCAE v5 will be used to grade AEs. For 
AEs not listed in the CTCAE v5, the investigator will be responsible for selecting the appropriate system 
organ and severity grade based on their clinical judgement. SAEs that occur after signing the consent form 
but prior to receiving study treatment will not be reported as serious unless the event was caused by a 
protocol procedure. 
 
See Section 16.0 for definitions and guidelines on monitoring and reporting of AEs and SAEs. 
 
9.2 
General guidelines about toxicity assessment and management in combination therapy 
Both non‐immune and immune‐related toxicities may occur on study. Any AE that occurs on study will be 
assessed for grade and attribution to either cabozantinib, pembrolizumab, or both agents. 

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Cabozantinib and pembrolizumab have class‐specific safety profiles based on their mechanisms of action 
but may also cause overlapping AEs. Examples of VEGFR TKI‐associated AEs caused by cabozantinib are 
hypertension and hand‐foot syndrome. Examples of immune‐related AEs caused by pembrolizumab are 
pneumonitis and endocrinopathies. Examples of overlapping AEs are diarrhea and ALT or AST elevations. 
To distinguish the toxicities of these two agents, the known toxicity profiles and typical timeline of 
toxicities associated with both study drugs should be taken into account.57 For instance, in the CELESTIAl 
trial, the median onset of diarrhea among patients who received cabozantinib was 4.1 weeks.21 Immune‐ 
related AEs may occur shortly after the first dose or several months after the last dose of pembrolizumab 
treatment, and may affect more than one organ system simultaneously. 
 
Therefore, if an AE is believed to be possibly related to or exacerbated by cabozantinib only, then it must 
be managed accordingly and cabozantinib may need to be interrupted and/or dose‐adjusted. In this 
setting, pembrolizumab may be continued if the patient can tolerate it as per discretion of the 
investigator. However, it is recommended to hold pembrolizumab as well in the setting of severe (grade 
3 or higher) AEs related to cabozantinib alone. 
 
In contrast, if an AE is believed to be possibly related to or exacerbated by pembrolizumab,, then both 
agents should be interrupted according to the guidelines below, even if the AE is not attributed to 
cabozantinib. 
 
 
For immune‐related AEs (irAEs), 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. Based on the severity of irAEs, pembrolizumab may be held or permanently discontinued and 
steroids may be administered. 
Guidance on dose modification of cabozantinib and pembrolizumab in the setting of specific AEs is 
provided in Sections 9.3 and 9.5, but management may differ from this guidance based on the clinical 
judgement of the investigator. 
 
If one agent needs to be discontinued indefinitely due to toxicity, the other agent may be continued if the 
patient can tolerate it as per discretion of the investigator. 
 
All dose interruptions and adjustments must be recorded clearly and accurately in the CRF, including dates 
of stopping and resuming drug(s), doses, and reasons for changes. In the event of a treatment pause, 
subsequent visits/cycles should not be delayed. 
 
 
9.3 
Information on cabozantinib toxicity 
 
AEs may occur within the first few weeks after starting cabozantinib (steady state reached at 
approximately 2 weeks). Cabozantinib‐related AEs that generally have an early onset include 
hypocalcemia, hypokalemia, thrombocytopenia, hypertension, PPES, abdominal pain, mucosal 
inflammation, constipation, diarrhea, and vomiting. 
 
AEs should be managed with supportive care at the earliest signs of toxicity. In all subjects, dose delays 
and reductions of cabozantinib to manage toxicity are allowed under the guidelines below. In general, 
grade 3 cabozantinib‐related AEs require dose interruption until AEs recover to grade 1, at which point 
treatment may be resumed at the next lower dose. Moreover, dose reductions are recommended for 

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grade 2 events that, if persistent, could become serious and/or intolerable. If cabozantinib is delayed by 
more than 4 weeks, it must be discontinued, unless there is reason to believe that the patient will benefit 
from resuming cabozantinib. In this case, resuming cabozantinib at dose reduction must be discussed with 
the PI. 
 
Furthermore, 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. 
 
If an AE is believed to be probably/definitely related to cabozantinib, and not related to pembrolizumab, 
then pembrolizumab may be continued even if cabozantinib needs to be interrupted or discontinued, as 
long as pembrolizumab is not expected to delay recovery or worsen the AE. 
 
9.3.1 
Gastrointestinal disorders 
 
GI perforation, GI fistula, and intra‐abdominal and pelvic abscess: After starting treatment with 
cabozantinib, subjects should be monitored for early signs of GI perforation such as abdominal pain, 
nausea, emesis, constipation, and fever especially if known risk factors for developing GI perforation or 
fistula are present. 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. Please see Section 9.5.2 for 
evaluation and management of diarrhea and specific dosing instructions for both cabozantinib and 
pembrolizumab. 
 
Nausea and vomiting: Antiemetic agents are recommended as clinically appropriate for treatment or 
prophylaxis of nausea and vomiting, along with supportive care. Patients should be monitored for 
dehydration and electrolyte abnormalities, and correction of fluid and electrolyte disturbances should be 
implemented. Antiemetic medications should be assessed for potential drug interactions (see Section8.0). 
 
9.3.2 
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. 
 
9.3.3 
Hemorrhage 
 
Hemorrhagic events, including serious and sometimes fatal events, have been reported with cabozantinib. 
Subjects should be monitored for bleeding with clinical and laboratory assessments while on study. The 
risk of hemorrhage in cabozantinib‐treated subjects with brain metastases has not been thoroughly 
analyzed. Subjects enrolled with treated and stable brain metastases should be monitored with a high 
index of suspicion if symptoms that could be due to a CNS hemorrhage occur. 
 
Cabozantinib should be discontinued in subjects with serious and life‐threatening bleeding events or 
recent hemoptysis (≥ 2.5 mL of red blood). For other clinically significant bleeding events, cabozantinib 
may be held and resumed after the bleeding resolves. 

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9.3.4 
Thromboembolic events 
 
Cancer patients are at increased risk of venous thromboembolic events. DVT and pulmonary embolism 
have been observed in clinical studies with cabozantinib, including fatal events. Subjects who develop a 
pulmonary embolism and/or DVT should have their study treatment interrupted until therapeutic 
anticoagulation is established. Treatment with cabozantinib may be resumed in subjects with DVT or 
pulmonary embolism if it is determined that the event is uncomplicated, the patient is relatively 
asymptomatic, and anticoagulation does not place them at a significant risk per discretion of the 
investigator. 
 
LMWHs are the preferred management for thrombotic events. Oral anticoagulants (e.g. warfarin or other 
coumarin‐related agents, direct thrombin or direct FXa inhibitors, antiplatelet agents, or chronic use of 
aspirin above low dose levels for cardioprotection per local applicable guidelines) are not allowed. 
 
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. 
 
9.3.5 
Hypertension 
 
BP should be monitored in a sitting position in a relaxed setting. Decisions to reduce or interrupt the dose 
of study treatment must be based on BP readings taken by an experienced health care provider and must 
be confirmed with a second measurement at least 5 minutes following the firstmeasurement. 
 
Cabozantinib should be discontinued in subjects with hypertensive emergency. 
 
The management of hypertension related to cabozantinib is outlined in Table 9.3.5.1. 

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Table 9.3.5.1. Management of hypertension associated with cabozantinib 
Criteria for dose modification 
Management and cabozantinib modification 
Subjects NOT receiving optimized anti‐hypertensive therapy 
> 150 mm Hg (systolic)a and 
< 160 mm Hg 
OR 
> 100 mm Hg (diastolic) and < 
110 mm Hg 
• 
Optimize antihypertensive medications by adding new 
antihypertensive medications and/or increase the dose of 
existing medications. 
• 
Reduce cabozantinib treatment by one dose level if optimal 
antihypertensive therapy (usually to include 3 agents) does not 
result in BP <150 mm Hg systolic or <100 mm Hg diastolic. 
• 
If subject is symptomatic, interrupt cabozantinib treatment and 
resume once BP <150 mm Hg systolic or <100 mm Hg diastolic 
and symptoms resolve. 
≥ 160 mm Hg (systolic) 
OR 
≥ 110 mm Hg (diastolic) 
• 
Reduce cabozantinib by one dose levelb or interrupt 
cabozantinib treatment per investigator discretion. 
• 
Add new anti‐hypertensive medications and/or increase the 
dose of existing medications. 
• 
If optimized antihypertensive therapy (usually to  include  
3 agents) does not result in BP < 150 mm Hg systolic or 
< 100 mm Hg diastolic, cabozantinib treatment should be 
interrupted and resumed at dose reduction (if not already 
done) when BP <150 mm Hg systolic or <100 mm Hg diastolic. 
• 
Cabozantinib treatment should be interrupted if upper limits of 
systolic BP (≥ 160 mm Hg) are sustained and not adequately 
manageable, if systolic BP is > 180 mm Hg or diastolic BP > 110 
mm Hg, or if subject is symptomatic. 
• 
Re‐start cabozantinib treatment at the most tolerable dose and 
re‐escalate only if BP falls to and is sustained at < 150 mm Hg 
systolic and < 100 mm Hg diastolic. 
Hypertensive emergencyc 
• 
Discontinue cabozantinib treatment. 
BP, blood pressure. 
a The investigator may decide to initiate or adjust antihypertensive treatment at a lower threshold than systolic BP 
>150 or diastolic BP >100 based on their clinical judgment and assessment of the individual subject. 
b Permitted dose levels are defined in Section 9.4. 
cHypertensive 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). 
 
9.3.6 
Stomatitis and mucositis 
 
Preventive measures before study treatment are recommended, 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 gentle 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. 

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Cabozantinib should be interrupted for drug‐related grade 3 stomatitis and mucositis until symptoms 
improve to grade 1, followed by resumption of drug at the next lower dose. 
 
9.3.7 
Skin and Subcutaneous Tissue Disorders 
 
Wound healing and surgery: Cabozantinib has the potential to cause wound healing complications and 
wound dehiscence, which may even occur long after a wound has been considered healed. Therefore, 
surgical and traumatic wounds must not only be completely healed prior to starting cabozantinib 
treatment, but must also be monitored for wound dehiscence, wound infection, and other signs of 
impaired wound healing while the subject is being treated with cabozantinib. If dehiscence occurs, 
cabozantinib treatment should not be restarted until complete healing has taken place. 
 
Treatment with cabozantinib should be stopped at least 28 days prior to scheduled surgery. The decision 
to resume treatment with cabozantinib after surgery should be based on clinical judgment of adequate 
wound healing. 
 
Palmar‐plantar erythrodysesthesia syndrome (PPES; also known as hand‐foot syndrome): skin rash 
(including blister, erythematous rash, macular rash, skin exfoliation, dermatitis acneiform, and papular 
rash), pruritus, dry skin, erythema, pigmentary changes, and alopecia have been reported with 
cabozantinib. All subjects on study should be advised on prophylactic measures including the use of 
emollients, removal of calluses, avoidance of exposure of hands and feet to hot water leading to 
vasodilatation, protection of pressure‐sensitive areas of hands and feet, and use of cotton gloves and 
socks to prevent injury and keep the palms and soles dry. 
 
Early manifestations include tingling, numbness, mild hyperkeratosis, and symmetrical red and swollen 
areas on the palms and soles. The lateral sides of the fingers or periungual zones may also be affected. 
Adequate interventions are required to prevent worsening of skin symptoms such as blisters, 
desquamations, ulcerations, or necrosis of affected areas. Analgesics may be required for pain control. 
Aggressive management of symptoms is recommended. Recommendations for treatment of PPES and 
dose modification of cabozantinib are summarized in Table 9.3.7.1. 
 
For other skin toxicities, including possible immune‐mediated skin rash, please see Section 9.5.4. 
 
Table 9.3.7.1. Management of hand‐foot syndrome (PPES) associated with cabozantinib 
Grade per CTCAE v5 
Management and cabozantinib modification 
Grade 1: Minimal skin 
changes or dermatitis 
(e.g. erythema, 
edema, or 
hyperkeratosis 
without pain) 
Cabozantinib treatment should be continued at the current dose. Start urea 
20% cream twice daily and consider mild‐moderate potency steroid topical.. 
If PPES worsens at any time or does not improve after 2 weeks, proceed to the 
intervention guidelines for Grade 2. 
Grade 2: Skin changes 
(e.g. peeling, blisters, 
bleeding, fissures, 
edema, 
or 
hyperkeratosis) with 
Cabozantinib treatment may be continued at same dose, dose‐reduced, 
and/or interrupted at the discretion of the treating investigator depending on 
the degree of symptoms. Continue urea 20% cream twice daily AND add a high 
potency steroid topical, and add analgesics for pain control if needed. If PPES 
worsens  or  affects  self‐care,  proceed  to  the  intervention  guidelines  for 

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pain; limiting 
instrumental ADL 
Grade 3. 
Grade 3: Severe skin 
changes (e.g. peeling, 
blisters, 
bleeding, 
fissures, edema, or 
hyperkeratosis) with 
pain; limiting self‐care 
ADL 
Interrupt cabozantinib treatment until severity decreases to Grade 1. 
Continue treatment of skin reaction with high potency steroid cream and 
analgesics. Resume study drug at a reduced dose if PPES recovers to Grade 
≤ 1. Discontinue subject from study treatment if PPES does not improve within 
4 weeks. 
CTCAE, Common Terminology Criteria for Adverse Events; NSAID, non‐steroidal anti‐inflammatory drug; PPES, 
palmar plantar erythrodysesthesia syndrome. 
1Permitted dose levels are defined in Section 9.4. 
 
9.3.8 
Osteonecrosis 
 
Osteonecrosis has been reported in subjects treated with cabozantinib. Additional risk factors include use 
of bisphosphonates and denosumab, chemotherapy and anti‐angiogenic drugs, use of corticosteroids, 
local radiotherapy, and dental or orofacial surgery procedures. 
 
Osteonecrosis of the jaw (ONJ) can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or 
periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing 
of the mouth or jaw after dental surgery may also be manifestations of osteonecrosis. 
 
Perform an oral examination prior to initiation of cabozantinib and periodically during cabozantinib 
treatment. Advise subjects regarding oral hygiene practice and to quickly report symptoms to Investigator. 
Caution should be used in subjects receiving bisphosphonates. 
 
Dental surgery or 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. 
 
9.3.9 
Proteinuria 
 
Proteinuria has been reported with cabozantinib. Proteinuria should be monitored by measuring UPCR 
once every 6 weeks (every 2 cycles) on treatment, and more frequently if abnormal. Table 9.3.9.1 provides 
treatment guidelines for proteinuria 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). 

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Table 9.3.9.1. Management of proteinuria associated with cabozantinib 
Severity of 
Management and cabozantinib modification 
proteinuria (UPCR) 
≤ 1 mg/mg (≤ 113.1 
mg/mmol) 
• 
No change in cabozantinib treatment or monitoring. 
> 1 and < 3.5 mg/mg 
(> 113.1 and < 395.9 
mg/mmol) 
• 
Consider confirming with a 24‐h protein assessment within 7 days. 
• 
No change in cabozantinib treatment required if UPCR ≤ 2 mg/mg or urine 
protein ≤ 2 g/24 h on 24‐h urine collection. 
• 
Dose reduce or interrupt cabozantinib treatment if UPCR > 2 mg/mg on 
repeat UPCR testing or urine protein > 2 g/24 h on 24‐h urine collection. 
Continue cabozantinib on a reduced dose if UPCR decreases to < 2 mg/mg. 
Consider interrupting cabozantinib treatment if UPCR remains > 2 mg/mg 
despite a dose reduction until UPCR decreases to < 2 mg/mg. Restart 
cabozantinib treatment at a reduced dose after a dose interruption. 
• 
After dose reduction or interruption, repeat UPCR within 7 days and once 
per week. If UPCR < 1 mg/mg on 2 consecutive readings, UPCR monitoring 
can revert to once monthly. (Second reading is confirmatory and can be 
done within 1 week of first reading.) If UPCR remains > 1 mg/mg and < 2 
mg/mg for 1 month or is determined to be stable (< 20% change) for 1 
month, check urine protein/creatinine once monthly as clinically indicated. 
≥ 3.5 mg/mg 
(≥ 395.9 mg/mmol) 
• 
Interrupt cabozantinib treatment pending repeat UPCR within 7 days and/or 
24‐h urine protein. 
• 
If ≥ 3.5 mg/mg on repeat UPCR, continue to interrupt cabozantinib 
treatment and check UPCR every 7 days. If UPCR decreases to < 2 mg/mg, 
restart cabozantinib treatment at a reduced dose and monitoring of urine 
protein/creatinine should continue weekly until the UPCR decreases to < 1 
mg/mg. If  UPCR remains  >  1  mg/mg  and <  2  mg/mg for  1  month  or is 
determined to be stable (< 20% change) for 1 month, check urine 
protein/creatinine once monthly or as clinically indicated. 
Nephrotic syndrome 
• 
Discontinue cabozantinib. 
RCC, renal cell carcinoma; UC, urothelial carcinoma; UPCR, urine protein/creatinine ratio. 
 
