Clinical trial NCT01908426
Conditions: Hepatocellular Carcinoma
Keywords: cabozantinib XL184 liver cancer hepatocellular carcinoma tyrosine kinase inhibitor MET kinase vascular endothelial growth factor receptor 2 (VEGFR2)
Sponsor: Exelixis
Start date: 2013-09-26; Completion date: 2021-01-12
Enrollment: 707 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the effect of Cabozantinib (XL184) compared with placebo on overall survival in subjects with advanced hepatocellular carcinoma who have received prior sorafenib.

Detailed description:

Arms: arm 1: Cabozantinib (XL184) 60 mg tablet once daily arm 2: Oral cabozantinib-matched placebo tablet once daily
Interventions: intervention 1: Cabozantinib tablets intervention 2: Placebo tablets
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
 
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This document (and all copies thereof) is the property of Exelixis, Inc. and contains valuable trade secrets and 
confidential information, including proprietary technical and business information (hereinafter "Confidential 
Information"). By accepting this document, you agree that the Confidential Information contained herein will not be 
disclosed to others without prior written authorization from Exelixis, Inc. and shall only be used for the purposes 
intended by the document. 
CLINICAL STUDY PROTOCOL 
A Phase 3, Randomized, Double-blind, Controlled Study of 
Cabozantinib (XL184) vs Placebo in Subjects with Hepatocellular 
Carcinoma Who Have Received Prior Sorafenib 
 
PROTOCOL NUMBER: 
XL184–309 
STUDY TREATMENT: 
Cabozantinib vs Placebo 
IND NUMBER: 
118,235 
EudraCT NUMBER: 
2013-001001-91 
SPONSOR: 
Exelixis, Inc. 
210 E. Grand Ave. 
South San Francisco, CA 94080  
MEDICAL MONITOR: 
Anne Borgman MD 
 
DATE FINAL: 
12 March 2013 
DATE AMENDED: 
23 April 2014 
AMENDMENT 1.0 
DATE AMENDED: 
 
12 July 2016 
AMENDMENT 2.0 
 
 
 
 


EXELIXIS-
PROTOCOL TITLE:
PROTOCOL NUMBER:
STUDY TREATMENT:
IND NUMBER:
EudraCT NUMBER:
SPONSOR:
MEDICAL MONITOR:
DATE FINAL:
DATE AMENDED:
DATE AMENDED:
PROTOCOL APPROVAL PAGE
A Phase 3, Randomized, Double-blind, Controlled Study
of Cabozantinib (XLl84) vs Placebo in Subjects with
Hepatocellular Carcinoma'Who Have Received Prior
Sorafenib
xL184-309
Cab ozantinib vs Placebo
118,235
2013-001001-91
Exelixis, Inc.
210F,. Grand Ave.
South San Francisco, CA 94080
Anne Borgman MD
12March2013
23 Apnl20I4
12luly 2016
Approval of
by Sponsor:
Yifah
, PhD
Executive Director, Clinical
search
Gisela Schwab,
President, Product Development and Medical Affairs,
& Chief Medical Officer, Development
lL
2-ÕL
AMENDMENT 1.0
AMENDMENT 2.0
J.[
Date
tz
Zolb
Date
Protocol XLl84-309 Amendment 2.0
Page 2 of 142


 
 
Protocol XL184-309 Amendment 2.0 
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PROTOCOL ACCEPTANCE FORM 
PROTOCOL TITLE:  
A Phase 3, Randomized, Double-blind, Controlled Study 
of Cabozantinib (XL184) vs Placebo in Subjects with 
Hepatocellular Carcinoma Who have Received Prior 
Sorafenib 
PROTOCOL NUMBER: 
XL184–309  
STUDY TREATMENT: 
Cabozantinib vs Placebo 
IND NUMBER: 
118,235 
EudraCT NUMBER: 
2013-001001-91 
SPONSOR: 
Exelixis, Inc. 
210 E. Grand Ave. 
South San Francisco, CA 94080 
MEDICAL MONITOR: 
Anne Borgman, MD 
DATE FINAL: 
12 March 2013 
DATE AMENDED: 
23 April 2014 
AMENDMENT 1.0 
DATE AMENDED: 
12 July 2016 
AMENDMENT 2.0 
 
 
 
By my signature below, I hereby state that I have read, and agree to abide by, the instructions, 
conditions, and restrictions of the protocol or protocol amendment referenced above. 
________________________________________________________________ 
Name of Investigator (print) 
 
________________________________________________________________ 
Name of Investigator (signature) 
 
 
Date 
 


 
 
 
Protocol XL184-309 Amendment 2.0 
Page 4 of 142 
 
PROTOCOL SYNOPSIS 
TITLE 
A Phase 3, Randomized, Double-blind, Controlled Study of Cabozantinib (XL184) vs Placebo in 
Subjects with Hepatocellular Carcinoma Who Have Received Prior Sorafenib 
RATIONALE  
Hepatocellular carcinoma (HCC) is the second highest cause of cancer-related deaths 
globally, behind only lung cancer. HCC is usually resistant to systemic chemotherapy. 
Sorafenib, a small-molecule inhibitor of vascular endothelial growth factor receptor 
(VEGFR) and other protein kinases, has been shown to improve the time to progression 
and overall survival in patients with HCC, who eventually progress and succumb to their 
disease despite treatment (Llovet 2008). At the time of initiation of this study, no drug 
has demonstrated efficacy in patients with inoperable or metastatic HCC that has 
progressed after treatment with sorafenib.  
MET and VEGF signaling have been implicated in tumor neo-angiogenesis, invasion, 
and dissemination, and in osteoblast and osteoclast function, while dysregulation of MET 
and VEGF pathway components has been associated with poor prognosis in multiple 
tumor types. Resistance to VEGF-targeted therapies may arise from the up-regulation of 
alternative pro-angiogenic and pro-invasive signaling pathways, including the MET 
pathway. Consistent with this, combined inhibition of the VEGF receptor (VEGFR) and 
MET results in efficacy enhanced over that achieved via inhibition of either pathway 
alone in some tumor models.  
Cabozantinib is an orally bioavailable tyrosine kinase inhibitor with potent activity 
against MET and VEGFR2, as well as a number of other receptor tyrosine kinases that 
have also been implicated in tumor pathobiology, including RET, KIT, AXL, and FLT3. 
Cabozantinib suppresses MET and VEGFR2 signaling, rapidly inducing apoptosis of 
endothelial and tumor cells, resulting in tumor regression in a variety of xenograft 
models. Cabozantinib prolonged survival in a MET-driven transgenic mouse model of 
HCC. In clinical studies, cabozantinib has demonstrated promising activity in multiple 
tumor types and in 2012 was approved by the US FDA for the treatment of progressive 
metastatic medullary thyroid cancer.  
A cohort of 41 subjects with HCC was enrolled in a Phase 2 randomized discontinuation 
study evaluating cabozantinib (Study XL184-203). The majority of subjects (78%) had 
received prior systemic therapy for the disease; over half (54%) had received prior 
sorafenib. Extrahepatic spread was present in 73% of subjects, consistent with a relatively 
poor prognosis. Within the first 12 weeks, 2 subjects had a confirmed partial response 
(PR) and 31 subjects had stable disease; the Week 12 disease control rate (PR plus stable 
disease) was 66%. Tumor regression appeared independent of prior sorafenib exposure.  


 
 
 
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The median OS for all treated subjects (n=41) from the initial cabozantinib dose as 
estimated by the Kaplan-Meier method was 11.5 months (95% CI: 7.3, 15.6) (data on 
file). The safety profile was similar to that of other tyrosine kinase inhibitors such as 
sorafenib, with manageable adverse events (AEs) during treatment.  
OBJECTIVES AND ENDPOINTS 
The objective of this study is to evaluate the effect of cabozantinib compared with 
placebo on overall survival in subjects with advanced HCC previously treated with 
sorafenib.  
Primary endpoint:   
• 
Overall survival (OS) 
Secondary endpoints:   
• 
Objective response rate (ORR) per RECIST 1.1 
• 
Progression-free survival (PFS) per RECIST 1.1 
Additional endpoints: 
• 
Safety and tolerability  
• 
Pharmacokinetics (PK) 
• 
Relationship of baseline and changes in biomarkers with treatment and/or clinical 
outcome  
• 
Health-related quality of life (HRQOL) as assessed by the EuroQol Health 
questionnaire instrument (EQ-5D-5L)  
STUDY DESIGN 
This is a Phase 3 multicenter, randomized, double-blinded, controlled trial of 
cabozantinib vs placebo, both with best supportive care. OS is the primary efficacy 
endpoint. Approximately 760 eligible subjects will be randomized in a 2:1 ratio to receive 
either cabozantinib or placebo.  
Subjects’ course of treatment will consist of the following periods: 
Pretreatment Period: Potential subjects will be screened to determine if they meet the 
required eligibility criteria. Qualifying screening assessments must be performed within 
28 days before randomization unless otherwise specified. 
Treatment Period: Subjects who meet all study eligibility criteria will be randomly 
assigned in a 2:1 ratio to the following treatment arms:  
• 
Cabozantinib arm: Oral cabozantinib (60 mg) qd  
• 
Placebo arm: Oral cabozantinib-matched placebo qd  
Randomization will be stratified by: 
• 
etiology of disease (HBV [with or without HCV], HCV [without HBV], or Other),  
• 
geographic region (Asia, Other Regions) 


 
 
 
Protocol XL184-309 Amendment 2.0 
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• 
the presence of extrahepatic spread of disease and/or macrovascular invasion 
(Yes, No).  
Subjects will receive study treatment as long as they continue to experience clinical 
benefit in the opinion of the investigator or until there is unacceptable toxicity or the need 
for subsequent systemic anticancer treatment or liver directed local anti-cancer therapy. 
Treatment may continue in this fashion after radiographic progression as long as the 
investigator believes that the subject is still receiving clinical benefit from study 
treatment and that the potential benefit of continuing study treatment outweighs potential 
risk.  
Subjects on both arms will be treated with best supportive care. This excludes systemic 
anti-cancer therapy and liver-directed local anti-cancer therapy. 
Crossover between treatment arms will not be allowed unless the study transitions to the 
Open-Label Phase (see Section 5.3 and Appendix B). 
Open-Label Phase: The Open-Label Phase will only be implemented upon decision by 
the Sponsor and discussion with regulatory authorities following review of the data. 
The study may transition to an Open-Label Phase if one of the planned analyses shows 
statistically-significant and clinically-meaningful evidence of improved OS. If the 
decision is made to enter the Open-Label Phase, study treatment will be unblinded and:  
• Subjects randomized to the placebo arm will have the option to crossover to 
receive treatment with cabozantinib if they meet the eligibility criteria for 
crossover to cabozantinib after treatment with placebo.   
• Subjects randomized to the cabozantinib arm who are still receiving study 
treatment, and subjects randomized to the placebo arm who are still receiving 
study treatment and do not crossover to cabozantinib, may continue on unblinded 
study treatment until a criterion for protocol-defined discontinuation has been 
met.  
• Subjects randomized to the cabozantinib arm who are in the post-treatment 
period, and subjects randomized to the placebo arm who do not crossover to 
cabozantinib and are in the post-treatment period, will continue with post-
treatment assessments as outlined in Table 12 of Appendix B. 
If the study transitions to the Open-Label Phase, enrollment will be discontinued. 
In the Open-Label Phase safety assessments will continue, efficacy and AFP assessments 
will be per standard of care; PK, biomarker, HRQOL, and health care resource utilization 
assessments will be discontinued. 
See Section 5.3 and Appendix B for more details. 
Maintenance Phase: When sufficient data have been collected to adequately evaluate all 
study endpoints, and upon site notification by the Sponsor, subjects remaining on study 
treatment will enter the study Maintenance Phase. Upon initiation of the Maintenance 


 
 
 
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Phase, the Sponsor considers the safety and efficacy profile of the drug within this study 
to have been sufficiently established for regulatory purposes. 
In the Maintenance Phase subjects will continue to receive study treatment until a 
criterion for protocol-defined discontinuation has been met (protocol Section 3.6.1). 
Subjects are to undergo periodic safety assessments (including local laboratory tests) and 
tumor assessments; the nature and frequency of these assessments are to be performed 
per standard of care. It is the Investigator’s responsibility to ensure that subject visits 
occur frequently enough and adequate assessments are performed to ensure subject 
safety. 
See Section 5.4 and Appendix C for more details.  
Post-Treatment Period:  The final safety assessment will occur at the post-treatment 
follow-up visit 30 (+14) days after the date of the decision to discontinue treatment) 
unless a Grade 3/4 AE or an SAE is determined to be ongoing. 
Radiographic tumor assessments and EQ-5D-5L assessments will continue on the 
protocol-defined schedule, regardless of whether study treatment is given, reduced, 
interrupted, or discontinued until the later of 8 weeks after radiographic progression per 
RECIST 1.1 as determined by the investigator or the date of the decision to permanently 
discontinue study treatment.  
Subjects will additionally be contacted approximately every 8 weeks after the post-
treatment follow-up visit to assess survival status and to document receipt of subsequent 
anticancer therapy. Every effort must be made to collect these protocol-specific 
evaluations unless consent to participate in the study is withdrawn.  
Assessments in the Post-Treatment period for subjects who discontinue study treatment 
in the Open-Label Phase are provided in Appendix B. 
Assessments in the Post-Treatment Period (including the post-treatment follow-up visit) 
are not required for subjects who discontinue study treatment in the Maintenance Phase 
(such subjects are to be followed per standard of care). Please see Appendix C. 
 
NUMBER OF SUBJECTS 
Approximately 760 eligible subjects will be randomized into the study at up to 200 global 
sites.  
All attempts will be made to ensure that approximately 50% of enrolled subjects are from 
Europe, North America, and Australia and that approximately 20% of enrolled subjects 
are from Asia. 


 
 
 
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TARGET POPULATION  
This study will enroll subjects with advanced HCC. Eligibility criteria for all subjects are 
below (eligibility criteria for subjects in the placebo arm who opt to crossover to receive 
cabozantinib if the study transitions to Open-Label Phase are in Appendix B): 
Inclusion Criteria 
 
1. Histological or cytological diagnosis of HCC (results of a previous biopsy will be 
accepted) 
2. The subject has disease that is not amenable to a curative treatment approach 
(eg, transplant, surgery, radiofrequency ablation)  
3. Received prior sorafenib  
4. Progression following at least 1 prior systemic treatment for HCC  
5. Recovery to ≤ Grade 1 from toxicities related to any prior treatments, unless the 
adverse events are clinically nonsignificant and/or stable on supportive therapy 
6. Age ≥ 18 years old on the day of consent 
7. ECOG performance status of 0 or 1 
8. Adequate hematologic function, based upon meeting the following laboratory criteria 
within 7 days before randomization: 
a. absolute neutrophil count (ANC) ≥ 1200/mm3 (≥ 1.2 x 109/L) 
b. platelets ≥ 60,000/mm3 (≥ 60 x 109/L) 
c. hemoglobin ≥ 8 g/dL (≥ 80 g/L) 
9. Adequate renal function, based upon meeting the following laboratory criteria within 
7 days before randomization: 
a. serum creatinine ≤ 1.5 × upper limit of normal or calculated creatinine clearance 
≥ 40 mL/min (using the Cockroft-Gault equation: (140 – age) x weight 
(kg)/(serum creatinine × 72 [mg/dL]) for males. (For females multiply by 0.85).  
AND 
b. urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.1 mg/mmol) or 24-hour 
urine protein < 1g   
10. Child-Pugh Score of A 
11. Total bilirubin ≤ 2 mg/dL (≤ 34.2 µmol/L) within 7 days before randomization 
12. Serum albumin ≥ 2.8 g/dL (≥ 28 g/L) within 7 days before randomization 
13. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)  < 5.0 upper 
limit of normal (ULN) within 7 days before randomization 


 
 
 
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14. Hemoglobin A1c (HbA1c) ≤ 8% within 28 days before randomization (if HbA1c 
results are unavailable [eg, hemoglobin variant], a fasting serum glucose 
≤ 160 mg/dL) 
15. Antiviral therapy per local standard of care if active hepatitis B (HBV) infection 
16. Capable of understanding and complying with the protocol requirements and signed 
informed consent   
17. Sexually active fertile subjects and their partners must agree to use medically 
accepted methods of contraception (eg, barrier methods, including male condom, 
female condom, or diaphragm with spermicidal gel) during the course of the study 
and for 4 months after the last dose of study treatment 
18. Female subjects of childbearing potential must not be pregnant at screening. Females 
of childbearing potential are defined as premenopausal females capable of becoming 
pregnant (ie, females who have had any evidence of menses in the past 12 months, 
with the exception of those who had prior hysterectomy). However, women who have 
been amenorrheic for 12 or more months are still considered to be of childbearing 
potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, 
ovarian suppression, low body weight, or other reasons. 
Exclusion Criteria 
1. Fibrolamellar carcinoma or mixed hepatocellular cholangiocarcinoma 
2. Receipt of more than 2 prior systemic therapies for advanced HCC. Additional prior 
systemic therapies used as adjuvant or local therapy are allowed. 
3. Any type of anticancer agent (including investigational) within 2 weeks before 
randomization 
4. Radiation therapy within 4 weeks (2 weeks for radiation for bone metastases) or 
radionuclide treatment (eg, I-131 or Y-90) within 6 weeks of randomization. Subject 
is excluded if there are any clinically relevant ongoing complications from prior 
radiation therapy. 
5. Prior cabozantinib treatment 
6. Known brain metastases or cranial epidural disease unless adequately treated with 
radiotherapy and/or surgery (including radiosurgery) and stable for at least 3 months 
before randomization. Eligible subjects must be without corticosteroid treatment at 
the time of randomization.  
7. Concomitant anticoagulation, at therapeutic doses, with anticoagulants such as 
warfarin or warfarin-related agents, low molecular weight heparin (LMWH), 
thrombin or coagulation factor X (FXa) inhibitors, or antiplatelet agents (eg, 
clopidogrel). Low-dose aspirin for cardioprotection (per local applicable guidelines), 
low-dose warfarin (≤ 1 mg/day), and low-dose LMWH are permitted.  
8. The subject has uncontrolled, significant intercurrent or recent illness including, but 
not limited to, the following conditions: 


 
 
 
Protocol XL184-309 Amendment 2.0 
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a. Cardiovascular disorders including 
i. Symptomatic congestive heart failure, unstable angina pectoris, or serious 
cardiac arrhythmias  
ii. Uncontrolled hypertension defined as sustained BP > 150 mm Hg systolic, 
or > 100 mm Hg diastolic despite optimal antihypertensive treatment 
iii. Stroke (including TIA), myocardial infarction, or other ischemic event 
within 6 months before randomization 
iv. Thromboembolic event within 3 months before randomization. Subjects 
with thromboses of portal/hepatic vasculature attributed to underlying 
liver disease and/or liver tumor are eligible 
b. Gastrointestinal (GI) disorders including those associated with a high risk of 
perforation or fistula formation: 
i. Tumors invading the GI tract, active peptic ulcer disease, inflammatory 
bowel disease (eg, Crohn’s disease), diverticulitis, cholecystitis, 
symptomatic cholangitis or appendicitis, acute pancreatitis or acute 
obstruction of the pancreatic duct or common bile duct, or gastric outlet 
obstruction 
ii. Abdominal fistula, GI perforation, bowel obstruction, intra-abdominal 
abscess within 6 months before  randomization,  
Note: Complete healing of an intra-abdominal abscess must be confirmed 
prior to randomization 
c. Major surgery within 2 months before randomization. Complete healing from 
major surgery must have occurred 1 month before randomization. Complete 
healing from minor surgery (eg, simple excision, tooth extraction) must have 
occurred at least 7 days before randomization. Subjects with clinically relevant 
complications from prior surgery are not eligible 
d. Cavitating pulmonary lesion(s) or endobronchial disease  
e. Lesion invading a major blood vessel including, but not limited to: inferior vena 
cava, pulmonary artery, or aorta. Subjects with lesions invading the portal 
vasculature are eligible. 
f. Clinically significant bleeding risk including the following within 3 months of 
randomization: hematuria, hematemesis, hemoptysis of >0.5 teaspoon (>2.5 mL) 
of red blood, or other signs indicative of pulmonary hemorrhage, or history of 
other significant bleeding if not due to reversible external factors 
g. Other clinically significant disorders such as:  
i. Active infection requiring systemic treatment, known infection with 
human immunodeficiency virus (HIV), or known acquired 
immunodeficiency syndrome (AIDS)-related illness.  Subjects with active 
hepatitis virus infection controlled with antiviral therapy are eligible. 
ii. Serious non-healing wound/ulcer/bone fracture 
iii. Malabsorption syndrome 
iv. Uncompensated/symptomatic hypothyroidism 
v. Requirement for hemodialysis or peritoneal dialysis 
vi. History of solid organ transplantation   


 
 
 
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9. Subjects with untreated or incompletely treated varices with bleeding or high risk for 
bleeding.  Subjects treated with adequate endoscopic therapy (according to 
institutional standards) without any episodes of recurrent GI bleeding requiring 
transfusion or hospitalization for at least 6 months prior to study entry are eligible. 
10. Moderate or severe ascites  
11. Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms within 
7 days before randomization 
Note: If the QTcF is > 500 ms in first ECG, a total of 3 ECGs should be performed. If 
the average of these 3 consecutive results for QTcF is ≤ 500 ms, the subject meets 
eligibility in this regard. 
12. Inability to swallow tablets  
13. Previously identified allergy or hypersensitivity to components of the study treatment 
formulations 
14. Pregnant or lactating females  
15. Diagnosis of another malignancy within 2 years before randomization, except for 
superficial skin cancers, or localized, low-grade tumors deemed cured and not treated 
with systemic therapy 
 
ESTIMATED STUDY DATES and LENGTH OF SUBJECT PARTICIPATION 
It is estimated that 25 months will be required to randomize approximately 760 subjects. 
The number of events required for the primary analyses of OS is expected to be observed 
approximately 38 months after the first subject is randomized.  
It is estimated that subjects will participate for an average of 3 to 5 months on study 
treatment. Subjects will be followed until death, withdrawal of consent from the study, or 
Sponsor decision to no longer collect these data.  
INVESTIGATIONAL REGIMEN DOSE/ ROUTE/ DURATION 
Subjects will take blinded study medication (tablets containing 60 mg of cabozantinib or 
placebo equivalent) once daily orally at bedtime. Required dose reductions will be in 
decrements of 20 mg cabozantinib or placebo equivalent. Subjects will continue blinded 
study treatment as long as they continue to experience clinical benefit in the opinion of 
the investigator or until unacceptable toxicity, the need for subsequent systemic 
anticancer therapy or liver-directed local anticancer therapy, or other reasons for 
treatment discontinuation.  
If the study transitions to the Open-Label Phase subjects will have the option to receive 
unblinded study drug. 


 
 
 
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COMPARATOR DRUG 
Placebo tablets that match cabozantinib tablets   
TUMOR ASSESSMENTS 
Radiographic tumor assessments at screening will include CT or MRI of the chest, 
abdomen, and pelvis (CAP) and a technetium bone scan. If MRI is used for the CAP 
evaluation a noncontrast CT chest must be obtained unless prohibited by local 
regulations. The same imaging modalities used at screening will be used for subsequent 
tumor assessments.  
CT/MRI assessments will be made at screening, 8 weeks after randomization, and every 
8 weeks thereafter. Disease status will be determined at the local site (ie. Investigator 
and/or radiologist) using RECIST version 1.1.  
CT/MRI of the chest/abdomen/pelvis should include a noncontrast study of at least the 
liver followed by contrast with triphasic CT imaging of the liver or liver MRI with 
gadolinium enhanced imaging. CT/MRI of the brain will be acquired at screening as 
clinically indicated (suspicion of brain metastasis). CT/MRI of the brain will be 
continued post-baseline only in subjects with documented brain metastases or as 
clinically indicated (suspicion of brain metastasis on study). MRI is the preferred method 
for brain imaging. 
Whole body technetium bone scans will be performed within local standard of care 
guidelines and results provided in original DICOM format. All subjects will have a bone 
scan at screening. Follow up scans will be performed at 8 and 16 weeks after 
randomization, and then every 16 weeks for subjects with documented bone lesions at 
screening or as clinically indicated (suspicion of bone metastasis on study).  
Radiographic assessments will continue on these schedules irrespective of whether study 
treatment is given, reduced, interrupted, or discontinued, until the later of 8 weeks after 
radiographic disease progression per RECIST 1.1 as determined by the investigator or the 
date of the decision to permanently discontinue study treatment (Appendix A). Detailed 
instructions for tumor imaging will be provided in a separate manual. 
A blood sample for alpha-fetoprotein (AFP) assessment will be obtained by central 
laboratory every 8 weeks to correlate with each radiographic disease assessment visit. 
If the study transitions to the Open-Label Phase or to the Maintenance Phase, tumor 
assessments will be done per standard of care; AFP will no longer be collected and 
analyzed by the central laboratory. AFP assessments may continue via local laboratory 
per standard of care. 
 
SAFETY ASSESSMENTS 
Adverse event (AE) seriousness, severity grade, and relationship to study treatment will 
be assessed by the investigator. Severity grade will be defined by the National Cancer 


 
 
 
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Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. 
The Exelixis Safety Committee and an Independent Data Monitoring Committee (IDMC) 
will be established to monitor the safety of the study on a regular basis. The membership 
and decision process of the IDMC is independent of the Sponsor and the clinical 
investigators.  
Subjects will undergo clinic visits every 2 weeks through Week 9 Day 1, and every 
4 weeks thereafter. A post-treatment follow-up visit will be performed between 30 (+14) 
days after the date of the decision to discontinue study treatment. Clinical safety 
assessments include physical examination, ECOG score, vital signs, 12-lead ECG, 
hematology, serum chemistries, coagulation panel, urinalysis, UPCR, and thyroid 
function panel. Subjects will be queried on AEs experienced during the study through 
30 days after the decision to discontinue study treatment.  
PHARMACOKINETICS (PK) 
Blood samples will be taken from all subjects according to the schedule in Appendix A in 
order to measure plasma concentration of cabozantinib and possible relevant metabolites. 
Results will be used to confirm exposure to cabozantinib and to further characterize the 
population PK models of cabozantinib and possible metabolite(s) in this population.  
If the study transitions to the Open-Label Phase or to the Maintenance Phase, 
PK assessments will no longer be collected. 
PHARMACOGENETICS 
Unless prohibited by local regulations, failure to grant informed consent for this purpose, 
or sponsor decision, a blood sample will be collected pre-dose on Day 1 of Week 1 for 
genotyping/single nucleotide polymorphism/copy number variation analysis to correlate 
genetic variation with PK, safety, tolerability of and response to study treatment.  
BIOMARKERS 
Assessment of biomarkers in plasma by multiplexed array will be performed. Serum bone 
biomarkers will also be assessed. In addition, circulating tumor cells (CTCs) may be 
analyzed in blood samples collected at selected sites. Samples for these assessments will 
be collected according to the schedule in Appendix A. 
In addition, tumor tissue (archival or recently biopsied) will be obtained at enrollment 
whenever available for exploratory analysis of MET and potentially other pathway 
components or modulators associated with the mechanism of action of cabozantinib, as 
predictive biomarkers. 
Collection of these samples may be halted early or sampling frequency may be reduced at 
the discretion of the Sponsor. If the study transitions to the Open-Label Phase or to the 
Maintenance Phase, biomarkers will no longer be collected. 


 
 
 
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HEALTH-RELATED QUALITY OF LIFE (HRQOL) 
Subjects will be requested to complete the EQ-5D-5L assessment at baseline (Week 1 
Day 1; day of first dose) and every 4 weeks through Week 25, then every 8 weeks until 
the later of 8 weeks after radiographic progression per RECIST 1.1 as determined by the 
investigator or the date of the decision to permanently discontinue study treatment 
(Appendix A). Assessments will continue on this schedule irrespective of whether study 
treatment is given, reduced, interrupted, or discontinued. 
If the study transitions to the Open-Label Phase or to the Maintenance Phase, 
HRQOL assessments will no longer be collected. 
STATISTICAL METHODS 
The primary efficacy analysis in this study is the comparison of overall survival (OS) in 
subjects treated with cabozantinib versus placebo. 
For the primary endpoint, OS is defined as the time from randomization to death due to 
any cause. The final analysis of OS is event-driven and will be conducted after at least 
621 deaths have been observed.  
Progression-free survival (PFS) and objective response rate (ORR) are the secondary 
endpoints. PFS is defined as the time from randomization to the earlier of either disease 
progression per RECIST 1.1 as determined by the investigator or death from any cause. 
ORR is defined as the proportion of subjects experiencing a confirmed complete response 
(CR) or confirmed partial response (PR) per RECIST 1.1. Inflation of Type I error 
associated with testing multiple endpoints will be controlled by employing a fixed-
sequence testing procedure and a modified Bonferroni procedure (dividing the alpha 
between the secondary endpoints: 0.04 for PFS, and 0.01 for ORR). The testing of the 
secondary endpoints (PFS and ORR) will occur only if the result of either an interim 
analysis or the final analysis of OS achieves statistical significance.  
Up to three event-driven analyses of OS are planned:  two interim analyses and a final 
analysis when 311, 466 and 621 deaths (ie, 50%, 75% and 100% information) have been 
observed respectively. Inflation of Type I error associated with interim analyses will be 
controlled using a Lan-DeMets O’Brien-Fleming alpha-spending function. Interim 
analysis of PFS and ORR are not planned. 
OS and PFS will be summarized descriptively using the Kaplan-Meier method. 
Inferential comparisons between treatment arms will use the stratified log-rank test. The 
hazard ratio (HR) will be estimated using a stratified Cox proportional hazards model. 
Stratification will be based on the stratification factors used for the randomization. The 
ORR and 95% confidence intervals (CIs) will be provided. Inferential comparisons 
between treatment arms will use the Fisher’s exact test. 
For OS, a total of 621 deaths planned with two interim analyses (at 50% and 75% 
information) and a final analysis provides the study with 90% power for a 2-sided log-
rank test with a 5% level of significance to detect a 31.6%  increase in OS (HR = 0.76). 
Assuming an 8.2 month median OS in the placebo arm and exponential distribution of 


 
 
 
Protocol XL184-309 Amendment 2.0 
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OS, this corresponds with an increase in median OS to 10.8 months in the cabozantinib 
arm. In the current design, the minimum observed effect that would result in statistical 
significance for OS at the two interim and final analyses are 42.1% improvement (HR = 
0.70) from 8.2 to 11.7 months, 25.7% improvement (HR = 0.80) from 8.2 to 10.3 months 
and 18.4% improvement (HR = 0.84) from 8.2 to 9.7 months, respectively. 
With an average accrual rate of 31.5 subjects per month and using a 2:1 treatment 
allocation ratio, a total of approximately 760 subjects (507 subjects in the cabozantinib 
arm and 253 subjects in the placebo arm) are required to observe the required number of 
events within the planned study duration (25 months accrual and approximately 38 
months to observe the required deaths for OS).  
Open-Label Phase: data for subjects who crossover from the placebo arm to receive 
cabozantinib, will be summarized separately and will not be included as part of the 
evaluation of either arm. 
Maintenance Phase: data for subjects who enter the Maintenance Phase will not be 
entered in the clinical database. Data from the safety database will be summarized or 
listed separately. 
 


 
 
 
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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ....................................................................................................4 
LIST OF ABBREVIATIONS ............................................................................................22 
1 
BACKGROUND ......................................................................................................25 
1.1 
Hepatocellular Carcinoma ...............................................................................25 
1.2 
MET and VEGFR2 in Hepatocellular Carcinoma ...........................................25 
1.3 
Cabozantinib ....................................................................................................26 
1.3.1 
Pharmacology ......................................................................................26 
1.3.2 
Nonclinical Toxicology .......................................................................28 
1.3.3 
Clinical Data ........................................................................................29 
1.4 
Rationale ..........................................................................................................34 
1.4.1 
Rationale for the Study of Cabozantinib in Hepatocellular Carcinoma34 
1.4.2 
Rationale for Study Design ..................................................................35 
1.4.3 
Rationale for Cabozantinib Dose Selection .........................................35 
1.4.4 
Rationale for Open-Label Phase ..........................................................37 
1.5 
Study Conduct ..................................................................................................37 
2 
STUDY OBJECTIVES AND ENDPOINTS ............................................................38 
2.1 
Objectives ........................................................................................................38 
2.2 
Endpoints .........................................................................................................38 
3 
STUDY DESIGN......................................................................................................39 
3.1 
Study Sites .......................................................................................................39 
3.2 
Estimated Study Dates and Duration of Subject Participation ........................39 
3.3 
Overview of Study Design ...............................................................................39 
3.4 
Treatment Groups and Randomization ............................................................41 
3.5 
Study Blinding .................................................................................................42 
3.5.1 
Blinding of Study Treatments ..............................................................42 
3.5.2 
Unblinding Procedure for Individual Subjects ....................................42 
3.6 
Discontinuation and Withdrawal .....................................................................43 
3.6.1 
Treatment Discontinuation...................................................................43 
3.6.2 
Study Withdrawal ................................................................................44 
4 
STUDY POPULATION ...........................................................................................45 
4.1 
Target Population .............................................................................................45 
4.2 
Inclusion Criteria .............................................................................................45 
4.3 
Exclusion Criteria ............................................................................................46 


 
 
 
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5 
STUDY ASSESSMENTS AND PROCEDURES ....................................................49 
5.1 
Pretreatment Period ..........................................................................................49 
5.2 
Treatment Period ..............................................................................................50 
5.3 
Open-Label Phase ............................................................................................52 
5.4 
Maintenance Phase...........................................................................................53 
5.5 
Post-Treatment Period .....................................................................................54 
5.5.1 
Post-Treatment Follow-Up Visit..........................................................54 
5.5.2 
Extended Follow-up .............................................................................54 
5.6 
Unscheduled Visits ..........................................................................................55 
5.7 
Instructions for Specific Procedures ................................................................55 
5.7.1 
Demographics, Medical and Cancer History .......................................55 
5.7.2 
Physical Examination...........................................................................56 
5.7.3 
Vital Signs ............................................................................................56 
5.7.4 
Electrocardiograms ..............................................................................56 
5.7.5 
Laboratory Assessments ......................................................................57 
5.7.6 
Disease Assessments ............................................................................60 
5.7.7 
Alpha Fetoprotein (AFP) .....................................................................61 
5.7.8 
Health-Related Quality of Life (HRQOL) Assessments .....................62 
5.7.9 
Health Care Resource Utilization ........................................................63 
5.7.10 
Pharmacokinetics (PK) ........................................................................63 
5.7.11 
Pharmacogenetics and Biomarkers ......................................................64 
5.7.12 
Child-Pugh Scoring ..............................................................................64 
6 
TREATMENT PROCEDURES ...............................................................................65 
6.1 
Blinded Study Drug Dosing .............................................................................65 
6.1.1 
Study Drug Administration on Week1 Day 1 (W1D1) .......................65 
6.1.2 
Subsequent Dose Administration .........................................................65 
6.2 
Study Medications ...........................................................................................66 
6.2.1 
Cabozantinib (XL184) .........................................................................66 
6.2.2 
Placebo .................................................................................................67 
6.3 
Compliance ......................................................................................................67 
6.4 
Study Treatment Accountability ......................................................................67 
6.5 
Blinded Study Drug Dose Modifications .........................................................67 
6.5.1 
Reductions and Interruptions ...............................................................67 
6.6 
Best Supportive Care (BSC) ............................................................................70 
6.7 
Warnings, Precautions, and Guidelines for Management of Potential 
Cabozantinib Adverse Events ..........................................................................70 
6.7.1 
General .................................................................................................70 
6.7.2 
Gastrointestinal Disorders ....................................................................71 


 
 
 
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6.7.3 
Hepatobiliary Disorders .......................................................................73 
6.7.4 
Hematological Disorders .....................................................................73 
6.7.5 
Fatigue, Anorexia, and Weight Loss ....................................................74 
6.7.6 
Skin Disorders ......................................................................................75 
6.7.7 
Hypertension ........................................................................................77 
6.7.8 
Thromboembolic Events ......................................................................78 
6.7.9 
Proteinuria ............................................................................................79 
6.7.10 
Corrected QTc Prolongation ................................................................80 
6.7.11 
Hemorrhagic Events.............................................................................81 
6.7.12 
GI Perforation/Fistula and Non-GI Fistula Formation.........................82 
6.7.13 
Osteonecrosis of the Jaw ......................................................................83 
7 
CONCOMITANT MEDICATIONS AND THERAPIES ........................................84 
7.1.1 
Allowed Therapies ...............................................................................84 
7.1.2 
Prohibited or Restricted Therapies .......................................................84 
8 
SAFETY ...................................................................................................................88 
8.1 
Adverse Events and Laboratory Abnormalities ...............................................88 
8.2 
Serious Adverse Events ...................................................................................88 
8.2.1 
Definitions............................................................................................88 
8.2.2 
Regulatory Reporting ...........................................................................90 
8.3 
Other Safety Considerations ............................................................................91 
8.3.1 
Laboratory Data ...................................................................................91 
8.3.2 
Pregnancy .............................................................................................91 
8.3.3 
Medication Errors ................................................................................92 
8.3.4 
Follow-up of Adverse Events ..............................................................92 
9 
STATISTICAL CONSIDERATIONS......................................................................94 
9.1 
Analysis Populations ........................................................................................94 
9.1.1 
Intent-to-Treat (ITT) Population ..........................................................94 
9.1.2 
Safety Population .................................................................................94 
9.2 
Primary Efficacy Endpoint ..............................................................................94 
9.2.1 
Definition .............................................................................................94 
9.2.2 
Primary Analysis ..................................................................................94 
9.2.3 
Exploratory Analyses ...........................................................................95 
9.3 
Secondary Efficacy Endpoints .........................................................................95 
9.3.1 
Progression-Free Survival (PFS) .........................................................95 
9.3.2 
Objective Response Rate (ORR) .........................................................96 
9.4 
Control of Type I Error ....................................................................................97 
9.5 
Health-Related Quality of Life (HRQOL) .......................................................98 


 
 
 
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9.6 
Pharmacokinetic Analysis ................................................................................98 
9.7 
Safety Analyses ................................................................................................98 
9.7.1 
Adverse Events ....................................................................................98 
9.7.2 
Laboratory Test Results .......................................................................99 
9.7.3 
Other Safety Endpoints ........................................................................99 
9.8 
Interim Analyses ..............................................................................................99 
9.9 
Power and Sample Size ..................................................................................100 
9.10 
Open-Label Phase ..........................................................................................100 
9.11 
Maintenance Phase.........................................................................................100 
10 
DATA QUALITY ASSURANCE ..........................................................................101 
11 
STUDY COMMITTEES ........................................................................................101 
11.1 
Exelixis Safety Committee ............................................................................101 
11.2 
Independent Data Monitoring Committee (IDMC) .......................................101 
11.3 
Clinical Steering Committee ..........................................................................102 
12 
ETHICAL ASPECTS .............................................................................................102 
12.1 
Local Regulations ..........................................................................................102 
12.2 
Informed Consent...........................................................................................103 
12.3 
Institutional Review Board/Ethics Committee ..............................................103 
12.4 
Disposition of Subject Samples .....................................................................104 
13 
CONDITIONS FOR MODIFYING THE PROTOCOL.........................................104 
14 
CONDITIONS FOR TERMINATING THE STUDY OR LIMITING DATA 
COLLECTION .......................................................................................................104 
15 
STUDY DOCUMENTATION, CASE REPORT FORMS, AND RECORDING 
KEEPING ...............................................................................................................104 
15.1 
Investigator’s Files and Retention of Documents ..........................................104 
15.2 
Source Documents and Background Data .....................................................105 
15.3 
Audits and Inspections ...................................................................................105 
15.4 
Case Report Forms .........................................................................................105 


 
 
 
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16 
MONITORING THE STUDY ................................................................................106 
17 
CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT RECORDS .106 
18 
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS..........107 
19 
REFERENCES .......................................................................................................108 
20 
APPENDICES ........................................................................................................113 
 
Appendix A: Schedule of Assessments ........................................................................ 114 
Appendix B: Open-Label Phase ................................................................................... 119 
Appendix C: Maintenance Phase.................................................................................. 127 
Appendix D: ECOG Performance Scale ....................................................................... 129 
Appendix E: Child-Pugh Scoring System .................................................................... 130 
Appendix F: Guidelines for Best Supportive Care ...................................................... 131 
Appendix G: Response Evaluation Criteria in Solid Tumors Version 1.1 ................... 132 
Appendix H: EuroQol questionnaire EQ-5D-5L, USA (English) sample version ....... 141 
 
LIST OF TABLES 
Table 1-1: 
Inhibition of Key Protein Kinases by Cabozantinib in Cells .................... 26 
Table 1-2: 
Inhibition of Key Protein Kinases by Cabozantinib in Biochemical Assays
 
27 
Table 1-4: 
Efficacy Results in Subjects with HCC During the 12-Week Lead-In Stage 
(Study XL184-203 RDT) .......................................................................... 31 
Table 5-1: 
Laboratory Panels ..................................................................................... 59 
Table 6-1: 
Cabozantinib Tablet Components and Composition ................................ 66 
Table 6-2: 
Placebo Tablet Components and Composition ......................................... 67 
Table 6-3: 
Dose Modification Criteriaa ...................................................................... 69 
Table 6-4: 
Dose Reductions ....................................................................................... 69 
Table 6-5: 
Dose Modification Criteria and Recommended Guidelines for Treatment-
emergent PPE Syndrome .......................................................................... 76 
Table 6-6: 
Guidelines for the Management of Treatment-emergent Hypertension ... 78 
Table 6-7: 
Management of Treatment-emergent Proteinuria ..................................... 80 
Table 12:  Schedule of Assessments Open-Label Phase ................................................ 124 
Table 13: Schedule of Assessments: Maintenance Phase ............................................... 128 


 
 
 
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LIST OF FIGURES 
Figure 1-1: 
Cabozantinib Administration Leads to Improved Survival in HCC Model
 
28 


 
 
 
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LIST OF ABBREVIATIONS 
Abbreviation or 
Term 
Definition 
AE 
adverse event 
AFP 
alpha fetoprotein 
AIDS 
acquired immunodeficiency syndrome 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the plasma drug concentration time curve 
AUC0-∞ 
AUC from the time of dosing to infinity 
AUC0-last 
AUC from the time of dosing to the time of the last quantifiable 
concentration  
β-HCG 
β-human chorionic gonadotropin 
BCLC 
Barcelona Clinic Liver Cancer 
BP 
blood pressure 
BSC 
best supportive care 
CAP 
chest, abdomen, and pelvis 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CL/F 
oral clearance 
CLIP 
Cancer of the Liver Italian Program 
CR 
complete response 
CRO 
contract research organization 
CT 
computerized tomography 
CTC 
circulating tumor cells 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTP 
closed testing procedure 
CYP 
cytochrome P450 
DVT 
deep vein thrombosis 
(e)CRF 
(electronic) case report form 
EC 
Ethics Committee 
ECG 
electrocardiogram 
ED50 
dose required for 50% tumor growth inhibition 
EGFR 
epithelial growth factor receptor 
EMEA 
European Medicines Agency 
FBE 
free base equivalent weight of cabozantinib 
FDA 
Food and Drug Administration 
FFPE 
formalin-fixed paraffin embedded 
FXa 
coagulation factor X 


 
 
 
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Abbreviation or 
Term 
Definition 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HbA1c 
hemoglobin A1c (glycosylated) 
HBV/HCV 
Hepatitis B virus/Hepatitis C virus 
HCC 
hepatocellular carcinoma 
HGF 
hepatocyte growth factor 
HIV 
human immunodeficiency virus 
HLM 
human liver microsomes 
HR 
hazard ratio 
IC50 
concentration required for 50% target inhibition 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IRB 
Institutional Review Board 
ITT 
intent to treat  
IVC 
intravenous contrast 
IVR 
interactive voice recognition 
IWR 
interactive web response 
Kiapp 
apparent inhibition constant 
LMWH 
low molecular weight heparin 
MedDRA 
Medical Dictionary for Regulatory Activities 
MET 
hepatocyte growth factor receptor protein 
MRI 
magnetic resonance imaging 
MTC 
medullary thyroid cancer 
MTD 
maximum tolerated dose 
NCCN 
National Comprehensive Cancer Network 
NSAID 
nonsteroidal anti-inflammatory drug 
NSCLC 
non-small cell lung cancer 
ONJ 
osteonecrosis of the jaw 
ORR 
objective response rate 
OS 
overall survival 
PE 
pulmonary embolism 
PFS 
progression-free survival 
PK 
Pharmacokinetics 
PPE 
palmar-plantar erythrodysesthesia  
PR 
partial response 
Qd 
once daily 
QT 
time interval in ECG reading 


 
 
 
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Abbreviation or 
Term 
Definition 
QTcF 
corrected QT interval by Fridericia 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RFA 
radiofrequency ablation 
ROW 
rest of world 
RPLS 
reversible posterior leukoencephalopathy 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SEM 
standard error of measurement 
SoD 
sum of the diameters 
SLD 
sum of longest diameters 
Tc 
Technetium 
TEAE 
treatment-emergent adverse event 
TIA 
transient ischemic attack 
t1/2 
half-life 
TKI 
tyrosine kinase inhibitor 
Tmax 
time to maximum concentration 
ULN 
upper limit of normal 
UPCR 
urine protein:creatinine ratio 
VEGF(R) 
vascular endothelial growth factor (receptor) 
V/F 
oral volume of distribution (V/F) 
VHL 
von Hippel-Lindau gene 
WBC 
white blood cell 
XL184 
Exelixis code name for investigational product cabozantinib 


 
 
 
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1 
BACKGROUND  
1.1 
Hepatocellular Carcinoma 
Hepatocellular carcinoma (HCC) is diagnosed in approximately 750,000 individuals and is the 
cause of almost 700,000 deaths worldwide each year (World Health Organization 2008). HCC is 
the second highest cause of cancer-related deaths globally, behind only lung cancer. In the US, 
age-adjusted incidence rates of HCC tripled between 1975 and 2005 (Altekruse 2009).  
Some patients who are found to have localized disease can undergo resection with curative intent 
and others can be treated with regional therapy (local ablation, chemoembolization, or other 
transcatheter therapies) but patients who present with advanced or unresectable disease or who 
recur after locoregional therapy have a dismal prognosis. HCC is usually resistant to systemic 
chemotherapy alone and thus chemotherapy is not recommended by international guidelines 
outside of a clinical trial (EASL-EORTC 2012). Sorafenib, a small-molecule inhibitor of the 
vascular endothelial growth factor receptor (VEGFR) and other protein kinases, has been shown 
in a placebo-controlled study to improve the time to progression and overall survival (OS) in 
patients with HCC (Llovet 2008) and is the only systemic therapy recommended for HCC 
(EASL-EORTC 2012; Kane 2009). The improvement observed in OS, however, was less than 
3 months and thus these patients eventually progress. At the time of initiation of this study, no 
drug has demonstrated efficacy in patients with inoperable or metastatic HCC that has 
progressed after treatment with sorafenib. Thus, additional, effective systemic therapy for HCC 
represents an unmet medical need.    
1.2 
MET and VEGFR2 in Hepatocellular Carcinoma 
The receptor tyrosine kinase MET and its cognate ligand hepatocyte growth factor (HGF) play 
an important role in diverse aspects of tumor pathobiology, including tumor growth, survival, 
neo-angiogenesis, invasion, and dissemination (Gherardi 2012). MET pathway activation and 
dysregulation have been implicated in multiple cancers, including HCC. Although its prevalence 
is not well characterized and may be influenced by source of tissue or methodology, MET has 
been found to be overexpressed in HCC compared with nontumor liver tissue, with higher MET 
expression linked to poorer prognosis (Kaposi-Novak 2006, Kiss 1997, Ueki 1997). Moreover, 
small-molecule inhibitors of MET have been shown to exhibit efficacy in preclinical models of 
HCC (You 2011a, Huynh 2012) and in early-phase clinical studies (Santoro 2013).  
The VEGFRs and ligands are central mediators of tumor neo-angiogenesis and 
lymphangiogenesis (Carmeliet 2011). High tumor microvessel density appears predictive of poor 


 
 
 
Protocol XL184-309 Amendment 2.0 
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disease-free survival after HCC resection, and tumor vascular invasion is a well-established 
negative prognostic factor (Tanaka 1989, Greten 2009). Resistance to VEGF-targeted therapies 
may arise from the up-regulation of alternative pro-angiogenic and pro-invasive signaling 
pathways, including the MET pathway. Consistent with this, combined inhibition of VEGFR and 
MET results in efficacy enhanced over that achieved via inhibition of either pathway alone in 
some tumor models (Aftab 2011, Sennino 2012a, Sennino 2012b, You 2011b).  
1.3 
Cabozantinib 
1.3.1 
 Pharmacology 
Cabozantinib exhibits potent inhibitory activity against several receptor tyrosine kinases that are 
known to influence tumor growth, metastasis, and angiogenesis. The primary targets of 
cabozantinib are MET, VEGFR2/KDR, and RET with cell-based IC50 (concentration associated 
with 50% inhibition) values of 8, 2 and 85 nM, respectively. In addition, cabozantinib inhibited 
phosphorylation of KIT, FLT3, and AXL with IC50 values of 5, 11, and 42 nM, respectively. The 
cell-based target inhibition profile of cabozantinib is shown in Table 1-1.  
Table 1-1: 
Inhibition of Key Protein Kinases by Cabozantinib in Cells 
Kinase 
IC50 
a 
nM 
MET 
8 
VEGFR2/KDR 
2 b 
RET 
85 
KIT 
5 
FLT-3 
11 
AXL 
42 
a 
IC50 = concentration required for 50% inhibition 
b 
VEGF-mediated ERK phosphorylation 
 
The biochemical target inhibition profile of cabozantinib is shown in Table 1-2. The IC50 values 
in biochemical kinase assays do not always translate evenly in vivo. For example, cabozantinib 
exhibits comparable potency against MET and VEGFR2 in cellular and in vivo assays, in spite of 
its apparent greater potency for inhibition of VEGFR2 in biochemical kinase assays. Hence, 
cabozantinib is a balanced inhibitor of MET and VEGFR2 that also inhibits a number of other 


 
 
 
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receptor tyrosine kinases implicated in tumor pathobiology, including RET, KIT, AXL, and 
FLT3.  
Table 1-2: 
Inhibition of Key Protein Kinases by Cabozantinib in Biochemical Assays 
Kinase 
IC50 ± SEM a 
nM 
MET 
1.8 ± 0.2 
VEGFR2/KDR 
0.035 ± 0.007 
RET 
9.8 ± 2.3 
TIE-2 
14.3 ± 2.8 
AXL 
7 
FLT-3 
14.4 ± 0.8 
KIT 
4.6 ± 0.5 
RON 
121±  8 
a 
IC50 = concentration required for 50% inhibition;  
SEM = standard error of the mean 
Data from pharmacodynamic experiments have shown that cabozantinib inhibits MET and 
VEGFR2 in vivo. Oral administration of cabozantinib resulted in blockade of MET 
phosphorylation in human lung tumor xenografts grown in nude mice, blockade of MET 
phosphorylation in livers of mice, and blockade of VEGFR2 phosphorylation in mouse lung 
tissue. For both targets, the duration of action of cabozantinib was sustained, with greater 
than 50% inhibition sustained for over 8 hours postdose at a single dose level of 100 mg/kg 
(Yakes 2011). In addition, oral administration of cabozantinib resulted in blockade of 
phosphorylation of mutationally activated RET in human medullary thyroid cancer (MTC) 
xenografts grown in nude mice (Bentzien et al, 2013).  
Treatment with cabozantinib results in anti-angiogenic effects in xenograft tumors, with 
disruption of the vasculature beginning within 24 hours after administration, and is associated 
with pro-apoptotic effects. These effects translate into significant tumor growth inhibition or 
tumor regression after cabozantinib treatment in multiple tumor models including MTC, breast 
cancer, lung carcinoma, and glioblastoma (Yakes 2011). Cabozantinib prolonged survival in a 
MET-driven transgenic mouse model of HCC (Cohn 2012) as illustrated in Figure 1-1. In 
additional preclinical studies, cabozantinib has also been shown to inhibit tumor invasiveness 


 
 
 
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and metastasis and the progression of tumors in bone (Yakes 2011, Schimmoller 2011, 
Mohammad 2012).  
Figure 1-1: 
Cabozantinib Administration Leads to Improved Survival in HCC Model 
 
Data courtesy of  D Yang and JM Bishop, UCSF 
Overall, the preclinical data generated in vivo demonstrate that the target profile of cabozantinib 
translates to potent anti-angiogenic activity and potent antitumor efficacy both in soft tissue and 
in bone. 
A summary of cabozantinib pharmacology is contained in the Investigator’s Brochure, which 
should be reviewed in conjunction with this study protocol. 
1.3.2 
Nonclinical Toxicology 
Cabozantinib nonclinical toxicology has been characterized in single- and repeat-dose studies in 
multiple species. Details can be found in the Investigator’s Brochure. 


 
 
 
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1.3.3 
Clinical Data 
In clinical studies, cabozantinib has been evaluated in multiple tumor types including medullary 
thyroid cancer, castration-resistant prostate cancer, ovarian cancer, breast cancer, hepatocellular 
carcinoma, nonsmall cell lung cancer, melanoma, differentiated thyroid cancer, renal cell 
carcinoma, and glioblastoma multiforme. To date, cabozantinib has demonstrated broad clinical 
activity in these tumor types and the capsule formulation has been approved in the US for the 
treatment of patients with progressive, metastatic medullary thyroid carcinoma (MTC) and in 
Europe for the treatment of adult patients with progressive, unresectable locally advanced or 
metastatic MTC. The cabozantinib tablet formulation has been approved in the US for the 
treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-
angiogenic therapy. The capsule and tablet formulations are not bioequivalent and are not 
interchangeable. Consult the Investigator’s Brochure for more detail. 
1.3.3.1 
Overall Safety Results 
Consult the current version of the Investigator’s Brochure for the most recent information on 
overall safety of cabozantinib. 
As of 29 February 2016, 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).   
The most frequently reported adverse events (AEs) occurring in ≥ 25% of subjects regardless of 
causality or grade in the single-agent cabozantinib studies, pooled analysis of 2410 subjects from 
company-sponsored clinical trials, were consistent across the various tumor types studied and 
comprised fatigue and diarrhea (both 61%), nausea (54%), decreased appetite (53%), vomiting 
and weight decrease ( both 36%), palmar-plantar erythrodysesthesia (PPE) syndrome (35%), and 
constipation (32%), hypertension (29%), dysgeusia (26%), and dysphonia (25%). The most 
frequently occurring AEs that were Grade 3 or higher in severity occurring in ≥ 5% of subjects 
were fatigue (15%), hypertension (14%), diarrhea (10%), anemia and PPE syndrome (both 8%), 
asthenia (7%), pulmonary embolism and decreased appetite (both 6%). The most frequently 
reported AEs of any grade that were attributed by the Investigator to cabozantinib occurring in ≥ 
25% of subjects were fatigue and diarrhea (both 53%), decreased appetite (45%), nausea (44%), 
PPE syndrome (34%), weight decreased (28%), vomiting, dysgeusia, hypertension, and 
dysphonia (each 25%).  


 
 
 
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The most frequent serious AEs (SAEs) occurring in ≥ 2% of subjects in the pooled single-agent 
cabozantinib studies were pulmonary embolism (5%), vomiting, dehydration, general physical 
health deterioration, pneumonia, and nausea (each 3%), anemia, diarrhea, and abdominal pain 
(each 2%). The SAEs most frequently considered related to cabozantinib occurring in ≥ 1% of 
subjects were pulmonary embolism, nausea, dehydration, diarrhea, vomiting, and fatigue. Across 
all single-agent cabozantinib trials, 22% of subjects discontinued treatment due to an AE 
(including events of disease progression). Fatigue (2.9%), general physical health deterioration 
(1.8%), asthenia (1.3%), decreased appetite (1.2%), nausea and diarrhea (both 1.0%) were the 
only reasons for discontinuation occurring in ≥1% of subjects.  
1.3.3.2 
Phase 1 Study of Cabozantinib in Japanese Subjects (Study XL184-014) 
XL184-014 was an open-label, multiple dose escalation monotherapy Phase 1 study of 
cabozantinib administered orally to Japanese subjects with advanced or metastatic solid tumors. 
The primary objective of this study was to establish the maximum tolerated dose (MTD) and 
recommended Phase 2 dose (RP2D, or dose range as appropriate) of cabozantinib in this patient 
population. The study consisted of Dose-Escalation Cohorts followed by an Expansion Cohort at 
MTD or RP2D. Twenty-three subjects were enrolled in the Dose-Escalation Phase for capsule 
and tablet cohorts; 26 subjects were treated at the tablet R2PD of 60 mg (note that 6 subjects 
were included in both categories). For further details please refer to the Investigator Brochure. 
1.3.3.3 
Study XL184-203 RDT 
Study XL184-203 RDT was a Phase 2 randomized discontinuation trial evaluating the efficacy 
and safety of cabozantinib in nine different advanced tumor types including a cohort of subjects 
with HCC (Verslype 2012). The study consisted of a 12-week Lead-in Stage in which all 
subjects received open-label cabozantinib at an initial dose of 100 mg/day freebase equivalent 
(FBE) and a Randomized Stage in which subjects with stable disease at Week 12 were 
randomized in a blinded manner to receive cabozantinib or placebo. Subjects who at Week 12 
had a PR or CR were continued on open-label cabozantinib.   
Key eligibility criteria for the HCC cohort included up to one line of prior systemic treatment, 
documented progressive disease, at least one measurable target lesion per original RECIST 1.0, 
platelets ≥ 60 x 109/L, hemoglobin ≥ 8 g/dL, and a Child-Pugh Score of A. Tumor assessments 
were performed using CT/MRI at baseline and every 6 weeks thereafter.  
Forty-one subjects treated in this study had HCC. Among these, median age was 61 years and 
most subjects were male. Thirty-seven percent were of Asian ancestry. The most common 


 
 
 
Protocol XL184-309 Amendment 2.0 
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etiologies for the HCC were Hepatitis B and C (both 24%). The majority of subjects (78%) had 
received prior systemic therapy for the disease; over half (54%) had received prior sorafenib. 
Extrahepatic spread was present in 73% of subjects, consistent with a relatively poor prognosis 
(Verslype 2012).   
1.3.3.3.1 Safety Results in Hepatocellular Carcinoma (Study XL184-203 RDT) 
The 41 subjects with advanced HCC treated with cabozantinib in Study XL184-203 RDT 
received an initial dose of 100 mg/day (FBE). Fifty-nine percent of subjects required at least 
1 dose reduction throughout both the Lead-in and Randomized Stages.  
The most frequently reported AEs during the study were consistent with those in subjects with 
other tumor types who received single-agent cabozantinib and included diarrhea (68%), fatigue 
(59%), palmar-plantar erythrodysesthesia (PPE) syndrome (54%), vomiting (42%), and nausea 
(39%). Common Grade 3 or higher AEs included diarrhea (22%), thrombocytopenia (17%), PPE 
syndrome (15%), aspartate aminotransferase (AST) increased (12%).  
1.3.3.3.2 Efficacy Results in Hepatocellular Carcinoma (Study XL184-203 RDT) 
Two subjects (5%) had a confirmed partial response (PR) during the 12-week Lead-in Stage 
(at any time through Week 12) and 31 subjects (76%) had stable disease (Table 1-3); the disease 
control rate (PR plus stable disease) at Week 12 was 66%. One subject with stable disease at 
Week 12 subsequently achieved a partial response. The 3 subjects with PRs were White; one 
each with HCC etiology of Hepatitis C, Hepatitis B, and Alcoholism.  Twenty-eight of 36 
subjects (78%) with a post-baseline scan had at least 1 scan demonstrating a reduction in 
measurable disease. 
Table 1-3: 
Efficacy Results in Subjects with HCC During the 12-Week Lead-In Stage 
(Study XL184-203 RDT) 
n (%) 
HCC Subjects  
N = 41 
Best objective response 
 
Complete response (CR) 
0 (0) 
Partial response (PR) 
2 (5) 
Stable disease 
31 (76) 
Progression 
3 (7) 
Inevaluable or missing1 
5 (12) 
Disease control rate at Week 12 (%)2 
27 (66) 
1 
No postbaseline tumor measurements available 


 
 
 
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2 
Disease control rate = CR+PR+stable disease 
 
Twenty-two of the 41 subjects enrolled in the Lead-in Stage were randomized at Week 12 to 
either placebo or continuing cabozantinib after demonstrating stable disease. Median PFS for all 
subjects from the initial cabozantinib dose was 5.2 months by Kaplan-Meier estimate and did not 
appear to be influenced by sorafenib pretreatment status (5.2 months for sorafenib pre-treated 
subjects [n=22] and 4.2 months for sorafenib naïve subjects [n=19]). No statistically significant 
difference in median PFS between randomized treatment groups was observed from the point of 
randomization: median PFS was 1.4 months (95% CI: 1.3, 4.2) for placebo and 2.5 months (95% 
CI: 1.3, 6.8) for cabozantinib.  
The median OS for all treated patients (n=41) from the initial cabozantinib dose as estimated by 
the Kaplan-Meier method was 11.5 months (95% CI: 7.3, 15.6) (data on file).  
1.3.3.4 
Clinical Pharmacokinetics (PK) of Cabozantinib 
A population PK analysis of cabozantinib was performed using data collected from 289 subjects 
with solid tumors including MTC following oral administration of 140 mg (FBE) daily doses as 
capsules. The predicted effective half-life is approximately 55 hours, the oral volume of 
distribution (V/F) is approximately 349 L, and the clearance (CL/F) at steady-state is estimated 
to be 4.4 L/hr. The terminal half-life (for predicting drug washout) is approximately 120 hours. 
Following oral administration of cabozantinib, median time to peak cabozantinib plasma 
concentrations (Tmax) ranged from 2 to 5 hours post-dose. Repeat daily dosing of cabozantinib at 
140 mg for 19 days resulted in 4- to 5-fold mean cabozantinib accumulation (based on AUC) 
compared to a single dose administration; steady state was achieved by Day 15. Cabozantinib is 
highly protein bound in human plasma (≥ 99.7%).  
A population PK analysis did not identify clinically relevant differences in clearance of 
cabozantinib between females and males or between Whites (89%) and non-Whites (11% [<4% 
were Asian]). Cabozantinib PK was not affected by age (20-86 years).  
A second PopPK analysis was conducted in subjects with renal cell carcinoma (RCC) who 
received repeated oral daily cabozantinib tablet dosing at 60 mg (with protocol-permitted dose 
reductions to 40 mg and 20 mg) combined with healthy subjects who received a single oral tablet 
dose of 20, 40, or 60 mg. This analysis indicated that for a White male subject the predicted 
terminal plasma half-life of cabozantinib was approximately 99 h; the terminal phase volume of 
distribution (Vz) was approximately 319 L; and the CL/F at steady-state was estimated to be 


 
 
 
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approximately 2.2 L/h. Female gender and Asian race were significant covariates on CL/F, and 
while the attributes were statistically significant, they were not deemed clinically meaningful 
given the magnitude of the effects. Further evaluation of the differences in the two PopPK 
analyses revealed that compared with other cancer patient groups (ie, RCC, castration-resistant 
prostate cancer [CRPC], glioblastoma multiforme [GB]), MTC subjects cleared cabozantinib 
faster and thus had lower dose-normalized steady-state plasma exposures. Several possible 
factors may underlie the higher cabozantinib clearance observed in the first PopPK analysis; 
however, an exact cause has yet to be identified. A PopPK analysis has been performed for 
another TKI (motesanib) in thyroid cancer patients and showed, similar to cabozantinib, that 
MTC patients had a higher (67% greater) oral clearance than patients with differentiated thyroid 
cancer (DTC; Lu et al 2010). The mechanistic basis for the difference in motesanib CL/F 
between MTC and DTC patients was also not identified. 
Exposure of cabozantinib was assessed in Japanese subjects in capsule and tablet formulations 
(Study XL184-014). At steady state, exposure, AUC increased slightly less than dose 
proportionally from 40 to 80 mg capsule doses and slightly more than dose proportionally from 
40 to 60 mg tablet doses. There was no clinically relevant difference in exposure between 
capsule and tablet formulations. Steady-state plasma exposures in Japanese subjects administered 
60-mg tablets were approximately 30% higher than reported in non-Japanese subjects 
administered 60-mg tablets (Study Report XL184-308). However, as this difference was within 
the range of inter-subject variability determined in Japanese (%CV= 34%) and non-Japanese 
subjects (%CV=48%), no firm conclusions may be drawn regarding differences in cabozantinib 
exposures between these two subject populations. 
In the mass balance study, within a 48-day collection period after a single dose of 14C-
cabozantinib in healthy subjects, approximately 81% of the total administered radioactivity was 
recovered with 54% in feces and 27% in urine. A PK study of cabozantinib in patients with renal 
impairment is ongoing. The results of a population PK analysis suggested that mild to moderate 
renal impairment (creatinine clearance value ≥30 mL/min) does not have a clinically relevant 
effect on the clearance of cabozantinib. The PK evaluation of cabozantinib has not been 
completed in patients with hepatic impairment (study is ongoing); preliminary data suggest that 
subjects with mild hepatic function impairment (Child-Pugh A) show a 61% higher plasma 
AUC0-∞ for cabozantinib as compared with matched healthy subjects (XL184-003). 
A high-fat meal increased Cmax and AUC values by 41% and 57%, respectively relative to fasted 
conditions in healthy subjects administered a single 140 mg oral cabozantinib dose.  