 
9.3.10 Nervous system disorders 
 
Cabozantinib appears to represent minimal risk of adverse neurological effects based on nonclinical Good 
Laboratory Practice (GLP)‐compliant toxicology studies. Dysphonia, dysgeusia, headache, dizziness, 
confusional state, convulsion, depression, memory impairment, hypoesthesia, peripheral neuropathy, 
insomnia, ataxia, and encephalopathy have been observed in clinical studies with cabozantinib. The 
development of any new or progressive, unexplained neurological symptoms should be assessed for 
underlying causes. 
 
RPLS has been reported. RPLS should be considered in any subject presenting with seizures, headache, 
visual disturbances, confusion or altered mental function. Cabozantinib treatment should be discontinued 
in subjects with RPLS. 
 
9.3.11 Hepatocellular toxicity 
 
Elevation of aminotransferases (ALT and AST): Evaluation of subjects with elevated transaminases or 
bilirubin should be individualized and guided by the presence of specific risk factors such as liver 

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conditions (e.g. liver cirrhosis, liver metastases, thrombosis of portal or hepatic vein), concomitant 
hepatotoxic medication, alcohol consumption, and cancer‐related causes. Specifically, pembrolizumab is 
a potential cause of immune‐mediated hepatitis and reactivation or flare of HBV or HCV in affected 
patients is a possibility. Please see Section 9.5.3 for evaluation and management of liver toxicity and 
specific dosing instructions for both cabozantinib and pembrolizumab. 
 
9.3.12 Infections and infestations 
 
Infections and abscesses should be treated with appropriate local care and systemic therapy. Cabozantinib 
should be interrupted if there are open wounds until adequate healing has taken place. For minor or mildly 
symptomatic infections (e.g. urinary tract infection, cellulitis), cabozantinib may be continued at the 
discretion of the investigator if the drug is believed to be unrelated and is not expected to worsen the 
infection. 
 
9.3.13 Blood and lymphatic system disorders 
 
Hematological toxicities (e.g. neutropenia, thrombocytopenia) have been observed after administration 
of cabozantinib. Subjects with hematologic toxicities may require additional or more frequent laboratory 
tests according to institutional guidelines. 
 
See Section 9.5.1 for guidance on dose modification of cabozantinib for hematologic toxicities. The use of 
colony‐stimulating growth factors may be considered for significant neutropenia (e.g. grade 3 or higher) 
believed to be related to cabozantinib. 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, with interruption of study treatment until resolution. 
 
Supportive care for thrombocytopenia or anemia, such as transfusions, may be considered according to 
institutional guidelines. However, if there is a recurrent need for transfusions or grade 3 events, dose 
reduction of cabozantinib to the next lower dose is recommended. 
 
9.3.14 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. 
 
For clinically significant fatigue (e.g. grade 3) related to or exacerbated by cabozantinib, dose interruption 
and/or dose reduction is recommended. 
 
9.3.15 Weight loss 
 
Anorexia and weight loss should be managed according to local standard of care including nutritional 
support. Pharmacologic therapy may be considered for appetite enhancement when not prohibited if 
there is minimal drug interaction with cabozantinib (see Section 8.4). 
 
For clinically significant weight loss or anorexia (e.g. grade 3) related to or exacerbated by cabozantinib, 
dose interruption and/or dose reduction is recommended. 

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9.3.16 QTc prolongation 
 
The effect of orally administered cabozantinib 140 mg once daily on QTc interval was evaluated in a 
placebo‐controlled study in subjects with medullary thyroid cancer. A mean increase in QTcF of 10‐15 ms 
was observed at 4 weeks after initiating cabozantinib treatment. A concentration‐QTc relationship could 
not be definitively established. Changes in cardiac wave form morphology or new rhythms were not 
observed. No cabozantinib‐treated subjects in this study had a QTcF > 500 ms. 
 
Review of the larger safety database (~5000 subjects exposed to cabozantinib in clinical trials and in post‐ 
marketing experience) confirmed the absence of safety concerns associated with QT prolongation. There 
were no events of torsades de pointes reported. 
 
Concomitant treatment with strong CYP3A4 inhibitors, which may increase cabozantinib plasma 
concentrations, should be avoided. 
 
An EKG should be obtained every 2 cycles on treatment. At any time on study, if there is an increase in 
QTcF to an absolute value > 500 ms, two additional EKGs must be performed with intervals not less than 
5 min apart within 30 min after the initial EKG. 
 
If the average QTcF from the three EKGs is > 500 ms, the following actions must be taken: 
 
• 
Interrupt cabozantinib treatment. 
• 
Hospitalize symptomatic subjects (e.g. palpitations, dizziness, syncope, orthostatic hypotension, 
ventricular arrhythmia on EKG) 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 for concomitant medications that may have contributed to QT prolongation, and if possible, 
discontinue these medications (http://www.qtdrugs.org). 
 
Subjects with QTc prolongation and symptoms must be monitored closely until the QTc elevation and 
symptoms have resolved. Cabozantinib treatment may be restarted at a reduced dose level if all of the 
following conditions are met: 
 
• 
Symptoms are determined to be unrelated to the QT interval prolongation. 
• 
The QTcF value > 500 ms is not confirmed. 
• 
Cabozantinib treatment has been interrupted through a minimum of 1 week following the return of 
the QTcF to ≤ 500 ms. 
• 
QT prolongation can be unequivocally associated with an event other than cabozantinib 
administration and is treatable/has been resolved. 
 
Following reinitiation of study treatment, EKGs 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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9.3.17 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 at least every 3 weeks while receiving cabozantinib. More frequent monitoring may 
be required. Standard clinical practice guidelines should be used for management of electrolyte disorders 
and may include oral or intravenous replacement. 
 
 
9.3.18 Angioedema 
 
Angioedema should be managed according to standard practice. The subject should be observed until 
symptoms resolve, with particular attention to effects on airway. If life‐threatening angioedema is 
probably or definitely related to cabozantinib, the drug must be discontinued. 
 
 
9.3.19 Endocrine disorders 
 
Treatment‐emergent elevation of thyroid‐stimulating hormone (TSH) has been observed with 
cabozantinib monotherapy treatment. Currently available data are insufficient to determine the 
mechanism of thyroid function test alterations and its clinical relevance. 
 
TSH elevation may also be related to immune‐mediated endocrinopathy caused by pembrolizumab, which 
occurs in 8% and 5% of patients in the KEYNOTE‐224 and KEYNOTE‐240 trials, respectively (mostly grade 
1‐2).35,36 TSH and free T4 and T3 should be checked at least every 6 weeks (every 2 cycles) on study. 
 
Regardless of whether it is related to cabozantinib and/or pembrolizumab, clinically symptomatic 
hypothyroidism should be treated with thyroxine replacement as per accepted clinical practice guidelines. 
See Section 9.5.5 for treatment guidelines for suspected immune‐mediated endocrine AEs. 
 
9.4 
Dose levels of cabozantinib 
 
Cabozantinib must be started at 40 mg orally once daily and reduced to 20 mg orally once daily (minimum 
dose) for toxicity. Cabozantinib must be discontinued permanently if the minimal dose is not tolerated. 
Re‐escalation to 40 mg once daily is not recommended, but may be allowed if there is a reason to believe 
that the patient will tolerate this dose after discussion with the PI. 
 
Table 9.4.1. Dose levels for cabozantinib 
Dose Adjustment Level 
Oral Dose 
Frequency 
0 (starting dose) 
40 mg 
Once daily 
‐1 
20 mg 
Once daily 
‐2 
Discontinue 
 
9.5 
Guidance on dose modification of cabozantinib and pembrolizumab for non‐immune and 
immune toxicities 
 
Both non‐immune and immune‐mediated toxicities may occur on study. 
 
The sections below provide guidance on dose modifications for TRAEs, in addition to management 
recommendations for cabozantinib‐specific toxicities discussed in Section 9.3. However, management 

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may differ from this guidance based on the clinical judgement of the investigator. In all patients, 
supportive care should be initiated to manage the AEs in addition to dose modification of study drugs. 
 
For potential irAEs, please refer to the ASCO Clinical Practice Guidelines for Management of Immune‐ 
Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy.58 
 
If dose is interrupted for TRAEs, cabozantinib must be resumed within 4 weeks of last dose, and pembrolizumab 
must be resumed within 12 weeks of last dose. Resuming drugs beyond these time points must be discussed with 
the Study PI. 
 
 
9.5.1 
Non‐immune toxicities 
 
Table 9.5.1.1 below provides guidance for dose modification for non‐immune toxicities in general. 
Pembrolizumab should be held if the AE is clinically severe and/or if pembrolizumab might delay recovery 
or worsen the AE. 
 
Table 9.5.1.1. General guidance on dose modification for non‐immune toxicities 
Grade per CTCAE v5 
Cabozantinib modification 
Pembrolizumab modification 
Hematologic TRAEs 
Grade 1 and 2 
• 
No modification. 
• 
No modification. 
Grade 3 or 4 
anemia, 
neutropenia, 
thrombocytopenia 
1 
 
 
 
 
 
 
 
 
 
 
 
Non‐hematologic TRAEs 
• 
Hold drug until recovery to 
grade 1, then restart at same 
dose level OR at reduced dose 
level (at the discretion of the 
investigator). 
• 
1st and 2nd recurrence: hold 
drug until recovery to grade 1, 
then restart at reduced dose 
level (if not already reduced) 
or 
discontinue 
drug 
(if 
previously reduced dose). 
• 
No 
modification. 
Consider 
holding 
drug 
if 
no 
improvement after holding 
cabozantinib. 
Grade 1 or 2 
• No modification (may be held for 
significantly 
symptomatic 
grade 2 toxicity). Supportive 
care as 
indicated. 
• 
No modification. 
Grade 3 
• 
Hold drug until recovery to grade 
1. If supportive care can be used 
and 
optimized 
to 
control 
symptoms, then restart at the 
same dose level. If grade 3 
toxicity occurred on maximal 
supportive care then restart at 
reduced dose level. 
• 
Hold drug until recovery to 
grade 
1 
(or 
pretreatment 
baseline), then restart drug. 

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• 
1st and 2nd recurrence despite 
optimal supportive care: hold 
drug until recovery to grade 1, 
then restart at reduced dose 
level (if not already reduced) or 
discontinue drug (if previously 
reduced dose). 
Grade 4 
• 
Hold drug and provide supportive 
care until recovery to grade 1, 
then restart at reduced dose level 
if the patient is deriving clinical 
benefit as determined by the 
treating investigator. 
• 
1st recurrence: discontinue drug. 
• 
Hold drug until recovery to grade 
1 (or pretreatment baseline), 
then restart drug. 
TRAE, treatment‐related adverse event. 
1Supportive transfusions and use of G‐CSF recommended as per institutional guidelines. 
Note: Continuation of study drugs in the setting of asymptomatic grade 3‐4 elevations of amylase/lipase is permitted 
after discussion with the study PI. 
 
 
9.5.2 
Diarrhea 
 
Diarrhea is a known toxicity of both cabozantinib and immune checkpoint inhibitors such as 
pembrolizumab. In the CELESTIAL trial of cabozantinib (starting dose of 60 mg daily) vs. placebo, 54% of 
patients treated with cabozantinib had diarrhea of any grade, and 10% had grade 3 diarrhea. The median 
time of onset of diarrhea was 4.1 weeks.21 In the KEYNOTE‐224 trial of pembrolizumab, 11% of patients 
experienced diarrhea (all grade 1‐2, no grade 3 or 4), while the rate of immune‐mediated colitis was 1%.35 
In the randomized KEYNOTE‐240 trial, diarrhea occurred in 16% of patients on the pembrolizumab arm 
(1.2% grade 3‐4).36 
 
The combination of multikinase inhibitor and immune checkpoint inhibitor may potentially increase 
diarrhea. However, the rate of diarrhea was similar with the combination of lenvatinib and 
pembrolizumab as observed in the early Phase 1b trial (any grade, 43%; grade 3, 3%) compared to 
lenvatinib alone (any grade, 39%; grade 3, 4%).10,38 
 
Enrolled patients should be closely monitored for diarrhea, and if present, attribution to cabozantinib or 
pembrolizumab or both must be carefully considered. Timing may guide attribution, as the onset of 
diarrhea related to cabozantinib tends to occur shortly after starting drug (e.g. within 2 weeks), while the 
median time to onset of immune‐related colitis related to pembrolizumab was 3.5 months with a median 
duration of 1.4 months. 
 
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. Examination 
of the perianal region should be performed for reported perianal symptoms in patients experiencing 
diarrhea during treatment with cabozantinib/pembrolizumab. Infections of the perianal region should be 
treated per local guidelines. 

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General management for diarrhea: 
 
• 
Monitor patients for signs and symptoms of colitis (e.g. diarrhea, abdominal pain, bloody stools, 
fever) and bowel perforation.Administration of antidiarrheal/antimotility agents is recommended 
at the first sign of diarrhea as initial management (e.g. loperamide 4 mg followed by 2 mg after 
each episode of diarrhea [maximum: 16 mg loperamide per day]). Some subjects may require 
treatment with more than one antidiarrheal agent, and the addition of diphenoxylate/atropine 
and/or tincture of opium can be considered. In addition, general supportive measures should be 
implemented, such as increasing oral hydration (+/‐ IV isotonic fluids), correcting electrolyte 
abnormalities, small frequent meals, and stopping lactose‐containing products, high‐fat meals 
and alcohol. When diarrhea resolves to baseline bowel habits, gradually add solid foods and 
discontinue or decrease antidiarrheal treatment after 12 h diarrhea‐free interval. 
• 
For grade 1 and 2 diarrhea: supportive measures as above. 
• 
For intolerable grade 2 diarrhea or grade 2 diarrhea >48 hours despite optimal supportive 
measures as above: 
o Obtain labs to rule out dehydration and electrolyte abnormalities. 
o Rule out infectious diarrhea (e.g. stool culture, C difficile toxin, enteric panel). 
o If diarrhea lasts > 7 days, consider imaging (e.g. CT abdomen/pelvis) and GI consult for 
colonoscopy for biopsy. 
• 
If infectious source is ruled out and diarrhea is persistent > 7 days, suspect immune‐mediated colitisFor severe 
and/or life‐threatening diarrhea: 
o Admit to hospital for IV hydration and electrolyte replacements. 
o Rule out infectious diarrhea (e.g. stool culture, C difficile toxin, enteric panel). 
o Obtain imaging (e.g. CT abdomen/pelvis) and GI consult for colonoscopy for biopsy. 
o 
• 
See Table 9.5.2.1 for dosing of cabozantinib and pembrolizumab in the setting of non‐immune 
diarrhea. For suspected immune‐mediated colitis, also follow guidelines in Table 9.5.5.1. 
 
 
Table 9.5.2.1. Guidance for diarrhea due to cabozantinib (non‐immune) 
Grade per CTCAE v5 
Cabozantinib modification 
Pembrolizumab modification 
Grade 1 (< 4 
stools/day over 
baseline) 
• 
Continue at same dose. 
• 
Continue at same dose. 
Grade 2 (4‐6 
stools/day over 
baseline) 
• 
Continue at same dose, or if 
intolerable grade 2 or grade 2 >48 
hours despite optimal supportive 
measures 
and 
anti‐diarrheals, 
hold drug until improvement to 
grade 1, then restart at same dose 
or at reduced dose (at the 
discretion of the investigator). 
• 
Continue at same dose. 

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Grade 3 (7 or more 
stools/day over 
baseline) 
• 
Hold drug until recovery to grade 
1, then restart at same dose (if 
best supportive care was not 
previously used) or at reduced 
dose (if diarrhea is uncontrolled 
despite best supportive care). 
• 
1st recurrence: hold drug until 
recovery to grade 1, then restart 
at reduced dose (if not already 
done) or discontinue drug (if dose 
previously reduced). 
• 
Hold drug until recovery to grade 1 
(or pretreatment baseline), then 
restart drug. 
Grade 4 (life‐ 
threatening) 
• 
Hold drug until recovery to grade 
1, then restart at reduced dose 
level if the patient is deriving 
clinical benefit as determined by 
the treating investigator. 
• 
1st recurrence: discontinue drug. 
• 
Hold drug until recovery to grade 1 
(or pretreatment baseline), then 
restart drug. 
 