 
 
 
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Cabozantinib is a substrate of CYP3A4 in vitro. Inhibition of CYP3A4 reduced the formation of 
the XL184 N-oxide metabolite by >80%. Inhibition of CYP2C9 had a minimal effect on 
cabozantinib metabolite formation (ie, a <20% reduction). Inhibition of CYP1A2, CYP2A6, 
CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP2E1 had no effect on cabozantinib metabolite 
formation. Cabozantinib AUC was increased 38% with coadministration of the strong CYP3A4 
inhibitor ketoconazole and decreased 77% with coadministration of the strong CYP3A4 inducer 
rifampin.  
Cabozantinib is a noncompetitive inhibitor of CYP2C8 (Kiapp = 4.6 μM), a mixed-type  inhibitor 
of both CYP2C9 (Kiapp = 10.4 μM) and CYP2C19 (Kiapp = 28.8 μM), and a weak competitive 
inhibitor of CYP3A4 (estimated Kiapp = 282 μM) in human liver microsomal (HLM) 
preparations. IC50 values >20 μM were observed for CYP1A2, CYP2D6, and CYP3A4 isozymes 
in both recombinant and HLM assay systems 
Cabozantinib is an inducer of CYP1A1 mRNA in human hepatocyte incubations (ie, 75-100% of 
CYP1A1 positive control β-naphthoflavone induction), but not of CYP1A2, CYP2B6, CYP2C8, 
CYP2C9, CYP2C19 or CYP3A4 mRNA or isozyme-associated enzyme activities. Cabozantinib 
at steady-state plasma concentrations (≥100 mg/day daily for a minimum of 21 days) showed no 
effect on single-dose rosiglitazone (a CYP2C8 substrate) plasma exposure (Cmax and AUC) in 
patients with solid tumors.  
Cabozantinib is an inhibitor (IC50 = 7.0 μM), but not a substrate, of P-gp transport activities in a 
bi-directional assay system using MDCK-MDR1 cells. Therefore, cabozantinib may have the 
potential to increase plasma concentrations of co-administered substrates of P-gp. 
Additional results from this and other clinical PK trials may be found in the Investigator 
Brochure. 
1.4 
Rationale 
1.4.1 
Rationale for the Study of Cabozantinib in Hepatocellular Carcinoma 
MET and VEGF signaling have been implicated in tumor neo-angiogenesis, invasion, and 
dissemination, and in osteoblast and osteoclast function, while dysregulation of MET and VEGF 
pathway components has been associated with poor prognosis in multiple tumor types. 
Cabozantinib prolonged survival in a MET-driven transgenic mouse model of HCC (Cohn 
2012).  


 
 
 
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In Phase 1 and 2 clinical studies, treatment with cabozantinib has resulted in tumor regression in 
multiple cancer types (Hussain 2011, Kurzrock 2011, Zhang 2010). The early clinical results of 
cabozantinib in advanced HCC presented in Section 1.3.3.3.2, while preliminary, appear 
promising. That, given the scarcity of available treatment modalities in this incurable disease, 
provides the rationale for a Phase 3 study in this disease setting.  
1.4.2 
Rationale for Study Design 
There are no approved therapies for the second-line treatment of HCC after progression 
following sorafenib. The guidelines of the National Comprehensive Cancer Network (NCCN 
2011) recommend best supportive care (BSC) or a clinical trial for this patient population. 
Furthermore, EORTC guidelines specifically recommend that second-line trials should be 
designed as placebo-controlled randomized trials.  
This is a randomized, double-blinded, controlled study of cabozantinib vs placebo for the 
treatment of HCC in subjects previously treated with sorafenib. Placebo has been chosen as the 
comparator in this study due to the lack of available second-line treatments for HCC. The 2:1 
randomization was selected as an incentive for subject participation in a placebo-controlled trial. 
All subjects will receive BSC in addition to the randomized study treatment (Appendix F).  
OS is the primary efficacy endpoint, with ORR and PFS as secondary endpoints. OS is an 
accepted regulatory and clinical endpoint and is the most appropriate endpoint for this 
population. In order to avoid confounding the OS endpoint, crossover to cabozantinib will not be 
permitted in this study.     
In addition, the standardized measure of health status EQ-5D-5L, developed by the EuroQol 
group, will be used in order to provide a generic measure of health for clinical appraisal 
(Herdman 2011). The questionnaire will be self-completed by the subjects. The objective will be 
to assess the time to deterioration of these outcomes as an endpoint supportive of the primary 
endpoint rather than to ascertain a treatment-related improvement in quality of life. 
1.4.3 
Rationale for Cabozantinib Dose Selection  
Data from a Phase 2 randomized discontinuation trial (XL184-203) of cabozantinib showed 
activity in multiple solid tumors including HCC and employed a dose of 100 mg daily, orally. 
This study enrolled a cohort of 41 subjects with advanced HCC. Subjects were required to have 
Child-Pugh class A scores at study entry. In this cohort encouraging anti-tumor activity was 
observed with 78% of subjects experiencing measurable disease regression in their target lesions 


 
 
 
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as their best response, a median PFS of 5.2 months, and a median OS of 11.5 months. The 
Week 12 disease control rate (PR or stable disease) was 66%. Fifty-nine percent of the HCC 
subjects required at least one dose reduction, resulting in a median average dose of 
approximately 66 mg/day. The median time to first dose reduction to 60 mg was 39.5 days. 
Subjects maintained disease control despite dose reductions as evidenced by the high rate of 
Week 12 disease control. 
Additionally, the 60 mg cabozantinib daily dose has been evaluated in two Phase 3 studies in 
metastatic castration-resistant prostate cancer. The choice of dose for these studies is supported 
by data from a Phase 1 and a Phase 2 study employing a 40 mg dose of cabozantinib (Smith 
2012, DeBono 2012); these studies showed improved tolerability compared to results from a 
cohort of subjects receiving the 100 mg dose of cabozantinib while maintaining anti-tumor 
activity. Therefore, a dose of 60 mg cabozantinib daily is expected to show antitumor activity.  If 
dose reductions are necessary, it is also expected that antitumor activity can be maintained at the 
lower doses. 
Finally, the 60 mg cabozantinib daily dose has demonstrated efficacy and safety in a Phase 3 
study in advanced renal cell cancer (RCC; Choueiri et al 2016, Choueiri et al 2015) leading to 
US approval of cabozantinib tablets in patients with advanced RCC who have received prior 
anti-angiogenic therapy. 
Trough level PK exposures obtained in study XL184-203 were similar across different tumor 
types including the HCC cohort. To further evaluate cabozantinib PK in subjects with impaired 
hepatic function, study XL184-003 was conducted. In the XL184-003 study, the PK for subjects 
with mild or moderate impaired hepatic function who received a single oral dose of 60 mg was 
evaluated relative to subjects with normal hepatic function. For the subjects with mild hepatic 
impairment (Child-Pugh class A), there was an 81% increase in exposure (AUC0-inf) compared 
with subjects with normal hepatic function. For the subjects with moderate hepatic impairment 
(Child-Pugh class B), there was a 63% increase in exposure (AUC0-inf) compared with subjects 
with normal hepatic function. Thus, for subjects with advanced HCC with mild or moderate 
hepatic impairment, the exposure (AUC) at steady-state would be expected to be comparable to 
and not markedly exceed the exposure seen in the Phase 2 study XL184-203 where 100 mg was 
the assigned dose. 
In summary, a dose of cabozantinib at 60 mg/day (FBE) is expected to provide increased 
tolerability while maintaining efficacy in subjects with advanced HCC initially observed in 


 
 
 
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Phase 2 while providing a safety margin for the expected increase in exposure in subjects with 
mild hepatic impairment compared to subjects with normal hepatic function.  
1.4.4 
Rationale for Open-Label Phase  
There are currently no approved therapies for treatment of advanced HCC following treatment 
with sorafenib. If one of the planned analyses shows statistically-significant and clinically-
meaningful evidence of improved OS, subjects who have been randomized to the placebo arm 
will have the option to crossover to receive cabozantinib if they meet specific eligibility criteria. 
The Open-Label Phase will only be implemented upon decision by the Sponsor and discussion 
with regulatory authorities following review of the data. 
The eligibility criteria for crossover are intended to ensure that the subjects who crossover to 
receive cabozantinib do not have predisposing risks for treatment with cabozantinib and that they 
are representative of the study population in whom overwhelming benefit has been determined. 
1.5 
Study Conduct 
This study will be conducted in compliance with Good Clinical Practice (GCP), including 
International Conference on Harmonisation (ICH) Guidelines and also consistent with the most 
recent accepted version of the Declaration of Helsinki. In addition, all applicable local laws and 
regulatory requirements relevant to the use of new therapeutic agents in the countries involved 
will be adhered to. 
The study will be conducted in compliance with the protocol. The appropriate Institutional 
Review Boards (IRBs) or Ethics Committees (ECs) must approve the protocol, any amendments, 
and the subject informed consent form (ICF) prior to implementation.  
Freely given written informed consent must be obtained from every subject prior to his 
participation in this clinical trial. The rights, safety, and well-being of participating subjects are 
the most important considerations and should prevail over interests of science and society. 
Study personnel involved in conducting this trial will be qualified by education, training, and 
experience to perform their respective task(s). This trial will not use the services of study 
personnel for whom sanctions have been invoked or there has been scientific misconduct or 
fraud (eg, loss of medical licensure, debarment, etc). 


 
 
 
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2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
The objective of this study is to evaluate the effect of cabozantinib compared with placebo—both 
in the setting of BSC—on OS in subjects with previously treated advanced HCC.  
2.2 
Endpoints 
Primary endpoint:   
• Overall survival (OS) 
Secondary endpoints:   
• Objective response rate (ORR) per RECIST 1.1 
• Progression-free survival (PFS) per RECIST 1.1 
Additional endpoints: 
• Safety and tolerability of cabozantinib 
• Pharmacokinetics (PK) 
• Relationship of baseline and changes in biomarkers with treatment and/or clinical outcome  
• Health-related quality of life (HRQOL) as assessed by the EuroQol Health questionnaire 
instrument (EQ-5D-5L)  


 
 
 
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3 
STUDY DESIGN 
3.1 
Study Sites 
This study will be conducted at up to 200 global clinical sites. 
3.2 
Estimated Study Dates and Duration of Subject Participation 
 It is estimated that it will take 25 months to randomize approximately 760 subjects at up to 200 
global sites. The number of events required for the primary analysis of OS is expected to be 
observed approximately 38 months after the first subject is randomized. It is estimated that 
subjects will participate for an average of 3 to 5 months on study treatment. Subjects will be 
followed until death (median of 8 to 12 months) or Sponsor decision to no longer collect these 
data. 
3.3 
Overview of Study Design 
This is a Phase 3 multicenter, randomized, double-blind, controlled trial of cabozantinib vs 
placebo in subjects with hepatocellular carcinoma who have received prior sorafenib. OS is the 
primary efficacy endpoint. Approximately 760 eligible subjects will be randomized in a 2:1 ratio 
to receive either cabozantinib or placebo as described in Section 3.4.  
Subjects’ course of treatment will consist of the following periods: 
Pretreatment Period: Potential subjects will be screened to determine if they meet the required 
eligibility criteria. Qualifying screening assessments must be performed within 28 days before 
randomization unless otherwise specified (Appendix A). Eligibility criteria based on laboratory 
values must use the central laboratory result (except for 24-hour urine protein test, if performed, 
and serum pregnancy test; Section 5.7.5). 
Treatment Period: Subjects who meet all study eligibility criteria will be randomly assigned in 
a 2:1 ratio to receive cabozantinib or placebo (Section 3.4).  
All attempts will be made to ensure that approximately 50% of enrolled subjects are from 
Europe, North America, and Australia and that approximately 20% of enrolled subjects are from 
Asia. 
Subjects will receive study treatment as long as they continue to experience clinical benefit in the 
opinion of the investigator or until there is unacceptable toxicity or the need for subsequent 
systemic anticancer treatment or liver-directed local anticancer therapy. Treatment may continue 


 
 
 
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after radiographic disease progression per RECIST 1.1 as determined by the investigator in the 
absence of subsequent systemic anticancer treatment or liver-directed local anticancer therapy as 
long as the investigator believes that the subject is still receiving clinical benefit from study 
treatment and that the potential benefit of continuing study treatment outweighs potential risk.  
Crossover between treatment arms will not be allowed unless the study transitions to the Open-
Label Phase (see Section 5.3 and Appendix B). 
Open-Label Phase: The Open-Label Phase will only be implemented upon decision by the 
Sponsor and discussion with regulatory authorities following review of the data. 
The study may transition to an Open-Label Phase if one of the planned analyses shows 
statistically-significant and clinically-meaningful evidence of improved OS. If the decision is 
made to enter the Open-Label Phase, study treatment will be unblinded and:  
• Subjects randomized to the placebo arm will have the option to crossover to receive 
treatment with cabozantinib if they meet the eligibility criteria for crossover to cabozantinib 
after treatment with placebo.   
• Subjects randomized to the cabozantinib arm who are still receiving study treatment, and 
subjects randomized to the placebo arm who are still receiving study treatment and do not 
crossover to cabozantinib, may continue on unblinded study treatment until a criterion for 
protocol-defined discontinuation has been met.  
• Subjects randomized to the cabozantinib arm who are in the post-treatment period, and 
subjects randomized to the placebo arm who do not crossover to cabozantinib and are in the 
post-treatment period, will continue with post-treatment assessments as outlined in Table 12 
of Appendix B. 
If the study transitions to the Open-Label Phase, enrollment will be discontinued. 
Screening of placebo subjects for crossover to cabozantinib will continue until the earlier of: 
• Six months from transition of the study to the Open-Label Phase or 
• The transition of the study to the Maintenance Phase 
In the Open-Label Phase safety assessments will continue, efficacy and AFP assessments will be 
per standard of care; PK, biomarker, HRQOL, and health care resource utilization assessments 
will be discontinued. 
See Section 5.3 and Appendix B for more details. 


 
 
 
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Maintenance Phase: When sufficient data have been collected to adequately evaluate all study 
endpoints, and upon site notification by the Sponsor, subjects remaining on study treatment will 
enter the study Maintenance Phase. Upon initiation of the Maintenance Phase, the Sponsor 
considers the safety and efficacy profile of the drug within this study to have been sufficiently 
established for regulatory purposes. 
In the Maintenance Phase subjects will continue to receive study treatment until a criterion for 
protocol-defined discontinuation has been met (protocol Section 3.6.1). Subjects are to undergo 
periodic safety assessments (including local laboratory tests) and tumor assessments; the nature 
and frequency of these assessments are to be performed per standard of care. It is the 
Investigator’s responsibility to ensure that subject visits occur frequently enough and adequate 
assessments are performed to ensure subject safety. See Section 5.4 and Appendix C for more 
details. 
Post-Treatment Period:  A post-treatment follow-up visit will occur 30 (+14) days after the 
date of the decision to discontinue study treatment.  
Radiographic tumor assessments, EQ-5D-5L, and Child-Pugh assessments will continue, 
regardless of whether study treatment is given, reduced, interrupted, or discontinued, until the 
later of 8 weeks after radiographic progression per RECIST 1.1 as determined by the investigator 
or the date of the decision to permanently discontinue study treatment.  
Subjects will be contacted approximately every 8 weeks after the post-treatment follow-up visit 
to assess survival status and to document receipt of subsequent anticancer therapy. Every effort 
must be made to collect these protocol-specific evaluations unless consent to participate in the 
study is withdrawn.  
Assessments in the Post-Treatment period for subjects who discontinue study treatment in the 
Open-Label Phase are provided in Appendix B. 
Assessments in the Post-Treatment Period (including the post-treatment follow-up visit) are not 
required for subjects who discontinue study treatment in the Maintenance Phase (such subjects 
are to be followed per standard of care). Please see Appendix C. 
3.4 
Treatment Groups and Randomization 
When an individual subject has been deemed eligible at the study site, the site representative will 
use the designated interactive voice response system/interactive web response system 


 
 
 
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(IVRS/IWRS) to enroll the subject into the study. Eligible subjects will be randomly assigned in 
a 2:1 ratio to the following treatment arms:  
• Cabozantinib arm: Oral cabozantinib (60 mg) qd  
• Placebo arm: Oral cabozantinib-matched placebo qd  
Randomization will be stratified by: 
• etiology of disease (HBV [with or without HCV], HCV [without HBV], or Other),  
• geographic region (Asia [includes Japan, Hong Kong, South Korea, Singapore, Malaysia, 
Philippines, Taiwan, Thailand, Vietnam], Other Regions) 
• the presence of extrahepatic spread of disease and/or macrovascular invasion (Yes, No).  
Randomization should occur as close as possible to the planned start of treatment (ie, within 24 
hours prior if practicable but no more than 3 days). Subjects are defined as enrolled in the study 
if randomized. Subjects who sign consent and are screened (to any degree, including 
rescreening) but never randomized are deemed permanent screen failures. 
If the study transitions to the Open-Label Phase subjects in the placebo arm who meet specific 
safety criteria will have the option to receive cabozantinib. 
Details about treatment regimens are provided in Section 6. 
3.5 
Study Blinding 
3.5.1 
Blinding of Study Treatments 
Study treatment assignment will be unknown to the subjects, investigators, study centers, 
Sponsor, and any contract research organization affiliated with the study other than those 
authorized to access treatment assignment for regulatory safety reporting and submission 
processes (see Section  8.2.2), interactive voice recognition/interactive web response (IVR/IWR) 
system administration and drug supply management. 
Cabozantinib-matched placebo will be packaged and color-, size-, and shape-matched to be 
indistinguishable from cabozantinib (Section 6.1).  
If the study transitions to the Open-Label Phase study treatment assignment will be unblinded 
and information provided to the Investigators. 
3.5.2 
Unblinding Procedure for Individual Subjects 
Blinding of study treatment is critical to the integrity of this clinical trial, and therefore if a 
subject’s treatment assignment is disclosed to the study site, the subject will have study treatment 


 
 
 
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discontinued. In the event of a medical emergency, the treating physician may decide that 
knowledge of the investigational product is critical to the subject’s management. In this rare 
situation, the treating physician may access the treatment information for this subject through the 
IVR/IWR system. The blind should only be broken for the specific subject in question, and 
before breaking the blind of an individual subject’s study treatment the investigator should have 
determined that the information will alter the subject’s immediate management. In the vast 
majority of cases, AEs may be properly managed without the need for unblinding (see 
Section  6.5). An unblinded notification, including the subject ID, treatment arm, and date of 
unblinding will be provided to the investigator and to the chair of the Independent Data 
Monitoring Committee (IDMC). A blinded notification that includes only the subject ID and the 
date of unblinding will be provided to the responsible medical monitor and the Sponsor’s Vice 
President of Drug Safety (or designee).  
3.6 
Discontinuation and Withdrawal 
3.6.1 
Treatment Discontinuation 
Subjects will receive study treatment until treatment discontinuation for any of the reasons listed 
below. Subjects may discontinue study treatment at any time without prejudice. If a subject 
discontinues study treatment, the reason will be documented in source documents. However, the 
subject will continue to be followed for safety as described in Section 5.5.1 and survival as 
described in Section 5.5.2; for subjects who discontinue study treatment prior to disease 
progression, disease assessments and HRQOL assessments should continue per the protocol-
defined schedule (Section 5.5.2). For subjects who discontinue study treatment, every effort must 
be made to continue protocol-specified evaluations and follow-up (Appendix A; Appendix B 
[Open-Label Phase]) unless the subject also withdraws consent to participate in all aspects of the 
study (see Section 3.6.2). Subjects who request to discontinue study procedures, may consent to 
allow follow-up for survival. Otherwise, all subjects will be followed until death or until a 
decision by the Sponsor is made to stop collection of these data. 
The following are possible reasons for discontinuation from study treatment: 
• Subject no longer experiences clinical benefit as determined by the investigator. If study 
treatment is withdrawn for this reason, the date of this decision is to be recorded and every 
effort should be made to continue safety evaluations and collection of subsequent treatment 
information and follow-up information for survival.  
• Unacceptable side effects the investigator feels may be due to study treatment, including any 
subject with a GI or non-GI perforation/fistula 
• The investigator feels it is not in the best interest of the subject to continue on study  


 
 
 
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• Participation in another clinical study using an investigational agent or investigational 
medical device 
• Necessity for treatment with nonprotocol systemic anticancer therapy  
• Receipt of liver-directed local anti-cancer therapy (eg, transarterial tumor embolization or 
chemoembolization, radiofrequency or microwave ablation, percutaneous ethanol or acetic 
acid ablation, injection or infusion of drug eluting or radiation-emitting beads, cryoablation, 
radiation therapy, including stereotactic radiotherapy, or surgery) 
• Necessity for withholding study drug for greater than 6 weeks for AEs, unless continuation 
of treatment is approved by the Sponsor 
• Refusal of sexually active fertile subjects (excluding subjects who have been sterilized) to 
use medically accepted methods of contraception 
• Pregnancy of a female subject  
• Request by the Sponsor  
• Subject request to discontinue study treatment  
• Unblinding of study treatment by the Investigator (prior to initiation of the Open-Label 
Phase) 
• Significant noncompliance with the protocol schedule in the opinion of the investigator or the 
Sponsor 
The Sponsor should be notified of all discontinuations of study treatment as soon as possible. If a 
subject fails to return for the protocol-defined visits, an effort must be made to determine the 
reason. If the subject cannot be reached by telephone, at a minimum, a registered letter should be 
sent to the subject (or the subject’s legal guardian) requesting contact with the study site.  
For subjects who withdraw or are withdrawn from study treatment, every effort must be made to 
continue protocol-specified evaluations and procedures through the post-treatment follow-up and 
extended follow-up visits unless consent to participate in the study is also withdrawn. All 
subjects will be followed until death, unless consent to do so is specifically withdrawn by the 
subject or until a decision by the Sponsor is made to stop collection of these data. 
3.6.2 
Study Withdrawal 
Subjects may withdraw their consent to participate in all aspects of the study including survival 
follow-up at any time without prejudice. If so, the reason for study consent withdrawal will be 
recorded in the source documents. No further study procedures or assessments will be performed 
or study data collected for this subject, other than the determination of survival status from 
public records such as government vital statistics or obituaries. Subjects who withdraw will not 
be replaced.  
 


 
 
 
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4 
STUDY POPULATION 
4.1 
Target Population 
This study will enroll subjects with advanced HCC. Eligibility criteria for this study have been 
carefully considered to ensure the safety of the study subjects and to safeguard the integrity of 
the study results. It is imperative that subjects fully meet all inclusion criteria and none of the 
exclusion criteria. The Sponsor will not grant waivers to study eligibility criteria. 
Eligibility criteria for all subjects are below (eligibility criteria for subjects in the placebo arm 
who opt to crossover to receive cabozantinib if the study transitions to Open-Label Phase are in 
Appendix B): 
4.2 
Inclusion Criteria 
1. Histological or cytological diagnosis of HCC (results of a previous biopsy will be accepted) 
2. The subject has disease that is not amenable to a curative treatment approach (eg, transplant, 
surgery, radiofrequency ablation)  
3. Received prior sorafenib 
4. Progression following at least 1 prior systemic treatment for HCC  
5. Recovery to ≤ Grade 1 from toxicities related to any prior treatments, unless the adverse 
events are clinically nonsignificant and/or stable on supportive therapy 
6. Age ≥ 18 years old on the day of consent 
7. ECOG performance status of 0 or 1 
8. Adequate hematologic function, based upon meeting the following laboratory criteria within 
7 days before randomization: 
a. absolute neutrophil count (ANC) ≥ 1200/mm3 (≥ 1.2 x 109/L) 
b. platelets ≥ 60,000/mm3 (≥ 60 x 109/L) 
c. hemoglobin ≥ 8 g/dL (≥ 80 g/L) 
9. Adequate renal function, based upon meeting the following laboratory criteria within 7 days 
before randomization: 
a. serum creatinine ≤ 1.5 × upper limit of normal or calculated creatinine clearance 
≥ 40 mL/min (using the Cockroft-Gault equation: (140 – age) x weight (kg)/(serum 
creatinine × 72 [mg/dL]) for males. (For females multiply by 0.85).  
AND 
b. urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.1 mg/mmol) or 24-hour urine 
protein < 1 g  
10. Child-Pugh Score of A  
11. Total bilirubin ≤ 2 mg/dL (≤ 34.2 µmol/L) within 7 days before randomization 
12. Serum albumin ≥ 2.8 g/dL (≥28 g/L) within 7 days before randomization 


 
 
 
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13. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)  < 5.0 upper limit of 
normal (ULN) within 7 days before randomization 
14. Hemoglobin A1c (HbA1c) ≤ 8% within 28 days before randomization (if HbA1c results are 
unavailable [eg, hemoglobin variant], a fasting serum glucose ≤ 160 mg/dL) 
15. Antiviral therapy per local standard of care if active hepatitis B (HBV) infection 
16. Capable of understanding and complying with the protocol requirements and signed 
informed consent   
17. Sexually active fertile subjects and their partners must agree to use medically accepted 
methods of contraception (eg, barrier methods, including male condom, female condom, or 
diaphragm with spermicidal gel) during the course of the study and for 4 months after the last 
dose of study treatment 
18. Female subjects of childbearing potential must not be pregnant at screening. Females of 
childbearing potential are defined as premenopausal females capable of becoming pregnant 
(ie, females who have had any evidence of menses in the past 12 months, with the exception 
of those who had prior hysterectomy). However, women who have been amenorrheic for 12 
or more months are still considered to be of childbearing potential if the amenorrhea is 
possibly due to prior chemotherapy, antiestrogens, ovarian suppression, low body weight, 
or other reasons. 
 
4.3 
Exclusion Criteria 
1. Fibrolamellar carcinoma or mixed hepatocellular cholangiocarcinoma 
2. Receipt of more than 2 prior systemic therapies for advanced HCC. Additional prior systemic 
therapies used as adjuvant or local therapy are allowed. 
3. Any type of anticancer agent (including investigational) within 2 weeks before 
randomization 
4. Radiation therapy (eg, I-131 or Y-90) within 4 weeks (2 weeks for radiation for bone 
metastases) or radionuclide treatment within 6 weeks of randomization (subject is excluded if 
there are any clinically relevant ongoing complications from prior radiation therapy)  
5. Prior cabozantinib treatment 
6. Known brain metastases or cranial epidural disease unless adequately treated with 
radiotherapy and/or surgery (including radiosurgery) and stable for at least 3 months before 
randomization. Eligible subjects must be without corticosteroid treatment at the time of 
randomization.  
7. Concomitant anticoagulation, at therapeutic doses, with anticoagulants such as warfarin or 
warfarin-related agents, low molecular weight heparin (LMWH), thrombin or coagulation 
factor X (FXa) inhibitors, or antiplatelet agents (eg, clopidogrel). Low dose aspirin for 
cardioprotection (per local applicable guidelines), low-dose warfarin (≤ 1 mg/day), and low-
dose LMWH are permitted. 
8. The subject has uncontrolled, significant intercurrent or recent illness including, but not 
limited to, the following conditions: 


 
 
 
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a. Cardiovascular disorders including 
i. Symptomatic congestive heart failure, unstable angina pectoris, or serious cardiac 
arrhythmias  
ii. Uncontrolled hypertension defined as sustained BP > 150 mm Hg systolic, or 
> 100 mm Hg diastolic despite optimal antihypertensive treatment 
iii. Stroke (including TIA), myocardial infarction, or other ischemic event within 
6 months before randomization 
iv. Thromboembolic event within 3 months before randomization. Subjects with 
thromboses of portal/hepatic vasculature attributed to underlying liver disease and/or 
liver tumor are eligible 
b. Gastrointestinal (GI) disorders including those associated with a high risk of perforation 
or fistula formation: 
i. Tumors invading the GI tract, active peptic ulcer disease, inflammatory bowel disease 
(eg, Crohn’s disease), diverticulitis, cholecystitis, symptomatic cholangitis or 
appendicitis, acute pancreatitis or acute obstruction of the pancreatic duct or common 
bile duct, or gastric outlet obstruction 
ii. Abdominal fistula, GI perforation, bowel obstruction, intra-abdominal abscess within 
6 months before  randomization,  
Note: Complete healing of an intra-abdominal abscess must be confirmed prior to 
randomization 
c. Major surgery within 2 months before randomization. Complete healing from major 
surgery must have occurred 1 month before randomization. Complete healing from minor 
surgery (eg, simple excision, tooth extraction) must have occurred at least 7 days before 
randomization. Subjects with clinically relevant complications from prior surgery are not 
eligible 
d. Cavitating pulmonary lesion(s) or endobronchial disease  
e. Lesion invading a major blood vessel including, but not limited to: inferior vena cava, 
pulmonary artery, or aorta).  Subjects with lesions invading the portal vasculature are 
eligible. 
f. Clinically significant bleeding risk including the following within 3 months of 
randomization: hematuria, hematemesis, hemoptysis of >0.5 teaspoon (>2.5 mL) of red 
blood, or other signs indicative of pulmonary hemorrhage, or history of other significant 
bleeding if not due to reversible external factors 
g. Other clinically significant disorders such as: 
i. Active infection requiring systemic treatment, known infection with human 
immunodeficiency virus (HIV), or known acquired immunodeficiency syndrome 
(AIDS)-related illness. Subjects with active hepatitis virus infection controlled with 
antiviral therapy are eligible. 
ii. Serious non-healing wound/ulcer/bone fracture 
iii. Malabsorption syndrome 
iv. Uncompensated/symptomatic hypothyroidism 


 
 
 
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v. Requirement for hemodialysis or peritoneal dialysis 
vi. History of solid organ transplantation  
9. Subjects with untreated or incompletely treated varices with bleeding or high risk for 
bleeding.  Subjects treated with adequate endoscopic therapy (according to institutional 
standards) without any episodes of recurrent GI bleeding requiring transfusion or 
hospitalization for at least 6 months prior to study entry are eligible.  
10. Moderate or severe ascites  
11. Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms within 7 days 
before randomization 
Note: If the QTcF is > 500 ms in first ECG, a total of 3 ECGs should be performed. If the 
average of these 3 consecutive results for QTcF is ≤ 500 ms, the subject meets eligibility in 
this regard. 
12. Inability to swallow tablets  
13. Previously identified allergy or hypersensitivity to components of the study treatment 
formulations 
14. Pregnant or lactating females 
15. Diagnosis of another malignancy within 2 years before randomization, except for superficial 
skin cancers, or localized, low-grade tumors deemed cured and not treated with systemic 
therapy 
 


 
 
 
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5 
STUDY ASSESSMENTS AND PROCEDURES 
In this study, study treatment will be administered orally on a continuous daily basis. This 
document generally presents scheduled times for study procedures by week (W) and day (D) 
(eg, W1D1, W3D1, etc.) relative to the date of the first dose of study treatment (defined as 
W1D1). Study W1D1 should occur within 3 days of randomization. 
All assessments for safety and HRQOL assessments will be scheduled based on W1D1. 
All assessments for efficacy (investigator assessed CT or MRI, bone scans) and AFP will be 
scheduled based on the date of randomization.  
Unscheduled visits for safety evaluation are allowed at any time. 
See Appendix A for the schedule of study procedures; Appendix B for assessments during the 
Open-Label Phase, Appendix C for the Maintenance Phase. 
5.1 
Pretreatment Period 
Informed consent must be obtained prior to initiation of any clinical screening procedure that is 
performed solely for the purpose of determining eligibility for research; however, evaluations 
performed as part of routine care prior to informed consent can be utilized as screening 
evaluations if permitted by the site’s IRB/EC policies. Informed consent may be obtained greater 
than 28 days before randomization. The investigator must ensure that the subject is consented 
based on the most recently IRB-approved version of the ICF. At informed consent, subjects will 
be assigned a subject identifier; subject identifiers are not to be re-assigned if a subject is 
determined to be ineligible, and subjects are to maintain their original identifier if re-screening is 
required or if the subject experiences a change in study site or investigator. 
Subjects will undergo screening assessments to determine eligibility and have baseline 
evaluations as outlined in Appendix A, including medical history and HCC etiology, prior cancer 
treatment, Child-Pugh classification, tumor morphology, physical examination and vital signs, 
12-lead ECG, clinical laboratory assessments, pregnancy test, and disease assessment and AFP. 
Biopsy will be required for those subjects that have not had previous histological or cytological 
diagnosis of HCC. Biopsy can be performed more than 28 days prior to randomization. Healing 
from biopsy must be complete at least 7 days prior to randomization. 
Prior to enrollment, all subjects will undergo central laboratory tests to determine hepatitis virus 
status, including hepatitis B core antibody, hepatitis B surface antigen, and hepatitis C antibody.  