 
9.5.3 
Liver toxicity 
 
HCC patients are at risk for a range of complications that can cause hepatic laboratory abnormalities with 
or without clinical decompensation. Moreover, temporary hepatic decompensation may occur especially 
in cirrhotic patients when exposed to a TKI. 
 
It may be difficult to distinguish these lab abnormalities related to cabozantinib from immune‐mediated 
hepatitis of pembrolizumab. Grade 3 immune‐related hepatitis was observed in 3% of patients who 
received pembrolizumab in the KEYNOTE‐224 trial,35 while 7% of patients treated with pembrolizumab in 

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the KEYNOTE‐240 trial experienced an immune‐mediated hepatic event, although no HBV/HCV flares 
occurred.36 Previous studies showed that immune‐mediated hepatitis typically occurs during the first 6‐ 
12 weeks after initiating an immune checkpoint inhibitor.59 Those with a history of chronic HCV or HBV 
infection also have the potential to experience virologic flares. 
 
Hepatic events of clinical interest (HECI) are defined as: 
 
• 
ALT: 
a: Among subjects with baseline ALT <2×ULN: ALT ≥5×ULN 
b: Among subjects with baseline ALT ≥2×ULN: ALT >3× the baselinelevel 
c: ALT >500 U/L regardless of baseline level 
• 
Total bilirubin: 
a: Total bilirubin >3.0 mg/dL 
• 
Regardless of laboratory values, hepatic decompensation diagnosed clinically, including: 
• 
New onset clinically detectable ascites requiring intervention for >3 days 
• 
Hepatic ncephalopathy 
 
General management for liver toxicity: 
 
• 
In the setting of liver toxicity indicated by abnormal liver function tests (e.g. ALT, AST, ALP, total 
bilirubin, INR), monitor liver function at least weekly until recovery to baseline orstabilization. 
• 
If there is grade 3 hepatic toxicity, it is recommended that both cabozantinib and pembrolizumab be 
interrupted and the patient be further evaluated. Consider causes of hepatitis and obtain appropriate 
workup, including disease progression, viral causes (HBV, HCV, EBV, CMV), drug‐ or alcohol‐induced 
hepatitis, herbals, infection, biliary obstruction, etc. 
• 
When an HECI occurs: 
• 
Hold study intervention and notify the Principal Investigator within 24 hours. All cases of 
retreatment after interruption of study intervention for HECI must be reported to the Principal 
Investigator and recorded in the database. 
• 
All participants should be considered for evaluation according to the directions below within 72 
hours of onset: 
o Consider obtaining a consultation with a hepatologist. 
o Obtain a work‐up for hepatitis if there is no underlying hepatitis, including hepatitis A, B, 
C, D, E, Epstein‐Barr virus, and cytomegalovirus. 
o Assess for ingestion of drugs/supplements with hepatotoxic potential. 
o Assess for alcohol ingestion. 
o Assess for potential bacterial infection, biliary obstruction, or occultgastrointestinal 
bleeding. 
o Repeat ALT, AST, total bilirubin, direct bilirubin, alkaline phosphatase, γ‐glutamyl 
transpeptidase, INR, and complete blood count with differential. 
o Measure HCV RNA viral load (applies only for participants who have current active HCV 
infection or had infection in the past). 
o HBV DNA, HBsAg, HBeAg, HBcAb (total and IgM), HBeAb, and HBsAb regardless of prior 
HBV status (Note: participants should be questioned about compliance with the use of 
antiviral agents). 
o Other laboratories or imaging studies as clinically indicated. 
• 
Consider liver biopsy if indicated.In the setting of HBV flare or change in HBV immunologic status: 
o Start antiviral therapy if appropriate 

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o Measure HBsAg and HBV DNA on weekly basis (if detected at the time of onset of HECI). 
o Evaluate the following every 2‐3 weeks if not detected at the time of onset of HECI 
• 
Anti‐HBe, HBe antigen, anti‐HBs, and HBV DNA levels (if not detected at the onset of HECI) 
• 
In the setting of HCV exacerbation in patients with positive HCV RNA, relapse of HCV in patients with previous 
antiviral treatment, or new HCV infection: 
o Recheck HCV genotype at the time of relapse of HCV RNA to rule out new infection. 
o Measure HCV RNA levels every 2 weeks. 
− 
Please discuss risk benefit with Principal Investigator prior to starting HCV antiviral therapy.‐ If there 
are other causes of liver dysfunction, treat accordingly (e.g. biliary obstruction). 
• 
The following table provides guidance on the dosing of cabozantinib and pembrolizumab in the setting 
of non‐immune liver toxicity. 
• 
If there is suspicion for possible pembrolizumab‐mediated hepatitis, alsofollow themanagementoutlined 
in Table 9.5.5.1: 
• 
Cabozantinib may be held up to 28 days, and pembrolizumab may be held up to 12 weeks. 
• 
Elevations >3 × ULN of ALT or AST concurrent with >2 × ULN total bilirubin without other explanation 
can indicate drug‐induced liver injury (DILI) due to cabozantinib. Cabozantinib should be permanently 
discontinued in cases determined to be DILI according to Hy’s Law review. 
• 
Study treatment should be discontinued indefinitely if grade 3 hepatic dysfunction is not reversed 
despite dose interruption and treatment of potential causes including immune‐mediated hepatitis. 
 
Table 9.5.3.1. Guidance for liver toxicity due to cabozantinib (non‐immune) 
Grade per CTCAE v5 
Cabozantinib modification1 
Pembrolizumab modification1 
ALT/AST > 5 x ULN if 
ALT/AST ≤ 2 x ULN at 
baseline OR ALT/AST 3‐ 
fold increase from D1 
level BUT NOT 
EXCEEDING 8 X ULN if 
ALT/AST > 2 x ULN at 
baseline 
• 
Hold drug until recovery to ≤ 
grade 2 ALT/AST elevation, then 
restart at reduced dose (consider 
resume at the same dose if other 
cause of liver toxicity found). 
• 
1st recurrence: discontinue drug. 
• 
 Hold drug until recovery to 
grade 1 (or pretreatment 
baseline), then restart drug. 
ALT or AST > 5 x ULN 
accompanied by total 
bilirubin ≥ 2 x ULN 
• 
Hold drug until recovery to ≤ 
grade 1 ALT/AST and bilirubin 
elevation 
or 
pre‐treatment 
baseline, then restart at reduced 
dose (consider resume at the 
same dose if other cause of liver 
toxicity found). 
• 
1st recurrence: discontinue. 
• 
Note: A patient with Gilbert’s 
syndrome should be managed 
according to observed elevation 
of ALT and/or AST if the observed 
bilirubin increase is below actual 
increased baseline bilirubin 
value. 
• 
Hold drug until recovery to 
grade 1 (or pretreatment 
baseline), then restart drug. 

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Total bilirubin > 3.0 
mg/dL irrespective of 
ALT/AST values 
• 
Hold drug until recovery to ≤ 
grade 1 ALT/AST and bilirubin 
elevation, then restart at reduced 
dose (consider resume at the 
same dose if other cause of liver 
toxicity found). 
• 
1st recurrence: discontinue. 
• 
Hold drug until recovery to 
grade 1 (or pretreatment 
baseline), then restart drug. 
• 
Note: For a patient with Gilbert’s 
syndrome, a continuation of 
cabozantinib 
might 
be 
considered at the discretion of 
the investigator if the observed 
bilirubin increase is below actual 
increased baseline bilirubin 
value. 
AST and/or ALT > 20 x 
ULN 
• 
Discontinue drug. 
• 
Hold drug until recovery to 
grade 1 (or pretreatment 
baseline), then restart drug. 
Hepatic 
encephalopathy not 
reversible and 
manageable by 
therapy2 
• 
Discontinue drug.2 
• 
Discontinue drug.2 
Child‐Pugh score > 8 
points2 
• 
Discontinue drug.2 
• 
Hold drug until Child‐Pugh score 
< 8, then resume at drug.2 
GI bleeding suggestive 
or portal hypertension 
(e.g. esophageal or 
gastric varices) 
• 
Discontinue drug. 
• 
Hold drug until bleeding has 
resolved 
and 
intervention 
completed if indicated (e.g. 
variceal banding) and patient is 
stable, then restart at the same 
dose as long as Child‐Pugh score 
< 
8 
and 
ALT/AST/bilirubin 
elevations are < grade 3. 
1Once dose reduced, cabozantinib dose cannot be increased. Cabozantinib may be held up to 28 days, and 
pembrolizumab may be held up to 12 weeks. 
2Some TKIs may cause hepatic encephalopathy, which is reversible and manageable. Patients with transient 
deterioration to Child Pugh score > 8 due to an ongoing reversible process such as treatable infection or dehydration 
can be reassessed for up to 2 weeks; if liver function improves to Child Pugh 5‐7, consider reintroduction of 
pembrolizumab monotherapy and subsequent reintroduction of cabozantinib 1‐2 weeks later if Child Pugh is 5‐6 
after discussion with study PI. 
 
9.5.4 
Skin toxicity other than PPES 
 
Dose modification of cabozantinib for hand‐foot reaction (or PPES) is covered in Section 9.3.7. Oher skin 
rashes or abnormalities may occur due to cabozantinib. 
 
General management of skin toxicities: 
 
• 
Optimize supportive measures, including topical emollients, oral antihistamines, and medium‐ to 
high potency topical corticosteroids. 
• 
For grade 2 and higher skin toxicity, monitor weekly for improvement. 

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• 
For grade 3 skin toxicity, consider referral to Dermatology. 
• 
If a grade 3 rash does not improve within 7 days after stopping cabozantinib and pembrolizumab 
and providing optimal supportive measures, suspect immune‐mediated skin toxicity. 
• 
See Table 9.5.4.1 for dosing of cabozantinib and pembrolizumab for non‐immune mediated skin 
toxicity. For immune‐mediated skin toxicity, see Table 9.5.5.1. 
 
Table 9.5.4.1. Guidance for non‐immune skin and subcutaneous toxicity other than PPES (e.g. rash, 
erthymatous, follicular, macular, dermatitis, pruritis). 
Grade per 
CTCAE v5 
Cabozantinib modification 
Pembrolizumab modification 
Grade 1 or 2 
• 
Continue at the same dose level. 
• 
Continue at the same dose level. 
Grade 3 
• 
Hold drug until recovery to grade 2 or 
less, then restart at same dose or at 
reduced dose (at the discretion of the 
investigator). 
• 
1st and 2nd recurrence: hold until 
recovery to grade 2 or less, then 
restart at reduced dose level (if not 
already reduced) or discontinue drug 
(if previously reduced dose). 
• 
Hold drug until recovery to grade 1 
(or pretreatment baseline), then 
restart drug. 
Grade 
4 
or 
Steven Johnson 
Syndrome of any 
grade 
• 
Hold drug until recovery to grade 2 or 
less, then restart at reduced dose. 
• 
1st recurrence: discontinue drug. 
• 
Hold drug until recovery to grade 1 
(or pretreatment baseline), then 
restart drug. 
 
 
9.5.5 
Immune‐related toxicities 
 
Immune‐related AEs (irAEs) may occur after the first dose or several months later. Workup should be 
performed to rule out other causes. Most irAEs are reversible when the immune checkpoint inhibitor is 
stopped and steroids and supportive care are initiated. Depending on severity of irAEs, pembrolizumab 
may be resumed after recovery (after completion of steroid taper) or permanently discontinued. 
 
The ASCO Clinical Practice Guidelines on the Management of Immune‐Related Adverse Events in Patients 
Treated with Immune Checkpoint Inhibitor Therapy58 provides a comprehensive overview of potential 
irAEs and management. Whenever possible, it is recommended that these guidelines befollowed. 
 
General management for irAEs: 
 
• 
Consider other causes and ensure adequate workup to rule out other etiology if applicable (e.g. 
infectious, drug‐induced). 
• 
Please see Table 9.5.5.1 for guidance on pembrolizumb dosing for specific irAEs. Whenever pembrolizumab is 
held for an irAE, cabozantinib should also be held. The latter can resumed when the irAE improves to grade 1 
(even if pembrolizumab has not been restarted yet, e.g. during steroid taper). 
. 

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Table 9.5.5.1. Dose modification and toxicity management guidelines for other immune‐related AEs.. 
General instructions: 
1. Even if the AE is not related to cabozantinib, hold cabozantinib whenever pembrolizumab is held for an 
irAE. 
2. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at 
least 4 weeks. 
3. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been 
reduced to Grade 1 and corticosteroid has been tapered. Pembrolizumab should be permanently 
discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be reduced to ≤10 
mg prednisone or equivalent per day within 12 weeks. 
4. For severe and life‐threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other 
immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
5. Cabozantinib may be restarted when the irAE improves to grade 1 at the discretion of the treating 
investigator. Cabozantinib should be restarted within 4 weeks of drug interruption (this may occur during 
steroid taper). If this must be restarted after 4 weeks after interruption for an irAE, please discuss with the 
Study PI. 
Immune‐related 
AEs 
Toxicity grade 
or conditions 
(CTCAEv5.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or 
other therapies 
Monitor and follow‐up 
Pneumonitis 
Grade 2 
Withhold 
• Administer 
corticosteroids 
(initial dose of 1‐2 
mg/kg prednisone or 
equivalent) followed 
by taper 
• 
Monitor participants for signs 
and 
symptoms of pneumonitis 
• 
Evaluate participants with 
suspected pneumonitis with 
radiographic imaging and 
initiate corticosteroid 
treatment 
• 
Add prophylactic antibiotics 
for opportunistic infections 
Grade 3 or 4, 
or recurrent 
Grade 2 
Permanently 
discontinue 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia 
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated 
with evidence 
of β‐cell 
failure 
Withhold 
• 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. 

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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 
discontinue1 
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 
discontinue1 
Hypothyroidism 
Grade 2‐4 
Continue 
• Initiate thyroid 
replacement 
hormones (eg, 
levothyroxine or 
liothyroinine) per 
standard of care 
• 
Monitor for signs and 
symptoms 
of thyroid disorders. 
Nephritis and 
Renal 
dysfunction 
Grade 2 
Withhold 
• Administer 
corticosteroids 
(prednisone 1‐2 
mg/kg or equivalent) 
followed by taper. 
• 
Monitor changes of renal 
function 
Grade 3 or 4 
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
• Based on severity of 
AE administer 
corticosteroids 
• Cabozantinib must 
be held until 
resolved to grade 0. 
• 
Ensure adequate evaluation to 
confirm etiology and/or 
exclude other causes 
Grade 3 or 4 
Permanently 
discontinue 
All other immune‐
related AEs 
Intolerable/ 
persistent 
Grade 2 
Withhold 
• Based on type and 
severity of AE 
administer 
corticosteroids 
• 
Ensure adequate evaluation to 
confirm etiology and/or 
exclude other causes 
Grade 3 
Withhold or 
discontinue 
based on the 
type of event. 
Events that 
require 
discontinuation 
include and not 
limited to: 
Gullain‐Barre 
Syndrome, 
encephalitis 
Grade 4 or 
recurrent 
Grade 3 
Permanently 
discontinue 

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9.5.6 
Pembrolizumab‐related infusion reaction 
Pembrolizumab may cause severe or life‐threatening infusion‐reactions including severe hypersensitivity 
or anaphylaxis. Signs and symptoms usually develop during or shortly after drug infusion and generally 
resolve completely within 24 hours of completion of infusion. Dose modification and toxicity management 
guidelines on pembrolizumab associated infusion reaction are provided in Table 9.5.6.1. No dose 
modification is required for cabozantinib. 
 
Table 9.5.6.1. 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 
Stop Infusion. 
Participant may be 
Requires therapy or 
Additional appropriate medical therapy may 
premedicated 1.5h (± 30 
infusion interruption 
but responds 
promptly to 
symptomatic 
treatment (e.g. 
antihistamines, 
NSAIDs, narcotics, IV 
include but is not limited to: 
• 
IV fluids 
• 
Antihistamines 
• 
NSAIDs 
• 
Acetaminophen 
• 
Narcotics 
minutes) prior to infusion of 
pembrolizumab with: 
Diphenhydramine 50 mg 
PO/IV (or equivalent dose of 
antihistamine). 
Acetaminophen 500‐1000 
mg PO (or equivalent dose 
fluids); prophylactic 
Increase monitoring of vital signs as medically 
of analgesic). 
medications indicated 
indicated until the participant is deemed 
for ≤24 hrs 
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 treatment. 
1. 
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. 
NOTE: 
For participants with Grade 3 or 4 immune‐related endocrinopathy where withhold of pembrolizumab is required, 
pembrolizumab may be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy 
or achieved metabolic control (in case of T1DM). 

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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. 
Participant is permanently discontinued 
from further study drug treatment. 
No subsequent dosing 
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 CTCAEv5 at http://ctep.cancer.gov. 
 
 
9.6 
Adverse events not related to study drugs 
 
If an AE is unrelated to either cabozantinib or pembrolizumab (e.g. symptoms due to disease, concomitant 
medication/procedure, other illness), cabozantinib and pembrolizumab may be continued or held at the 
discretion of the investigator. In general, treatment may be continued if the AE is not treatment‐related 
and not clinically significant, the patient is relatively asymptomatic and stable with good performance 
status, and if treatment will not delay recovery or worsen the AE. If treatment is held for AEs unrelated 
to treatment, cabozantinib and pembrolizumab should be resumed at the same doses as previously 
within 4 weeks. 

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10.0 
STUDY CALENDAR 
 
Table 10.1 summarizes the trial procedures to be conducted at various timepoints. It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the investigator. 
Furthermore, additional evaluations/testing not outlined in this table may be deemed necessary by the 
Principal Investigator for reasons related to participant safety. 
 
Table 10.1. Baseline schedule of activities 
 
1 cycle = 21 days 
Baseline17 
Cycle 1 
Cycle 2+ 
Treatment 
discontinuation 
visit19 
Follow‐ 
up20 
Day 
118 
Day 8 
(± 2 
days) 
Day 15 
(± 2 
days) 
Day 1 
(± 2 days) 
(+ 7 days) 
(± 7 
days) 
TREATMENT 
Cabozantinib1 
X 
X 
X 
X 
Pembrolizumab2 
X 
X 
REQUIRED 
ASSESSMENTS 
Informed 
consent/HIPAA 
X 
Inclusion/exclusion 
criteria3 
X 
Medical and smoking 
history 
X 
Disease 
and 
treatment history 
X 
Vital signs, physical 
exam, ECOG status, 
weight4 
X 
X 
X 
X 
X 
X 
Height5 
X 
AE and medications 
assessment6 
X 
X 
X 
X 
X 
X 
Cabozantinb 
Drug 
Diary Collection7 
X 
X 
X 
CBC and differential8 
X 
X 
X 
X 
X 
Serum chemistry8 
X 
X 
X 
X 
X 
PT/INR, PTT 
X 
X 
X 
X 
Lactate 
dehydrogenase 
X 
Hepatitis C antibody 
(+/‐ HCV RNA)9 
X 
Hepatitis 
B 
core 
antibody10 
X 
Hepatitis B surface 
antigen and/or HBV 
X 
X 
(q2C starting 

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DNA10 
at C3) 
TSH with reflex T411 
X 
X 
(q2C starting 
at C3) 
Cortisol11 
X 
X 
(q2C starting 
at C3) 
Amylase11 
X 
X 
(q2C starting 
at C3) 
Lipase11 
X 
X 
(q2C starting 
at C3) 
Urinary protein to 
creatinine ratio11 
X 
X 
(q2C starting 
at C3) 
EKG11 
X 
X 
(q2C starting 
at C3) 
Esophagoduo‐ 
denoscopy (EGD) 12 
X 
Pregnancy 
test 
(WOCP only) 
X 
Vital status, date of 
progression 
if 
applicable 
X 
X 
DISEASE 
ASSESSMENT 
Alpha fetoprotein13 
X 
X 
(q3C starting 
at C4) 
X 
Radiologic 
imaging 
by CT or MRI14 
X 
X 
(q3C starting 
at C4) 
X 
X 
CORRELATIVE 
STUDIES 
Archival tumor tissue 
for 
research 
purposes if available. 
Otherwise, 
fresh 
biopsy is optional.15 
X 
Blood collection16 
X 
X 
X 
(C2D1 only) 
 
Footnotes 
1Daily continuously starting at Cycle 1 Day 1. See Section 9.0 for dose modifications. 
2Dosed on Day 1 of each 3‐week cycle. See Section 9.0 for dose modifications. 
3See Section 5.0 for inclusion and exclusion criteria. 
4Vital signs include: blood pressure, pulse, respiratory rate, oxygen saturation, temperature. Blood 
pressure and pulse should be taken at rest while sitting. Physical exam should be performed at baseline, 
on Day 1 of each cycle, and at the treatment discontinuation visit. A focused physical exam may be 

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performed if clinically indicated at Cycle 1 Day 8 and 15. 
5Height only needs to be obtained at baseline. 
6AE assessment using CTCAE v5. All TRAEs will be followed until resolution, return to baseline, or deemed 
clinically insignificant by the treating investigator, including those that occur during the 30‐day period 
after treatment discontinuation. In addition, any SAE related to treatment occurring more than 30 days 
after treatment discontinuation will be followed until either resolution, return to baseline, or 
determination by the investigator that the event has become stable or irreversible. 
7A new diary will be distributed on Day 1 of each cycle and collected on Day 1 of the next cycle. See 
Appendix 2 for a template of the Cabozantinib Drug Diary. 
8CBC and differential includes: hemoglobin, hematocrit, leukocyte count, neutrophils (segmented and 
bands), lymphocytes, monocytes, eosinophils, basophils, and platelets. Serum chemistry includes: sodium, 
bicarbonate, potassium, calcium, magnesium, magnesium, phosphate, glucose, albumin, total protein, 
blood urea nitrogen, creatinine, alanine aminotransferase, aspartate aminotransferase, alkaline 
phosphatase, and total bilirubin. In addition to the scheduled labs as indicated in the table, more frequent 
lab monitoring may be initiated by the investigator in the event of AEs. 
9HCV RNA is obtained if hepatitis C virus antibody (HCV Ab) is positive. There is no need to repeat serology 
or RNA during the study. 
10If hepatitis B virus core antibody (HBcAb) and surface antigen (HBsAg) at baseline are negative, no further 
testing is needed. If HBcAb+ and/or HBsAg+, HBV DNA should be obtained at baseline. If a patient is 
HBcAb+ and HBsAg‐ at baseline, HBsAg should be obtained every 2 cycles on study starting at cycle 3 and 
HBV DNA is obtained if HBsAg becomes positive. If a patient is HBcAb+ and HBsAg+, HBV DNA should be 
obtained every 2 cycles on study starting at cycle 3. 
11These tests should be obtained at baseline (within 14 days prior to registration) and repeated every 2 
cycles on study starting at cycle 3. 
12EGD must be done within 6 months prior to study initiation to assess for and treat esophageal and gastric 
varices. 
13Alpha fetoprotein (AFP) should be measured at baseline (within 14 days prior to registration). If 
abnormal at baseline, it should be measured on Day 1 of every 3 cycles starting at cycle 4, and at the 
treatment discontinuation visit. 
14Disease assessment using multiphasic (four‐phase) contrast CT or MRI of abdomen/pelvis, as well as CT 
chest with or without contrast should be done at baseline (within 28 days prior to registration), and every 
9 weeks on treatment (every 3 cycles). If there is disease progression and the patient continues on 
treatment beyond progression, repeat imaging must be performed 4 weeks later to confirm progression. 
As clinically indicated, bone scan and contrast imaging of neck may be obtained to monitor disease (see 
Section 13.3). For the treatment discontinuation visit, the most recent scans are used. For patients who 
come off study for toxicity, subsequent restaging scans will be requested and assessed at least every 4 
months for up to 2 years from study start date to document the date of progression. 
15Archival tumor tissue is acceptable (paraffin‐embedded tumor core biopsy or surgical specimen). If 
archival tissue is not available, baseline core needle biopsy may be performed (if safe and feasible). 
16Pre‐treatment Blood will be collected and stored for correlative studies. Research blood will be collected 
on Cycle 1 Day 1 and Day 8, as well as Cycle 2 Day 1. 
17Informed consent/HIPAA, medical/smoking history, AE/medication assessment, physical exam/ECOG, 
and assessment of inclusion/exclusion criteria are completed within 28 days prior to registration. Baseline 
lab investigations are completed within 14 days prior to registration, including pregnancy test for women 
of child‐bearing potential (WOCP) and AFP. Baseline imaging for disease assessment may be obtained 
within 28 days prior to registration. 
18Cycle 1 day 1 testing need not be repeated if completed within 7 days prior. 
19The treatment discontinuation visit should occur 30 days (+7 days) after the last dose of cabozantinib or 
pembrolizumab (whichever is latest). Most recent scans are used for the treatment discontinuation visit. 
Note: if a participant initiates a new anti‐cancer therapy within 30 days after the last dose of trial 

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treatment, the treatment discontinuation visit must occur before the first dose of the new therapy and 
AEs occurring until that point will be collected. 
20All patients who were treated will be followed for survival every 4 months with phone calls for up to 3 
years from study start date. Patients who came off study for toxicity will be followed for progression with 
visits or by request of outside medical records every 4 months up to 3 years from study start date, where 
progression will be assessed by requesting and obtaining subsequent restaging scans. Subsequent anti‐ 
neoplastic therapy will be collected if available. 
Abbreviations: C, cycle; q2C, every 2 cycles. 
 
11.0 
STUDY ASSESSMENTS 
 
11.1 
Baseline/screening evaluations 
Within 28 days prior to registration: 
• 
Informed consent and HIPAA authorization will be obtained according to ICH/GCPguidelines 
prior to performing any study‐specific procedures. 
• 
Medical and smoking history will be recorded. 
o Medical history must include all active conditions and any condition diagnosed within 
the prior 10 years that are considered to be clinically significant by the investigator. 
Details regarding the disease for which the participant has enrolled in this study will 
be recorded separately and not listed as medical history. 
• 
Disease details and treatments will be recorded. 
o This information will include: BCLC stage at diagnosis and current BCLC stage, and all 
prior cancer treatments (e.g. surgery, ablation, liver‐directed therapy). 
• 
Assessment of vital signs, physical examination, assessment of ECOG status, weight, height, 
baseline AEs and medications. 
o Medication history will include any prior medication use within 28 days before 
starting on study, including indication and any protocol‐related washout 
requirement. Treatment for the disease for which the participant has enrolled in this 
study will be recorded separately and not listed as a prior medication. 
• 
Assessment of eligibility based on inclusion/exclusion criteria by treatment investigator 
(Section 5.0). 
• 
Multiphasic contrast CT or MRI of abdomen/pelvis and CT chest with or without contrast for 
baseline disease assessment, as well as confirmation of measurable disease and at least 1 
appropriate target lesion per RECIST v1.1. As clinically indicated, bone scan and contrast‐ 
imaging of neck may be obtained. 
• 
Archival tissue will be requested if available. If archival tissue is not available, an optional fresh 
core biopsy may be performed (if safe and feasible). 
o For patients who had prior next‐generation gene sequencing analysis of their tumor, 
the gene sequencing assay results will be requested. 
 
Within 14 days prior to registration: 
 
• 
CBC with differential (including hemoglobin, hematocrit, leukocyte count, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, and platelets). 
• 
Serum chemistry (including sodium, bicarbonate, potassium, calcium, magnesium, 
magnesium, phosphate, glucose, albumin, total protein, blood urea nitrogen, creatinine, 
alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and total 
bilirubin). 

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• 
PT/INR and PTT. 
• 
Lactate dehydrogenase (LDH) 
• 
Pregnancy test by serum HCG (for women of child‐bearing potential only). 
• 
Alpha fetoprotein. 
11.2 
On study evaluations 
 
Patients will be monitored for response to therapy (disease assessment, see Section 13.0) every 9 weeks 
(every 3 cycles), and for AEs continuously from the time of consent to 30 days after discontinuation of 
drug. 
 
Cycles 1 Days 1, 8, 15 
 
NOTE: Cycle 1 day 1 testing does not need to be repeated if completed within 7 days prior. 
 
• 
Assessment of vital signs, physical examination, ECOG status, and weight. 
• 
Assessment of AEs and medications. Medication start/stop dates and indication for use during 
the study will be recorded. 
• 
CBC with differential (Days 1 and 15 only) (including hemoglobin, hematocrit, leukocyte count, 
neutrophils, lymphocytes, monocytes, eosinophils, basophils, and platelets). 
• 
Serum chemistry (Days 1 and 15 only) (including sodium, bicarbonate, potassium, calcium, 
magnesium, magnesium, phosphate, glucose, albumin, total protein, blood urea nitrogen, 
creatinine, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and 
total bilirubin). 
• 
PT/INR, PTT(Day 1 only). 
 
Cycles 2+ Day 1 (± 2 days): 
 
• 
Throughout the trial, patients will complete the Cabozantinib Drug Diary (Appendix 2). This 
will be collected on Day 1 of each cycle. 
• 
Assessment of vital signs, physical examination, ECOG status, and weight. 
• 
Assessment of AEs and medications. Medication start/stop dates and indication for use during 
the study will be recorded. 
• 
CBC with differential (including hemoglobin, hematocrit, leukocyte count, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils, and platelets). 
• 
Serum chemistry (including sodium, bicarbonate, potassium, calcium, magnesium, 
magnesium, phosphate, glucose, albumin, total protein, blood urea nitrogen, creatinine, 
alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and total 
bilirubin). 
• 
PT/INR, PTT. 
 
Every 2 cycles starting at Cycle 3 Day 1 (± 2 days): 
 
• 
HBsAg (for patients who are HBcAb+ and HBsAg‐ at baseline), or HBV DNA (for patients who 
are HBcAb+ and HBsAg+ at baseline). If HBsAg becomes positive on study, HBV DNA should 
then be followed. 
• 
TSH with reflex T4, cortisol, amylase, lipase. 
• 
Urinary protein to creatinine ratio. 
• 
EKG. 

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At the end of every 3 cycles (prior to Cycles 4, 7, 10, etc): 
Multiphasic contrast CT or MRI of abdomen/pelvis, as well as CT chest with or without contrast for disease 
assessment as per RECIST v1.1. The same imaging technique should be used throughout the study. If there 
is disease progression and the patient continues treatment beyond progression, repeat imaging must be 
obtained 4 weeks later to confirm PD. As clinically indicated, bone scan and contrast‐imaging of neck may 
be obtained. 
 
Every 3 cycles starting at Cycle 4 Day 1 (± 2 days): 
 
• 
Alpha fetoprotein level (if abnormal at baseline). 
 
11.3 
Assessment of safety parameters at baseline and during study treatment 
 
Laboratory assessments 
 
Blood samples will be collected at the time points specified and analysed in a laboratory facility at the 
local investigational site. In the event of AEs or lab abnormalities, additional tests and/or more frequent 
lab monitoring may be obtained at the discretion of the treating investigator. 
 
Safety laboratory assessment at baseline and on treatment must include at least the following 
parameters. Also see Appendix 3. 
 
At baseline and every cycle 
Complete blood 
count 
Hemoglobin, hematocrit, leukocyte count, neutrophils, lymphocytes, 
monocytes, eosinophils, basophils, platelets 
Serum chemistry 
Sodium, bicarbonate, potassium, calcium, magnesium, magnesium, 
phosphate, glucose, albumin, total protein, blood urea nitrogen, creatinine, 
alanine aminotransferase, aspartate aminotransferase, alkalinephosphatase, 
total bilirubin. Glomerular Filtration Rate (GFR) will be estimated by the 
Cockcroft‐Gault formula using serum creatinine values (see Appendix 7). 
Coagulation 
PT/INR, PTT 
Miscellaneous 
LDH (baseline only) 
At baseline and every 2 cycles 
Hepatitis B virus 
At baseline: HBcAb and HBsAg. 
On study: 
• 
HBsAg (for patients who are HBcAb+ and HBsAg‐ at baseline), or HBV DNA 
(for patients who are HBcAb+ and HBsAg+ at baseline). 
• 
If HBsAg becomes positive on study, HBV DNA should then be followed. 
Monitoring for 
immune toxicity 
TSH with reflex T4, cortisol, amylase, lipase 
Urine protein 
Urinary protein to creatinine ratio 
QTc 
EKG 

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Assessment of other safety parameters 
• 
Physical examination, ECOG performance score 
 
A physical examination will be performed at screening and at the time points specified in the 
Study Calendar. 
 
A full physical exam serves as a clinical tumor assessment and should include cardiopulmonary 
and abdominal examinations and an assessment of the mental and neurological status. 
Wherever possible, the same investigator should perform this examination. 
 
Measurement of height (in cm), body weight (in kg) and body temperature and the evaluation 
of the ECOG performance score will be performed at the time points specified in the Study 
Calendars. 
 
• 
Vital signs 
 
Vital signs include blood pressure and pulse after resting and sitting for at least 5 minutes, 
respiratory rate, oxygen saturation, and temperature. These will be recorded at the screening 
visit and at the time points specified in the Study Calendar. 
 
• 
Demographics and history 
 
Demographics (sex, birth date), information on smoking history, and pre‐existing medical 
conditions will be collected during the screening visit. 
 