 
 
 
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The hepatitis virus status test results by central laboratory are not required to randomize a 
subject.  Either historical hepatitis virus results or the results of hepatitis virus status from the 
central laboratory can be used to randomize a subject. However, if the hepatitis virus results have 
been received at the site prior to randomization, then the central laboratory results should be used 
to randomize the subject.   
Study eligibility is based on a subject meeting all of the study inclusion criteria and none of the 
exclusion criteria at screening. Qualifying screening assessments, with the exception of tumor 
biopsy, must be performed within 28 days before randomization (within 7 days before 
randomization for laboratory tests and other selected assessments [see Appendix A]).  
5.2 
Treatment Period 
Subjects eligible after completing all screening evaluations will be randomly assigned in a 2:1 
fashion to receive cabozantinib or placebo (Sections 3.4 and 6).  
Study W1D1 is defined as the first day of blinded study drug treatment—either cabozantinib or 
placebo (see Section 6.1.1). (For subjects who are randomized but not treated, W1D1 is defined 
as day of randomization.) 
Subjects should receive their first dose of study drug treatment within 3 days after 
randomization. See Appendix A for requirement for repeat assessments needed before first dose 
to confirm suitability for study treatment (Appendix B for subjects in the placebo arm for the 
Open-Label Phase). 
Please refer to Appendix A (Appendix B for Open-Label Phase) and Section 5.7.5 for handling 
of all samples for laboratory assessments.  
While the subject is receiving study treatment, the subject’s clinical status is to be evaluated by 
the treating physician at each clinic visit to confirm that the subject is suitable for continuing 
study treatment. Clinical laboratory results from samples obtained during clinic visits and tumor 
assessments from imaging visits are to be reviewed promptly by the treating physician for the 
same purpose.  
Subjects will receive study treatment as long as they continue to experience clinical benefit in the 
opinion of the investigator until the earlier of unacceptable toxicity, the need for subsequent 
systemic anti-cancer therapy or liver-directed local anti-cancer therapy, or until any of the other 
reasons for treatment discontinuation described in Section 3.6.1. Treatment with study drug may 


 
 
 
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continue after radiographic disease progression per RECIST 1.1 has been determined by the 
investigator, as long as the investigator believes that the subject is still receiving clinical benefit 
from study treatment and that the potential benefit of continuing study treatment outweighs 
potential risk.  
Crossover between treatment arms will not be allowed unless the study transitions to the Open-
Label Phase (see Section 5.3 and Appendix B).  
Clinic visits for safety evaluations will occur prior to dosing on W1D1 and at minimum every 
2 weeks (± 3 days) after treatment is initiated through W9D1 and then every 4 weeks (± 5 days) 
thereafter independent of any dose interruptions. The final safety assessment will occur at the 
post-treatment follow-up visit 30 (+14) days after the date of the decision to discontinue 
treatment) unless a Grade 3/4 AE or an SAE is determined to be ongoing (see Section 8.3.4).  
If study treatment is interrupted, investigators should perform additional safety assessments 
weekly or more frequently as clinically indicated. Results of safety assessments should be 
reviewed as soon as they become available in order to make timely decisions regarding the 
continuation, interruption, or restarting of study treatment.  
Radiographic tumor assessments (Section 5.7.6) and HRQOL assessments (Section 5.7.8) should 
be performed according to the schedule in Appendix A (Appendix B for the Open-Label Phase, 
Appendix C for the Maintenance Phase [HRQOL will not be assessed in the Open-Label Phase 
or Maintenance Phase]).  
In accordance with the ITT principle, HRQOL, and radiographic tumor assessments, as well as 
survival follow-up, are to be performed per protocol even for subjects randomized but who never 
receive study treatment. For such subjects, W1D1 is defined as the date of randomization. 
Child-Pugh Score every 8 weeks (± 5 d) after randomization (W9D1, W17D1 etc). Child-Pugh 
assessments should continue regardless of whether study treatment is given, reduced, interrupted, 
or discontinued until the later of 8 weeks after radiographic progression per RECIST 1.1 as 
determined by the investigator or the date of the decision to permanently discontinue study 
treatment. (Please see Appendix B for the Open-Label Phase, Child-Pugh assessments will be 
discontinued for the Maintenance Phase). 


 
 
 
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Blood samples for pharmacogenetic, plasma biomarker, serum bone marker analyses, and 
potential CTC analysis (Section 5.7.11) will be collected according to the schedule in Appendix 
A. (These assessments will be discontinued for the Open-Label Phase or Maintenance Phase.) 
In addition, tumor tissue (archival or recently biopsied) will be obtained (Section 5.7.11) at 
enrollment whenever available for exploratory analysis of MET and potentially other pathway 
components or modulators associated with the mechanism of action of cabozantinib as predictive 
biomarkers. 
Blood samples for determination of plasma concentrations of cabozantinib and potentially 
relevant metabolites (Section 5.7.10) will be performed according to the schedule in Appendix 
A. (These assessments will be discontinued for the Open-Label Phase or Maintenance Phase.) 
The schedule for assessments should be maintained independent of any dose interruptions. 
5.3 
Open-Label Phase 
The Open-Label Phase will only be implemented upon decision by the Sponsor and discussion 
with the regulatory authorities following review of the data. 
The study may transition to an Open-Label Phase if one of the planned analyses shows 
statistically-significant and clinically-meaningful evidence of improved OS. If the decision is 
made to enter the Open-Label Phase, study treatment will be unblinded and:  
• Subjects randomized to the placebo arm will have the option to crossover to receive 
treatment with cabozantinib if they meet the eligibility criteria for crossover to cabozantinib 
after treatment with placebo.   
• Subjects randomized to the cabozantinib arm who are still receiving study treatment, and 
subjects randomized to the placebo arm who are still receiving study treatment and do not 
crossover to cabozantinib, may continue on unblinded study treatment until a criterion for 
protocol-defined discontinuation has been met.  
• Subjects randomized to the cabozantinib arm who are in the post-treatment period, and 
subjects randomized to the placebo arm who do not crossover to cabozantinib and are in the 
post-treatment period, will continue with post-treatment assessments as outlined in Table 12 
of Appendix B. 
If the study transitions to the Open-Label Phase, enrollment will be discontinued. 


 
 
 
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Screening of placebo subjects for crossover to cabozantinib will continue until the earlier of: 
• Six months from transition of the study to the Open-Label Phase or 
• The transition of the study to the Maintenance Phase 
In the Open-Label Phase safety assessments will continue, efficacy and AFP assessments will be 
per standard of care; PK, biomarker, HRQOL, and health care resource utilization assessments 
will be discontinued. 
See Appendix B for more details. 
 
5.4 
Maintenance Phase 
When sufficient data have been collected to adequately evaluate all study endpoints, and upon 
site notification by the Sponsor, subjects remaining on study treatment will enter the study 
Maintenance Phase. Upon initiation of the Maintenance Phase, the Sponsor considers the safety 
and efficacy profile of the drug within this study to have been sufficiently established for 
regulatory purposes. 
In the Maintenance Phase subjects will continue to receive study treatment until a criterion for 
protocol-defined discontinuation has been met (protocol Section 3.6.1). Subjects are to undergo 
periodic safety assessments (including local laboratory tests) and tumor assessments; the nature 
and frequency of these assessments are to be performed per standard of care. It is the 
Investigator’s responsibility to ensure that subject visits occur frequently enough and adequate 
assessments are performed to ensure subject safety. 
In order to continue to capture important safety information on subjects still enrolled in the 
study, reporting of SAEs and other reportable events (pregnancy and medication errors with 
sequelae) is to continue per protocol Section 8.2. 
Further, the following events (whether serious or not) are to be reported using the same process 
as for reporting SAEs described in protocol Section 8.2 (though SAE reporting timeline 
requirements do not apply to non-serious events reported in these categories): 
• Adverse Events (serious or not) leading to cabozantinib treatment discontinuation 
• Adverse Events (serious or not) leading to cabozantinib dose modification (ie, causing 
cabozantinib to be withheld or reduced) 


 
 
 
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Other non-serious adverse events will not be collected by the Sponsor as they are unlikely to 
meaningfully change the safety profile established in earlier phases of this study. 
Study drug accountability is to continue as described in Section 6.4. 
See Maintenance Phase Schedule of Assessments (Appendix B). To receive study treatment 
supplies it may be necessary for subjects to visit the study site more frequently than clinic visits 
for safety and tumor evaluations performed per standard of care. 
Site monitoring visits will occur at a reduced frequency to ensure adherence to GCP, protocol 
compliance, adequate subject safety follow-up, study drug accountability, and reporting of SAEs 
and other reportable events. 
During the Maintenance Phase no data are to be entered into electronic case report forms. Study 
central laboratory samples are not to be obtained. Do not submit local laboratory results to the 
study local laboratory management vendor, radiographic images to the study central imaging 
vendor, or ECGs to the study central imaging vendor. 
5.5 
Post-Treatment Period 
5.5.1 
Post-Treatment Follow-Up Visit 
Subjects who discontinue from study treatment will return to the site, 30 (+14) days after the date 
of the decision to discontinue study treatment. During the Post-Treatment Follow-Up Visit, 
safety assessments will be performed. Please refer to Appendix A for a description of all the 
assessments at this visit. (Assessments in the Post-Treatment period for subjects who discontinue 
study treatment in the Open-Label Phase are provided in Appendix B.) 
Adverse events are to be documented and/or followed as described in Section 8.3.4. 
Assessments in the Post-Treatment Period (including the post-treatment follow-up visit) are not 
required for subjects who discontinue study treatment in the Maintenance Phase (such subjects 
are to be followed per standard of care). Please see Appendix C. 
5.5.2 
Extended Follow-up 
Following treatment discontinuation for whatever reason, subjects will continue to be followed 
either via clinic visit or telephone contact approximately every 8 weeks for the following 
information unless the subject withdraws consent from all aspects of the study: 
• Survival status of subject or date of death and primary cause of death 


 
 
 
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• Receipt of subsequent anticancer therapies (drug or procedure name and dates) 
Radiographic disease assessments, EQ-5D-5L, and Child-Pugh assessments are to continue in 
the Extended Follow-Up period as necessary per the schedule for these assessments in Appendix 
A. 
Subjects will be followed until death or until the Sponsor’s decision to no longer collect these 
data.  
At each contact, the investigator (or designee) will determine if the subject died, and if so, record 
the date and cause of death. All efforts must be undertaken by the study sites to determine the 
date of death (or date subject last known alive at the time of a data cut-off). This may include, 
but not necessarily be limited to telephone contacts, communication at study visits, registered 
letters, and reviews of local obituaries and government death records. If subject is lost to follow-
up, multiple attempts to contact must be made and documented in the subject records.  
5.6 
Unscheduled Visits 
If the investigator determines that a subject should be monitored more frequently or with 
additional imaging and/or laboratory parameter assessments than indicated by the protocol-
defined visit schedule these unscheduled visits or assessments are permitted. The laboratory 
assessments should be done by the central laboratory; however, if the results are needed 
immediately, they may be done by the local laboratory and the results forwarded to the 
management vendor for handling of local laboratory data. In such instances a sample for central 
laboratory analysis should also be collected. Any imaging studies performed to assess disease 
status will be collected. 
If study treatment is interrupted, during the intervening time between the last dose and the time 
drug is restarted the study site should perform unscheduled visits weekly or more frequently as 
clinically indicated to monitor subject safety and appropriateness for re-treatment with study 
treatment. 
5.7 
Instructions for Specific Procedures 
5.7.1 
Demographics, Medical and Cancer History 
Demographics at screening will include date of birth (or age if date of birth is not allowed to be 
collected by local regulations), medical and cancer history, surgical history, radiation therapy 
history, and systemic anti-cancer treatment history including names and administration dates of 
all VEGFR-targeting tyrosine kinase inhibitors. 


 
 
 
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Baseline assessments will include information pertinent for staging (eg, tumor morphology, 
macrovascular invasion and/or extrahepatic spread, sites of disease, and extent of liver 
involvement) and documentation of the etiology of HCC based on the subject’s medical records.  
5.7.2 
Physical Examination 
Physical examinations will include height (screening visit only), weight, ECOG performance 
status, and an assessment of the following systems: skin, head, eyes, ears, nose, throat, 
respiratory system, cardiovascular system, gastrointestinal system, neurological condition, blood 
and lymphatic systems, and the musculoskeletal system. A symptom-directed physical 
examination including performance status will be conducted on W1D1 before first dose of study 
treatment. Any ongoing / intercurrent condition prior to first dose will be captured in source 
documents and on a CRF. 
5.7.3 
Vital Signs 
Vital signs include 5-minute sitting blood pressure, pulse, respiratory rate, and temperature will 
be assessed at screening, at all regularly scheduled visits, and at all unscheduled visits (if 
possible). 
5.7.4 
Electrocardiograms 
Standard 12-lead equipment will be used for all ECGs. The Fridericia formula is depicted below 
for calculation of the corrected QT interval (QTcF). 
 
QT = measured QT interval in milliseconds; RR = measured R to R interval (which can 
be derived from the heart rate as 60/heart rate) 
 
ECGs to establish eligibility must be done within 7 days prior to randomization (Appendix A 
[Appendix B for the Open-Label Phase]). To confirm suitability for treatment after 
randomization, ECGs must be repeated on W1D1 prior to administering the first dose of study 
treatment unless the screening tests were performed within 10 days prior to W1D1. 
At screening, if the initial QTcF is > 500 ms, a total of 3 ECGs each separated by at least 
3 minutes should be performed. If the average of the 3 results for QTcF is ≤ 500 ms, the subject 
is eligible for the study.   


 
 
 
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During the study, single ECG assessments will be performed as indicated in Appendix A. If 
cardiac abnormalities are detected or suspected, two additional ECGs must be performed at 
intervals at least 3 minutes apart in order to confirm the finding. If at any time while on study 
there is an increase in average QTcF >500 ms, study treatment must be immediately interrupted 
and instructions in Section 6.7.10 for continued monitoring of QTc must be followed. 
Abnormalities in the ECG that lead to a change in subject management (eg, dose reduction or 
delay, treatment discontinued, requirement for additional medication or monitoring) or that result 
in clinical symptoms are considered clinically significant for the purposes of this study and 
should be reported as AEs by the Investigator. If values meet criteria defining them as serious, 
they must be reported as SAEs (Section 8.2).  
5.7.5 
Laboratory Assessments 
Laboratory analytes that will be measured for this study are listed in Table 5-1. The schedule for 
laboratory assessments is provided in Appendix A (Appendix B for Open-Label Phase). 
Hematology, serum chemistry, coagulation, UPCR (and components), AFP, hepatitis virus 
testing (at Screening), and thyroid function tests are to be performed by a central laboratory, 
including unscheduled visits (if possible).  Central laboratory results will be provided to the 
investigator with the exception of AFP which will not be provided to the investigator until the 
decision to discontinue study treatment.  Local laboratory assessments for these panels are 
permitted for these assessments if the results are required by the investigator in a rapid timeframe 
(such as for monitoring of AEs), but may not be used to establish eligibility. Local laboratory 
results for these panels must be forwarded to the study local laboratory management vendor if 
performed in lieu of the central laboratory assessment at any scheduled or unscheduled visit. In 
rare, exceptional circumstances and with approval of the Sponsor, local laboratory result may be 
allowed for the purpose of determining eligibility in the event that the result of an individual test 
performed at the central laboratory is unavailable. 
Routine (dipstick) urinalysis, microscopic urine examination, and serum pregnancy tests are to 
be done by local laboratory. Results or status from these tests will be recorded on CRFs and will 
not be submitted to the study local laboratory management vendor. 
Tests for 24-hour urine protein tests, if performed to determine eligibility or at any scheduled or 
unscheduled visit (see Section 6.7.9), are to be done by local laboratory and the lab results 
forwarded to the study local laboratory management vendor. 


 
 
 
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Laboratory tests to establish eligibility (with the exception of HbA1c) must be done within 
7 days prior to randomization (Appendix A). HbA1c will only be tested at screening to confirm 
eligibility and must be done within 28 days prior to randomization. For subjects whose HbA1c 
results are unavailable (eg, hemoglobin variant), a fasting serum glucose test result can be used 
after sponsor approval. Hepatitis virus testing will only be tested at screening and must be done 
within 28 days prior to randomization. All pregnancy tests must be conducted on serum samples. 
If the investigator suspects the subject is clinically deteriorating during the screening period, 
additional unscheduled laboratory tests (eg, albumin, bilirubin) should be performed by the local 
laboratory before randomization to confirm that the subject remains suitable for study treatment 
and amenable to study participation commensurate with the goals of the clinical trial. 
To confirm suitability for treatment after randomization, laboratory tests (except for pregnancy 
test) must be repeated on W1D1 prior to administering the first dose of treatment unless the 
screening tests were performed within 10 days prior to W1D1 or the subject has experienced a 
change in clinical status. A serum pregnancy test for females of child-bearing potential must be 
repeated before dosing on W1D1 unless the screening was performed within 7 days prior to 
W1D1. 


 
 
 
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Table 5-1: 
Laboratory Panels 
Central Laboratory 
If performed by local laboratory in lieu of central lab assessment, submit results to study local laboratory 
management vendor 
Hematology 
Serum chemistry 
Urine chemistry 
• White blood cell count (WBC) with 
differential (neutrophils [absolute 
neutrophil count; ANC], basophils, 
eosinophils, lymphocytes, monocytes) 
• hematocrit 
• platelet count 
• red blood cell count 
• hemoglobin 
• reticulocytes 
 
Coagulation 
• Prothrombin time/international 
normalized ratio (PT/INR) 
• Partial thromboplastin time (PTT) 
 
 
Other Parameters 
• Alpha-fetoprotein (AFP)b 
  
• albumin 
• total alkaline phosphatase 
• amylase 
• alanine aminotransferase (ALT) 
• aspartate aminotransferase (AST) 
• blood urea nitrogen (BUN) 
• calcium (corrected)  
• bicarbonate 
• chloride 
• creatinine 
• γ-glutamyltranspeptidase (GGT) 
• glucose 
• lactate dehydrogenase (LDH) 
• lipase  
• magnesium 
• phosphorus 
• potassium 
• sodium 
• total bilirubin 
• conjugated bilirubin 
• unconjugated bilirubin  
• total protein  
• hemoglobin A1c, glycosylated 
(HbA1c; screening) 
• Protein (spot urine; fully 
quantitative) 
• Creatinine (fully 
quantitative)  
• Urine protein/creatinine 
ratio (UPCR; spot urine) a  
Thyroid function 
• Thyroid stimulating 
hormone (TSH) 
• Free T4 (required at 
screening; after screening 
only if TSH is outside 
normal range) 
 
Hepatitis Virus Statusb 
• Hepatitis B surface antigen, 
Hepatitis B core antibody, 
Hepatitis C antibody 
 
Local Laboratory 
Submit only 24-hour urine protein test results to study local laboratory management vendor 
Urinalysis (Dipstick or Routine) 
Microscopic Urine Examination 
Pregnancy (serum) 
• pH 
• specific gravity 
• ketones 
• protein 
• glucose 
• nitrite 
• urobilinogen 
• leukocyte esterase 
• blood 
 
24-Hour Urine 
• 24-hour urine proteina 
• Perform at the discretion of the 
investigator based on results or 
routine urinalysis or as clinically 
indicated 
• β-human chorionic 
gonadotropin (β-HCG) 
 
 
Chemistry (serum) (only if 
HbA1c results are 
unavailable) 
• glucose (fasting) 
 
a 
When UPCR exceeds 1, a repeat UPCR or a 24-hour urine protein and creatinine should be performed to confirm the result 
(see Table 6-7) 
b  If the study transitions to the Open-Label Phase AFP and hepatitis virus status will not be assessed by central laboratory. 
These parameters can be assessed locally per standard of care as necessary, please see Appendix B. 


 
 
 
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Clinically significant laboratory abnormalities should be reported as AEs by the Investigator. In 
general, laboratory abnormalities that lead to a change in subject management (eg, dose withheld 
or reduced, treatment discontinued; requirement for additional medication or monitoring) are 
considered to be clinically significant. If laboratory values constitute part of an event that meets 
criteria defining it as serious, the event (and associated laboratory values) must be reported as a 
serious AE (SAE) (see Section 8.2).  
In cases of discordance on AE grading between duplicate local and central labs, the lab 
abnormality with the higher grade should be referenced for AE reporting purposes. 
5.7.6 
Disease Assessments 
5.7.6.1 
General 
Radiographic tumor assessments at screening will include CT or MRI of the chest, abdomen, and 
pelvis (CAP) and a technetium bone scan. A noncontrast CT of the chest must be performed 
(unless prohibited by local regulations) if an MRI CAP study is performed. For at least the liver 
evaluation a noncontrast study followed by a triphasic CT (arterial, portal and delayed venous) 
post contrast study or a liver MRI with gadolinium imaging must be obtained. The same imaging 
modalities used at screening will be used for subsequent tumor assessments. CT/MRI of the 
brain will be acquired at screening as clinically indicated (suspicion of brain metastasis). 
CT/MRI of the brain will be continued post-baseline only in subjects with documented brain 
metastases or as clinically indicated (suspicion of brain metastasis on study).  MRI is the 
preferred method for brain imaging and should be done for imaging of the brain if possible. CT 
of the brain is an alternative.  
CT/MRI assessments will be made at screening, 8 weeks after randomization, and every 8 weeks 
thereafter. Disease status will be determined at the local site (ie. Investigator and/or radiologist) 
using RECIST version 1.1 (Appendix G). Screening scans will be evaluated by the investigator 
for evidence of extrahepatic spread and/or macrovascular invasion for the purpose of subject 
stratification at randomization. 
The following are recommendations for CT or MRI imaging during the conduct of this study. 
For screening (baseline) and all scheduled follow-up imaging examinations, CT of the 
chest/abdomen/pelvis should include contrast with triphasic (arterial, portal and delayed venous 
phase) imaging of the liver. A noncontrast liver study must be acquired (at least at baseline). If 
MRI is used for the CAP study then a noncontrast CT of the chest must be obtained (unless 


 
 
 
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prohibited by local regulations). For imaging of the liver, MRI with gadolinium enhanced 
imaging may be substituted for the contrast enhanced triphasic CT scan. Volume acquisition CT 
reconstructed every 3-5 mm contiguously with a soft tissue filter should be performed. MRI 
scans should be performed using a body coil and reconstruction every 3-5 mm without gap. For 
all follow-up CT (or MRI) examinations, the same dose and rate of contrast agent and the same 
delay from injection to scanning (ie, each phase) should be used. If at a follow-up imaging time 
point there is a contraindication to use of contrast (eg, impaired renal function) then a 
noncontrast CT or MRI should be performed. 
Whole body bone scan images must be acquired using any technetium based isotope and injected 
with a dose in accordance with local standards. The time from injection to scan acquisition 
should be same at each time point and images acquired with a delay from injection according to 
local standards. All subjects will have a bone scan at screening. Follow-up scans will be 
performed at 8 and 16 weeks after randomization, and every 16 weeks thereafter for subjects 
with documented bone lesions on the whole body bone scan at screening. 
CT/MRI and bone scan assessments will continue on this schedule irrespective of whether study 
treatment is given, reduced, interrupted, or discontinued, until the later of 8 weeks after 
radiographic disease progression per RECIST 1.1 as determined by the investigator or the date of 
the decision to permanently discontinue study treatment (Appendix A).  
The Sponsor or designee will collect all on-study scans in original DICOM format for possible 
independent review and analysis.  
Detailed instructions for tumor imaging will be provided in a separate manual. 
If the study transitions to the Open-Label Phase or to the Maintenance Phase, tumor assessments 
will be done per standard of care. 
5.7.7 
Alpha Fetoprotein (AFP) 
A blood sample for alpha-fetoprotein (AFP) will be obtained at the time of each radiographic 
disease assessment visit according to the schedule in Appendix A. Assessments will continue 
irrespective of whether study treatment is given, reduced, interrupted, or discontinued, until the 
later of 8 weeks after radiographic disease progression per RECIST 1.1 as determined by the 
investigator or the date of the decision to permanently discontinue study treatment. 


 
 
 
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Samples for AFP measurement will be analyzed by a central laboratory, and the results will not 
be provided to the investigators until the decision to discontinue study treatment.  
If the study transitions to the Open-Label Phase or to the Maintenance Phase, AFP will no longer 
be collected and analyzed by the central laboratory. AFP assessments may continue via local 
laboratory per standard of care. 
 
5.7.8 
Health-Related Quality of Life (HRQOL) Assessments 
The standardized measure of health status EQ-5D-5L, developed by the EuroQol group, will be 
used in order to provide a generic measure of health for clinical appraisal (Herdman 2011). EQ-
5D-5L has two pages (Appendix H): a descriptive page with five dimensions which assesses 
changes in mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, and 
global health in patients. Each dimension can be reported on 5 levels (no problems, slight 
problems, moderate problems, severe problems, and extreme problems). The second page has a 
0-100 visual analogue scale which records the respondent’s self-rated health between 100 (‘the 
best health you can imagine’) and 0 (‘the worst health you can imagine’) and serves as a 
quantitative measure of health by the individual respondents.  
The questionnaire will be self-completed by the subject. Assessments are to continue according 
to the schedule in Appendix A, irrespective of whether study treatment is given, reduced, 
interrupted, or discontinued, until radiographic tumor assessments are discontinued. 
Subjects should complete the questionnaire on the day of the visit prior to seeing study site 
personnel. Subjects should not receive any information on their most recent medical results prior 
to completing the questionnaires in order to not influence their reporting. At clinic visits, 
questionnaires should be carefully reviewed by study site personnel. If a clinic visit is not 
possible, subjects should complete the questionnaire per schedule and return it to the site. Every 
effort should be made by the site to retrieve all completed questionnaires including the 
assessment following radiographic progression or discontinuation of study treatment.  
Translated copies of the EQ-5D-5L questionnaire and instructions for filling them out will be 
provided to each study site in a separate study manual. The EQ-5D-5L questionnaire may be 
omitted in patients who speak a language for which there is not an approved translation of this 
tool. 


 
 
 
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If the study transitions to the Open-Label Phase or to the Maintenance Phase, HRQOL 
assessments will be discontinued. 
5.7.9 
Health Care Resource Utilization 
Health care resource utilization parameters will be collected for each SAE reported during the 
study. These comprise emergency room visits, hospital admissions, intensive care unit 
admissions, and length of stay.  
If the study transitions to the Open-Label Phase or to the Maintenance Phase, health care 
resource utilization assessments will be discontinued. 
5.7.10 
Pharmacokinetics (PK) 
Pharmacokinetic sample collection is required in all subjects unless otherwise approved by the 
Sponsor.  
The concentration of cabozantinib and possible relevant metabolites will be measured in PK 
samples according to the schedule in Appendix A. Subjects will be asked to record the time of 
the dose taken the night before PK samples are collected.  
The scheduled PK sample should be taken whether or not study drug is administered on that day. 
Each PK sample should be collected approximately 8 or more hours after the previous dose of 
study drug and if study drug will be administered on that day, prior to study drug administration. 
The investigator will ask the subject for the date and time of the most recent prior dose of study 
treatment and this information will be recorded on the appropriate CRF page. Collection of these 
blood samples may be halted early or sampling frequency may be reduced at the discretion of the 
Sponsor. 
Cabozantinib plasma concentrations will be measured using a validated bioanalytical method. 
The concentration of cabozantinib in these samples will be used to confirm exposure to 
cabozantinib and to further characterize the population PK models of cabozantinib and possible 
relevant metabolite(s) in this subject population. These concentration data may also be used to 
explore the relationship of exposure and clinical safety parameters (eg, selected AEs) or clinical 
response.  
Detailed instructions for sample preparation will be provided in a separate manual.  


 
 
 
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If the study transitions to the Open-Label Phase or to the Maintenance Phase, PK assessments 
will be discontinued. 
5.7.11 
Pharmacogenetics and Biomarkers 
Unless prohibited by local regulations, failure to grant informed consent for this purpose, or 
sponsor decision, a blood sample will be collected pre-dose on Day 1 of Week 1 for 
genotyping/single nucleotide polymorphism/copy number variation analysis to correlate genetic 
variation with PK, safety, tolerability of and response to study treatment.  
Assessment of biomarkers in plasma by multiplexed array will be performed. These may include 
target receptors and ligands (eg, VEGF-A, HGF, soluble VEGFR2, and MET) and other markers 
related to cabozantinib mechanism of action and/or HCC. Serum bone biomarkers will also be 
assessed. In addition, CTCs may be analyzed in blood samples collected at selected sites. 
Samples for these studies will be collected according to the schedule in Appendix A. 
In addition, tumor tissue (archival or recently biopsied) will be obtained at enrollment whenever 
available for exploratory analysis of MET and potentially other pathway components or 
modulators associated with the mechanism of action of cabozantinib, as predictive biomarkers. 
Formalin-fixed paraffin embedded (FFPE) tumor blocks are preferred but in cases where this is 
not possible, 10 unstained freshly-cut FFPE slides should be obtained. 
Detailed instructions for sample preparation and shipping will be provided in a separate manual.  
Collection of these samples may be halted early or sampling frequency may be reduced at the 
discretion of the Sponsor. 
If the study transitions to the Open-Label Phase or to the Maintenance Phase, biomarker 
assessments will be discontinued. 
5.7.12 
Child-Pugh Scoring 
Child-Pugh score will be based on the Modified Child-Pugh classification of severity of liver 
disease (Pugh 1973, Lucey 1997) according to the degree of ascites, total bilirubin and albumin, 
prothrombin time, and degree of encephalopathy.  The Child-Pugh scoring system is located in 
Appendix E.  The Child-Pugh score to confirm study eligibility will be derived locally by the 
site.  Determination of severity of ascites and encephalopathy will be made by clinical 
assessment.   


 
 
 
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6 
TREATMENT PROCEDURES 
6.1 
Blinded Study Drug Dosing  
The start of study drug dosing should occur as soon after randomization as practical, ie, within 
24 hours if possible but no more than 3 days after. Subjects will take the tablet(s) once daily at 
bedtime except for Day 1 Week 1: the first dose of study treatment will be administered in the 
clinic so that each subject can be observed for initial tolerability (see Section 6.1.1). Subsequent 
doses will be self-administered at home. Any unused study treatment must be returned to the 
study site for drug accountability and disposal.  
The assigned dose is 60 mg cabozantinib (or placebo) given once daily, which should be 
maintained in the absence of treatment-emergent toxicity. Guidelines for these potential dose 
alterations are discussed in Section 6.5.  
While on study treatment, subjects are to be instructed not to eat grapefruit, Seville oranges, or 
products made with these fruits (including juice, jams, or candies) while on study. See 
Section 7.1.2 for other potential drug interactions.  
If the study transitions to the Open-Label Phase, study treatment assignments will be unblinded 
and subjects will have the option to receive unblinded study drug (Appendix B). 
6.1.1 
Study Drug Administration on Week1 Day 1 (W1D1) 
On the first day of treatment, the subject should fast (with the exception of water) for at least 
2 hours before receiving study drug. Required study examinations and blood draws should be 
done during this time, prior to any study treatment administration. Upon completion of the 
2-hour fast, the subject should take the tablets with a minimum of 8 oz (240 mL) of water in the 
clinic and then continue to fast for 1 hour while under observation.  
6.1.2 
Subsequent Dose Administration 
Subjects should fast (with the exception of water) for at least 2 hours after eating the evening 
meal before taking their dose of study drug. After the 2-hour fast and before going to bed, 
subjects are to take the tablets with a minimum of 8 oz (240 mL) water with no more food intake 
for at least 1 hour postdose. If the subject’s schedule requires taking cabozantinib during the day, 
the subject should be instructed to follow the same fasting recommendations.  
Subjects should be instructed to not make up vomited doses or missed doses and to maintain the 
planned dosing schedule. Subjects should not make up for missed doses if more than 12 hours 


 
 
 
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have elapsed after the time the subject would usually take study drug. In the event of missed 
doses, subjects should not take two doses to make up for the one the subject missed. 
Dose reductions and interruptions due to tolerance issues are outlined in Section 6.5.1. 
Subjects will receive blinded study drug as long as they continue to experience clinical benefit in 
the opinion of the investigator or until the earlier of unacceptable toxicity, the need for 
subsequent systemic anticancer therapy/liver-directed local anticancer therapy, or until any of the 
other reasons for treatment discontinuation described in Section 3.6.  
Treatment may continue after disease progression per RECIST 1.1 has been determined by the 
investigator as long as the investigator believes that the subject is still receiving clinical benefit 
from study treatment and that the potential benefit of continuing study treatment outweighs 
potential risk.  
6.2 
Study Medications 
6.2.1 
Cabozantinib (XL184) 
The Sponsor will provide adequate supplies of cabozantinib, which will be supplied as 60-mg 
and 20-mg yellow film-coated tablets. The 60-mg tablets are oval and the 20-mg tablets are 
round. The components of the tablets are listed in Table 6-1. 
Table 6-1: 
Cabozantinib Tablet Components and Composition 
Ingredient  
Function 
% w/w 
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 
All study medication will be stored at controlled room temperature and inventoried according to 
applicable regulations. Further information on storage and handling will be provided in the 
pharmacy manual. 


 
 
 
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6.2.2 
Placebo 
Subjects randomized to the placebo arm will receive cabozantinib-matched placebo which will 
be indistinguishable in shape, size, color, and packaging from the active cabozantinib tablets. 
The composition of the placebo tablets are listed in Table 6-2. Dosing instructions are identical 
to that for the cabozantinib arm. 
Table 6-2: 
Placebo Tablet Components and Composition 
Ingredient  
Function 
% w/w 
Microcrystalline Cellulose (Avicel PH-102) 
Filler 
99.5 
Magnesium Stearate 
Lubricant 
0.5 
Opadry Yellow Film Coating which includes  
HPMC 2910/hypromellose 6 cp, titanium dioxide, 
triacetin, and iron oxide yellow 
Film Coating 
4.0 
 
6.3 
Compliance  
Subject compliance with outpatient study treatment regimens will be assessed by the site using 
drug dispensing and return records, progress notes about dose reductions/holds and subject 
interview. These data will not be directly recorded in the electronic case report form (CRF); 
rather, the CRF will capture intervals of constant dose and reasons for changes in dose level 
(eg, a new record completed each time a dose level changes, including periods where no dose 
was taken, and the reason for a dose level change). 
6.4 
Study Treatment Accountability 
The investigator or designee will maintain accurate records of receipt of all study treatment 
including dates of receipt. In addition, accurate records will be kept regarding when and how 
much study treatment is dispensed and used by each subject in the study. Reasons for deviation 
from the expected dispensing regimen must also be recorded. At completion of the study, to 
satisfy regulatory requirements regarding drug accountability, all unused study treatment will be 
reconciled and destroyed according to applicable regulations.  
6.5 
Blinded Study Drug Dose Modifications 
6.5.1 
Reductions and Interruptions  
Subjects will be monitored continuously for AEs while on study from the time of signing 
informed consent through 30 days after the date of the decision to permanently discontinue study 
treatment. Subjects will be requested to notify their physician immediately for any occurring AE. 


 
 
 
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Causality assessment of AEs should include at minimum confounding factors such as disease 
and concomitant medications. Adverse event severity will be categorized according to CTCAE 
v.4.0.  
The following should be taken into consideration in decisions regarding dose modifications 
(reductions or interruptions): 
• 
As a general approach all AEs should be managed with supportive care at the earliest signs of 
toxicity. Should this be ineffective, dose reductions or interruptions should be considered to 
prevent worsening of toxicity. 
• 
Dose modification criteria for study treatment are shown in Table 6-3. Doses may be 
modified at any time on study treatment.  
• 
The assigned dose for study treatment is 60 mg qd. Two dose reductions will be permitted 
(Table 6-4): 
o 60 mg qd to 40 mg qd (level 1) 
o 40 mg qd to 20 mg qd (level 2) 
• 
Dose modifications may also occur in the setting of lower grade toxicity than defined in 
Table 6-3, if the investigator feels it is in the interest of a subject’s safety. 
• 
Dose interruptions of study treatment for any reason are allowed for up to 6 weeks. 
Restarting treatment after interruptions longer than 6 weeks may be allowed with approval of 
the Sponsor  
• 
All treatment modifications should be entered into CRFs within 72 hours. 
Guidelines for the management of specific AEs such as GI disorders, hepatobiliary disorders, 
blood system disorders, constitutional disorders, skin disorders, hypertension, thromboembolic 
events, proteinuria, QTc prolongation, hemorrhagic events, GI perforation/fistula and non-GI 
fistula formation, and osteonecrosis of the jaw are provided in Section 6.7.  


 
 
 
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Table 6-3: 
Dose Modification Criteriaa 
Toxicity Criteria  
Recommended Guidelines for Management 
Grade 1 AEs 
• 
Continue study treatment if AE is tolerated 
Grade 2 AEs which are intolerable and 
cannot be adequately managed  
• 
At the discretion of the investigator, study treatment 
should be dose reduced or interrupted. 
Note: It is recommended that dose interruptions be as brief as 
possible.  
Grade 3 (except clinically non-relevant 
laboratory abnormalities) 
• 
Study treatment should be interrupted unless the toxicity 
can be easily managed with a dose reduction and optimal 
medical care.  
Grade 4 AEs (except clinically 
non-relevant laboratory abnormalities) 
• 
Subjects should have their study treatment interrupted 
immediately.  
Discontinue study treatment unless the following criteria 
are met:  
Subject is deriving clear clinical benefit as determined by the 
investigator and agreed by the Sponsor 
Toxicity can be managed with a dose reductionb following 
recovery to Grade 1 (or baseline) and optimal medical care  
AE, adverse event. 
Note: The dose delay and modification criteria for specific medical conditions are provided in Section 6.7. 
For re-treatment criteria of study treatment after a dose hold see Section 6.5.1.1. 
a Study treatment dose adjustment is only needed if the toxicity was deemed related to study treatment or 
had an unclear relationship to study treatment. 
b For dose reduction levels, see Table 6-4. 
 
Table 6-4: 
Dose Reductions 
Assigned dose  
First Dose Level Reduction 
Second Dose Level Reduction 
60 mg of study treatment oral qd 
40 mg of study treatment oral qd 
20 mg of study treatment oral qd 
qd, once daily 
All study treatment must be discontinued if a qd dose of 20 mg cabozantinib/matched placebo (minimum dose) is 
not tolerated 
 
If the study transitions to the Open-Label Phase, study treatment will be unblinded and dose 
modifications will occur in an open-label fashion. 
 


 
 
 
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6.5.1.1 
Dose Reinstitution and Reescalation 
If the subject recovers from his or her AEs to CTCAE v.4.0 Grade ≤ 1 or to the baseline value 
(or lower) and the AE was unrelated to study treatment, then study treatment may be restarted 
with no change in dose.  
If the subject recovers from his or her AEs to Grade ≤ 1 or to the baseline value (or lower) the 
toxicity was deemed possibly related to study treatment, then study treatment may be restarted at 
a reduced dose (see Table 6-4 for the schedule of dose reductions). Subjects receiving a daily 
dose of 20 mg may be restarted at the same dose if deemed safe at the discretion of the 
investigator. Subjects unable to tolerate a daily dose of 20 mg will discontinue study treatment. 
Re-escalation to the previous dose, (but not higher than 60 mg/day) may be allowed at the 
discretion of the investigator and agreement of the Sponsor but no sooner than 2 weeks beyond 
resolution of AEs that led to the dose reduction. Dose re-escalation is not allowed for a dose 
reduction triggered by myelosuppression or by Grade 4 AEs affecting major organs (eg, central 
nervous system, cardiac, hepatic, renal). 
6.6 
Best Supportive Care (BSC) 
To ensure that BSC is equally available to all subjects entered into the trial, subjects will be seen 
and evaluated every 2 weeks up to Week 9 and then every 4 weeks thereafter as outlined in 
Section 5.2. Interval history and indicated physical examinations and laboratory tests will be 
monitored regularly and equally for all subjects, permitting prompt recognition of abnormalities. 
Treatment with BSC will be instituted promptly, as clinically appropriate, for all subjects with 
symptoms or complications. 
General guidelines for other aspects of BSC are found in Appendix F.  
6.7 
Warnings, Precautions, and Guidelines for Management of Potential 
Cabozantinib Adverse Events 
6.7.1 
General 
The side effect profile of cabozantinib includes GI symptoms (such as nausea, vomiting, and 
diarrhea, mucositis/stomatitis), fatigue/asthenia, anorexia, weight loss, skin disorders including 
PPE syndrome, elevated liver function tests (including alanine aminotransferase [ALT] and 
AST), increased pancreatic enzymes with rare cases of overt pancreatitis, hypothyroidism, QTc 
prolongation, as well as side effects associated with inhibition of VEGF signaling. The latter of 
these include arterial and venous thrombotic events such as deep vein thrombosis (DVT), 


 
 
 
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pulmonary embolism (PE), transient ischemic attack, and myocardial infarction; hypertension; 
hemorrhagic events; proteinuria, wound complications, and rare cases of GI perforation, fistulae 
formation and rectal/perirectal abscess, osteonecrosis, and reversible posterior 
leukoencephalopathy (RPLS). Please refer to the Investigator’s Brochure for additional details. 
As with all investigational products, unknown AEs may occur.  Subjects should be monitored 
closely throughout their study participation for all AEs. As with other agents in development, 
additional AEs are unknown. As of 22 October 2013, in studies with cabozantinib, angioedema 
has been reported to occur in ~0.1% of subjects treated. 
The predicted effective plasma half-life of cabozantinib is 55 hours. Thus, when initiating 
therapy with cabozantinib, it will take most subjects 2-3 weeks to reach steady state after daily 
dosing. If AEs attributable to cabozantinib occur within the initial 3-week period of dosing, early 
intervention with dose modifications may be justified for AEs that, if worsened, could potentially 
be dangerous or debilitating, since without a dose adjustment, systemic exposure of cabozantinib 
might be expected to increase after the onset of the AE. 
Management of fatigue, anorexia, diarrhea, nausea, skin disorders, vomiting, rash, hypertension, 
proteinuria, elevated ALT and AST, myelosuppression, mucositis, hypothyroidism, and cardiac 
disorders are presented in this section as these have been observed in previous studies with 
cabozantinib or represent common class effect toxicity. In addition, guidelines to minimize the 
risk for potential SAEs such as GI and non-GI perforation and fistula formation, hemorrhagic 
events, and osteonecrosis of the jaw (ONJ) are provided in this section.  
Please refer to the Investigator’s Brochure for additional practice guidelines and management 
recommendations for side effects potentially related to cabozantinib treatment; available 
information on potential risk of congenital, familial, and genetic disorders; and guidelines on 
management of cabozantinib overdose.  
6.7.2 
Gastrointestinal Disorders  
The most common GI AEs reported in clinical studies with cabozantinib are diarrhea, oral pain, 
dyspepsia, stomatitis, and dysphagia.  
Diarrhea 
Subjects should be instructed to notify their physician immediately at the first signs of poorly 
formed or loose stool or an increased frequency of bowel movements. Administration of 


 
 
 
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antidiarrheal/antimotility agents is recommended at the first sign of diarrhea as initial 
management. Some subjects may require concomitant treatment with more than one antidiarrheal 
agent. When therapy with antidiarrheal agents does not control the diarrhea to tolerable levels, 
study treatment should be temporarily interrupted or dose reduced per Table 6-3.  
In addition, general supportive measures should be implemented including continuous oral 
hydration, correction of fluid and electrolyte abnormalities, small frequent meals, and stopping 
lactose-containing products, high fat meals and alcohol.  
For more information please refer to the current Investigator’s Brochure. 
Nausea and Vomiting 
Antiemetic agents are recommended as clinically appropriate at the first sign of nausea and 
vomiting or as prophylaxis to prevent emesis, along with supportive care according to clinical 
practice guidelines. The 5-HT3 receptor antagonists are recommended over chronic use of NK-1 
receptor antagonists and dexamethasone (NK-1 receptor antagonists can induce or inhibit 
CYP3A4, and glucocorticoids induce CYP3A4 and thus could lower cabozantinib exposure (see 
Section 7.1.2.1). Caution is also recommended with the use of nabilone, which is a weak 
inhibitor of CYP3A4. 
Stomatitis and Mucositis 
Preventive measures may include a comprehensive dental examination to identify any potential 
complications before study treatment is initiated. Removal of local factors should be instituted as 
indicated, such as modification of ill-fitting dentures and appropriate care of gingivitis.  
During study treatment good oral hygiene and standard local treatments such as nontraumatic 
cleansing and oral rinses (eg, with a weak solution of salt and baking soda) should be 
maintained. The oral cavity should be rinsed and wiped after meals, and dentures should be 
cleaned and brushed often to remove plaque. Local treatment should be instituted at the earliest 
onset of symptoms. Obtain bacterial/viral culture if oral infection is suspected and treat infection 
as clinically indicated. When stomatitis interferes with adequate nutrition and local therapy is not 
adequately effective, dose reduction or temporary withholding of study treatment should be 
considered. 


 
 
 
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6.7.3 
Hepatobiliary Disorders 
Elevations of ALT, AST, and total bilirubin have been observed during treatment with 
cabozantinib.  
A subject who has ALT, AST, and total bilirubin ≤ 3.0 X ULN at baseline and who develops 
≥ Grade 3 elevated ALT, AST, or total bilirubin should have study treatment interrupted and the 
dose reduced as outlined in Tables Table 6-3 and Table 6-4.  
Subjects on this study may enter the study with elevations of AST/ALT up to 5 X ULN at 
baseline. Elevations of aminotransferases when hepatic tumors are present may not require dose 
modifications if there are no progressive changes in the aminotransferases (less than a doubling) 
and if there are no progressive elevations in serum total bilirubin concentration or coagulation 
factors. Cabozantinib treatment should be interrupted when transaminase increases are 
accompanied by progressive elevations of total bilirubin, and/or elevations of coagulation tests 
(eg, International Normalized Ratio [INR]). More frequent monitoring of transaminases should 
be considered and study treatment should be held until the etiology of the abnormalities is 
determined and these abnormalities are corrected or stabilize at clinically acceptable levels. If 
hepatic toxicity resolves during a temporary hold and was deemed related to study treatment, 
then study treatment may be restarted at a reduced dose. Study treatment should be discontinued 
if hepatic dysfunction is not reversible despite temporary interruption of study treatment. 
Elevations > 3x ULN of ALT or AST concurrent with > 2xULN total bilirubin without other 
explanation can indicate drug-induced liver injury and drug should be permanently discontinued. 
If possible, hepatotoxic concomitant medications should be discontinued in subjects who develop 
increased values of ALT, AST, or total bilirubin.  
Evaluation of subjects with elevated transaminases or total bilirubin should be individualized and 
guided by the presence of specific risk factors such as illnesses which affect liver function 
(eg, infectious and non-infectious causes of hepatitis, liver cirrhosis, thrombosis of portal or 
hepatic vein), concomitant hepatotoxic medication, alcohol consumption, and cancer related 
causes. AEs which are based on hepatic dysfunction should be managed according to locally 
accepted clinical practice, including monitoring of appropriate laboratory functions. 
6.7.4 
Hematological Disorders 
Hematological toxicities (ie, neutropenia and thrombocytopenia) and associated complications 
have been observed after administration of cabozantinib and may be managed with dose 


 
 
 
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interruptions and/or dose reductions. Use of granulocyte colony-stimulating factor support for 
neutrophil recovery is allowed per investigator discretion in accordance with the American 
Society of Clinical Oncology Guidelines.  
Complete blood counts with differentials and platelets should be performed during treatment on 
the schedule indicated in Appendix A. Subjects with hematologic toxicities may require 
additional or more frequent laboratory tests according to institutional guidelines.  
Febrile neutropenia or evidence of infection associated with neutropenia must be assessed 
immediately and treated aggressively according to institutional guidelines. 
Dose reductions or dose interruptions for anemia are not mandated but can be applied as 
clinically indicated. Supportive care such as red blood cell transfusions may be given as 
clinically indicated.  
6.7.5 
Fatigue, Anorexia, and Weight Loss 
Fatigue has been reported during treatment with cabozantinib. Common causes of fatigue such as 
anemia, deconditioning, emotional distress (depression and/or anxiety), nutrition, sleep 
disturbance, and hypothyroidism should be ruled out and/or these causes treated according to 
standard of care. Individual nonpharmacological and/or pharmacologic interventions directed to 
the contributing and treatable factors should be given. Pharmacological management with 
psychostimulants such as methylphenidate should be considered after disease specific 
morbidities have been excluded. Note: Chronic use of modafinil should be avoided because of its 
potential to reduce cabozantinib exposure (see Investigator’s Brochure).  
Dose reduction of study treatment should be considered when general or pharmacological 
measures have not been successful in reducing symptoms. Dose interruption may be considered 
for Grade ≥ 3 fatigue despite optimal management, at the investigator’s discretion. 
Anorexia and weight loss should be managed according to local standard of care including 
nutritional support. Pharmacologic therapy such as megestrol acetate should be considered for 
appetite enhancement. Should these interventions prove ineffective, dose hold and reductions 
may be considered for Grade ≥ 3 anorexia or weight loss. If anorexia and/or weight loss do not 
recur after a dose reduction, dose of study treatment may be reescalated to the previous dose.  


 
 
 
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6.7.6 
Skin Disorders 
Palmar-plantar erythrodysesthesia (PPE) syndrome 
PPE syndrome (also known as hand-foot syndrome), skin rash (including blisters, erythematous 
rash, macular rash, skin exfoliation, dermatitis acneiform, and papular rash), pruritus, dry skin, 
and erythema have been reported in cabozantinib-treated subjects. All subjects on study should 
be advised on prophylactic skin care. This includes the use of hypoallergenic moisturizing 
creams, ointment for dry skin, and sunscreen with sun protection factor ≥ 30; avoidance of 
exposure of hands and feet to hot water; protection of pressure-sensitive areas of hands and feet; 
and use of thick cotton gloves and socks to prevent injury and to keep the palms and soles dry. 
Subjects with skin disorders should be carefully monitored for signs of infection (eg, abscess, 
cellulitis, or impetigo). 
Early signs of PPE syndrome include tingling, numbness, and slight redness or mild 
hyperkeratosis. Early manifestations include painful, symmetrical red and swollen areas on the 
palms and soles. The lateral sides of the fingers or peri-ungual zones may also be affected. 
Adequate interventions are required to prevent worsening of skin symptoms such as blisters, 
desquamations, ulcerations, or necrosis of affected areas. Aggressive management of symptoms 
is recommended, including early dermatology referral. Treatment guidelines for PPE related to 
blinded study drug (referred to as “study treatment”) are presented in Table 6-5. 
In the case of study treatment-related skin changes, the investigator may request that additional 
assessments be conducted with the subject’s consent. These assessments may include digital 
photographs of the skin changes and/or a biopsy of the affected skin and may be repeated until 
the skin changes resolve.  


 
 
 
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Table 6-5: 
Dose Modification Criteria and Recommended Guidelines for Treatment-
emergent PPE Syndrome 
CTCAE v.4.0 Grade  
Action To Be Taken  
Grade 1 
• 
Study treatmenta may be continued at the current dose if PPE syndrome is 
clinically insignificant and tolerable. Otherwise, study treatmenta should be 
reduced to the next lower dose level. Start urea 20% cream twice daily AND 
clobetasol 0.05% cream once daily. Reassess at least weekly; if PPE syndrome 
worsens at any time or does not improve after 2 weeks, proceed to the 
intervention guidelines for Grade 2. 
Grade 2  
• 
Study treatmenta may be continued if PPE is tolerated. Study treatment should 
be dose reduced or interrupted if PPE is intolerable. Continue urea 20% cream 
twice daily and clobetasol 0.05% cream once daily and add analgesics 
(eg, NSAIDs/gamma-aminobutyric acid agonists) for pain control if needed. 
Reassess at least weekly; if PPE does not improve within 2 weeks or worsens 
or affects self-care, proceed to the intervention guidelines for Grade 3. 
Grade 3 
• 
Interrupt study treatmenta until severity decreases to Grade 1 or 0. Continue 
treatment of skin reaction with clobetasol 0.05% cream twice daily AND 
analgesics. Resume study drug at a reduced dose if PPE syndrome recovers to 
Grade ≤ 1. Discontinue subject from study if intolerable PPE syndrome recurs 
at a reduced dose or if PPE syndrome does not improve within 6 weeks. 
CTCAE, Common Terminology Criteria for Adverse Events; GABA, gamma-amino butyric acid; NSAID, non-steroidal anti-
inflammatory drug; PPE, Palmar Plantar Erythrodysesthesia. 
a Study treatment includes both cabozantinib and matched placebo. 
 
Wound Healing and Surgery  
VEGF inhibitors can cause wound healing complications and wound dehiscence which may 
occur even long after a wound has been considered healed. Therefore, surgical and traumatic 
wounds must have completely healed prior to starting study treatment and be monitored for 
wound dehiscence or wound infection while the subject is being treated with study drug.  
Study treatment should be stopped at least 28 days prior to scheduled surgery. The decision to 
resume study treatment after surgery should be based on clinical judgment of adequate wound 
healing. Study treatment should be interrupted for any wound healing complication. Study 
treatment should be discontinued in subjects with serious or chronic wound healing 
complications. 


 
 
 
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6.7.7 
Hypertension 
Hypertension is a common class effect of drugs that inhibit VEGF pathways and has been 
reported in subjects treated with cabozantinib. 
Blood pressure should be monitored in a constant position at each visit (either sitting or supine). 
Treatment guidelines for hypertension deemed related to blinded study drug are presented in 
Table 6-6. In general, subjects with known hypertension should be optimally managed prior to 
study entry. Decisions to decrease or hold the dose of study treatment must be based on BP 
readings taken by a medical professional and must be confirmed with a second measurement at 
least 5 minutes following the first measurement. Other than for hypertension requiring 
immediate therapy, the presence of new or worsened hypertension should be confirmed at a 
second visit before taking therapeutic action. It is recommended that this second visit occurs 
within 1 week. 


 
 
 
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Table 6-6: 
Guidelines for the Management of Treatment-emergent Hypertension 
Criteria for Dose Modificationa 
Blinded Study Dose Modification 
Subjects NOT receiving optimized antihypertensive therapy 
> 150 mm Hg (systolic) and < 160 
mm Hg 
OR 
> 100 mm Hg (diastolic) and < 110 
mm Hg 
 
• 
Optimize antihypertensive treatment by adding new or additional 
antihypertensive medications and/or increase dose of existing 
medications. 
• 
Reduce study 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 study treatment 
≥ 160 mm Hg (systolic) 
OR 
≥ 110 mm Hg (diastolic) 
 
• 
Reduce study treatment by 1 dose level 
• 
Add new or additional antihypertensive medications and/or increase 
dose of existing medications and monitor subject closely for 
hypotension. If optimized antihypertensive therapy (usually to include 
3 agents) does not result in BP < 150 mm Hg systolic or < 100 mm Hg 
diastolic, study treatment should be dose reduced further or interrupted 
• 
Study treatment should be dose interrupted if upper limits of BP (≥ 160 
mm Hg systolic or ≥ 110 mm Hg diastolic) are sustained and not 
adequately manageable or if BP is > 180 mm Hg systolic or > 120 mm 
Hg diastolic or if subject is symptomatic. 
• 
Restart study treatment at the most tolerable dose and reescalate only if 
BP falls to and is sustained at < 140 mm Hg systolic and < 90 mm Hg 
diastolic. 
Hypertensive emergencyb or 
hypertensive encephalopathy   
• 
Discontinue study treatment 
a   The investigator may decide to initiate or adjust antihypertensive treatment at a lower threshold than systolic BP > 150 mm Hg  
or diastolic BP > 100 mm Hg based on their clinical judgment and assessment of the individual subject. 
b   Hypertensive emergency is defined as uncontrolled elevated blood pressure with clinical evidence of progressive or impending 
end-organ damage (ie, myocardial infarction/ischemia, intracranial hemorrhage, cerebral ischemia, pulmonary edema, 
encephalopathy, kidney damage) 
6.7.8 
Thromboembolic Events 
Thromboembolic complications are frequent in cancer patients due to procoagulant changes 
induced by the malignancy or anticancer therapy including inhibitors of VEGF pathways. DVT 
and PE have been observed in clinical studies with cabozantinib; including fatal events (please 
refer to the Investigator’s Brochure). Subjects who develop a PE or DVT should have study 
treatment held until therapeutic anticoagulation with heparins (LMWH) is established. (Note: 
therapeutic anticoagulation with oral anticoagulants is prohibited.)   


 
 
 
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Study treatment may be resumed in subjects with PE or DVT if it is determined that the event is 
uncomplicated, they are deriving benefit from study treatment, and that anticoagulation does not 
place them at a significant risk that outweighs the benefit of resuming treatment. During 
treatment with anticoagulants, subjects need to be monitored on an ongoing basis for bleeding 
risk and signs of bleeding. Subjects with life-threatening PE or DVT should have study treatment 
discontinued unless toxicity can be managed and subject is deriving clear clinical benefit as 
determined by the investigator and agreed by the Sponsor. 
Subjects who develop portal/hepatic vessel thrombosis may not require anticoagulation. The 
decision regarding anti-coagulation in such cases is at the discretion of the investigator and 
within the context of standard of care. 
Arterial thrombotic events (eg, transient ischemic attack, myocardial infarction) have been 
observed rarely in studies with cabozantinib. Subjects should be evaluated for preexisting risk 
factors for arterial thrombotic events such as diabetes mellitus, hyperlipidemia, hypertension, 
coronary artery disease, history of tobacco use, and cardiac or thromboembolic events that 
occurred prior to initiation of study treatment. Study treatment should be discontinued in subjects 
who develop an acute myocardial infarction or any other clinically significant arterial 
thromboembolic complication. 
6.7.9 
Proteinuria 
Proteinuria is an anticipated AE with the inhibition of VEGF pathways and has been observed in 
cabozantinib clinical studies, and nephrotic syndrome has been reported with cabozantinib and 
other inhibitors of VEGF pathways.  
During each safety assessment visit, proteinuria will be quantified by measuring the urine 
protein-to-creatinine (UPCR) ratio performed by the central lab. In addition, urine dipstick 
analysis performed by the local lab will be done at least every 8 weeks and more as clinically 
indicated. Management of proteinuria will be based on UPCR results provided by the central lab 
(see Table 6-7). 
As dipstick results from the local labs may be available prior to the UPCR results from the 
central lab, they can be used by the investigator for interim management. In the case of 
proteinuria, if the dipstick analysis shows proteinuria ≥ 3+, study treatment should be interrupted 
until the UPCR results are available and more definitive management can be applied. 


 
 
 
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Table 6-7: 
Management of Treatment-emergent Proteinuria 
Severity of Proteinuria  
(UPCR) 
Action To Be Taken 
≤ 1 mg/mg  
(≤ 113.1 mg/mmol) 
• 
No change in study treatment or monitoring 
 
> 1 and < 3.5 mg/mg 
(> 113.1 and <395.9 mg/mmol) 
 
• 
No change in study treatment required  
• 
Consider confirming with a 24-hour protein excretion within 7 days 
• 
Repeat UPCR within 7 days and once per week. If UPCR < 1 on 2 
consecutive readings, UPCR monitoring can revert to protocol-specific 
times. (Second reading is confirmatory and can be done within 1 week of 
first reading.) 
≥ 3.5 mg/mg 
(≥ 395.9 mg/mmol) 
 
 
• 
Hold study treatment pending repeat UPCR within 7 days and/or 24-hour 
urine protein.  
• 
If ≥ 3.5 on repeat UPCR, continue to hold study treatment and check UPCR 
every 7 days. If UPCR decreases to < 2, restart study treatment at a reduced 
dose and monitoring of urine protein/creatinine should continue weekly 
until the UPCR decreases to < 1.  
Nephrotic syndrome 
• 
Discontinue study treatment 
UPCR = Urine Protein Creatinine Ratio 
6.7.10 
Corrected QTc Prolongation 
The effect of orally administered cabozantinib at 140 mg/day (FBE) on QTc interval was 
evaluated in a randomized, double-blinded, placebo-controlled Phase 3 study in patients with 
MTC (Study XL184-301). A mean increase in QT interval corrected by Fridericia (QTcF) of 
10-15 ms was observed at 4 weeks after initiating cabozantinib. A concentration-QTc 
relationship could not be definitively established. Changes in cardiac wave form morphology or 
new rhythms were not observed. No cabozantinib treated patients on this study had a QTcF > 
500 ms during the QT evaluation period.  
Only subjects with a baseline QTcF ≤ 500 ms are eligible for this study. Subjects will have ECGs 
performed at times designated by the protocol (Section 5.2). 
If at any time on study there is an increase in QTcF interval to an absolute value > 500 ms, 
within 30 minutes after the initial ECG, 2 additional ECGs must be performed each with 
intervals approximately 3 minutes apart.  


 
 
 
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If the average QTcF from the 3 ECGs is > 500 ms, the following actions must be taken: 
• Withhold study treatment 
• Immediately notify the Sponsor 
• Hospitalize symptomatic subjects (eg, with palpitations, dizziness, syncope, orthostatic 
hypotension, a significant ventricular arrhythmia on ECG) for a thorough cardiology 
evaluation and management 
• Consider cardiology consultation for asymptomatic subjects for evaluation and management 
• Check electrolytes, especially magnesium and potassium; correct abnormalities as clinically 
indicated 
• Check concomitant medications for any medication that may have contributed to QT 
prolongation, and if possible, discontinue these medications (see http://www.qtdrugs.org) 
• Send ECGs to central ECG laboratory (see ECG study manual) 
• Repeat ECG triplicates hourly until the average QTcF is ≤ 500 ms 
Study 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 by the central ECG laboratory or a QTcF 
> 500 ms confirmed by the central laboratory returns to ≤ 500 ms 
• Study treatment has been interrupted through a minimum of 1 week following the return of 
the QTcF to ≤ 500 ms 
• Sponsor has reviewed all available information and has agreed to the continuation of study 
treatment 
Following reinitiation of study treatment, ECGs must be repeated weekly for 2 weeks, then every 
2 weeks for 1 month, then according to the protocol-defined time points. 
Study 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 (confirmed by central ECG lab) after reinitiation of study 
treatment at a reduced dose 
6.7.11 
Hemorrhagic Events 
Hemorrhagic events have been reported with approved drugs that inhibit VEGF pathways as well 
as with cabozantinib. In order to mitigate risk of severe hemorrhage, subjects should be 
evaluated for potential bleeding risk factors prior to initiating study treatment and monitored for 
bleeding events with serial complete blood counts and physical examination while on study. Risk 
factors for hemorrhagic events may include (but may not be limited to) the following: 


 
 
 
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• Tumor of the lung with cavitary lesions or tumor lesions which invades, encases, or abuts 
major blood vessels. The anatomic location and characteristics of tumor as well as the 
medical history must be carefully reviewed in the selection of subjects for study treatment. 
• Recent or concurrent radiation  
• Active peptic ulcer disease, ulcerative colitis, and other inflammatory GI diseases 
• Underlying medical conditions which affect normal hemostasis (eg, deficiencies in clotting 
factors and/or platelet function, or thrombocytopenia) 
• Concomitant medication with anticoagulants or other drugs which affect normal hemostasis 
• History of clinically significant hemoptysis 
Discontinue study treatment in subjects who experience a severe bleeding complication. 
6.7.12 
GI Perforation/Fistula and Non-GI Fistula Formation 
GI perforation/fistula and non-GI fistula formation have been reported with approved drugs that 
inhibit VEGF pathways as well as with cabozantinib. Carefully monitor for episodes of 
abdominal pain, especially in subjects with known risk factors for developing GI 
perforation/fistula or non-GI fistula, to allow for early diagnosis. Such risk factors include (but 
may not be limited to) the following: 
GI perforation/fistula: 
• Intra-abdominal tumor/metastases invading GI mucosa  
• Active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, diverticulitis, 
cholecystitis or symptomatic cholangitis, or appendicitis  
• History of abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess 
• Prior GI surgery (particularly when associated with delayed or incomplete healing). 
Complete healing following abdominal surgery or resolution of intra-abdominal abscess must 
be confirmed prior to initiating study treatment  
Additional risk factors include concurrent chronic use of steroid treatment or nonsteroidal 
anti-inflammatory drugs. Constipation indicative of bowel obstruction should be monitored and 
effectively managed.  
Non-GI fistula: 
• Complications from radiation therapy have been identified as a possible predisposing risk 
factor for non-GI fistula formation in subjects undergoing treatment with VEGF pathway 
inhibitors (eg, bevacizumab). Subjects are excluded from this study if there are any clinically 
relevant ongoing complications from prior radiation therapy (ie, radiation esophagitis or 
other inflammation of the viscera). 