Information on the etiology of HCC, including history of HBV, HCV, alcohol abuse, non‐ 
alcoholic steatohepatitis, or other will be collected at the screening visit. Specifically, for 
patients known to have HBV or HCV, details on prior anti‐viral therapy, dates of therapy and 
response will be recorded. 
 
The date of first diagnosis of HCC (month and year are sufficient) and tumor histology if prior 
pathology results are available will be reported in the CRF. Moreover, BCLC stage at initial 
diagnosis and current BCLC stage will be recorded, as well as the current number and 
locations of metastatic sites (liver, lung, lymph nodes, peritoneum, other), presence of 
vascular invasion (specify location). Previous treatments including surgery, catheter‐based 
therapy, and radiotherapy will be documented, including start and end dates (month and 
year are sufficient) and the best response obtained (complete response, partial response, 
stable disease, progressive disease, unknown). 
 
 
11.4 
Evaluations at treatment discontinuation (at 30 days [+ 7 days] following last doseof 
cabozantinib or pembrolizumab) 
 
• 
Collection of the Cabozantinib Drug Diary, if not previously collected. 
• 
Assessment of vital signs, physical examination, ECOG status, and weight. 
• 
Assessment of AEs and medications. Medication start/stop dates and indication for use during 
the study will be recorded. 
• 
CBC with differential. 

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• 
Serum chemistry. 
• 
PT/INR and PTT. 
• 
Alpha fetoprotein. 
• 
Most recent imaging will be used for the treatment discontinuation visit: multiphasic contrast 
CT or MRI of abdomen/pelvis, as well as CT chest with or without contrast. As clinically 
indicated, bone scan and contrast‐imaging of neck may also be obtained. 
 
 
11.5 
Post‐study follow‐up 
 
Subjects will return approximately 30 days after their last dose of cabozantinib or pembrolizumab (i.e. 
treatment discontinuation visit) to complete end‐of‐study assessments (see Section 11.4). Unused study 
drug will be returned by the subject. If a participant initiates a new anti‐cancer therapy within 30 days 
after the last dose of trial treatment, the treatment discontinuation visit must occur before the first dose 
of the new therapy. 
 
All treatment‐related AEs will be followed until resolution, return to baseline, or deemed clinically 
insignificant by the treating investigator, including those that occur during the 30‐day period after 
treatment discontinuation. Moreover, any known SAE attributed to study treatment that occurs more 
than 30 days after treatment discontinuation must be followed until either resolution, return to baseline, 
or determination by the investigator that the event has become stable or irreversible; all concomitant 
medications for these SAEs after 30 days from treatment discontinuation must also be recorded. 
 
For patients who discontinue study treatment due to toxicities or reasons other than progressive disease, 
subsequent imaging, if available, will be requested every 4 months up to 2 years from study start date to 
document time of progression after coming off study. For patients who come off study due to progressive 
disease, patients will be followed for survival every 4 months up to 2 years from study start date (no scans 
will be required). Moreover, subsequent anti‐neoplastic therapy receive after study discontinuation will 
be collected, if available. 
 
12.0 
CRITERIA FOR TREATMENT DISCONTINUATION 
 
Participants may discontinue study intervention at any time for any reason or be dropped 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 if study intervention is 
inappropriate, the study plan is violated, or for administrative and/or other safety reasons. Specific details 
regarding procedures to be performed at study intervention discontinuation are provided in Sections 11.4 
and 11.5. 
 
A patient will be discontinued from study treatment under the following circumstances: 
 
• 
Progressive disease (PD) as per RECIST v1.1 or the subject no longer experiences clinical 
benefit as determined by the investigator (see Section 12.1 for criteria for continuing 
treatment beyond progression). 
• 
Unacceptable toxicities despite supportive therapy and dose reduction/modification. 

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• 
Discontinuation of pembrolizumab for recurrent grade 2 pneumonitis. 
• 
An AE or intercurrent illness/condition or personal circumstance which, in the opinion of the 
investigator, places the participant at unnecessary risk from continued administration of study 
intervention. 
• 
Any progression or recurrence of another malignancy, or any occurrence of another 
malignancy that requires active treatment. 
• 
Constraints of this protocol are detrimental to the patient’s health. 
• 
Necessity for treatment with other anticancer agents or other treatment prohibited by 
protocol. 
• 
TRAE that results in interruption of cabozantinib > 4 weeks and pembrolizumab > 12 weeks, 
unless there is unequivocal evidence that the subject is benefitting. In this situation, a subject 
may be able to restart therapy upon resolution of the toxicity and with agreement of the Study 
PI. 
• 
Patient requests discontinuation. 
• 
Sexually active subjects who refuse to use medically accepted barrier methods of 
contraception (Appendix 8) during the course of the study and for 4 months after 
discontinuation of study treatment. 
• 
Women who become pregnant or are breastfeeding. 
• 
Request by regulatory agencies for termination of treatment of an individual subject or all 
subjects under the protocol. 
• 
Significant noncompliance with the protocol schedule in the opinion of the investigator. 
• 
Discontinuation of pembrolizumab may be considered for participants who have attained a 
confirmed CR and have been treated for at least 8 cycles (at least 24 weeks), receiving at least 
2 further cycles of cabozantinib and pembrolizumab beyond the date when the initial CR was 
declared. 
• 
Completion of 2 years of therapy. 
• 
Participant has any of the following non‐overdose HECIs that are not reversible and 
manageable by therapy (see below). (Note: Temporary hepatic decompensation may occur in 
patients with cirrhosis exposed to TKIs.) 
o ALT >20 × ULN (confirmed within 1 week) 
o Drug‐related total bilirubin >10 x ULN 
o CP score of > 8 points 
o Hepatic encephalopathy 
o Recurrence of a severe or life‐threatening event, or of any of the laboratory 
abnormalities listed above, that are presumed to beimmune‐related 
o Uncontrolled ascites 
• 
Subject is lost to follow‐up. 
 
Patients who come off study should be evaluated at 30 days (+ 7 days) after the last dose of cabozantinib 
or pembrolizumab (whichever is latest). AE assessment and reporting for patients who discontinue study 
treatment are described in Section 16.3.2. Furthermore, subjects who come off study for reasons other 
than PD will be followed for progression, and all patients who come off study will be followed for survival 
every 4 months for up to 2 years from study start date. 

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12.1 
Treatment beyond progression 
Cases of pseudo‐progression have been documented in certain tumor types treated with immune‐ 
oncology agents.60 Patients with initial disease progression on imaging (i.e. PD by RECIST v1.1, iUPD by 
iRECIST, see Section 13.0) may be allowed to continue on study treatment if they meet all of the criteria 
below: 
 
• 
Patient is tolerating treatment. 
o Note: Patients are allowed to continue beyond progression on monotherapy cabozantinib 
(any dose) or pembrolizumab if the other agent was previously discontinued due to 
toxicity. 
• 
Patient is deriving clinical benefit from ongoing treatment as assessed by the investigator. 
• 
Patient continues to meet eligibility criteria. 
• 
Disease progression is asymptomatic and does not pose a risk of a serious complication (e.g. 
progression in vertebral metastasis expected to lead to fracture or cord compression with further 
growth). 
• 
Patient has stable ECOG performance status and is not expected to decline in the nearfuture. 
• 
Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (e.g. radiation to CNS metastases). 
 
Patients who meet the above criteria and continue study treatment beyond progression must sign a 
consent form to do so. 
 
If a patient continues treatment beyond progression, repeat imaging will be obtained at 4 weeks to 
confirm PD (i.e. iCPD by iRECIST). If there is confirmed disease progression, it is generally recommended 
that the study treatment be discontinued. However, if the patient appears to be deriving clinical benefit 
from treatment and is clinically stable, treatment beyond confirmed PD may be continued with permission 
obtained from the PI. If disease appears stable and PD cannot be confirmed on subsequent scans (i.e. 
response remains iUPD), then the patient may continue on study as long as clinically stable. See Section 
13.2 for iRECIST criteria. Table 12.1.1 provides guidance on treatment after radiologic evidence of PD. 
 
Table 12.1.1. Imaging and treatment after first radiologic evidence of progressive disease. 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
First radiologic 
Repeat imaging 
May continue study 
Repeat imaging at 
Discontinue 
evidence of PD 
by RECIST 1.1 
at 4 to 8 weeks 
to confirm PD. 
treatment at the 
Investigator’s 
discretion while 
awaiting 
confirmatory tumor 
imaging by site by 
iRECIST. 
4 to 8 weeks to 
confirm PD per 
Investigator’s 
discretion only. 
treatment 
Repeat tumor 
No additional 
Discontinue 
No additional 
Not applicable 
imaging confirms 
PD (iCPD) by 
iRECIST per 
Investigator 
assessment 
imaging 
required. 
treatment 
(exception is 
possible upon 
consultation with 
imaging required. 

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Principal 
Investigator 
Repeat tumor 
imaging shows 
iUPD by iRECIST 
per Investigator 
assessment 
Repeat imaging 
at 4 to 8 weeks 
to confirm PD. 
May occur at 
next regularly 
scheduled 
imaging visit. 
Continue study 
treatment at the 
Investigator’s 
discretion. 
Repeat imaging at 
4 to 8 weeks to 
confirm PD per 
Investigator’s 
discretion only. 
Discontinue 
treatment 
Repeat tumor 
Continue 
Continue study 
Continue regularly 
May restart study 
imaging shows 
iSD, iPR, or iCR 
by iRECIST per 
Investigator 
assessment. 
regularly 
scheduled 
imaging 
assessments. 
treatment at the 
Investigator’s 
discretion. 
scheduled imaging 
assessments. 
treatment if 
condition has 
improved and/or 
clinically stable 
per Investigator’s 
discretion. Next 
tumor image 
should occur 
according to the 
regular imaging 
schedule. 
iCPD = iRECIST confirmed progressive disease; iCR = iRECIST complete response; iRECIST = modified Response 
Evaluation Criteria in Solid Tumors 1.1 for immune‐based therapeutics; iSD = iRECIST stable disease; iUPD = 
iRECIST unconfirmed progressive disease; PD = progressive disease; RECIST 1.1 = Response Evaluation Criteria in 
Solid Tumors 1.1. 
 
13.0 
GUIDELINES FOR DISEASE EVALUATION 
 
The primary endpoint of this study is ORR by RECIST v.1.1. Secondary endpoints include DCR by RECIST 
v1.1, as well as ORR and DCR by iRECIST. Response criteria will be assessed by a central radiology team 
(OncoRad) at the University of Washington.60,61 
 
 
13.1 
Tumor assessment by RECIST v1.1 (primary endpoint) 
 
13.1.1 Definitions for measurable disease and target lesions 
 
Criteria for target lesions 
 
• 
Lesions that are ≥ 10 mm (long axis) on CT (slice thickness 5 mm or less) or MRI 
• 
Lymph nodes must be ≥ 15 mm (short axis) on CT (slice thickness 5 mm or less) orMRI 
• 
Up to 5 target lesions in total can be reported, and a maximum of 2 lesions per organ 
• 
Target lesions should be the largest and most reproducible lesions on repeatassessments 
• 
Target lesions should be representative of all involved organs 

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Notes: 
− 
The lymphatic system is considered one organ in RECIST v1.1. Therefore, a maximum of 2 
lymph nodes that are classified as target lesions should be reported on the RECIST CRF. 
− 
Lesions that were previously radiated or ablated cannot be target lesions unless there was 
subsequent radiographic progression at those sites. 
 
Criteria for non‐target lesions 
 
• 
Any lesions that don’t meet the criteria for target lesions or are above the reporting limit for 
target lesions 
• 
All other sites of disease that are <10 mm (long axis) on CT or MRI 
• 
Lymph nodes that are ≥10 to <15 mm in the short axis on CT or MRI 
• 
Lesions truly non‐measurable such as ascites, leptomeningeal disease, pleural and pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung 
• 
Lesions that are not suitable for repeat measurement, e.g. abutting other structures or likely 
to coalesce with other lesions 
• 
Multiple non‐target lesions in the same organ should be reported as a single non‐target lesion, 
e.g. multiple liver metastases 
 
Note: The lymphatic system is considered one organ in RECIST v1.1. Therefore, multiple lymph 
nodes that are classified as non‐target lesions should be reported as a single non‐target lesion on 
the RECIST CRF. 
 
Measurable disease 
 
• 
Lesions that can be accurately measured in the longest dimension as ≥10 mm by CT scan, ≥20 
mm by chest X Ray, ≥10mm by caliper on clinical exam. Malignant lymph nodes need to be ≥ 
15 mm (short axis) on CT. 
 
Non‐measurable disease 
 
• 
All other lesions that do not fit the criteria for measurable disease. All definitions are outlined 
in RECIST v1.1 reference.61 
 
13.1.2 Definitions of response 
 
12.1.2.1 
Evaluation of response of target lesions 
 
Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether 
target or non‐target) must have a reduction in short axis to < 10mm). 
 
Partial response (PR): At least a 30% decrease in the sum target lesions, taking as reference the baseline 
sum diameters. 
 
Progressive disease (PD): At least a 20% increase in the sum target lesions, taking as reference the smallest 
sum on study recorded since the treatment started, or the appearance of one or more new lesions. In 

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addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 
5 mm. 
 
Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to quality for PD, 
taking as reference the smallest sum diameters since the treatment started. 
 
12.1.2.2 
Evaluation of response of non‐target lesions 
 
Complete response: Disappearance of all non‐target lesions and normalization of tumor marker level. All 
lymph nodes must be non‐pathological in size (< 10 mm short axis). 
 
Incomplete response/stable disease: Persistence of one or more non‐target lesion(s) and/or maintenance 
of tumor marker level above the normal limits. 
 
Progressive disease: Appearance of 1 or more new lesions and/or unequivocal progression of existing non‐ 
target lesion(s). 
 
13.1.3 Evaluation of overall response 
 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference the smallest measurements recorded since the treatment 
started to determine response and progression). 
 
Target lesions 
Non‐target lesions 
New lesion 
Overall response 
CR 
CR 
No 
CR 
CR 
Non‐CR/Non‐PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non‐PD or not all evaluated 
No 
PR 
SD 
Non‐PD or not all evaluated 
No 
SD 
Not all evaluated 
Non‐PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
Subjects with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be classified as having “symptomatic 
deterioration”. Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. When the 
evaluation of complete response depends on this determination, it is recommended that the residual 
lesion be investigated (fine needle aspirate/biopsy) to confirm the complete response status. 
 
13.1.4 Definitions for response evaluations 
 
First documentation of response: The time between initiation of therapy and first documentation of PR 
or CR. 

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Duration of response: Duration of overall response ‐ the period measured from the time that 
measurement criteria are met for complete or partial response (whichever status is recorded first) until 
the first date that recurrent or progressive disease is objectively documented, taking as reference the 
smallest measurements recorded since treatment started. 
 
Duration of overall complete response: The period measured from the time that measurement criteria 
are met for complete response until the first date that recurrent disease is objectively documented. 
 
Duration of stable disease: The period measured from the time that stable disease is documented until 
the first date that progressive disease is objectively documented. 
 
Time to progression: A measurement from the study enrollment until the criteria for disease progression 
are met (or death occurs), taking as reference the smallest measurements recorded since the therapy 
started. 
 
Overall survival: The overall survival time for each subject is the number of days from the day of first 
treatment to the earlier of (1) death (from any cause) or (2) the last date of subject contact. If the survival 
time does not correspond to the subject's death, then it is treated as censored. 
 
 
13.2 
Tumor assessment by iRECIST (secondary endpoints) 
 
To account for the possible unique pattern of immune‐mediated tumor responses, evaluation by iRECIST 
will also be performed as secondary objectives. Below is a general summary of the iRECIST criteria. Please 
refer to Seymour et al. 2017 for the full iRECIST guidelines.60 Responses assigned under iRECIST are 
designated with the prefix ‘i’ (immune). 
 
13.2.1 Similarities and differences between iRECIST and RECIST v1.1 
 
In iRECIST, the definitions are identical to RECIST v1.1 for the following: 
 
− 
Measurable and non‐measurable disease including nodal disease 
− 
Numbers and sites of target lesions 
− 
Calculation of sum of diameters (SoD) 
− 
CR, PR, SD, duration 
− 
Confirmation of CR or PR (for non‐randomized trials) 
− 
PD for target and non‐target lesions 
 
However, the management of new lesions and determination of progression differ: 
 
− 
For target lesions, the first PD by RECIST v1.1 is iUPD (immune unconfirmed PD). 
− 
iUPD must be confirmed 4‐8 weeks later by imaging. 
o iCPD (immune confirmed PD) is established if there is a further increase in SoD of 
target disease from iUPD of at least 5mm. 
o If there is subsequent iPR, iCR, or iSD (determined by RECIST v1.1 compared to 
baseline), then the iUPD date is ignored and the status is reset. 
o If there is no change detected from iUPD, then the timepoint response remains iUPD 

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− 
Treatment past iUPD is considered only if the patient is clinically stable. 
− 
iUPD can be assigned multiple times as long as iCPD is not confirmed at the nextassessment. 
− 
Assignment of non‐target lesions follows similar rules. 
− 
New target lesions are recorded separately and not included in SoD of target lesions identified 
at baseline; the sum of diameters for the new target lesions is determined. 
o Appearance of new lesions results in iUPD, which requires confirmation at 4‐8 weeks. 
o iCPD is assigned if, on next imaging, additional new lesions appear, there is an 
increase in new lesions (at least 5mm), or appearance of new lesions. 
 