 
 
 
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Discontinue all study treatment in subjects who have been diagnosed with GI or non-GI 
perforation/fistula. 
6.7.13 
Osteonecrosis of the Jaw 
Osteonecrosis of the jaw (ONJ) has been reported with use of anti-angiogenic drugs and 
bisphosphonates and denosumab in cancer patients. Additional risk factors for ONJ have been 
identified such as use of corticosteroids, chemotherapy, local radiotherapy, poor oral hygiene, 
smoking, dental or orofacial surgery procedures, and cancer disease itself. Osteonecrosis has 
been reported in subjects treated with cabozantinib, the details of which are provided in the 
current version of Investigator’s Brochure. As a preventive measure, invasive dental procedures 
should be avoided if possible. In cases where dental procedures are unavoidable, the risks and 
benefits of a dental procedure and the extent of the procedure as well as the risk of developing 
osteonecrosis of the jaw need to be considered when deciding on the duration of a temporary 
study treatment interruption. If clinically possible, study treatment should be held for 
approximately 4 weeks prior to a dental procedure and resumed after complete healing has 
occurred. 
Subjects with any documented case of osteonecrosis should have study treatment interrupted, 
and appropriate clinical management should be initiated. Reinitiation of study treatment must be 
discussed with and approved by the Sponsor on a case-by-case basis. 


 
 
 
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7 
CONCOMITANT MEDICATIONS AND THERAPIES 
All concomitant medications used by the subject (including prescription and over-the-counter 
medications, transfusions, vitamins, herbal remedies, and nutritional supplements) during the 
period from 28 days before randomization through 30 days after the date of the decision to 
permanently discontinue study treatment are to be recorded in the CRF.  
7.1.1 
Allowed Therapies 
Antiemetics and antidiarrheal medications are allowed prophylactically according to standard 
clinical practice if clinically indicated.  
Granulocyte colony-stimulating factors are acceptable while the subject is enrolled in the study. 
However, these should not be administered prophylactically before initial treatment with study 
drug. Transfusions should be used in accordance with institutional guidelines. 
Hormone replacement and short-term systemic steroid treatment may be utilized as indicated by 
standard clinical practice while the subject is enrolled in the study.  
The protocol does not restrict the use of heparins at prophylactic doses. Therapeutic doses of 
heparins are allowed after randomization if clinically indicated for supportive treatment and the 
benefit outweighs the risk per the investigator’s discretion (see Section 6.7.8). During treatment 
with anticoagulants, subjects need to be monitored on an ongoing basis for bleeding risk and 
signs of bleeding. Therapeutic doses of oral anticoagulants (eg, warfarin or warfarin-related 
agents, thrombin or FXa inhibitors, antiplatelet agents such as clopidogrel) are not allowed after 
randomization until study treatment is permanently discontinued. 
Potential drug interactions with cabozantinib are summarized in Section 7.1.2.1 and are 
discussed in more detail in the Investigator’s Brochure.  
Subjects with active HBV should be on appropriate antiviral therapy. 
7.1.2 
Prohibited or Restricted Therapies 
The following therapies are prohibited while the subject is on study treatment: 
• any investigational agent or investigational medical device  
• any drug or herbal product used specifically for the treatment of HCC 
• therapeutic doses of oral anticoagulants (eg, warfarin or warfarin-related agents, thrombin or 
FXa inhibitors, antiplatelet agents such as clopidogrel) 
• interferon treatment 


 
 
 
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Liver-directed local anti-cancer therapy (eg, transarterial tumor embolization or 
chemoembolization, radiofrequency or microwave ablation, percutaneous ethanol or acetic acid 
ablation, injection or infusion of drug eluting or radiation-emitting beads, cryoablation, radiation 
therapy [including stereotactic radiotherapy], or surgery) or systemic antitumor therapies are not 
permitted on study treatment. If a subject requires additional systemic anticancer treatment or 
liver-directed local anti-cancer therapy, study treatment must be discontinued. Palliative external 
radiation to bone metastasis or skin/subcutaneous metastasis, is allowed but discouraged unless 
medically unavoidable. Subjects who have such intervention may be considered inevaluable for 
certain efficacy endpoints.  
Erythropoietic-stimulating agents (eg, epoetin alfa and darbepoetin alfa) should not be used 
based on a report of increased risk of tumor recurrence/progression associated with 
erythropoietin (Wright 2007). 
The chronic co-administration of strong CYP3A4 inducers should be avoided (Section 7.1.2.1). 
Other drugs that induce CYP3A4 should be used with caution because these drugs have the 
potential to decrease exposure (AUC) to cabozantinib. Selection of alternate concomitant 
medications with no or minimal CYP3A4 enzyme induction potential is recommended.  
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.  
Coadministration of strong CYP3A4 inhibitors and other drugs that inhibit CYP3A4 should be 
avoided because these drugs have the potential to increase exposure (AUC) to cabozantinib 
(Section 7.1.2.1). Selection of alternate concomitant medications with no or minimal CYP3A4 
enzyme inhibition potential is recommended.  
Additional information on potential drug interactions with cabozantinib is provided in Section 
7.1.2.1.  
7.1.2.1 
Potential Drug Interactions with Cabozantinib  
Cytochrome P450: Data from a clinical drug interaction study (Study XL184-008) show that 
clinically relevant steady-state concentrations of cabozantinib appear to have no marked effect 
on the 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 with CYP2C8 


 
 
 
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(ie, CYP2C9, CYP2C19, CYP2D6, CYP1A2, and CYP3A4). In vitro data indicate that 
cabozantinib is unlikely to induce cytochrome P450 enzymes, except for possible induction of 
CYP1A1 at high cabozantinib concentrations (30 μM).  
Cabozantinib is a CYP3A4 substrate and a weak substrate for CYP2C9 (but not a CYP2D6, 
CYP2C8, CYP2C19, CYP2B6, or CYP1A2 substrate), based on data from in vitro studies. 
Results from a clinical pharmacology study, XL184-006, showed that concurrent administration 
of cabozantinib with the strong CYP3A4 inducer, rifampin, resulted in an approximately 77% 
reduction in cabozantinib exposure (AUC values) after a single dose of cabozantinib in healthy 
volunteers. Co-administration of cabozantinib with strong inducers of the CYP3A4 family 
(eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, 
and St. John’s Wort) may significantly decrease cabozantinib concentrations. The chronic use of 
strong CYP3A4 inducers should be avoided. Other drugs that induce CYP3A4 should be used 
with caution because these drugs have the potential to decrease exposure (AUC) to cabozantinib. 
Selection of alternate concomitant medications with no or minimal CYP3A4 enzyme induction 
potential is recommended.  
Caution must be used when discontinuing treatment with a strong CYP3A4 inducer in a subject 
who has been concurrently receiving a stable dose of cabozantinib, as this could significantly 
increase the exposure to cabozantinib.  
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 
(eg, boceprevir, conivaptan, posaconazole, ketoconazole, itraconazole, clarithromycin, 
atazanavir, indinavir, nefazodone, nelfinavir, saquinavir, ritonavir, lopinavir, telaprevir, 
telithromycin, and voriconazole) may increase cabozantinib concentrations. Grapefruit and 
Seville oranges may also increase plasma concentrations of cabozantinib. Strong CYP3A4 
inhibitors and other drugs that inhibit CYP3A4 should be avoided because these drugs have the 
potential to increase exposure (AUC) to cabozantinib. Selection of alternate concomitant 
medications with no or minimal CYP3A4 enzyme inhibition potential is recommended.  
Please refer to the Flockhart drug interaction tables and FDA websites for lists of substrates, 
inducers, and inhibitors of selected CYP450 isozyme pathways (see 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx  


 
 
 
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and 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio
nsLabeling/ucm080499.htm ).  
Protein Binding: Cabozantinib is highly bound (approximately 99.9%) to human plasma 
proteins. Therefore, highly protein bound drugs should be used with caution with cabozantinib 
because there is a potential displacement interaction that could increase free concentrations of 
cabozantinib and/or a co-administered highly protein-bound drug (and a corresponding increase 
in pharmacologic effect). Factors that influence plasma protein binding may affect individual 
tolerance to cabozantinib. Therefore, concomitant medications that are highly protein bound 
(eg, diazepam, furosemide, dicloxacillin, and propranolol) should be used with caution. Because 
warfarin is a highly protein bound drug with a low therapeutic index, administration of oral 
anticoagulants at therapeutic doses is not allowed in subjects receiving cabozantinib due to the 
potential for a protein binding displacement interaction. 
Other Interactions: As food increases exposure levels of cabozantinib, fasting recommendations 
should be followed (Section 6.1). 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. Additional details related to these overall conclusions can be found in the 
investigator brochure. 
Administration of the proton pump inhibitor (PPI) esomeprazole resulted in no clinically-
relevant effect on cabozantinib plasma PK in healthy volunteers. Therefore, concomitant use of 
gastric pH modifying agents (ie, PPIs, H2 receptor antagonists, and antacids) is not 
contraindicated in subjects administered cabozantinib. (Note: Cimetidine should be avoided 
because of its potential to interfere with CYP3A4 mediated metabolism of cabozantinib). 
Drugs that prolong QTc interval: Drugs known to prolong QTc interval should be avoided. 
Additional details regarding potential drug interactions with cabozantinib can be found in the 
investigator brochure.  
 
 


 
 
 
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8 
SAFETY 
8.1 
Adverse Events and Laboratory Abnormalities 
An AE is any untoward medical occurrence in a patient or clinical investigation subject who has 
been enrolled in a clinical study and who may have been administered an investigational product, 
regardless of whether or not the event is assessed as related to the study treatment. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, regardless 
of whether or not the event is assessed as related to the investigational product.  This definition 
also includes events associated with medication errors and uses of the investigational product 
outside of what is in the protocol, including misuse and abuse.  Preexisting medical conditions 
that worsen during a study should be recorded as AEs. Abnormal laboratory values, ECG 
findings, or vital signs are to be recorded as AEs if they meet the criteria described in 
Section 8.3. 
All untoward events that occur after informed consent through 30 days after the date of the 
decision to discontinue study treatment are to be recorded by the investigational site. At each 
scheduled and unscheduled visit, AEs are to be identified and assessed based upon study 
procedures, routine and symptom-directed clinical investigations, and subject query/report.  
Assessment of the relationship of the AE to the study treatment by the investigator will be based 
on the following two definitions: 
• Not Related: An event is assessed as not related to study treatment if it is attributable to 
another cause and/or if there is no evidence to support a causal relationship. 
• Related: An event is assessed as related to study treatment when there is a reasonable 
possibility that the study treatment caused the event. Reasonable possibility means there is 
evidence to suggest a causal relationship between the drug and the event. This event is called 
a suspected adverse reaction. A suspected adverse reaction implies a lesser degree of 
certainty about causality than adverse reaction, which means any adverse event caused by a 
drug. 
8.2 
Serious Adverse Events 
The SAE definition and reporting requirements are in accordance with the ICH Guideline for 
Clinical Safety Data Management, Definitions and Standards for Expedited Reporting, 
Topic E2A. 
8.2.1 
Definitions 
An SAE is defined as any untoward medical occurrence that at any dose: 


 
 
 
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• Results in death. 
• Is immediately life-threatening (ie in the opinion of the investigator, the AE places the 
subject at immediate risk of death; it does not include a reaction that, had it occurred in a 
more severe form, might have caused death). 
• Requires inpatient hospitalization or results in prolongation of an existing hospitalization. 
• Results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
• Is a congenital anomaly or birth defect. 
• Is an important medical event that may not be immediately life-threatening, result in death, or 
require hospitalization, but may be considered an SAE when, based upon appropriate medical 
judgment, it jeopardizes the subject or may require medical or surgical intervention to 
prevent one of the outcomes listed above. 
As soon as an investigator becomes aware of an AE that meets the criteria for an SAE, the 
investigator should document the SAE to the extent that information is available. 
These SAEs, regardless of causal relationship, must be reported to the Sponsor or designee 
immediately (within 24 hours of the investigator’s knowledge of the event) by submitting the 
completed SAE report form and any other pertinent SAE information as indicated on the SAE 
Reporting form (or in the SAE Reporting form Completion Guidelines) and confirming the 
report was received. Forms for reporting SAEs and contact information will be provided to the 
study sites. Significant follow-up information (as defined in the SAE Reporting form Completion 
Guidelines) must also be reported immediately (within 24 hours of the investigator’s awareness 
of the new information).  
Serious adverse events that must be recorded on an SAE Reporting form include the following: 
• All SAEs that occur after informed consent and through 30 days after the date of the decision 
to discontinue study treatment (or the date the subject is deemed to be a screen failure). 
• Any SAEs assessed as related to study treatment or study procedures, even if the SAE occurs 
more than 30 days after the date of the decision to discontinue study treatment. 
Serious adverse events that occur after the initiation of study treatment through 30 days after the 
date of the decision to discontinue study treatment must also be recorded on the AE CRF page. 
The minimum information required for SAE reporting includes identity of investigator, site 
number, subject number, an event description, SAE term(s), the reason why the event is 
considered to be serious (ie, the seriousness criteria) and the investigator’s assessment of the 
relationship of the event to study treatment. Additional SAE information including medications 


 
 
 
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or other therapeutic measures used to treat the event, action taken with the study treatment 
because of the event, and the outcome/resolution of the event will be recorded on the SAE form. 
In all cases, the investigator should continue to monitor the clinical situation and report all 
material facts relating to the progression or outcome of the SAE. Furthermore, the investigator 
may be required to provide supplementary information as requested by the Exelixis Drug Safety 
personnel or designee. 
When reporting SAEs, the following additional points should be noted: 
• When the diagnosis of an SAE is known or suspected, the investigator should report the 
diagnosis or syndrome as the primary SAE term, rather than as signs or symptoms. Signs and 
symptoms may then be described in the event description.  
• Death should not be reported as an SAE, but as an outcome of a specific SAE, unless the 
event preceding the death is unknown. Terms of “Unexplained Death” or “Death from 
unknown origin” may be used when the cause is unknown. In these circumstances the cause 
of death must be investigated and the diagnosis amended when etiology identified. If an 
autopsy was performed, the autopsy report should be provided.  
• While most hospitalizations necessitate reporting of an SAE, some hospitalizations do not 
require SAE reporting, as follows:  
o Elective or previously scheduled surgeries or procedures for preexisting conditions that 
have not worsened after initiation of treatment (eg, a previously scheduled ventral hernia 
repair). SAEs must, however, be reported for any surgical or procedural complication 
resulting in prolongation of the hospitalization. 
o Pre-specified study hospitalizations for observation. 
o Events that result in hospital stays of fewer than 24 hours and that do not require 
admission (eg, an emergency room visit for hematuria that results in a diagnosis of 
cystitis and discharge to home on oral antibiotics). 
• SAEs must be reported for any surgical or procedural complication resulting in prolongation 
of the hospitalization.  
8.2.2 
Regulatory Reporting 
Exelixis Drug Safety (or designee) will process and evaluate all SAEs as soon as the reports are 
received. For each SAE received, Exelixis will make a determination as to whether the criteria 
for expedited reporting have been met. 
Exelixis Drug Safety (or designee) will assess the expectedness of each SAE. The current 
cabozantinib Reference Safety Information will be used as the reference document for assessing 
the expectedness of the event with regard to cabozantinib.  


 
 
 
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The Sponsor or its designee is responsible for reporting relevant SAEs to the relevant regulatory 
authorities, and participating investigators, in accordance with ICH guidelines and/or local 
regulatory requirements.  
Reporting of SAEs by the investigator to his or her IRB/EC will be done in accordance with the 
standard operating procedures and policies of the IRB/EC. Adequate documentation must be 
maintained showing that the IRB/EC was properly notified.  
As a general rule, the treatment blind will be broken by authorized Sponsor and/or CRO 
(contract research organization) personnel prior to reporting an SAE which meets the criteria for 
expediting reporting to the Regulatory Authorities and to some central ECs. Other than those 
involved in the unblinding and submission processes, the investigator, Sponsor, and CRO staff 
will remain blinded to the treatment assignment. 
8.3 
Other Safety Considerations 
8.3.1 
Laboratory Data 
All laboratory data obtained during the course of the study, comprising both central laboratory 
assessments required by this protocol and any other clinical investigations, should be reviewed. 
Clinically significant laboratory abnormalities should be reported as AEs by the Investigator. In 
general, laboratory abnormalities that lead to a change in subject management (eg, dose withheld 
or reduced, treatment discontinued; requirement for additional medication or monitoring) are 
considered to be clinically significant.  
8.3.2 
Pregnancy 
Use of medically accepted methods of contraception is very important during the study and for 
4 months post-study treatment. If a subject becomes pregnant during the study, she will be taken 
off study treatment. She will be followed through the end of her pregnancy and the infant should 
have a follow-up at least 6 months after birth. If a female partner of a male subject becomes 
pregnant during the study, the pregnant female partner will be asked to consent to be followed 
through the end of her pregnancy and the infant should have a follow-up for at least 6 months 
after birth. 
The investigator must inform Exelixis of the pregnancy. Forms for reporting pregnancies will be 
provided to the study sites upon request. The outcome of a pregnancy (for a subject or for the 
partner of a subject) and the medical condition of any resultant offspring must be reported to 
Exelixis or designee. Any birth defect or congenital anomaly must be reported as an SAE and 


 
 
 
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any other untoward events occurring during the pregnancy must be reported as AEs or SAEs, as 
appropriate. 
8.3.3 
Medication Errors 
Medication error is defined as the administration of study drug medication outside or above the 
established dosing regimens per the specific protocol. Any overdose or medication error 
(excluding missing doses) that results in an AE or SAE requires reporting within 24 hours to the 
Sponsor or designee. Forms for reporting medication errors will be provided to the study sites. 
In case of overdose, the Sponsor Medical Monitor or designee should be contacted promptly to 
discuss how to proceed. Any AEs that occur as a result of an overdose have to be treated 
according to clinical standard practice.  
In the event of overdose, renal and metabolic clinical laboratory parameters should be monitored 
at least weekly or as deemed clinically appropriate to assess any possible changing trends. In the 
case of any laboratory abnormalities resulting from an overdose, laboratory parameters should be 
continued to be monitored until any abnormalities return to baseline levels. Supportive measures 
should be undertaken as clinically indicated, with particular attention to fluid and electrolyte 
status, electrocardiographic changes, and hydration. Study drug should be held until it is 
determined that it is safe to restart. 
Please refer to the Investigator’s Brochure for additional management recommendations for an 
overdose of study treatment. 
8.3.4 
Follow-up of Adverse Events 
All SAEs that are ongoing 30 days after the date of the decision to discontinue study treatment, 
and AEs assessed Grade 3 or 4 that led to study treatment discontinuation that are ongoing 
30 days after the date of the decision to discontinue study treatment, are to be followed until 
either: 
• the AE has resolved  
• the AE has improved to Grade 2 or lower  
• the investigator determines that the event has become stable or irreversible. 
This requirement also applies to related SAEs that occur > 30 days after the date of the decision 
to discontinue study treatment. 


 
 
 
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The status of all other AEs that are ongoing 30 days after the date of the decision to discontinue 
study treatment will be documented as of the Post-Treatment Follow-Up Visit. 


 
 
 
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9 
STATISTICAL CONSIDERATIONS 
Details of the planned analyses will be provided in a separate Statistical Analysis Plan (SAP) that 
will be finalized before the first interim analysis is conducted. The statistical principles applied 
in the design and planned analyses of this study are consistent with ICH E9 and FDA Guidance 
for Industry: Clinical Trial Endpoints for the Approval of Cancer Drug and Biologics (2007).  
9.1 
Analysis Populations 
The following populations will be employed for statistical analyses. 
9.1.1 
Intent-to-Treat (ITT) Population 
The ITT population will consist of all subjects who are randomized, regardless of whether any 
study treatment or the correct study treatment is received.  
9.1.2 
Safety Population 
The Safety population will consist of all subjects who receive any amount of treatment. Subjects 
who receive both treatments in error will be summarized in the cabozantinib arm.  
9.2 
Primary Efficacy Endpoint 
The primary efficacy endpoint is duration of OS. 
9.2.1 
Definition 
Duration of OS is defined as the time from the randomization to the death due to any cause. For 
subjects who are alive at the time of data cutoff or are permanently lost to follow-up, duration of 
OS will be right censored at the date the subject was last known to be alive.  
9.2.2 
Primary Analysis 
The primary analysis of OS will be performed using the ITT population.  
Hypothesis testing between the two treatment arms will be performed using the stratified log-
rank test at the 2-sided α=0.05 level of significance. The stratification factors are those used to 
stratify the randomization (see Section 3.4). 
The median duration of OS and the associated 95% confidence interval (CI) for each treatment 
arm will be estimated using the Kaplan-Meier method. The hazard ratio (HR) will be estimated 
using a Cox regression model and will include the same stratification factors described above. 


 
 
 
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The analysis of OS is event-based. Up to three analyses of OS are planned: two interim analyses 
and a final analysis occurred when 311, 466 and 621 deaths (ie, 50%, 75% and 100% 
information) have been observed respectively. Inflation of Type I error associated with interim 
analyses will be controlled using a Lan-DeMets O’Brien-Fleming alpha-spending function. The 
critical p-values for rejecting the null hypothesis will be 0.0031, 0.0183 and 0.044 at the time 
when 311, 466 and 621 deaths (50%, 75% and 100% information) are observed respectively. The 
actual critical values will depend upon the true number of events observed at each analysis. The 
interim analyses of OS are also described in Section 9.8. 
At a analysis timepoint, if the p-value for the stratified log-rank test is less than the critical value 
for rejecting the null hypothesis and the HR (λ_cabozantinib/ λ_placebo) is < 1, the null 
hypothesis of no difference in OS will be rejected and it will be inferred that OS is superior in 
the cabozantinib arm compared with the placebo arm. 
9.2.3 
Exploratory Analyses 
Exploratory analyses of the effect of baseline characteristics, stratification factors, and other 
variables will be conducted using Cox regression models and subgroup analyses performed 
employing Kaplan-Meier methods. 
9.3 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints for this study are duration of progression-free survival (PFS) 
and objective response rate (ORR). Formal hypothesis tests are planned for the secondary 
efficacy endpoints. 
9.3.1 
Progression-Free Survival (PFS) 
Duration of PFS is defined as the time from randomization to the earlier of the following events: 
progressive disease or death due to any cause.  
The primary analysis of PFS will be performed using the ITT population and will include 
radiographic progression events as determined by the investigator per RECIST 1.1 and deaths. 
Clinical deterioration or radiographic progression determined by the investigator will not be 
considered progression events in the primary analysis. 
General censoring rules for the primary analysis of PFS are described below: 
• Subjects who receive subsequent anti-cancer therapy before experiencing an event will be 
right censored at the date of the last tumor assessment prior to the date of initiation of 


 
 
 
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subsequent therapy. If there is no such tumor assessment post randomization, the subject will 
be right censored on the date of randomization. 
• Subjects who have not experienced an event (and are not otherwise censored) at the time of 
data cutoff will be right censored on the date of their last tumor assessment post 
randomization. If there is no such tumor assessment post randomization, the subject will be 
right censored on the date of randomization.   
• Subjects who miss two or more scheduled tumor assessments followed by an event will be 
right censored on the date of their most-recent tumor assessment prior to the missing 
assessments. If there is no such tumor assessment post randomization, the subject will be 
right censored on the date of randomization. 
 
The hypothesis testing of PFS between the two treatment arms will be performed using the 
stratified log-rank test at the 2-sided α=0.04 level of significance. The stratification factors are 
those used to stratify the randomization (see Section 3.4). 
The median duration of PFS and the associated 95% CI for each treatment arm will be estimated 
using the Kaplan-Meier method. The HR will be estimated using a Cox regression model and 
will include the same stratification factors described above. 
The testing of PFS will occur only if the result of either an interim analysis or the final analysis 
of OS achieves statistical significance. If the p-value for the stratified log-rank test for PFS is 
less than 0.04 and the HR (λ_cabozantinib/ λ_placebo) is < 1, the null hypothesis of no 
difference in PFS will be rejected and it will be inferred that PFS is superior in the cabozantinib 
arm compared with the placebo arm. 
Supportive (sensitivity) analyses of PFS will be defined in the SAP using alternative event 
definitions (eg, including clinical deterioration as an event) and censoring schemes to account for 
partial or completely missing assessments, address bias due to tumor assessment timing, and 
evaluate the impact of potentially informative censoring.  
Exploratory analyses of the effect of baseline characteristics, stratification factors, and other 
variables will be conducted using Cox regression models and subgroup analyses performed 
employing Kaplan-Meier methods. 
9.3.2 
Objective Response Rate (ORR) 
The ORR is defined as the proportion of subjects experiencing a confirmed complete response 
(CR) or confirmed partial response (PR) per RECIST 1.1. The tumor response will be assessed 
by investigator. 


 
 
 
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Hypothesis testing will be performed using the Fisher’s exact test at the 2-sided α=0.01 level of 
significance. 
Point estimates of ORR, the difference in ORR between the two treatment arms, and associated 
confidence intervals will be provided. 95% CIs will be calculated using exact methods except for 
the difference in ORR between the two treatment arms which will use asymptotic confidence 
limits. 
If sufficient responses are observed, additional supportive analyses will be conducted using 
appropriate methods to adjust for stratification factors. 
The primary analysis of ORR will be performed for those subjects who have measurable disease 
at baseline within the ITT population. Subjects who do not have any post-randomization tumor 
assessments will be counted as non-responders. 
The testing of ORR will occur only if the result of either an interim analysis or the final analysis 
of OS achieves statistical significance. If the p-value for the two-sided Fisher’s exact test is less 
than 0.01 and the point estimate for ORR in the cabozantinib arm is higher than that in the 
placebo arm, the null hypothesis of no difference in ORR will be rejected and it will be inferred 
that ORR is superior in the cabozantinib arm compared with the placebo arm. 
9.4 
Control of Type I Error 
The multiplicity issue resulting from analysis of one primary endpoint (OS), two secondary 
efficacy endpoints (PFS and ORR), and planning two interim analyses for testing OS will be 
addressed by employing a fixed-sequence testing procedure, applying a modified Bonferroni 
procedure (dividing the alpha between the secondary endpoints), and implementing an alpha-
spending function. 
Up to three event-driven analyses of OS are planned: two interim analyses and a final analysis 
(see detail in section 9.2.2). Inflation of Type 1 error associated with interim analyses will be 
controlled using a Lan-DeMets O’Brien-Fleming alpha-spending function.  
Interim analysis of PFS and ORR are not planned. The testing of these two secondary endpoints 
will occur only if the result of either an interim analysis or the final analysis of OS achieves 
statistical significance. PFS and ORR will be tested in parallel. PFS will be tested at the 2-sided 
α=0.04 level of significance and ORR will be tested at the 2-sided α=0.01 level of significance. 


 
 
 
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All other statistical evaluations of efficacy will be considered exploratory. 
9.5 
Health-Related Quality of Life (HRQOL) 
The standardized measure of health status EQ-5D-5L will be used to provide a generic measure 
of health for clinical appraisal (Section 5.7.8). EQ-5D-5L includes six questions: mobility, self-
care, usual activities, pain/discomfort, anxiety/depression, and global health score. The 
questionnaires will be self-completed by the subjects until disease progression.  
Details of the planned analyses for these outcomes will be provided in the SAP 
9.6 
Pharmacokinetic Analysis 
Descriptive statistics (eg, number, mean and/or median, standard deviation, and coefficient of 
variation) will be used to summarize the concentration-time data for each study visit. Where 
appropriate, these data may be combined with data from other studies as part of a meta-analysis. 
The influence of exposure on biomarker changes, clinical safety parameters (eg, selected AEs) or 
clinical response may also be explored. The results of the PK analysis will be evaluated in 
conjunction with available safety data.  
9.7 
Safety Analyses 
All safety analyses will be performed using the Safety population. No formal statistical 
comparisons between the two treatment arms are planned. 
9.7.1 
Adverse Events 
Adverse event terms recorded on the CRFs will be mapped to preferred terms using the 
MedDRA dictionary. The investigator will classify the severity of AEs using the CTCAE v4.0 
and will judge each event to be “not related” or “related” to study treatment. 
A treatment emergent adverse event (TEAE) is defined as any event that begins or worsens on or 
after date of first dose of study treatment. In general, only TEAEs with an onset date prior to the 
date of the decision for treatment discontinuation + 30 days will be tabulated in summary tables. 
The frequency and percentage of subjects with TEAEs will be tabulated for overall incidence by 
system organ class and preferred term by treatment arm. Related TEAEs, serious TEAEs, related 
serious TEAEs, TEAEs resulting in study treatment discontinuation and TEAEs resulting in 
study treatment modification (either dose reduction or dose delay) will be similarly summarized. 
TEAEs and related TEAEs will also be summarized for worst reported severity within each 
subject.  


 
 
 
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At each level of summarization, a subject will be counted only once for each AE preferred term  
he/she experiences within that level (ie, multiple episodes of events with the same preferred 
terms will be counted only once). 
All reported subject deaths will be summarized by treatment arm, cause of death, and 
relationship to study treatment. 
9.7.2 
Laboratory Test Results 
Selected laboratory test results will be summarized by treatment arm to evaluate worst post-
baseline CTCAE grade and shifts or changes from baseline.  
9.7.3 
Other Safety Endpoints 
Changes or shifts from baseline in vital signs, ECOG and QTc interval will be summarized by 
treatment arm. 
The number of subjects experiencing dose reduction, delay, and/or discontinuation due to an AE 
will be provided. 
Concomitant medications will be standardized using the World Health Organization (WHO) 
drug dictionary and summarized by class and preferred term. 
9.8 
Interim Analyses 
The size of the trial is based upon the most accurate assumptions currently available and 
provides high power to detect what the Sponsor believes is the smallest clinically meaningful 
difference in OS under these assumptions. However, as there is uncertainty in the assumptions, 
interim analyses provide an opportunity to stop the trial early if the treatment benefit of 
cabozantinib is larger than expected, potentially allowing cabozantinib to become available 
sooner to this patient population. 
Two interim analyses for primary endpoint of OS are planned. The interim analyses will be 
conducted at the time when 311 and 466 deaths have been observed respectively. It is anticipated 
that this will be at approximately the 50% and 75% information fraction respectively for OS. 
Type I error for the interim analysis will be controlled by a Lan-DeMets O’Brien-Fleming alpha 
spending function as described in Section 9.4. The actual critical values employed at the interim 
and final analyses of OS will depend upon the actual information fraction at the time of the 
interim analyses. 


 
 
 
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If the planned first or second interim OS analysis achieves overwhelming evidence of efficacy 
(p-value = 0.0031 or 0.0183, respectively) in favor of cabozantinib, analyses of the secondary 
endpoints will be performed as planned. Interim analyses will be evaluated by the IDMC (see 
Section 11.2). Monitoring guidance will be provided to allow the study to be stopped early if the 
null hypothesis for OS is rejected in favor of cabozantinib. A nonbinding boundary for harm will 
be used by the IDMC to help evaluate subject safety. Stopping for futility is not planned. 
9.9 
Power and Sample Size 
For OS, a total of 621 deaths planned with two interim analyses (at 50% and 75% information) 
and a final analysis provides the study with 90% power for a 2-sided log-rank test with a 5% 
level of significance to detect a 31.6%  increase in OS (HR = 0.76). Assuming an 8.2 month 
median OS in the placebo arm (based upon the BRISK trial; Llovet 2012) and exponential 
distribution of OS, this corresponds with an increase in median OS from 8.2 months to 10.8 
months in the cabozantinib arm. In the current design, the minimum observed effect that would 
result in statistical significance for OS at the two interim and final analyses are 42.1% 
improvement (HR = 0.70) from 8.2 to 11.7 months, 25.7% improvement (HR = 0.80) from 8.2 to 
10.3 months and 18.4% improvement (HR = 0.84) from 8.2 to 9.7 months at two interim and 
final analyses respectively. 
With an average accrual rate of 31.5 subjects per month and using a 2:1 treatment allocation 
ratio, an approximate total of 760 subjects (507 subjects in cabozantinib arm and 253 subjects in 
placebo arm) are required to observe the required number of events within the planned study 
duration (25 months accrual and approximately 38 months to observe the required deaths for 
OS). 
Power and sample size estimates were estimated using EAST v5 by Cytel Software. 
9.10 
Open-Label Phase 
Data for subjects who crossover from the placebo arm to receive cabozantinib, will be 
summarized separately and will not be included as part of the evaluation of either arm. 
9.11 
Maintenance Phase 
Data for subjects who enter the Maintenance Phase will not be entered in the clinical database. 
Data from the safety database will be summarized or listed separately. 
 