13.2.2 Timepoint response using iRECIST 
 
Target 
lesions 
Non‐target 
lesions 
New 
lesions 
Timepoint 
response with no 
previous iUPD in 
any category1 
Timepoint response with previous 
iUPD in any category 
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 
with 
decrease 
from  last 
timepoint 
iUPD 
with 
no change, 
or decrease 
from 
last 
timepoint 
Yes 
Not applicable 
New lesions confirm iCPD if new 
lesions were previously identified and 
have increased in size (>=5mm in the 
sum of diameters for new lesion target 
or any increase for new lesion non‐ 
target) or number; if no change is seen 
in new lesions (size or number) from 
last timepoint, assignment remains 
iUPD 
iSD, iPR, iCR iUPD 
No 
iUPD 
Remains iUPD unless iCPD is confirmed 
by a further increase in size of non‐ 
target disease (does not need to meet 
RECIST v1.1 criteria for unequivocal 
progression) 
iUPD 
Non‐iCR/ 
non‐iUPD, 
or iCR 
No 
iUPD 
Remains iUPD unless iCPD is confirmed 
by a further increase in SoD >=5mm; 
otherwise, assignment remains iUPD 
iUPD 
iUPD 
No 
iUPD 
Remains iUPD unless iCPD is confirmed 
by a further increase in previously 
identified target lesion iUPD in SoD 
>=5mm or non‐target lesion iUPD 
iUPD 
iUPD 
Yes 
iUPD 
Remains iUPD unless iCPD is confirmed 
by a further increase in previously 
identified target lesion iUPD in SoD 
>=5mm,   previously    identified non‐ 

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target iUPD, or increase in size of 
number of new lesions previously 
identified 
Non‐iUPD 
or 
progression 
Non‐iUPD 
or 
progression 
Yes 
iUPD 
Remains iUPD unless iCPD is confirmed 
by increase in size or number of new 
lesions previously identified 
Adapted from Seymour et al. 2017.60 
1Preivously identified in assessment immediately before this timepoint. 
Target lesions, non‐target lesions, and new lesions defined according to RECIST v1.1. In the absence of 
pseudoprogression, RECIST v1.1 and iRECIST categories for CR, PR, SD would be the same. 
Abbreviations: “I” indicates immune responses assigned using iRECIST; iCR, complete response; iPR, partial response; 
iSD, stable disease; iUPD, unconfirmed progressive disease; non‐iCR/non‐iUPD, criteria for neither CR not PD have 
been met; iCPD, confirmed progressive disease; RECIST, Response Evaluation Criteria in Solid Tumors. 
 
 
13.3 
Methods of measurement 
 
Imaging‐based evaluation is required for assessment of response to study treatment. The same imaging 
modality must be used throughout the study to measure disease. 
 
Imaging: Only CT or MRI are acceptable forms of imaging for response assessment. Conventional CT and 
MRI should be performed with cuts of 5 mm or less in slice thickness contiguously. This applies to tumors 
of the chest, abdomen and pelvis. Head and neck tumors and those of extremities usually require specific 
protocols. All other forms of assessment, including chest x‐ray, ultrasound, PET without diagnostic CT, and 
endoscopy, will not be used for disease measurement. 
 
As per NCCN guidelines for the management of hepatocellular carcinoma, it is recommended that disease 
assessment be performed using multiphasic contrast CT or MRI of abdomen/pelvis, as well as CT chest 
with or without contrast. As clinically indicated, bone scan and contrast‐imaging of neck may be obtained 
to monitor disease. 
(Principles 
of 
Imaging, 
NCCN 
guidelines 
version 
1.2019, 
Hepatocellular 
Carcinoma, 
https://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf) 
 
Alpha fetoprotein (AFP): AFP may be elevated in patients with hepatocellular carcinoma and/or cirrhosis. 
AFP should be obtained at screening for all patients. If abnormal at baseline, it should be obtained on 
Cycle 1 Day 1, and every 3 cycles afterwards until treatmentdiscontinuation. 
 
Cytology and histology: Cytologic confirmation of the neoplastic nature of any effusion that appears or 
worsens during treatment is required when the measurable tumor has met response or stable disease 
criteria. 
 
Clinical examination: Clinically detected lesions will only be considered measurable when they are 
superficial (e.g. skin nodules, palpable lymph nodes). For skin lesions, documentation by color 
photography, including a ruler to estimate size of the lesion, is recommended. Photographs should be 
retained at the institution. 

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14.0 
DRUG INFORMATION 
 
Drug supplies will be labeled in accordance with regulatory requirements. Receipt and dispensing of trial 
medication must be recorded by an authorized person at the trial site. Clinical supplies must be stored in 
a secure, limited‐access location, and may not be used for any purpose other than that stated in the 
protocol. 
 
 
14.1 
Cabozantinib 
 
14.1.1 Composition and formulation 
 
Cabozantinib tablets are supplied by Exelixis as film‐coated tablets containing cabozantinib malate 
equivalent to 20 mg of cabozantinib. They also contain microcrystalline cellulose, lactose anhydrous, 
hydoxypropyl cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate and 
Opadry® yellow. The 20‐mg tablets are round. Doses of 40 mg will comprise two 20‐mg tablets. The 
components of the tablets are listed in Table 14.1.1.1. 
 
Table 14.1.1.1. Cabozantinib tablet components and composition 
Ingredient 
Function 
% w/w1 
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 
1 weight fraction, expressed in percentage; HPMC, hydroxypropyl methylcellulose 
 
 
14.1.2 Storage and handling 
 
Refer to the Pharmacy Manual for full details on storage and handling of cabozantinib. Cabozantinib 
tablets should be stored according to the temperature range listed on the product label and should not 
be crushed or chewed. Patients should store the cabozantinib capsules in the original package provided 
and be instructed to keep all medication out of reach of children. 
 
14.1.3 Administration 
 
Subjects will receive cabozantinib 20 mg oral tablets and will start at a dose of 40 mg once daily. Dosage 
will be adjusted for toxicity (see Section 9.0). 
 
Cabozantinib must be taken on an empty stomach. Subjects must be instructed not to eat for at least 2 
hours before and at least 1 hour after taking cabozantinib. Subjects should be instructed to take their 

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cabozantinib dose at approximately the same time every day. If a subject misses a dose, the dose may be 
taken later only if it is within 12 hours of when the missed dose should have been taken. The missed dose 
should not be made up if it is within 12 hours of the next scheduled dose. 
 
Cabozantinib tablets should be swallowed whole with at least 8 ounces of water. The tablets should not 
be crushed. 
 
14.1.4 Treatment accountability 
 
Patients are required to complete the Cabozantinb Drug Diary and return all drug bottles and unused 
tablets. The number of tablets dispensed and returned will be recorded and reconciled with the diary. 
 
The investigator or designee will maintain accurate records of receipt of all study treatment including 
dates of receipt. In addition, accurate records will be kept regarding the date, lot number, and how much 
study treatment is dispensed and used by each subject in the study. Reasons for deviation from the 
expected dispensing regimen must also be recorded. At completion of the study, to satisfy regulatory 
requirements regarding drug accountability, all unused study treatment will be reconciled and destroyed 
according to applicable state, federal, and local regulations. 
 
 
14.2 
Pembrolizumab 
 
14.2.1 Formulation and preparation 
 
Pembrolizumab is supplied by Merck in solution form for injection at a concentration of 100 mg/4 mL. 
Please refer to the Pharmacy Manual for a comprehensive description of pembrolizumab preparation. 
 
14.2.2 Storage and handling 
 
Pembrolizumab must be stored securely under storage conditions as specified on the drug label and in 
the Pharmacy Manual. 
 
14.3.3 Treatment accountability 
 
The investigator or designee is responsible for keeping accurate records of the clinical supplies of 
pembrolizumab received from Merck, the amount dispensed and returned for each subject, 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 as per institutional policy. It is the responsibility of the investigator or designee 
to arrange for disposal of all empty containers, following the procedures for proper disposal as per 
applicable federal, state, local and institutional guidelines. Records of disposed drug must be kept. 

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15.0 
BIOLOGICAL CORRELATIVE STUDIES 
 
 
15.1 
Tissue collection 
 
Archival tumor tissue will be requested, collected, and stored ambiently if available. If archival tissue is 
not available, an optional fresh tumor biopsy may be performed if safe and feasible. Tissue will be stored 
for future correlative studies in order to assess correlations of biomarkers with efficacy from cabozantinib 
and pembrolizumab in HCC patients. 
 
If applicable, archival tumor tissue will be obtained from paraffin embedded specimens. Two unstained 
slides will be required for correlative studies. For patients undergoing fresh tumor biopsy, 3 cores will be 
obtained to assure at least 50 mm2 of tissue needed for analysis (see below). 
 
In addition, research blood will be collected on Cycle 1 Day 1and Day 8 and Cycle 2 Day 1. 
 
All samples will be coded with the patient number. These samples and any data generated can be linked 
back to the patient only by the study site personnel. Samples will be safely stored at ‐70oC until they are 
assayed. 
 
Samples will be retained at the University of Washington for a maximum of 15 years after the last patient 
visit for the study, or for a shorter period if imposed by the IRB. This retention period enables use of new 
technologies, response to questions from regulatory agencies, and investigation of variable response that 
may not be observed until later in the development cabozantinib and pembrolizumab in HCC. Regardless 
of the technology utilized, data generated will be used only for the specific research scope described in 
this section. The correlative studies will be planned as detailed in sections 15.2‐15.4. 
 
 
15.2 
Immunohistochemistry (IHC) 
 
Archival or fresh tumor tissue will be immunophenotyped by a comprehensive multiplex IHC assay in the 
Immunopathology Core at Fred Hutchinson Cancer Center in order to detect a range of immune cell subsets 
and their distribution in tumor, including CD8+ and CD4+ effector T cells, regulatory T cells, macrophages, 
myeloid derived suppressor cells. 
 
In addition, IHC will also be performed to assess the intratumoral levels of MET and various markers of 
immune checkpoint pathways (e.g. PD‐1/PD‐L1/PD‐L2, CTLA‐4, LAG3, TIM3). The intratumoral immune 
profile will be characterized and correlated with response to treatment. 
 
 
15.3 
RNA sequencing 
 
Archival or fresh tumor tissue will be analyzed by RNA sequencing and gene set enrichment assay to 
explore immune gene expression signatures (e.g. IFN‐g signature, tumor inflammation signature) and 
activated or suppressed cell pathways that might predict response to cabozantinib and pembrolizumab. 
Moreover, the mutational profile and T cell receptor clonality profile of tumors will be assessed. Signatures 
associated with tumor response will be explored. 

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15.4 
Flow cytometry and cytokine assays 
 
Peripheral blood (at baseline, Cycle 1 Day 8, Cycle 2 Day 1) will be analyzed by flow cytometry for immune 
cell subpopulations (e.g. CD8+/CD4+/regulatory T cells, myeloid derived suppressor cells). Furthermore, 
serum at the same timepoints will be assayed by the Luminex® cytokine panel. Changes in immune cell 
subsets and cytokine profiles in response to cabozantinib and pembrolizumab will be assessed and 
correlated with treatment outcomes. 
 
 
 
16.0 
ADVERSE EVENT ASSESSMENT AND REPORTING 
 
The safety of cabozantinib and pembrolizumab will be evaluated and recorded. Specifically, these are the 
safety endpoints of interest: 
 
• 
Type, incidence, and severity grade (as defined by NCI CTCAE v5) of AEs and SAEs, as well as 
relatedness of AEs/SAEs to cabozantinib, pembrolizumab or both; 
• 
AEs/SAEs leading to dose reduction; 
• 
AEs/SAEs leading to permanent treatment discontinuation; 
• 
Causes of death. 
 
16.1 
Definitions 
 
Adverse event (AE): An AE is any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal relationship with this 
treatment. An adverse event can therefore be any unfavorable and unintended sign (e.g. an abnormal 
laboratory finding), symptom, or disease temporarily associated with the use of a medicinal product, 
whether or not considered related to the medicinal product. An adverse event can arise from any use of 
the drug (e.g. off‐label use, use in combination with another drug) and with any route of administration, 
formulation, or dose, including an overdose. This definition also includes AEs associated with medication 
errors and uses of the investigational product outside what is in the protocol, including misuse and abuse. 
Pre‐existing medical conditions that worsen during the study should be recorded as AEs. Abnormal vital 
signs, ECG, physical examination, and laboratory test results will be recorded as AEs if they are CTCAE v5 
grade 3 or above, require clinical intervention, or are otherwise judged clinically relevant by the 
investigator. 
 
Worsening of the underlying disease is not considered an AE; however clinical events associated with 
worsening of disease may be reportable as AEs, including the new onset of or increase in pain. 
 
Serious adverse event (SAE): The SAE definition and reporting requirements are in accordance with the 
International Conference of Harmonisation (ICH) Guideline for Clinical Safety Data Management: 
Definitions and Standards for Expedited Reporting, Topic E2A. 
 
An SAE is defined as any untoward medical occurrence that at any dose: 
 
• 
Results in death; 

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• 
Is life‐threatening (i.e. in the opinion of the investigator, the AE places the subject at risk of death; 
it does not include an event that, had it occurred in a more severe form, might have caused death); 
• 
Requires inpatient hospitalization or results in prolongation of an existing hospitalization; 
o Note: while most hospitalizations necessitate reporting of an SAE, some hospitalizations 
do not require SAE reporting, as follows: 
 
Events that occurred during the screening period after the patient signed the 
consent form but before initiation of study treatment (however, events related 
to screening procedures should be reported as SAEs); 
 
Elective or previously scheduled surgeries or procedures for pre‐existing 
conditions that have not worsened after initiation of treatment (however, SAEs 
must be reported for any surgical complication resulting in unexpected 
prolongation of the hospital admission); 
 
Events that result in hospital stays of fewer than 24 hours and that do not require 
admission (e.g. ER visit with diagnosis of urinary tract infection with discharge 
home on oral antibiotics); 
 
Hospitalizations that are planned for administrative or social reasons during the 
study (e.g. days on which infusion takes place, long distance from home to site) 
will not be recorded as SAEs (however, any event that requires prolongation of a 
planned hospitalization will be recorded as an SAE). 
• 
Results in persistent or significant disability or incapacity: 
o Note: The term “disability” refers to events that result in a substantial disruption of a 
subject’s ability to conduct normal life function. 
• 
Is a congenital anomaly or birth defect; 
• 
Is an important medical event (IME): 
o Note: The term “important medical event” refers to an event that, based upon 
appropriate medical judgment, may not be immediately life‐threatening or result in death 
or hospitalization, but may jeopardize the subject or require intervention to prevent one 
of the other serious outcomes listed. 
o Examples of IMEs: intensive treatment in the ER or at home for allergic bronchospasm; 
blood dyscrasias, or convulsions that do not result in hospitalization; or development of 
product dependency or product abuse. 
• 
Is a new cancer (other than HCC); 
• 
Is associated with an overdose. 
 
Unexpected: An AE that is not listed in the investigator’s brochure describing the risks of the study drug, 
or is not listed at the specificity or severity that has been observed. 
 
Severity of AE: The severity of AEs will be classified according to the NCI CTCAE v5, which describes grades 
of severity from 1 (mild) through 5 (fatal). 
 
 
16.2 
Attribution to study treatment 
 
Assessment of the relationship or relatedness of an AE to study treatment (cabozantinib, pembrolizumab) 
or protocol procedure will be performed by the investigator who is a qualified physician, using the 
respective Investigator’s Brochures as a references. Relevant factors for this determination include 
exposure history, temporal relationship, reaction to de‐challenge or re‐challenge, and confounding factors 
such as concomitant medication, concomitant diseases, and relevant history. 