 
 
 
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10 
DATA QUALITY ASSURANCE 
Accurate and reliable data collection will be assured by verification and cross-check of the CRFs 
against the investigator’s records by the study monitor (source document verification) and by the 
maintenance of a drug–dispensing log by the investigator. Data collected on paper CRFs, if any, 
will be entered into a computer database. If CRFs are employed, authorized study site personnel 
will enter data directly into a computer database. Study databases will be subject to electronic 
and manual quality assurance procedures. 
11 
STUDY COMMITTEES 
11.1 
Exelixis Safety Committee 
The Exelixis Safety Committee is established to ensure a quarterly review of product safety data 
and consists of the Chief Medical Officer, Vice President of Drug Safety, Vice President(s) of 
Clinical Research and Clinical Development, and representatives from the following functional 
areas: Regulatory Affairs, Biostatistics, Clinical Research and Medical Affairs. It is the 
responsibility of this Committee to review all available safety data (AE and SAEs) from ongoing 
Exelixis clinical trials and other sources (including post-marketing safety surveillance) in order 
to assess and monitor evolving safety trends, evaluate potential changes to clinical trial protocols 
based on safety analysis, and, ultimately, to safeguard subject safety. This investigational product 
will be reviewed by the Exelixis Safety Committee quarterly. The ESC will review blinded 
(pooled) data from this study. Additional ad hoc meetings will convene as required to address 
specific safety concerns.  
11.2 
Independent Data Monitoring Committee (IDMC) 
An IDMC will be established to monitor the safety of the study on a regular basis. The 
committee will operate independently from the Sponsor and the clinical investigators. To 
minimize the potential introduction of bias, these individuals will not have any direct contact 
with the study site personnel or subjects. IDMC members will be selected for their expertise in 
oncology and/or biostatistics.  
This IDMC will convene periodically (at a minimum twice yearly) and the start date will depend 
on subject accrual rates. The primary responsibilities of the IDMC are to: 
• Review the accumulating safety data on a regular and an ad hoc basis 
• Evaluate the results of the planned interim analyses of OS 
• Make recommendations to the Sponsor regarding the continued conduct of the study based 
upon their evaluation of safety and efficacy data. 


 
 
 
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Safety data will be provided at regular intervals to the IDMC in the form of unblinded summary 
reports or data listings. To allow the evaluation of safety in the context of potential benefit, OS 
data (including Kaplan-Meier curves) may be reviewed by the IDMC at the time of safety 
summary reviews. The IDMC will have access to subjects’ individual treatment assignments. 
Unblinded safety and efficacy summaries will be produced for the IDMC by an independent 
statistical center designated by the Sponsor. 
General stopping rules are as follows: 
• The IDMC members will use their expertise, experience and judgment to evaluate the safety 
data from the trial and recommend to Exelixis whether the trial should continue, be modified, 
or be stopped early for safety concerns. No formal rules for making these recommendations 
based upon safety data are planned. 
• Stopping early for overwhelming evidence of efficacy or harm is based upon formal interim 
analyses of OS when 50% and 75% of total deaths have occurred. The critical p-values for 
rejecting the null hypothesis, as determined by the Lan-DeMets O’Brien-Fleming alpha 
spending function, will be 0.0031 and 0.0183 at the time when 311 and 466 deaths (50% and 
75% information) are observed respectively. The actual critical value will depend upon the 
actual information fraction at the time of the interim analysis. 
• Stopping early for futility is not planned. 
The IDMC will communicate major safety concerns and recommendations regarding study 
modification or termination to Exelixis senior management. 
Details of the composition, role, operational considerations, and stopping guidelines will be 
provided in a separate IDMC charter. 
 
11.3 
Clinical Steering Committee  
The Clinical Steering Committee consists of key opinion leaders in the area of HCC who will 
provide critical scientific guidance including, but not limited to, protocol design and 
implementation and will be instrumental in the interpretation of clinical study results.  
 
12 
ETHICAL ASPECTS 
12.1 
Local Regulations 
The study must fully adhere to the principles outlined in GCP ICH E6 Tripartite Guideline 
(January 1997) and remain consistent with the most recent accepted version of the Declaration of 


 
 
 
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Helsinki. The investigator will ensure that the conduct of the study complies with the basic 
principles of GCP as outlined in the current version of 21 CFR, subpart D, Part 312, 
“Responsibilities of Sponsors and Investigators,” Part 50, “Protection of Human Subjects,” and 
Part 56, “Institutional Review Boards.”  
12.2 
Informed Consent 
Sample ICFs will be supplied to each site. The Sponsor or its designee must review any proposed 
deviations from the sample ICF. The final IRB/EC-approved document must be provided to the 
Sponsor for regulatory purposes. 
It is the responsibility of the investigator, or a person designated by the investigator, to obtain 
written informed consent from each subject (or the subject’s legally authorized representative) 
participating in this study after adequate explanation of the aims, methods, anticipated benefits, 
and potential hazards of the study. In the case where the subject is unable to read, an impartial 
witness should be present during the entire informed consent discussion. After the subject has 
orally consented to participation in the trial, the witness’ signature on the form will attest that the 
information in the consent form was accurately explained and understood. A copy of the ICF 
must be provided to the subject or to the subject’s legally authorized representative. If applicable, 
the ICF will be provided in a certified translation of the subject’s language. 
The CRF for this study contains a section for documenting informed subject consent, and this 
must be completed appropriately. Signed ICFs must remain in each subject’s study file and must 
be available for verification by study monitors at any time. 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, given a copy of the revised form, and give their consent to continue in the 
study. 
12.3 
Institutional Review Board/Ethics Committee 
This study is being conducted under a United States Investigational New Drug application and 
other regulatory applications, as applicable. 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 the current federal regulations. The investigator will send a letter or 
certificate of IRB/EC approval to the Sponsor (or designee) before subject enrollment and 
whenever subsequent modifications to the protocol are made. 


 
 
 
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12.4 
Disposition of Subject Samples 
Protocol-defined analyses are anticipated to result in depletion of all or almost all of the research 
samples. Any leftover samples will be destroyed following conclusion of the study. If a subject 
requests destruction of their tissue and blood samples, the Sponsor will destroy the samples. The 
Sponsor will notify the Investigator in writing that the samples have been destroyed. 
13 
CONDITIONS FOR MODIFYING THE PROTOCOL 
Protocol modifications will be prepared, reviewed, and approved by the Sponsor. 
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 when the change involves only logistical or administrative 
aspects of the trial (eg, change in monitor, change of telephone number). 
14 
CONDITIONS FOR TERMINATING THE STUDY OR LIMITING DATA 
COLLECTION 
The Sponsor reserves the right to terminate the study at any time. Each investigator reserves the 
right to terminate their participation in the study at any time. Should this be necessary, both 
parties will arrange the procedures on an individual study basis after review and consultation. In 
terminating the study, the Sponsor and the investigator will assure that adequate consideration is 
given to the protection of the subjects’ interests. 
15 
STUDY DOCUMENTATION, CASE REPORT FORMS, AND RECORDING 
KEEPING 
15.1 
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) investigator’s study file and (2) subject 
clinical source documents. 
The investigator’s study file will contain, as applicable, the protocol and protocol amendments, 
CRFs, query forms, IRB/EC and governmental approval with correspondence, sample informed 
consent, drug records, staff curriculum vitae and authorization forms, and other appropriate 
documents and correspondence. 


 
 
 
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Subject clinical source documents (usually predefined by the project to record key efficacy and 
safety parameters independent of the CRFs) include subject hospital/clinic records, physician’s 
and nurse’s notes, appointment book, original laboratory reports, ECG, electroencephalogram, 
MRI, X-ray, pathology and special assessment reports, signed ICFs, subject diaries, 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 2 years following the last marketing 
application approval date for the study treatment in the indication being investigated, 2 years 
after the investigation is completed or discontinued, or for a time consistent with local regulatory 
requirements. After that period of time, the documents may be destroyed subject to local 
regulations with prior written permission from the Sponsor. If the investigator wants to assign 
the study records to another party or move them to another location, the Sponsor must be notified 
in advance. 
If the investigator cannot guarantee the archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and the Sponsor to 
store these in a sealed container outside of the study site so that they can be returned sealed to the 
investigator in case of a regulatory audit. When source documents are required for the continued 
care of the subject, appropriate copies should be made for storing outside of the study site. 
15.2 
Source Documents and Background Data 
Upon request, the investigator will supply the Sponsor with any required background data from 
the study documentation or clinic records. This is particularly important when CRFs (if paper) 
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. 
15.3 
Audits and Inspections 
The investigator should understand that source documents for this study should be made 
available to appropriately qualified personnel from the Exelixis Quality Assurance Unit (or 
designee), or to health authority inspectors after appropriate notification. The verification of the 
CRF data must be by direct inspection of source documents. 
15.4 
Case Report Forms 
The term “case report form” includes, as applicable, paper forms, electronic data capture screens 
or forms for studies that utilize electronic data capture. For randomized subjects, all and only 
data for the procedures and assessments specified in this protocol and required by the case report 


 
 
 
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forms should be submitted on the appropriate CRF (unless transmitted to the Sponsor or a 
designee electronically, eg, central laboratory data). Data from some procedures required by the 
protocol, such as physical exams, will be recorded only on the source documents. Additional 
procedures and assessments may be performed as part of the investigator’s institution or medical 
practice standard of care. Data from assessments associated with the follow-up of AEs should be 
recorded on unscheduled CRF pages. Otherwise, data for unscheduled or additional assessments 
should remain in the subject’s medical record and should not be recorded on CRFs unless 
specifically requested.  
The CRF (paper or electronic) must be completed and signed by the investigator or authorized 
delegate from the study staff. This also applies to records for those subjects who fail to complete 
the study or are randomized and never treated. If a subject stops dosing or terminates from the 
study, the dates and reasons must be noted on the CRF.  
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 reported to the Sponsor in the CRF 
and in all required reports. 
16 
MONITORING THE STUDY  
The responsible Sponsor monitor (or designee) will contact and visit the investigator regularly 
and will be allowed on request to inspect the various records of the trial (CRFs and other 
pertinent data) provided that subject confidentiality is maintained in accordance with local 
requirements. 
The monitor is responsible for inspecting the CRFs at regular intervals throughout the study, to 
verify the adherence to the protocol and the completeness, consistency, and accuracy of the data 
being entered on them. The monitor should have access to laboratory test reports and other 
subject records needed to verify the entries on the CRF. The investigator (or designee) must 
agree to cooperate with the monitor to ensure that any problems detected in the course of these 
monitoring visits are resolved.  
17 
CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT RECORDS 
The investigator must assure that subjects’ anonymity will be maintained and that their identities 
are protected from unauthorized parties. On CRFs or other documents submitted to the Sponsor, 


 
 
 
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subjects should be identified by an identification code and not by their names. The investigator 
should keep a subject enrollment log showing codes, names, and addresses. The investigator 
should maintain documents not for submission to the Sponsor (eg, subjects’ written consent 
forms) in strict confidence. 
18 
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS 
The results of this study may be published or presented at scientific meetings. The investigator 
agrees to submit all manuscripts or abstracts to the Sponsor for review at least 30 days before 
submission. This allows the Sponsor to protect proprietary information and to provide comments 
based on information from other studies that may not yet be available to the investigator.  
In the event that the Sponsor coordinates a publication or presentation of study results, the 
participation of the investigator, or other representatives of the study site, or Sponsor personnel 
as named author(s) shall be determined in accordance with the Sponsor’s policy. Authorship will 
be assigned in accordance with contribution to design, execution, and interpretation and analysis 
of the study. 
The Sponsor may, at its sole option, provide funding to support the development, submission, 
and/or presentation of publications for scientific/medical journals or conferences. For 
publications coordinated by the Sponsor, the Sponsor may also provide funding to support travel 
and conference registration for the presenting author to attend the conference for the sole purpose 
of presenting the publication. 


 
 
 
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19 
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20 
APPENDICES 


 
 
 
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Appendix A: Schedule of Assessments 
The schedule of required assessments is presented in this appendix. Following randomization, assessments for safety and EQ-5D-5L 
are to occur corresponding with study weeks [eg, Week 5 Day 1 (W5D1)] which are fixed from Week 1 Day 1 (W1D1) defined as the 
date of the first dose of study treatment. W1D1 should occur within 3 days after randomization (see Section 6.1). All assessments for 
radiographic efficacy (CT, MRI, bone scans) will be scheduled based on the date of randomization (see Section 5) and are to be 
performed even for subjects randomized but never treated. For such subjects, W1D1 is defined as the date of randomization. In the 
absence of toxicity, all scheduled safety visits should occur within ± 3 days of the nominal time for the first 9 weeks and within 
± 5 days of the nominal visit day thereafter, unless otherwise indicated. If study treatment is interrupted or missed after W1D1, 
assessments should continue following the schedule described below. 
Unscheduled safety assessments are to be performed weekly or more frequently as clinically indicated. Other unscheduled visits are 
permitted whenever necessary. See Section 5.6 for further details. 
See Appendix B for Schedule of Assessments during the Open-Label Phase and Appendix C for Schedule of Assessments during the 
Maintenance Phase. 
 
 
 
 
 
 
 


 
 
 
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Pre-randomization 
Post-randomization 
 
 
 
 
 
Screening  
(before 
randomization)a 
W1D1  
(≤ 3d after 
randomization) 
W3D1 
(±3 d) 
W5D1 
(±3 d) 
W7D1 
(±3 d) 
W9D1 
(±3 d) 
Beyond Week 9 
(±5 d) 
30-day Post-
Treatment 
Follow-Up  
(+14 d) 
Extended 
Follow-Up 
Informed consent (Section 12.2) 
Xb 
 
 
 
 
 
 
 
 
Demographics, medical history, prior 
cancer TX (Section 5.7.1) 
 ≤ 28 d  
 
 
 
 
 
 
 
 
Biopsy to establish histological or 
cytological diagnosis of HCC (for 
subjects with no previous histological or 
cytological diagnosis of HCC; Section 
5.1) 
Xb 
 
 
 
 
 
 
 
 
Hep B core antibody, Hep B surface 
antigen, and Hep C antibody; (Section 
5.1)  
≤ 28 d 
 
 
 
 
 
 
 
 
Child-Pugh Score (Appendix E) 
≤ 7 d 
Child-Pugh Score every 8 weeks (± 5 d) after randomization (W9D1, W17D1 etc). Child-Pugh assessments should continue regardless 
of whether study treatment is given, reduced, interrupted, or discontinued until the later of 8 weeks after radiographic progression per 
RECIST 1.1 as determined by the investigator or the date of the decision to permanently discontinue study treatment 
Physical exam (PE) + weight  
(Section 5.7.2) 
≤ 7 d  
(with height) 
X (prior to first dose; 
symptom-directed PE) 
X 
X 
X 
X 
Every 4 wks  
(W13D1, W17D1 etc) 
X 
 
Vital signs (Section 5.7.3) 
≤ 7 d 
X (prior to first dose) 
X 
X 
X 
X 
Every 4 wks  
(W13D1, W17D1 etc) 
X 
 
ECOG (Appendix D: ECOG 
Performance Scale) 
≤ 7 d 
X (prior to first dose) 
X 
X 
X 
X 
Every 4 wks  
(W13D1, W17D1 etc) 
X 
 
12-lead ECG with QTc (Section 5.7.4)c 
≤ 7 d 
X (prior to first dose)d 
X 
X 
 
X 
 
X 
 
Hematology by central lab 
(Section 5.7.5) e 
≤ 7 d 
X (prior to first dose)d 
X 
X 
X 
X 
Every 4 wks  
(W13D1, W17D1 etc) 
X 
 
Serum chemistry by central lab 
(Section 5.7.5) e 
≤ 7 d 
X (prior to first dose)d 
X 
X 
X 
X 
Every 4 wks  
(W13D1, W17D1 etc) 
X 
 
Coagulation panel by central lab 
(Section 5.7.5) e 
≤ 7 d 
X (prior to first dose)d 
X 
X 
X 
X 
Every 4 wks  
(W13D1, W17D1 etc) 
X 
 
UPCR  by central lab (Section 5.7.5) e 
≤ 7 d 
X (prior to first dose)d 
X 
X 
X 
X 
Every 4 wks  
(W13D1, W17D1 etc) 
X 
 


 
 
 
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Pre-randomization 
Post-randomization 
 
 
 
 
 
Screening  
(before 
randomization)a 
W1D1  
(≤ 3d after 
randomization) 
W3D1 
(±3 d) 
W5D1 
(±3 d) 
W7D1 
(±3 d) 
W9D1 
(±3 d) 
Beyond Week 9 
(±5 d) 
30-day Post-
Treatment 
Follow-Up  
(+14 d) 
Extended 
Follow-Up 
Fasting serum glucose by local lab  (only 
if HbA1c result is unavailable; Section 
5.7.5) 
≤ 28 d 
 
Urinalysis by local lab (Section 5.7.5) e 
≤ 7 d 
 
 
 
 
X 
Every 8 wks  
(W17D1, W25D1 etc) 
X 
 
Serum pregnancy test by local lab 
(Section 5.7.5) e 
≤ 7 d 
X (prior to first dose)d 
 
X 
 
X 
Every 4 wks  
(W13D1, W17D1 etc) 
X 
 
Thyroid function panel by central lab 
(Section 5.7.5) e 
≤ 28 d 
X (prior to first dose)d 
 
 
 
X 
Every 8 wks  
(W17D1, W25D1 etc) 
X 
 
AFP by central lab (Section 5.7.7) e 
≤ 28 d 
AFP every 8 weeks (± 5 d) after randomization (W9D1, W17D1 etc). Assessments should continue regardless of whether study 
treatment is given, reduced, interrupted, or discontinued until the later of 8 weeks after radiographic progression per RECIST 1.1 as 
determined by the investigator or the date of the decision to permanently discontinue study treatment 
Disease assessment (CT/MRI) (Section 
5.7.6) 
≤ 28 d 
CT/MRI every 8 weeks (± 5 d) after randomization (W9D1, W17D1 etc). Tumor assessments should continue regardless of whether 
study treatment is given, reduced, interrupted, or discontinued until the later of 8 weeks after radiographic progression per RECIST 1.1 
as determined by the investigator or the date of the decision to permanently discontinue study treatment 
Disease assessment (bone scan) (Section 
5.7.6) 
≤ 28 d 
Subjects with a documented bone lesions at screening will undergo bone scans at W9D1, W17D1 (± 5 d) then every 16 weeks 
(W33D1, W49D1 etc) after randomization. Assessments should continue regardless of whether study treatment is given, reduced, 
interrupted, or discontinued until the later of 8 weeks after radiographic progression per RECIST 1.1 as determined by the investigator 
or the date of the decision to permanently discontinue study treatment 
EQ-5D-5L (Section 5.7.8)g 
 
X (prior to first dose) 
Every 4 weeks (W5D1, W9D1 etc) through Week 25 then every 8 weeks regardless of whether study 
treatment is given, reduced, interrupted, or discontinued until the later of 8 weeks after radiographic 
progression per RECIST 1.1 as determined by the investigator or the date of the decision to permanently 
discontinue study treatment 
Archival or recently biopsied tumor 
tissue (Section 5.7.11)f 
 
X 
 
 
 
 
 
 
 
PK blood sample (pre-dose) (Section 
5.7.10)h 
 
 
X 
X 
 
X 
 
 
 
Pharmacogenetic blood sample 
(Section 5.7.11) 
 
X (prior to first dose) 
 
 
 
 
 
 
 
Plasma sample for biomarkers 
(Section 5.7.11) 
 
X (prior to first dose) 
X 
X 
 
X 
 
 
 


 
 
 
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Pre-randomization 
Post-randomization 
 
 
 
 
 
Screening  
(before 
randomization)a 
W1D1  
(≤ 3d after 
randomization) 
W3D1 
(±3 d) 
W5D1 
(±3 d) 
W7D1 
(±3 d) 
W9D1 
(±3 d) 
Beyond Week 9 
(±5 d) 
30-day Post-
Treatment 
Follow-Up  
(+14 d) 
Extended 
Follow-Up 
Serum sample for bone markers 
(Section 5.7.11) 
 
X (prior to first dose) 
X 
X 
 
X 
 
 
 
Blood sample for potential CTC analysis 
(selected sites) (Section 5.7.11) 
 
X (prior to first dose) 
 
X 
 
 
 
 
 
Concomitant medications (Section 7) 
 
 
 
 
 
 
 
 
 
Adverse events (Section 8) 
 
 
 
 
 
 
 
 
 
Study treatment 
 
Given in clinic on W1D1 and taken once daily at home thereafter until discontinuation 
 
Study drug accountability (Section6.4) 
 
X 
X 
X 
X 
X 
Every 4 wks 
 
 
Survival, poststudy treatment 
(Section 5.5) 
 
 
 
 
 
 
 
 
Every 
8 wks 
AFP = alpha fetoprotein; CTC = circulating tumor cells; TSH = thyroid stimulating hormone 
a 
Results of screening assessments must be reviewed by the investigator before randomization to confirm that the subject meets the eligibility criteria. 
b 
Informed consent may be obtained greater than 28 days prior to randomization, but must be provided before any study-specific procedures are performed; however 
evaluations performed as part of routine care prior to informed consent can be utilized as screening evaluations if permitted by the site’s IRB/EC policies. Biopsy to 
establish histological or cytological diagnosis of HCC can occur > 28 days prior to randomization. Healing from biopsy must be complete at least 7 days prior to 
randomization. 
c 
Additional ECGs should be performed if clinically indicated 
d 
This assessment is intended to confirm suitability for treatment after randomization. If this assessment has been performed during screening within 10 days (7 days for 
pregnancy test) prior to first dose (W1D1), this assessment does not need to be performed on W1D1 unless the subjects’ clinical status has changed (eg, onset of new 
symptoms indicative of clinical deterioration). If the assessment is performed on W1D1, the results must be available to and reviewed by the investigator prior to any 
treatment being administered.  
e 
See Section 5.7.5 and separately provided Laboratory Manual for more detailed information on laboratory assessments. If the investigator suspects the subject is clinically 
deteriorating during the screening period, additional unscheduled laboratory tests (eg, albumin, bilirubin) should be performed by the local laboratory before randomization 
to confirm that the subject remains suitable for study treatment and amenable to study participation commensurate with the goals of the clinical trial. 
f 
Tumor tissue (archival or recently biopsied) will be obtained at enrollment whenever available. Formalin-fixed paraffin embedded (FFPE) tumor blocks are preferred but in 
cases where this is not possible, 10 unstained freshly cut FFPE slides should be obtained. 
g 
EQ-5D-5L forms should be administered and collected prior to any other study-related activities for scheduled visits. Questionnaires should be completed prior to the clinic 
visit or if completed on the day of the visit prior to seeing the study site personnel.  


 
 
 
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h 
For each on-treatment visit, the PK sample should be collected approximately 8 or more hours after the previous dose of study treatment and should be collected prior to 
study treatment administration. The investigator will ask the subject for the date and time of the most recent prior dose of study treatment, and this information will be 
recorded on the appropriate CRF page. 


 
 
 
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Appendix B: Open-Label Phase 
The Open-Label Phase will only be implemented upon decision of the Sponsor and discussion with the regulatory authorities 
following review of the data 
The study may transition to an Open-Label Phase if one of the planned analyses shows statistically-significant and clinically-
meaningful evidence of improved OS. If the decision is made to enter the Open-Label Phase, study treatment will be unblinded. 
• Subjects randomized to the placebo arm will have the option to crossover to receive treatment with cabozantinib if they meet 
the eligibility criteria for crossover to cabozantinib after treatment with placebo. The subjects randomized to the placebo arm 
who opt to crossover, will enter a screening period during which their eligibility for receipt of cabozantinib after treatment with 
placebo will be determined. Subjects randomized to the placebo arm who crossover to receive treatment with cabozantinib will 
continue on unblinded study treatment until a criterion for protocol-defined discontinuation has been met (protocol Section 
3.6.1).  
• Subjects randomized to the cabozantinib arm who are still receiving study treatment, and subjects randomized to the placebo 
arm who are still receiving study treatment and do not crossover to cabozantinib, may continue on unblinded study treatment 
until a criterion for protocol-defined discontinuation has been met (protocol Section 3.6.1).  
• Subjects randomized to the cabozantinib arm who are in the post-treatment period, and subjects randomized to the placebo arm 
who do not crossover to cabozantinib and are in the post-treatment period, will continue with post-treatment assessments as 
outlined in Table 12.  
Screening of placebo subjects for crossover to cabozantinib will continue until the earlier of: 
• Six months from transition of the study to the Open-Label Phase or 
• The transition of the study to the Maintenance Phase 


 
 
 
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Assessments for the Open-Label Phase are outlined in Table 12. 
Data for subjects who crossover from the placebo arm to receive cabozantinib, will be summarized separately and will not be included 
as part of the evaluation of either arm. 
If the study transitions to the Open-Label Phase prior to completing enrollment, enrollment will be discontinued. 
Eligibility Criteria for Crossover to Cabozantinib Following Treatment with Placebo 
(Note that the numbering of the criteria is maintained from the start of the study [Section 4.2 Inclusion Criteria and Section 4.3 
Exclusion Criteria]. “Not applicable” rows below refer to eligibility criteria from the start of the study that are not relevant for the 
Open-Label Phase as these subjects have either already fulfilled the criteria upon study entry, or the criteria are not a requirement for 
the Open-Label Phase.) 
Inclusion Criteria 
1. Not applicable 
2. Not applicable 
3. Not applicable 
4. Not applicable 
5. Recovery to ≤ Grade 1 from toxicities related to any prior treatments, unless the adverse events are clinically nonsignificant and/or 
stable on supportive therapy 
6. Not applicable 
7. ECOG performance status of 0 or 1 
8. Adequate hematologic function, based upon meeting the following laboratory criteria within 7 days before crossover:  
a. absolute neutrophil count (ANC) ≥ 1200/mm3 (≥ 1.2 x 109/L) 
b. platelets ≥ 60,000/mm3 (≥ 60 x 109/L) 
c. hemoglobin ≥ 8 g/dL (≥ 80 g/L) 


 
 
 
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9. Adequate renal function, based upon meeting the following laboratory criteria within 7 days before crossover:  
a. serum creatinine ≤ 1.5 × upper limit of normal or calculated creatinine clearance ≥ 40 mL/min (using the Cockroft-Gault 
equation: (140 – age) x weight (kg)/(serum creatinine × 72 [mg/dL]) for males. (For females multiply by 0.85).  
AND 
b. urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.1 mg/mmol) or 24-hour urine protein < 1 g  
10. Child-Pugh Score of A 
11. Total bilirubin ≤ 2 mg/dL (≤ 34.2 µmol/L) within 7 days before crossover 
12. Serum albumin ≥ 2.8 g/dL (≥28 g/L) within 7 days before crossover 
13. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)  < 5.0 upper limit of normal (ULN) within 7 days before 
crossover 
14. Not applicable 
15. Antiviral therapy per local standard of care if active hepatitis B (HBV) infection 
16. Capable of understanding and complying with the protocol requirements and signed informed consent 
17. Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception (eg, barrier 
methods, including male condom, female condom, or diaphragm with spermicidal gel) during the course of the study and for 
4 months after the last dose of study treatment 
18. Female subjects of childbearing potential must not be pregnant at screening. Females of childbearing potential are defined as 
premenopausal females capable of becoming pregnant (ie, females who have had any evidence of menses in the past 12 months, 
with the exception of those who had prior hysterectomy). However, women who have been amenorrheic for 12 or more months are 
still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, ovarian 
suppression, low body weight, or other reasons. 
 
Exclusion Criteria 
1. Not applicable 
2. Receipt of more than 2 prior systemic therapies for advanced HCC. Additional prior systemic therapies used as adjuvant or local 
therapy are allowed. 


 
 
 
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3. Any type of anticancer agent (including investigational) within 2 weeks before crossover 
4. Radiation therapy (eg, I-131 or Y-90) within 4 weeks (2 weeks for radiation for bone metastases) or radionuclide treatment within 
6 weeks of crossover (subject is excluded if there are any clinically relevant ongoing complications from prior radiation therapy)  
5. Prior cabozantinib treatment 
6. Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including 
radiosurgery) and stable for at least 3 months before crossover. Eligible subjects must be without corticosteroid treatment at the 
time of crossover.  
7. Concomitant anticoagulation, at therapeutic doses, with anticoagulants such as warfarin or warfarin-related agents, low molecular 
weight heparin (LMWH), thrombin or coagulation factor X (FXa) inhibitors, or antiplatelet agents (eg, clopidogrel). Low dose 
aspirin for cardioprotection (per local applicable guidelines), low-dose warfarin (≤ 1 mg/day), and low-dose LMWH are permitted. 
8. The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions: 
a. Cardiovascular disorders including 
i. Symptomatic congestive heart failure, unstable angina pectoris, or serious cardiac arrhythmias  
ii. Uncontrolled hypertension defined as sustained BP > 150 mm Hg systolic, or > 100 mm Hg diastolic despite optimal 
antihypertensive treatment 
iii. Stroke (including TIA), myocardial infarction, or other ischemic event within 6 months before crossover 
iv. Thromboembolic event within 3 months before crossover. Subjects with thromboses of portal/hepatic vasculature attributed 
to underlying liver disease and/or liver tumor are eligible 
b. Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation: 
i. Tumors invading the GI tract, active peptic ulcer disease, inflammatory bowel disease (eg, Crohn’s disease), diverticulitis, 
cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic duct or 
common bile duct, or gastric outlet obstruction 
ii. Abdominal fistula, GI perforation, bowel obstruction, intra-abdominal abscess within 6 months before  crossover,  
Note: Complete healing of an intra-abdominal abscess must be confirmed prior to crossover 
c. Major surgery within 2 months before crossover. Complete healing from major surgery must have occurred 1 month before 
crossover. Complete healing from minor surgery (eg, simple excision, tooth extraction) must have occurred at least 7 days 
before crossover. Subjects with clinically relevant complications from prior surgery are not eligible 
d. Cavitating pulmonary lesion(s) or endobronchial disease  


 
 
 
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e. Lesion invading a major blood vessel including, but not limited to: inferior vena cava, pulmonary artery, or aorta).  Subjects 
with lesions invading the portal vasculature are eligible. 
f. Clinically significant bleeding risk including the following within 3 months of crossover: hematuria, hematemesis, hemoptysis 
of >0.5 teaspoon (>2.5 mL) of red blood, or other signs indicative of pulmonary hemorrhage, or history of other significant 
bleeding if not due to reversible external factors 
g. Other clinically significant disorders such as: 
i. Active infection requiring systemic treatment, known infection with human immunodeficiency virus (HIV), or known 
acquired immunodeficiency syndrome (AIDS)-related illness. Subjects with active hepatitis virus infection controlled with 
antiviral therapy are eligible. 
ii. Serious non-healing wound/ulcer/bone fracture 
iii. Malabsorption syndrome 
iv. Uncompensated/symptomatic hypothyroidism 
v. Requirement for hemodialysis or peritoneal dialysis 
vi. History of solid organ transplantation  
9. Subjects with untreated or incompletely treated varices with bleeding or high risk for bleeding.  Subjects treated with adequate 
endoscopic therapy (according to institutional standards) without any episodes of recurrent GI bleeding requiring transfusion or 
hospitalization for at least 6 months prior to crossover are eligible.  
10. Moderate or severe ascites  
11. Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms within 7 days before crossover 
Note: If the QTcF is > 500 ms in first ECG, a total of 3 ECGs should be performed. If the average of these 3 consecutive results 
for QTcF is ≤ 500 ms, the subject meets eligibility in this regard. 
12. Inability to swallow tablets  
13. Previously identified allergy or hypersensitivity to components of the study treatment formulations 
14. Pregnant or lactating females 
15. Diagnosis of another malignancy within 2 years before crossover, except for superficial skin cancers, or localized, low-grade 
tumors deemed cured and not treated with systemic therapy 


 
 
 
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Table 8:  Schedule of Assessments Open-Label Phase  
For subjects who crossover from the placebo arm to cabozantinib, W1D1 will be the first day of unblinded cabozantinib treatment.  
For subjects randomized to the cabozantinib arm and subjects randomized to the placebo arm who do not crossover, study week and 
day will be counted from time of first dose of blinded treatment. In the absence of toxicity, all scheduled safety visits should occur 
within ± 3 days of the nominal time for the first 9 weeks and within ± 5 days of the nominal visit day thereafter, unless otherwise 
indicated. If study treatment is interrupted or missed after W1D1, assessments should continue following the schedule described 
below.  