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The relationship to study treatment or procedure will be described by the following: definite, probable, 
possible, unlikely, or unrelated. For simplification of reporting, AEs may be grouped as: 
 
• 
Not Related (unlikely, unrelated): an AE that is not associated with the study treatment and is 
attributable to another cause or there is no evidence to support a causal relationship; 
 
• 
Related (definite, probable, possible): an AE where a causal relationship between the event and 
the study treatment is a reasonable possibility. A reasonable causal relationship is meant to 
convey that there are facts (e.g. evidence such as de‐challenge/re‐challenge) or other clinical 
arguments to suggest a causal relationship. 
 
Attribution to study drugs for abnormal liver function lab tests should be considered carefully in the 
context of oncology patients. There should be no evidence of biliary obstruction, such as elevated alkaline 
phosphatase, progression of malignancy, or other explanation (viral hepatitis, other hepatotoxicdrugs). 
 
 
16.3 
Parameters of assessment for AEs and SAEs 
 
AEs and SAEs must be assessed by the treating investigator and recorded based on the following 
parameters. 
 
Parameter 
Description 
CTCAE v5 
grade 
Grade 1 
Mild; asymptomatic   or mid symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or non‐invasive intervention indicated; 
limiting age‐appropriate instrumental ADL. 
Grade 3 
Severe or medically significant but not immediately life‐threatening; 
hospitalization or prolongation or hospitalization indicated; disabling; 
limiting self‐care ADL. 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE 
Seriousness 
Does AE meet the definition of an SAE? (see Section 16.1 for definition) 
Duration 
Record the start and stop dates of the adverse event or ongoing. If less than 1 day, 
indicate the length of time. 
Action 
taken 
Did the AE cause each of the study drugs to be: held, dose reduced, discontinued, no 
action taken? 
Relationship 
to study 
drug(s) 
What is the relationship of the AE to each of the study drug: unrelated, unlikely related, 
possibly related, probably related, definitely related? (see Section 16.2) 
Treatment 
required 
Was treatment required for the AE (e.g. antibiotic, supportive medication)? 
Outcome 
Is AE: ongoing, improved, stable, worsened, resolved? 

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16.4 
Monitoring and recording AEs 
 
16.4.1 Responsibility for adverse event monitoring 
 
Investigators (principal investigator, sub‐investigators) and appropriately qualified clinical research staff 
will review participants’ treatment activity, clinical status, and safety information/AEs on an ongoing basis. 
 
16.4.2 Time frame for AE monitoring 
 
AEs will be monitored from the time of informed consent through 30 days following the final dose of 
cabozantinib or pembrolizumab (whichever is lates). AEs with an onset date prior to informed consent will 
be recorded only in the case of worsening of the AE during study participation. All AEs will be followed 
until resolution, return to baseline, or deemed clinically insignificant by the treating investigator, even if 
they occur after treatment discontinuation for up to 30 days (or until the patient starts subsequent 
anticancer therapy, whichever is earliest). 
 
SAEs of any cause will be monitored from the time of informed consent through 30 days and SAEs 
attributed to study procedure or treatment occurring more than 30 days after treatment discontinuation 
must be followed until either resolution, return to baseline, or determination by the investigator that the 
event has become stable or irreversible. 
 
All pregnancies and exposure during breastfeeding will be monitored and reported from the time of 
treatment initiation through 120 days following cessation of study treatment, or 30 days following 
cessation of study treatment if the participant initiates new anticancer therapy must be reported by the 
investigator. If pregnancy or lactation exposure occurs, the site must also contact the subject at least 
monthly and document the participant’s status until the pregnancy has been completed or terminated. 
 
Additionally, any SAE brought to the attention of an investigator at any time outside of the time period 
specified above must be reported immediately by the investigator if the event is considered to be drug‐ 
related. 
 
16.4.3 Laboratory data 
 
All laboratory data required by this protocol and any other clinical investigations should be reviewed. Any 
abnormal value that leads to a change in subject management (e.g. dose reduction or delay or 
requirement for additional medication or monitoring) or that is considered to be of clinical significance by 
the investigator should be reported as an AE or SAE as appropriate. 
 
16.4.4 Recording AEs 
 
All AEs, serious and non‐serious, will be recorded in study‐specific CRF forms. AE terms recorded on the 
CRF will be mapped to preferred terms using the Medical Dictionary for Regulatory Activities (MedDRA). 
For each AE, the investigator will provide the onset date, end date, severity grade (defined by NCI CTCAE 
v5), seriousness, action taken with the study drug(s), treatment required, and outcome (see Section 16.3). 
The list of medications administered for the treatment of the AEs will be recorded. 
 
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. 

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16.5 
Requirements for reporting AEs 
 
16.5.1 SAE reporting 
 
As soon as an investigator becomes aware of an AE that meets the definition of ‘serious,’ this must be 
documented on an SAE Report Form or in an electronic database and include the following: (i) all SAEs 
that occur from the time of informed consent until 30 days after the treatment discontinuation, and (ii) 
all SAEs attributed to study treatment or procedure occurring more than 30 days after treatment 
discontinuation. 
 
These SAEs and their follow‐up must be reported within 24 hours to the Exelixis Drug Safety and Merck 
Global Safety: 
 
• 
Any SAE occurring from the time of consent until treatment initiation if it causes the patient 
to be excluded from the trial, or if is the result of a protocol‐specified intervention, including 
but not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure 
• 
Any SAE occurring on study regardless of causality from the time of consent until 30 days after 
treatment discontinuation 
• 
Any SAE attributed to study treatment or procedure occurring more than 30 days after 
treatment discontinuation 
 
All reportable SAEs must be sent to the following contacts within 24 hours of the PI’s knowledge of the 
event: 
 
• 
Exelixis: reports must be sent to Exelixis Drug Safety, drugsafety@exelixis.com or fax 650‐837‐ 
7392 
• 
Merck: reports must be sent to Merck Global Safety, fax 215‐661‐6229 
 
The PI will perform adequate due diligence with regards to obtaining follow‐up information on incomplete 
reports. All follow‐up information must be sent to Exelixis and Merck within 24 hours of the PI’s receipt of 
the new information. Upon request, queriesmay be issued for follow‐up information. 
 
16.5.2 Reporting of pregnancy and lactation 
 
Any pregnancy or lactation exposure that occurs from the time of treatment initiation through 120 days 
following cessation of treatment, or 30 days following cessation of treatment if the participant initiates 
new anticancer therapy, whichever is earlier, must be immediately reported by the investigator. All 
reported pregnancies must be followed to the completion/termination of the pregnancy, which must also 
be reported when available. 
 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, blighted 
ovum, fetal death, intrauterine death, miscarriage, stillbirth, or other disabling or life‐threatening 
complication to the mother or newborn must be reported as serious events (Important Medical Events). 
If the pregnancy continues to term, the outcome (health of infant) must also be reported. Such events 

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must be reported within 24 hours to Exelixis Drug Safety and Merck Global Safety (see Section 16.4.1 for 
contact information). 
 
If a male participant impregnates his female partner, the Principal Investigator must be informed 
immediately and the pregnancy must be reported as well as described above. 
 
16.5.3 Reporting of pembrolizumab overdose 
 
For purposes of this study, an overdose of pembrolizumab is defined as any dose of 1,000 mg or greater 
(≥5 times the indicated dose). No specific 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 AE is attributed to an overdose of pembrolizumab, it must be reported as an SAE, even if no other 
seriousness criteria are met. 
 
If an overdose of pembrolizumab is taken without any associated clinical symptoms or abnormal 
laboratory results, the overdose is reported as a non‐serious Event of Clinical Interest (ECI), using the 
terminology “accidental or intentional overdose without adverse effect.” 
 
All reports of overdose with and without an AE must be reported within 24 hours to Exelixis and Merck 
(see Section 16.4.1 for contact information). 
 
16.5.4 Events of clinical interest 
 
Selected non‐serious and serious AEs are also known as Events of Clinical Interest (ECI) and must be 
reported within 2 working days to Merck Global Safety (Attn: Worldwide Product Safety; FAX 215‐661‐ 
6229) and Exelixis Drug Safety (drugsafety@exelixis.com or fax 650‐837‐7392). 
 
Any ECI occurring on study regardless of causality from the time of consent until 30 days after treatment 
discontinuation must be reported. 
 
ECIs for this trial include: 
1. Overdose of pembrolizumab that is not associated with clinical symptoms or abnormal laboratory 
results (see Section 16.4.3); 
2. Elevated AST or ALT ≥ 3X ULN and elevated total bilirubin ≥ 2X ULN and, at the same time, ALP < 2X 
ULN. 
• 
Any ECI occurring from the time of consent until treatment initiation if it causes the patient 
to be excluded from the trial, or if is the result of a protocol‐specified intervention, including 
but not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure 
 
16.5.5 Regulatory reporting 
 
The Investigator will assess the expectedness of each related AE. The current cabozantinib Reference 
Safety Information (Appendix K of the most recent approved Investigator Brochure) and the 
pembrolizumab Investigator’s Brochure will be used as the reference documents for assessing the 
expectedness of the event with regards to cabozantinib and pembrolizumab, respectively. 

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• 
Expedited reporting will be conducted in accordance with FHCRC/Cancer Consortium IRB 
policies.Specifically, requirements include reporting unanticipated problems involving risks to 
research participants or others to the FHCRC/Cancer Consortium IRB within 10 calendar days of 
the investigator’s awareness of the problem. AEs that are (1) unexpected, (2) related or possibly 
related to the research, and (3) suggest that the research presents a greater risk of harm than was 
previously known or recognized, are among the unanticipated problems subject to these reporting 
policies. Exelixis and Merck reserve the right to upgrade the Investigator assessment of an SAE. 
• 
Institutions shall promptly provide all information requested by Exelixis and Merck regarding all 
adverse events occurring during the conduct of the study. 
• 
Exelixis and Merck will provide relevant product safety updates and notifications, as necessary. 
 
Any AE that does not meet expedited reporting criteria may be reported at the time of continuing review. 
 
17.0 
STATISTICAL CONSIDERATIONS 
 
17.1 
Sample size calculation 
 
The primary objective of this study is to evaluate the ORR in patients with advanced HCC treated with 
cabozantinib and pembrolizumab. This Phase 2 trial will be based on Simon’s optimal two‐stage design. 
 
The null ORR is assumed to be 20%, which was the ORR (by RECIST v1.1) observed in the sorafenib‐naïve 
group treated with nivolumab in the CheckMate 040 trial.8 Early phase data with lenvatinib and 
pembrolizumab as first‐line treatment showed an ORR of 35% in the expansion phase and an ORR of 42% 
in the overall patient population (DLT evaluation and expansion phase) using mRECIST criteria.38 
Therefore, the null hypothesis that the true ORR is 20% will be tested against a one‐sided alternative that 
the assumed‐true ORR with the tested combination is 38% by RECIST v1.1. The target assumed‐true ORR 
of 38% is believed to adequately represent the potential activity of cabozantinib and pembrolizumab. 
 
Using Simon’s optimal two‐stage design, 13 patients will be accrued in the first stage. If there are 2 or 
fewer patients with response (CR or PR) (an observed rate of 15% or less), the study will be suspended for 
lack of sufficient efficacy. Otherwise, 16 additional patients will be accrued for a total of 29 patients. The 
null hypothesis (of an ORR of 20%) will be rejected if 9 or more patients have a tumor response (CR or PR) 
out of 29 patients (an observed ORR of at least 31%). This design yields a type I error rate of 0.10 and 
power of 80% when the true ORR is 38%. 
 
An accrual period of 24 months and follow‐up period of 12 months are anticipated. More than 29 patients 
may be screened and/or enrolled depending on screen fails or dropouts before starting treatment. 
 
17.2 
Statistical methods 
 
The primary endpoint is ORR per RECIST v1.1, while secondary endpoints include ORR by iRECIST, ORR and 
DCR by iRECIST, median PFS, and median OS. Only patients who have been on treatment with both 
cabozantinib and pembrolizumab concurrently for more than 42 days in the first 3 cycles (i.e. received 
treatment for two‐thirds of the cycle) will be included in the analysis of the primary endpoint. Patients 
who have received any duration of study treatment will be evaluable for safety. 

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Binary endpoints will be summarized by percentages and associated confidence intervals. ORR will also be 
represented by a waterfall plot. The distribution for survival times will be estimated using the method of 
Kaplan‐Meier; associated landmark time percentages and the median value will be based on this. 
Confidence intervals for median values will use the Brookmeyer‐Crowley method. Any toxicity with at least 
5% prevalence has at least an 77% chance of being observed among 29 patients. 
 
For the exploratory objectives, archival or fresh tumors from all patients will be analyzed by IHC, the 
presence of specific immune cell subsets and protein marker expression, as well as the staining pattern 
and location within tumors will be described. The frequencies of immune cell subset will be obtained from 
flow cytometry at various timepoints, and cell changes from baseline to post‐treatment timepoints will be 
averaged across patients. The association between immune cell, biomarker expression, gene expression 
signature, or cytokine level with ORR will be evaluated using Spearman correlation, where p<0.05 is 
considered significant. 
 
18.0 
DATA AND SAFETY MONITORING PLAN 
 
18.1 
Trial monitoring 
 
Institutional support of trial monitoring will be in accordance with the FHCRC/University of Washington 
Cancer Consortium Institutional Data and Safety Monitoring Plan. Under the provisions of this plan, FHCRC 
Clinical Research Support (CRS) coordinates data and compliance monitoring conducted by consultants, 
contract research organizations, or FHCRC employees unaffiliated with the conduct of the study. 
Independent monitoring visits occur at specified intervals determined by the assessed risk level of the 
study and the findings of previous visits per the institutional DSMP. It will be the monitor’s responsibility 
to inspect the CRFs at regular intervals throughout the study to verify both adherence to the protocol and 
the completeness, consistency, and accuracy of the data being entered on them. 
 
In addition, protocols are reviewed at least annually and as needed by the Consortium Data and Safety 
Monitoring Committee (DSMC), FHCRC Scientific Review Committee (SRC), and the FHCRC/University of 
Washington Cancer Consortium Institutional Review Board (IRB). The review committees evaluate accrual, 
adverse events, stopping rules, and adherence to the applicable data and safety monitoring plan for 
studies actively enrolling or treating subjects. The IRB reviews the study progress and safety information 
to assess continued acceptability of the risk‐benefit ratio for human subjects. Approval of committees as 
applicable is necessary to continue the study. 
 
The trial will comply with the standard guidelines set forth by these regulatory committees and other 
institutional, state and federal guidelines. 
 
18.2 
Data and safety review 
Investigators will conduct continuous review of data and patient safety. At least monthly review meetings 
are required and will include: PI, data manager, study coordinator, and other members as per the PI’s 
discretion (e.g. sub‐investigators, nurses). 
 
Review of data and patient safety will be reviewed during these meetings, including: 
 
• 
The number of patients enrolled in the protocol 
• 
Any significant toxicities experienced by patients enrolled 
• 
Dose modifications and responses observed 

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19.0 
STUDY DOCUMENTATION AND RECORD‐KEEPING 
 
19.1 
Investigator’s files and retention of documents 
 
The investigator must maintain adequate and accurate records to enable the conduct of the study to be 
fully documented and the study data to be subsequently verified. These documents should be classified 
into two separate categories as follows: (1) the investigator’s study file, and (2) subjects’ clinical source 
documents. 
 
The investigator’s study file will contain the protocol and protocol amendments, CRFs, query forms, IRB/EC 
and governmental approvals with correspondence, sample informed consent, drug records, staff 
curriculum vitae and authorization forms, any other records required under the Protocol, and other 
appropriate documents and correspondence. 
 
Subjects’ clinical source documents include the subjects’ hospital/clinic records; physicians’ and nurses’ 
notes; original laboratory, ECG, X‐ray, pathology and special assessment reports; signed informed consent 
forms; consultant letters; and subject screening and enrollment logs. 
 
The investigator must keep these two categories of documents on file for at least the latest of (a) 2 years 
following the marketing application approval date for the study treatment in the indication being 
investigated, or (b) 2 years after the investigation is completed or discontinued, or (c) for a period of time 
consistent with local regulatory requirements, whichever is longest. After that period, the documents may 
be destroyed subject to local regulations with prior written permission from Exelixis/Merck. If the 
investigator wants to assign the study records to another party or move them to another location, 
Exelixis/Merck must be notified in advance. 
 
19.2 
Source documents and background data 
 
Upon request, the investigator will supply its licensees and collaborators with any required background 
data from the study documentation or clinic records. This is particularly important when CRFs are illegible 
or when errors in data transcription are suspected. In case of special problems or governmental queries 
or requests for audit inspections, it is also necessary to have access to the complete study records, 
provided that subject confidentiality is protected. 
 
19.3 
Audits and inspections 
 
The investigator should understand that source documents for this study must be made available, after 
appropriate notification, to qualified personnel from the Exelixis or Merck Quality Assurance Unit (or 
designee) or to health authority inspectors. The verification of the CRF data must be by direct inspection 
of source documents. 
 
19.4 
Case report forms 
 
For enrolled subjects, only data from the procedures and assessments required by the CRFs should be 
entered on the appropriate CRF. Other are recorded only on the source documents and will not be 
transcribed to CRFs. Additional procedures and assessments may be performed as part of the 

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investigator’s institution or medical practice standard of care and may not be required for CRF entry. 
 
For each subject enrolled, the CRF (paper or electronic) must be completed and signed by the PI or 
authorized delegate from the study staff. 
 
All paper forms should be typed or filled out using indelible ink and must be legible. Errors should be 
crossed out but not obliterated, the correction inserted, and the change initialed and dated by the 
investigator or his or her authorized delegate. 
 
The investigator should ensure the accuracy, completeness, legibility, and timeliness of the data in the 
CRFs and in all required reports. 
 
20.0 
PROTOCOL MODIFICATIONS 
 
Protocol modifications or amendments must be reviewed and approved by Exelixis and Merck prior to 
implementation. All protocol modifications must be submitted to the IRB/EC for information and approval 
in accordance with local requirements and to regulatory agencies if required. Approval must be obtained 
before any changes can be implemented, except for changes necessary to eliminate an immediate hazard 
to study subjects or those that involve only logistical or administrative aspects of the trial (e.g. change in 
monitor or change of telephone number). 
 
21.0 
TERMINATION OF STUDY 
 
At any time, the study may be terminated prior to completion of planned enrollment and achievement of 
objectives if there is evidence that the study regimen is not tolerable at the lower dose limits stated in the 
protocol, or if interim data analysis demonstrates lack of efficacy of study treatment. In terminating the 
study, the investigator will ensure that adequate consideration is given to the protection of the subjects’ 
interests. 
 
Upon study termination, the investigator shall cease enrolling subjects into the study and shall discontinue 
conduct of the study as soon as is medically practicable. The IRB will be notified about the completion or 
early termination of the trial. 
 
22.0 
ETHICAL ASPECTS 
 
 
22.1 
Local regulations 
 
The study must fully adhere to the principles outlined in ICH Good Clinical Practice (GCP) and local 
regulations on the conduct of clinical research.). 
 
 
22.2 
Institutional review board/ethics committee 
 
This protocol (and any modifications) and appropriate consent procedures must be reviewed and 
approved by an IRB/EC. This board must operate in accordance with current local, regional, and federal 
regulations. The investigator will send a letter or certificate of IRB/EC approval to Exelixis and Merck (or 
designee) before subject enrollment and whenever subsequent modifications to the protocol are made. 

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22.3 
Confidentiality of trial documents and subject regions 
 
The investigator must assure that subjects’ anonymity will be maintained and that their identities are 
protected from unauthorized parties. On CRFs or other documents, subjects should be identified by 
identification codes and not by their names. The investigator should keep a subject enrollment log 
showing codes, names, and addresses. The investigator should maintain documents (e.g. subjects’ written 
consent forms) in strict confidence. 
 
All tumor scans, research samples, photographs, and results from examinations, tests, and procedures 
may be sent to Exelixis and Merck, and its partners or designees for review. 
 
23.0 
PUBLICATION OF DATA 
 
The PI holds the primary responsibility for publication of the study results, provided that the PI will provide 
Exelixis and Merck with a copy of any proposed publication or release: 
 
• 
(a) for abstracts, slide presentations or posters, at least five (5) business day prior to submission 
(in the case of abstracts) or first public presentation (in the case of slide presentations and 
posters); and 
• 
(b) at least thirty (30) days in advance of first submission and each subsequent submission in the 
case of manuscripts and also comply with any provisions regarding publication that are agreed to 
between the University of Washington and Exelixis and Merck in the Clinical Trial Agreement 
related to this study. 
 
 
24.0 
APPENDICES 
 
Appendix 1: Abbreviations and definitions 
 
Abbreviation or 
term 
Definition 
AE 
Adverse event: any untoward medical occurrence in a patient or clinical 
investigation patient administered a pharmaceutical product and that does not 
necessarily have a causal relationship with this treatment. An adverse event can 
therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. 

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ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AUC 
area under the curve 
AST 
aspartate aminotransferase 
BP 
blood pressure 
CBC 
complete blood count 
CI 
confidence interval 
CMV 
Cytomegalovirus 
CR 
complete response 
CRF/eCRF 
case report form/electronic case report form 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DCR 
disease control rate 
DILI 
drug‐induced liver injury 
DNA 
deoxyribonucleic acid 
DSMC 
data and safety monitoring committee 
DVT 
deep venous thrombosis 
EBV 
Epstein‐Barr virus 
eDC: 
Electronic Data Capture. A computer database where clinical trial data are 
entered and validated. 
ECOG 
Eastern Cooperative Oncology Group 
EKG 
electrocardiogram 
Enrollment: 
The act of assigning a patient to a treatment. Patients who are enrolled in the 
trial are those who have been assigned to a treatment. 
Enter: 
Patients entered into a trial are those who sign the informed consent form 
directly. 
ERB/IRB 
ethical review board / institutional review board 
FFPE 
formalin‐fixed, paraffin‐embedded 
GCP 
good clinical practice 
GFR 
glomerular filtration rate 
GLP 
good laboratory practice 
GI 
gastrointestinal 
Hb 
hemoglobin 
HBeAb 
hepatitis B e‐antigen antibody 
HBeAg 
hepatitis B e‐antigen antigen 
HBcAb 
hepatitis B core antibody 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HR 
hazard ratio 
i (prefix) 
immune 
IB 
investigator’s brochure 
ICF 
informed consent form 

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iCPD 
immune confirmed progressive disease 
IHC 
immunohistochemistry 
INR 
international normalized ratio 
Investigational 
product (IP): 
A pharmaceutical form of an active ingredient or placebo being tested or used as 
a reference in a clinical trial, including products already on the market when used 
or assembled (formulated or packaged) in a way different from the authorized 
form, or marketed products used for an unauthorized indication, or marketed 
products used to gain further information about the authorized form. 
irAE 
immune‐related adverse event 
IRB 
institutional review board 
iUPD 
immune unconfirmed progressive disease 
IV 
intravenous 
LMWH 
low molecular weight heparin 
NSAIDS 
non‐steroidal anti‐inflammatory drugs 
MI 
myocardial infarction 
MRI 
magnetic resonance imaging 
OS 
overall survival 
ORR 
objective response rate 
PI 
principal investigator 
PD 
progressive disease 
PD‐1 
programmed cell death 1 
PE 
physical exam 
PET 
positron emission tomography 
PFS 
progression‐free survival 
PK 
pharmacokinetic 
PO 
orally 
PPES 
palmar‐plantar erythrodyesthesia syndrome 
PR 
partial response 
PTT 
partial prothrombin time 
QTc 
corrected QTc interval (QTcF: QTc calculated by Fredericia formula) 
RECIST 
Response Evaluation Criteria In Solid Tumors 
iRECIST 
immune RECIST 
mRECIST 
modified RECIST 
RBC 
red blood cell 
Reporting 
database: 
A point‐in‐time copy of the collection database. The final reporting database is 
used to produce the analyses and output reports for interim or final analyses of 
data. 
Re‐screen: 
To screen a patient who was previously declared a screen failure for the same 
study. 
RPLS 
reversible posterior leukoencephalopathy syndrome 
SAE 
serious adverse event 
Screen: 
The act of determining if an individual meets minimum requirements to become 
part of a pool of potential candidates for participation in a clinical study. 
Screen failure: 
Patient who does not meet one or more criteria required for participation in a 
trial. 
SD 
stable disease 

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TEAE 
treatment‐emergent adverse event 
TIA 
transient ischemic attack 
TRAE 
treatment‐related adverse event 
TSH 
thyroid‐stimulating hormone 
UPCR 
urine protein to creatinine ratio 
ULN 
upper limit of normal 
WBC 
white blood cell 
WOCP 
women of child‐bearing potential 

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Appendix 2. Cabozantinib Drug Diary 
 
Today’s Date: 
_ 
Participant Study ID:    
 
 
Participant Initials:  
 
Cycle Number:   
 
 
INSTRUCTIONS TO THE PARTICIPANT: 
1. Complete one form for each cycle (21 days). 
2. You will take 40 mg of Cabozantinib (2) x (20 mg pills) once a day. Or 20 mg of Cabozantinib if 
dose reduced (1) x (20 mg pill). 
• Cabozantinib must be taken daily on an empty stomach. You must not to eat for at least 2 hours 
before and at least 1 hour after taking Cabozantinib. 
• Take your Cabozantinib dose at approximately the same time every day. 
• Cabozantinib pills should be swallowed whole with at least 8 ounces of water. 
3. Record the date, the number of pills you took, and the time that you took them. 
4. If you have any comments or notice any side effects, please record them in the comments 
column. 
5. Please bring your pill bottle and this form to your physician when you go to your next 
appointment. 
6. Please record missed or skipped doses. Do not share your drug supply. Wash your hands after 
touching the pills. 
• The dose may be taken later only if it is within 12 hours of when the missed dose should have 
been taken. 
• The missed dose should not be made up if it is within 12 hours of the next scheduled dose. 
7. The tablets should not be crushed. Grapefruit, grapefruit juice, Seville oranges, star fruit, 
and their products should be avoided. 
Date 
Day 
DOSE 
Comments 
Number of Pills 
Taken 
Time dose was taken 
1 
2 
3 
4 
5 
6 
7 
8 
9 

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10 

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11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
Participant’s Signature:  
 
Date:   
 
Physician’s office will complete this section: 
Number of tablets dispensed:  
Date of pills dispensed:   
 
Participant’s planned daily dose:   
 
Total number of pills taken  this month:   
 
Has the patient missed any study medication? 
 
Yes 
No 
Comments:  
 
Study Personnel Signature:  
Date:   
 
 
Medical EMERGENCY: 911 (such as chest pain, seizure, sudden shortness of breath, etc.) 
 
 
Research Coordinator:  
/ Weekday Pager Number:   
 
24‐hour EMERGENCY pager: 206‐598‐6190 

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Appendix 3: Clinical laboratory tests 
 
Hematology (at screening and on study) 
Hemoglobin 
Hematocrit 
Leukocytes (WBC) 
Neutrophils (segmented and bands) 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Platelets 
Serum chemistry (at screening and on study) 
Sodium 
Bicarbonate (CO2) 
Potassium 
Calcium 
Magnesium 
Phosphate 
Glucose 
Albumin 
Total protein 
Blood urea nitrogen (BUN) 
Creatinine 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Alkaline phosphatase (ALP) 
Total bilirubin 
Coagulation (at screening and on study) 
International normalized ratio (INR) 
Partial thromboplastin time (PTT) 
HBV/HCV status 
At screening: 
− 
HCV Ab (if positive, obtain HCV RNA) 
− 
HBcAb, HbsAg (if either or both are 
positive, obtain HBV DNA) 
On study: 
− 
HBcAb+ and HBsAg‐ at baseline: 
obtain HBsAg every 2 cycles starting at 
cycle 3 (and HBV DNA if positive) 
− 
HBcAb+ and HBsAg+ at baseline: 
obtain HBV DNA every 2 cycles 
starting at cycle 3 
Other 
immune‐related 
AE 
monitoring 
(at 
screening and every 2 cycles on study starting at 
cycle 3) 
TSH, free T4 and T3 
Cortisol 
Amylase 
Lipase 
Urine protein (at screening and every 2 cycles 
starting at cycle 3) 
Urine protein to creatinine ratio 
Tumor marker (at screening and every 3 cycles 
starting at cycle 4) 
Alpha fetoprotein 
Serum pregnancy test (women of childbearing 
potential only) at screening only 

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Appendix 4: Strong inducers and inhibitors of CYP3A 
 
Cabozantinib is a CYP3A4 substrate and a weak substrate for CYP2C9. 
 
If possible, strong inducers of CYP3A4 (see below) should be avoided and substituted by alternative 
medications at the discretion of the treating physician. If they must be used, the patient must be on a 
stable dose. 
 
Strong inducers of CYP3A: apalutamide, carbamazepine, enzalutamide, fosphenytoin, lumacafotor, 
mitotane, phenobarbital, phenotyoin, primidone 
 
If possible, strong inhibitors of CYP3A4 (see below) should be avoided and substituted by alternative 
medications at the discretion of the treating physician. Grapefruit or grapefruit juice should be avoided. 
 
 
Strong inhibitors of CYP3A: atazanavir, boceprevir, clarithromycin, cobicistat and cobicista containing 
coformulations, darunavir, idelalisib, indinavir, itraconazole, ketoconazole, lopinavir, mifepristone, 
nefazodone, nelfinavir, ombitasvir‐paritaprevir‐ritonavir, ombitasvir‐paritaprevir‐ritonavir plus dasabuvir, 
posaconazole, ritonavir and ritonavir containing coformulations, saquinavir, telaprevir, telithromycin, 
voriconazole. 
 
Please refer to the drug interaction tables at the following websites for lists of substrates, inducers, and 
inhibitors of selected CYP450 isozyme pathways: 
 
Http://medicine.iupui.edu/clinpharm/ddis/table.aspx 
 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLab 
eling/ucm080499.htm). 
 
Appendix 5: ECOG performance status scale 
 
Performance status 
Definition 
0 
Fully active; no performance restrictions. 
1 
Strenuous physical activity restricted; fully ambulatory and able to carry out 
light work. 
2 
Capable of all selfcare but unable to carry out any work activities. Up and 
about >50 percent of waking hours. 
3 
Capable of only limited selfcare; confined to bed or chair >50 percent of 
waking hours. 
4 
Completely disabled; cannot carry out any selfcare; totally confined to bed 
or chair. 
 
Appendix 6: Child‐Pugh score calculation for cirrhosis mortality 
 
 
Parameter 
Point 
1 
2 
3 
Total bilirubin 
<2 mg/dL (<34.2 
umol/L) 
2‐3 mg/dL (34.2‐51.3 
umol/L) 
>3 mg/dL (>51.3 
umol/L) 

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Albumin 
>3.5 g/dL (>35 g/L) 
2.8‐3.5 g/dL (28‐35 g/L) 
<2.8 g/dL (<28 g/L) 
INR 
<1.7 
1.7‐2.2 
>2.2 
Ascites 
Absent 
Easily controlled 
Poorly controlled 
Encephalopathy1 
None 
Grade 1‐2 
Grade 3‐4 
1Encephalopathy grades: 
Grade 0: normal consciousness, personality, neurological examination, electroencephalogram 
Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps waves 
Grade 2: lethargic, time‐disoriented, inappropriate, asterixis, ataxia, slow triphasic waves 
Grade 3: somnolent, stuporous, place‐disoriented, hyperactive reflexes, rigidity, slower waves 
Grade 4: unrousable coma, no personality/behavior, decerebrate, slow 2‐3 cps delta activity 
 
 
Child‐Pugh score 
Class 
1‐year survival (%) 
2‐year survival (%) 
5‐6 
A 
100 
85 
7‐9 
B 
80 
60 
10‐15 
C 
45 
35 
 
Sources: 
Child CG and Turcotte JG. Surgery and portal hypertension. In: The liver and portal hypertension. 
Philadelphia: Saunders 1964:50‐64. 
Pugh et al. Transfection of the oesophagus for bleeding esophageal varices. Br J Surg 1973;60. 
 
Appendix 7: Cockcroft‐Gault equation for determining creatinine clearance (CrCl) 
 
The Cockcroft‐Gault equation is to be used for calculating CrCl from local laboratory results. 
 
For serum creatinine concentration in mg/dL: 
CrCl = 
(140 – age) x (wt) x 0.85 (if female), or x 1.0 (if male) 
(mL/min) 
 
72 x serum creatinine (mg/dL) 
 
For serum creatinine concentration in umol/L: 
CrCl = 
(140 – age) x (wt) x 0.85 (if female), or x 1.0 (if male) 
(mL/min) 
 
0.81 x serum creatinine (umol/L) 
 
Age in years, weight (wt) in kilograms. 
Source: Cockcroft and Gault 1976. 

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Appendix 8: Highly effective methods of contraception 
 
• 
Combined oral contraceptive pill and mini‐pill 
• 
NuvaRing® 
• 
Implantable contraceptives 
• 
injectable contraceptives (such as Depo‐Provera®) 
• 
Intrauterine device (such as Mirena® and ParaGard®) 
• 
Contraceptive patch for women <90 Kg (<198 pounds) 
• 
Bilateral tubal occlusion or hysterectomy with bilateral salpingo‐oophorectomy 
• 
Vasectomy 

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