 
 
 
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Screening  
(before 
crossover)a 
W1D1  
 
W3D1 
(±3 d) 
W5D1 
(±3 d) 
W7D1 
(±3 d) 
W9D1 
(±3 d) 
Beyond Week 9 
(±5 d) 
30-day Post-
Treatment Follow-
Up (+14 d) 
Extended 
Follow-Up 
Informed consent (Section 12.2) 
X b 
 
 
 
 
 
 
 
 
Interval medical history  
Xc 
 
 
 
 
 
 
 
 
Child-Pugh Score (Appendix E) 
≤ 7 d 
Child-Pugh Score every 8 weeks (± 5 d) after crossover (W9D1, W17D1 etc). Assessments should continue regardless of whether 
study treatment is given, reduced, interrupted, or discontinued until the date of the decision to permanently discontinue study treatment 
Physical exam (PE) + weight  
(Section 5.7.2) 
≤ 7 d  
(with height) 
X (prior to first dose; 
symptom-directed PE) 
X 
X 
X 
X 
Every 4 wks  
(W13D1, W17D1 etc) 
X 
 
Vital signs (Section 5.7.3) 
≤ 7 d 
X (prior to first dose) 
X 
X 
X 
X 
Every 4 wks  
(W13D1, W17D1 etc) 
X 
 
ECOG (Appendix D) 
≤ 7 d 
X (prior to first dose) 
X 
X 
X 
X 
Every 4 wks  
(W13D1, W17D1 etc) 
X 
 
12-lead ECG with QTc (Section 5.7.4)d 
≤ 7 d 
X (prior to first dose)e 
X 
X 
 
X 
 
X 
 
Hematology by central lab 
(Section 5.7.5) f 
≤ 7 d 
X (prior to first dose)e 
X 
X 
X 
X 
Every 4 wks  
(W13D1, W17D1 etc) 
X 
 
Serum chemistry by central lab 
(Section 5.7.5) f 
≤ 7 d 
X (prior to first dose)e 
X 
X 
X 
X 
Every 4 wks  
(W13D1, W17D1 etc) 
X 
 
Coagulation panel by central lab 
(Section 5.7.5) f 
≤ 7 d 
X (prior to first dose)e 
X 
X 
X 
X 
Every 4 wks  
(W13D1, W17D1 etc) 
X 
 
UPCR  by central lab (Section 5.7.5) f 
≤ 7 d 
X (prior to first dose)e 
X 
X 
X 
X 
Every 4 wks  
(W13D1, W17D1 etc) 
X 
 
Urinalysis by local lab (Section 5.7.5) f 
≤ 7 d 
 
 
 
 
X 
Every 8 wks  
(W17D1, W25D1 etc) 
X 
 
Serum pregnancy test by local lab 
(Section 5.7.5) f 
≤ 7 d 
X (prior to first dose)e 
 
X 
 
X 
Every 4 wks  
(W13D1, W17D1 etc) 
X 
 
Thyroid function panel by central lab 
(Section 5.7.5) f 
≤ 28 d 
X (prior to first dose)e 
 
 
 
X 
Every 8 wks  
(W17D1, W25D1 etc) 
X 
 
Disease assessment 
Per Standard of Care 
Concomitant medications (Section 7) 
 
 
 
 
 
 
 
 
 
Adverse events (Section 8) 
 
 
 
 
 
 
 
 
 
Study treatment 
 
Given in clinic on W1D1 and taken once daily at home thereafter until discontinuation 
 
Study drug accountability (Section 6.4) 
 
X 
X 
X 
X 
X 
Every 4 wks 
 
 
Survival, poststudy treatment 
(Section 5.5) 
 
 
 
 
 
 
 
 
Every 
8 wks 


 
 
 
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TSH = thyroid stimulating hormone 
a 
Screening assessments must be reviewed by the investigator before crossover to confirm that the subject meets the eligibility criteria. Only subjects randomized to the 
placebo arm who opt to crossover to receive cabozantinib will undergo screening. Subjects randomized to the cabozantinib arm and subjects randomized to the placebo arm 
who do not crossover will continue study assessments according to the Week and Day from time of first dose of blinded treatment.   
b 
Informed consent may be obtained greater than 28 days prior to crossover, but must be provided before any study-specific procedures are performed; however evaluations 
performed as part of routine care prior to informed consent can be utilized as screening evaluations if permitted by the site’s IRB/EC policies. The Investigator must ensure 
that the subject consents on the most recent version of the ICF. 
c 
Interval medical history will be collected for subjects randomized to the placebo arm who undergo screening for crossover and who have discontinued blinded study 
treatment > 30 days prior to W1D1 of crossover. All adverse events that were experienced ≤ 30 days after discontinuation of blinded study treatment will be collected on 
the adverse event CRF. 
d 
Additional ECGs should be performed if clinically indicated 
e 
This assessment is intended to confirm suitability for treatment after crossover. If this assessment has been performed during screening within 10 days (7 days for 
pregnancy test) prior to first dose of unblinded cabozantinib (W1D1), this assessment does not need to be performed on W1D1 unless the subjects’ clinical status has 
changed (eg, onset of new symptoms indicative of clinical deterioration). If the assessment is performed on W1D1, the results must be available to and reviewed by the 
investigator prior to any treatment being administered.  
f 
See Section 5.7.5 and separately provided Laboratory Manual for more detailed information on laboratory assessments. If the investigator suspects the subject is clinically 
deteriorating during the screening period, additional unscheduled laboratory tests (eg, albumin, bilirubin) should be performed by the local laboratory before crossover to 
confirm that the subject remains suitable for study treatment and amenable to study participation commensurate with the goals of the clinical trial. 
  


 
 
 
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Appendix C: Maintenance Phase 
When sufficient data have been collected to adequately evaluate all study endpoints, and upon site notification by the Sponsor, 
subjects remaining on study treatment will enter the study Maintenance Phase. Upon initiation of the Maintenance Phase, the Sponsor 
considers the safety and efficacy profile of the drug within this study to have been sufficiently established for regulatory purposes. 
In the Maintenance Phase subjects will continue to receive study treatment until a criterion for protocol-defined discontinuation has 
been met (protocol Section 3.6.1). Subjects are to undergo periodic safety assessments (including local laboratory tests) and tumor 
assessments; the nature and frequency of these assessments are to be performed per standard of care. It is the Investigator’s 
responsibility to ensure that subject visits occur frequently enough and adequate assessments are performed to ensure subject safety. 
In order to continue to capture important safety information on subjects still enrolled in the study, reporting of SAEs and other 
reportable events (pregnancy and medication errors with sequelae) is to continue per protocol Section 8.2. 
Further, the following events (whether serious or not) are to be reported using the same process as for reporting SAEs described in 
protocol Section 8.2 (though SAE reporting timeline requirements do not apply to non-serious events reported in these categories): 
• Adverse Events (serious or not) leading to cabozantinib treatment discontinuation 
• Adverse Events (serious or not) leading to cabozantinib dose modification (ie, causing cabozantinib to be withheld or reduced) 
Other non-serious adverse events will not be collected by the Sponsor as they are unlikely to meaningfully change the safety profile 
established in earlier phases of this study. 
Study drug accountability is to continue as described in Section 6.4. 
See Maintenance Phase Schedule of Assessments (Table 9). To receive study treatment supplies it may be necessary for subjects to 
visit the study site more frequently than clinic visits for safety and tumor evaluations performed per standard of care. 


 
 
 
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Site monitoring visits will occur at a reduced frequency to ensure adherence to GCP, protocol compliance, adequate subject safety 
follow-up, study drug accountability, and reporting of SAEs and other reportable events. 
During the Maintenance Phase no data are to be entered into electronic case report forms. Study central laboratory samples are not to 
be obtained. Do not submit local laboratory results to the study local laboratory management vendor, radiographic images to the study 
central imaging vendor, or ECGs to the study central imaging vendor. 
Table 9: Schedule of Assessments: Maintenance Phase 
 
Assessment 
Study Period / Visit 
While Subject is Receiving Study Treatment 
(Until Treatment Permanently Discontinued) 
Post-Treatment 
Follow-Up Visit 
Study treatment dispensing and drug accountability 
Every 4 weeks 
a 
Study treatment 
Daily until a criterion for discontinuation is met 
 
Safety evaluation 
Clinical exam and local laboratory assessments per SOC 
Frequency per standard of care 
Reporting of SAEs and other reportable events (pregnancy and 
medication errors with sequelae)  
Submit reports to Sponsor per Section 8.2 
Reporting of adverse events (serious or not): 
• leading to cabozantinib treatment discontinuation 
• leading to cabozantinib dose modification (ie, causing 
cabozantinib to be withheld or reduced) 
Submit reports to the Sponsor per the same process as for reporting SAEs in Section 8.2.  
(SAE reporting timeline requirements do not apply to non-serious events reported in these categories) 
Tumor assessments 
Imaging methods per SOC 
Frequency per standard of care 
 
SOC = standard of care 
No data will be entered into electronic case report forms. Do not submit local laboratory results to the study local laboratory management vendor, radiographic images to the study 
central imaging vendor, or ECGs to the study central imaging vendor. 
a A post-treatment visit may be required for the purpose of  returning  all unused study medication still in the subject’s possession. 
 


 
 
 
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Appendix D: ECOG Performance Scale  
Score 
Description 
0 
Normal activity. Fully active, able to carry on all predisease performance without 
restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory 
and able to carry out work of a light or sedentary nature (eg, light housework, office 
work). 
2 
In bed < 50% of the time. Ambulatory and capable of all self-care, but unable to carry 
out any work activities. Up and about more than 50% of waking hours. 
3 
In bed > 50% of the time. Capable of only limited self-care, confined to bed or chair 
more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined 
to bed or chair. 
5 
Dead 
 


 
 
 
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Appendix E: Child-Pugh Scoring System 
Modified Child-Pugh classification of severity of liver disease (Pugh 1973, Lucey 1997) 
according to the degree of ascites, total bilirubin and albumin, prothrombin time, and degree of 
encephalopathy. Each measure is scored 1-3, with 3 indicating greatest severity: 
 
Points assigned 
Parameter 
1 
2 
3 
Ascites 
absent 
slight 
moderate 
Total bilirubin, mg/dL 
≤ 2 
2–3 
> 3 
Albumin, g/dL 
> 3.5 
2.8–3.5 
< 2.8 
Prothrombin time 
 
 
 
Seconds over control 
1–3 
4–6 
> 6 
or 
 
 
 
INR 
< 1.8 
1.8–2.3 
> 2.3 
Encephalopathy 
none 
Grade 1–2 
Grade 3–4 
Child-Pugh score (A, B, or C) based on total score from the above point assignments: 
Grade 
Points 
1-year 
survival 
2-year 
survival 
A:  well-compensated disease 
5–6 
100% 
85% 
B: significant functional compromise 
7–9 
80% 
60% 
C: decompensated disease 
10–15 
45% 
35% 
 


 
 
 
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Appendix F: Guidelines for Best Supportive Care 
The following general guidelines should be utilized to provide subjects with BSC:  
Analgesia 
• Pain assessment with prescriptions for nonnarcotic or narcotic analgesics, as required, except 
that nonsteroidal anti-inflammatory agents should not be used in treatment of pain, because 
they are known to induce renal failure in patients with decompensated liver disease 
• Management of toxicities from analgesic medication including constipation, nausea or 
gastritis 
Liver decompensation  
• GI bleeding, hepatic encephalopathy, ascites, and bacterial infections should be treated as in 
patients with nonneoplastic liver disease  
Treatment of infections 
• Antibiotics for peritonitis, pneumonia and other infections, as required 
Nutritional support 
Psychological support 
• Management of depression and anxiety by medication and/or counseling as clinically 
appropriate 
Anemia 
• Transfusions may be given to maintain hemoglobin as clinically indicated, but erythroid 
growth factors should not be used 
The following liver-directed or systemic antitumor therapies are not considered part of BSC: 
• transarterial tumor embolization or chemoembolization 
• radiofrequency or microwave ablation 
• percutaneous ethanol or acetic acid ablation 
• injection or infusion of drug eluting or radiation-emitting beads 
• cryoablation 
• radiation therapy, including stereotactic radiotherapy (palliative external radiation to bone 
metastasis or skin/subcutaneous metastasis, is allowed but discouraged unless medically 
unavoidable) 
• liver transplantation 
• systemic chemotherapy or molecularly targeted therapies 
 


 
 
 
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Appendix G: Response Evaluation Criteria in Solid Tumors Version 1.1 
Adapted from Eisenhauer 2009 
Definitions 
Baseline: Baseline is defined as the most recent assessment performed prior to randomization. 
Baseline assessments must be performed within the period defined in the protocol eligibility 
criteria.  
Measurable lesions: Except for lymph nodes as described below, measurable lesions are defined 
as those that can be accurately measured in at least 1 dimension (longest diameter to be recorded) 
as ≥ 10 mm with CT scan (if CT scans have slice thickness greater than 5 mm the minimum size 
for a measurable lesion is twice the slice thickness).  
• To be considered pathologically enlarged and measurable, a lymph node must be ≥ 15 mm in 
short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater 
than 5 mm). At baseline and in follow-up, only the short axis will be measured and recorded. 
• MRI may be substituted for contrast-enhanced CT for lesions at some anatomical sites, but 
not for lesions in the lungs. The minimum size for measurability is the same as for CT (10 
mm) as long as the scans are performed with slice thickness of 5 mm and no gap. If MRI is 
performed with thicker slices, the size of a measurable lesion at baseline should be twice the 
slice thickness. In the event there are interslice gaps, this also needs to be considered in 
determining the size of measurable lesions at baseline. 
Nonmeasurable lesions: All other lesions (or sites of disease), including small lesions (longest 
diameter < 10 mm or pathological lymph nodes with ≥ 10 to < 15 mm short axis), are considered 
nonmeasurable. Lymph nodes that have a short axis < 10 mm are considered nonpathological 
and are not be recorded or followed. Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/ pulmonitis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI), are considered as nonmeasurable.  
Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, are to be identified as target lesions and measured 
and recorded at baseline. Target lesions are to be selected on the basis of their size (lesions with 
the longest diameter), be representative of all involved organs, and be those that lend themselves 
to reproducible repeated measurements. It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance the next largest lesion 
which can be measured reproducibly should be selected. Target lesions will be measured at each 


 
 
 
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assessment (longest axis for nonnodal lesions, shortest axis for measurable malignant nodal 
lesions). 
Nontarget lesions: All other lesions (or sites of disease) including all non-measurable lesions 
(including pathological lymph nodes with ≥10 to <15 mm short axis) and all measurable lesions 
over and above the 5 target lesions are to be identified as non-target lesions and recorded at 
baseline. Measurements of these lesions are not required, but the presence, absence, or in rare 
cases unequivocal progression of each is to be recorded throughout follow-up. Lymph nodes that 
have a short axis <10 mm are considered non-pathological and are not to be recorded or 
followed.  
To be considered progression of non-target lesions in the presence of measurable disease, 
unequivocal progression is defined as substantial worsening in non-target disease such that, even 
in the presence of SD or PR in target disease, the overall tumor burden has increased sufficiently 
to merit discontinuation of the therapy.  
Special Consideration 
Lesions by clinical examination 
Lesions by clinical examination will not be used for response in this study. 
Cystic lesions 
• Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor nonmeasurable) since they are, by 
definition, simple cysts. 
• Cystic lesions thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if noncystic 
lesions are present in the same patient, these are preferred for selection as target lesions. 
Bone lesions 
• Bone scan, PET scan or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross-sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
• Blastic bone lesions are non-measurable. 


 
 
 
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Lesions with prior local treatment 
• Lesions situated in a previously irradiated area, or in an area subjected to other loco-regional 
therapy, are not considered measurable.  
Imaging Methods 
The same method of assessment and the same technique used to characterize each identified and 
reported lesions at baseline should be used during each follow-up assessment. All measurements 
should be taken and recorded in metric notation using a ruler or calipers. Imaging based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being followed 
cannot be imaged but assessed by clinical examination (referring to biopsy-proven visible 
lesion(s) on the chest). 
Chest x-ray: Chest x-ray will not be used for response assessment in this study. 
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion is twice the slice thickness. MRI is 
also acceptable in certain situations (eg, for body scan) except for lung.  
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI 
is variable globally. As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease. 
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans. Body scans 
should be performed with breath-hold scanning techniques, if possible. 
Positron emission tomography will not be used for response assessment in this study. 
Ultrasound: Ultrasound will not be used for response assessment in this study 


 
 
 
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Bone scans will be used to assess the presence or disappearance of the bone component of bone 
lesions. CT or MRI scan will be used to confirm ambiguous results of bone scans. Preferred 
method for confirmation is MRI.  
Tumor Markers: Tumor markers may be evaluated for changes but will not be used to determine 
progressive disease in this study. 
Cytology, Histology: The cytological confirmation of the neoplastic origin of any effusion that 
appears or worsens during treatment when the measurable tumor has met criteria for response or 
stable disease will be considered malignant unless cytologically confirmed.  
Time Point Assessments 
The frequency and schedule of tumor assessments is defined in the protocol. The schedule is to 
be maintained regardless of whether study treatment is held or discontinued. 
At baseline, tumors and lymph nodes are classified and documented as target or nontarget per the 
definitions provided above. It is possible to record multiple nontarget lesions involving the same 
organ as a single item (eg, ‘multiple liver metastases’). 
At all postbaseline (follow-up) evaluations the baseline classification (target, nontarget) is to be 
maintained and lesions are to be documented and described in a consistent fashion over time 
(eg, recorded in the same order on source documents). 
At each assessment, a sum of the diameters (longest for nonnodal lesions, short axis for nodal 
lesions) for all target lesions will be calculated and included in source documents. The baseline 
sum of the diameters (SoD) will be used as reference to further characterize any objective tumor 
regression in the measurable dimension of the disease. The lowest SoD (nadir) since (and 
including) the baseline value will be used as reference for evaluating progression. 
After baseline, target lesions should have the actual size documented, if possible, even if the 
lesions become very small. If in the opinion of the radiologist the lesion has likely disappeared, 0 
mm should be recorded. If the lesion is present but too small to measure, an indicator for ‘too 
small to measure’ should be included in source documents. 
Nontarget lesions are to be assessed qualitatively (present, resolved, or unequivocal progression) 
and new lesions, if any, are to be documented separately. 


 
 
 
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At each evaluation, progression status is to be determined based upon the time point status for 
target lesions, nontarget lesions, and new lesions. 
Finding of new lesions should not be attributable to differences in scanning technique, change in 
imaging modality or findings thought to represent something other than tumor. Necrosis of pre-
existing lesions as part of a response to treatment should be excluded before defining a ‘new’ 
cystic lesion. A lesion identified on a follow-up study in an anatomical location that was not 
scanned at baseline is considered a new lesion. If a new lesion is equivocal because of its small 
size, repeat scans need to confirm there is definitely a new lesion, and progression should be 
declared using the date of the initial scan. 
Time point progression can be based solely on bone scans if there is unequivocal evidence of 
new bone scan lesions. New bone scan lesions will be considered malignant in the absence of 
correlative imaging or clinical data that demonstrate lesions are not malignant. Follow up 
imaging may be required to ensure new lesions are unequivocal. Increases in the density or size 
of bone scan lesions present at baseline cannot be the basis of progression. 


 
 
 
Protocol XL184-309 Amendment 2.0 
Page 137 of 142 
RESPONSE CRITERIA 
Target Lesion Time Point Response (TPR) 
Complete Response     
(CR) 
• 
Disappearance of all target lesions. All pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 
10 mm. 
Partial Response 
(PR) 
• 
At least a 30% decrease in SoD of target lesions, taking as a 
reference the baseline SoD 
Stable Disease (SD) 
• 
Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD. 
Progressive Disease     
(PD) 
• 
At least a 20% increase in the SoD of target lesions, taking as a 
reference the smallest (nadir) SoD since (and including) baseline. In 
addition to the relative increase of 20%, the SoD must also 
demonstrate an absolute increase of at least 5 mm. 
Not Applicable (NA) 
• 
No target lesion identified at baseline. 
Unable to Evaluate     
(UE) 
• 
One or more target lesions are not imaged and the remainder of the 
SoD compared with the nadir SoD does not meet the criterion for 
PD. 
SoD, baseline sum of diameters (longest for non-nodal lesions; short axis for nodal lesions) 
If the target lesion for a subject meet the criteria for both PR and PD at a given time point, the target lesion 
response is PD. 
If the nadir of SoD is 0 (ie, the subject had a prior target lesion CR), the reappearance of any prior target 
lesion to any degree constitutes PD. 
 
 
Non-Target Lesion Time Point Response (TPR) 
Complete Response      
(CR) 
• 
Disappearance of all non-target lesions. All lymph nodes must be 
non-pathological in size (<10 mm short axis) 
Non-CR / Non-PD 
• 
Persistence of one or more non-target lesion(s). 
Progressive Disease      
(PD) 
• 
Unequivocal progression of non-target lesions. Unequivocal 
progression should normally trump target lesion status. It must be 
representative of overall disease status change, not a single lesion 
increase 
Not Applicable (NA) 
• 
No non-target lesions identified at screening 
Unable to Evaluate       
(UE) 
• 
One or more non-target lesions are not imaged and the remaining 
non-target lesions do not meet the criterion for PD. 
 


 
 
 
Protocol XL184-309 Amendment 2.0 
Page 138 of 142 
 
 
New Lesion Time Point Response (TPR) 
Yes 
• 
Lesion present at follow-up visit either for the very first time or re-
appearing (ie, lesion was present at baseline, disappeared at a 
follow-up visit and re-appeared later). On bone scan, a single new 
lesion may not be sufficient to qualify as PD. Confirmation should 
be obtained by performing CT or MRI of the area of concern to 
confirm ambiguous results of bone scan. Preferred method for 
confirmation is MRI. 
No 
• 
No new lesions present at follow-up. 
Unable to Evaluate         
(UE) 
• 
Subject not assessed or incompletely assessed for new lesions. 
 


 
 
 
Protocol XL184-309 Amendment 2.0 
Page 139 of 142 
Evaluation of Overall Timepoint Response (TPR) 
Target Lesion TPR 
Non-target lesion TPR 
New lesion TPR 
Overall TPR 
CR 
CR or NA 
No 
CR* 
CR 
Non-CR/non-PD 
No 
PR* 
CR 
UE 
No 
PR* 
PR 
Non-PD or NA or UE 
No 
PR* 
SD 
Non-PD or NA or UE 
No 
SD 
UE 
Non-PD 
No 
UE 
PD 
Any 
No or Yes or UE 
PD 
Any 
PD 
No or Yes or UE 
PD 
Any 
Any 
Yes 
PD 
NA 
CR 
No 
CR* 
NA 
Non-CR/Non-PD 
No 
Non-CR/non-PD 
NA 
UE 
No 
UE 
Non-PD 
Non-PD 
UE 
UE 
CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease, UE, unable to 
evaluate; NA, not applicable (no such lesions at screening); Any, CR, PR, SD, PD, NA, or UE. 
The overall response at a given time point does not depend upon the overall response assigned at any 
prior time point. 
*Subjects with an overall response of CR or PR must have a repeat tumor assessment performed no less 
than 4 weeks after the criteria for response are first met. However, the presence or absence of 
confirmation is not considered when assigning a time point response. 
 
Confirmation 
The main goal of confirmation of objective response is to avoid overestimating the response rate 
observed. For subjects with an overall response of PR or CR at a given time point, changes in 
tumor measurements must be confirmed by repeat assessments that should be performed no less 
than 4 weeks after the criteria for response are first met. However, the presence or absence of 
confirmation is not considered when assigning a time point response. Longer intervals as 
determined by the study protocol may also be appropriate.  


 
 
 
Protocol XL184-309 Amendment 2.0 
Page 140 of 142 
Best Overall Response 
Best overall response, incorporating confirmation requirements, will be derived during statistical 
analysis from the series of time point responses and need not be considered when assigning 
response at each time point. 
 


 
 
 
Protocol XL184-309 Amendment 2.0 
Page 141 of 142 
Appendix H: EuroQol questionnaire EQ-5D-5L, USA (English) sample version 
Under each heading, please check the ONE box that best describes your health TODAY 
 
MOBILITY 
I have no problems walking   
 
 
 
 
I have slight problems walking  
 
 
 
 
I have moderate problems walking 
  
 
 
 
I have severe problems walking 
  
 
 
 
I am unable to walk 
 
 
 
 
 
 
 
SELF-CARE 
I have no problems washing or dressing myself  
 
 
I have slight problems washing or dressing myself   
 
I have moderate problems washing or dressing myself  
 
I have severe problems washing or dressing myself   
 
I am unable to wash or dress myself   
 
 
 
 
USUAL ACTIVITIES (e.g. work, study, housework, family or leisure activities) 
I have no problems doing my usual activities  
 
 
I have slight problems doing my usual activities  
 
 
I have moderate problems doing my usual activities  
 
I have severe problems doing my usual activities  
 
 
I am unable to do my usual activities  
 
 
 
 
PAIN / DISCOMFORT 
I have no pain or discomfort   
 
 
 
 
I have slight pain or discomfort  
 
 
 
 
I have moderate pain or discomfort   
 
 
 
I have severe pain or discomfort  
 
 
 
 
I have extreme pain or discomfort  
 
 
 
 
 
ANXIETY / DEPRESSION 
I am not anxious or depressed  
 
 
 
 
I am slightly anxious or depressed  
 
 
 
 
I am moderately anxious or depressed  
 
 
 
I am severely anxious or depressed   
 
 
 
I am extremely anxious or depressed  
 
 
 
 


 
 
 
Protocol XL184-309 Amendment 2.0 
Page 142 of 142 
• We would like to know how good or bad your health is  
TODAY. 
• This scale is numbered from 0 to 100. 
• 100 means the best health you can imagine. 
0 means the worst health you can imagine. 
• Mark an X on the scale to indicate how your health is TODAY. 
• Now, please write the number you marked on the scale in the box 
below.  
 
 
 
 
 
YOUR HEALTH TODAY = 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
USA (English) © 2009 EuroQol Group. EQ-5D™ is a trade mark of the EuroQol Group 
 
10 
0
20 
30 
40 
50 
60 
80 
70 
90 
100 
5
15 
25 
35 
45 
55 
75 
65 
85 
95 
The best health      
 you can imagine 
The worst health    
 you can imagine 

SAP_001.pdf: 
ExpLIXIS"
Xl84-309: Statistical Analysis Plan
A Phase 3, Randomized, Double-blind, Controlled Study of Cabozantinib (XLl84) vs
Placebo in Subjects with Hepatocellular Carcinoma Who Have Received Prior Sorafenib
Version 2.0
Date: 08 Jun 2016
Prepared by:
O8J.¡rre 2-016
Milan Mangeshkar
Date
Senior Director,
Exelixis
075"12ot b
Approved by:
Approved by:
Approved by:
Colin
Vice President, Development Operations,
Exelixis
Anne
MD
Vice President, Clinical Development,
Exeiixis
Gisela
MD
President, Product Dev and Medical Affairs
& CMO, Exelixis
ef J<-c<- Lo I (o
v
Date
(ç,
Date
Date
2at b
Approved by:
Lisa
Date
Vice President, ReguÌatory Affairs &
Quality Assurance, Exelixis
CONFIDENTIAL
This document (and all copies thereofl is the property of Exelixis, [nc. and contains valuable trade secrets
and confidential inþrmation, including proprietary technical and business information ftereinafter
"Confidential Information"). By accepting this document, you agree that the Confidentiøl Information
contained herein will not be disclosed to others without prior written authorization from Exelixis, Inc. and
shall only be usedfor the purposes intended by the document.
20/þ


 
XL184-309 Statistical Analysis Plan Version 2.0 / Exelixis, Inc. /08 June 2016   
Page 2 of 56 
 
TABLE OF CONTENTS 
TABLE OF CONTENTS .....................................................................................................2 
LIST OF APPENDICES ......................................................................................................4 
LIST OF ABBREVIATIONS ..............................................................................................5 
1 
ADMINISTRATIVE STRUCTURE AND VERSION HISTORY ............................8 
2 
STUDY DESCRIPTION ..........................................................................................10 
2.1 
Study Design ....................................................................................................10 
2.2 
Study Treatment ...............................................................................................11 
2.3 
Study Objectives and Endpoints ......................................................................11 
2.3.1 
Primary Efficacy Endpoint ..................................................................11 
2.3.2 
Secondary Efficacy Endpoint ..............................................................11 
2.3.3 
Additional Endpoints ...........................................................................12 
2.4 
Power and Sample Size Justification ...............................................................12 
2.5 
Randomization and Blinding ...........................................................................13 
3 
ANALYSIS POPULATIONS ..................................................................................13 
3.1 
Intent to Treat ...................................................................................................13 
3.2 
Safety Population .............................................................................................14 
3.3 
Per Protocol Population ...................................................................................14 
4 
GENERAL CONVENTIONS ..................................................................................14 
4.1 
Definition of Baseline ......................................................................................14 
4.2 
Definition of Study Day ...................................................................................15 
4.3 
Visit Window Calculation................................................................................15 
4.4 
Missing and Partial Data ..................................................................................16 
4.5 
Safety Observation Period ...............................................................................16 
4.6 
Definition of Prior, Concomitant, and Subsequent Therapy ............................16 
4.7 
Software ...........................................................................................................16 
4.8 
Changes to Planned Analyses ..........................................................................17 
5 
STUDY POPULATION SUMMARIES ..................................................................17 
5.1 
Enrollment........................................................................................................17 
5.2 
Disposition .......................................................................................................17 
5.3 
Demographic and Baseline Characteristics .....................................................17 
5.4 
Medical History ...............................................................................................20 
5.5 
Cancer History and Current Disease Status .....................................................20 


 
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6 
TREATMENTS AND MEDICATIONS ..................................................................22 
6.1 
Prior Anti-Cancer and Radiation Therapy .......................................................22 
6.2 
Prior and Concomitant Medications ................................................................23 
6.3 
Study Treatment Exposure ...............................................................................23 
6.4 
Study Treatment Modifications .......................................................................24 
6.5 
Study Treatment Non-Compliance and Dosing Errors ....................................25 
6.6 
Non-Protocol Anti-cancer Therapy ..................................................................25 
6.7 
Post-randomization Surgery/Procedure ...........................................................26 
6.8 
Concomitant Transfusions ...............................................................................26 
7 
EFFICACY ANALYSES .........................................................................................26 
7.1 
Primary Efficacy Endpoint (OS) ......................................................................26 
7.1.1 
Definition .............................................................................................26 
7.1.2 
Hypothesis............................................................................................27 
7.1.3 
Primary Analysis ..................................................................................27 
7.1.4 
Exploratory Analyses ...........................................................................28 
7.2 
Secondary Efficacy Endpoints .........................................................................28 
7.2.1 
Progression-Free Survival (PFS) .........................................................28 
7.2.2 
Objective Response Rate (ORR) .........................................................31 
7.3 
Control of Type I Error ....................................................................................33 
7.4 
Interim Analyses ..............................................................................................33 
7.5 
Exploratory Efficacy Endpoints .......................................................................34 
7.5.1 
Health-Related Quality of Life (HRQOL) ...........................................34 
7.5.2 
Duration of Objective Response ..........................................................36 
7.5.3 
Time to Objective Response ................................................................36 
7.5.4 
Alpha-fetoprotein (AFP) ......................................................................37 
7.5.5 
Serum Bone Markers ...........................................................................37 
7.5.6 
Child-Pugh Scores ...............................................................................37 
7.5.7 
Health Care Resource Utilization ........................................................38 
7.5.8 
Pharmacokinetics (PK) ........................................................................38 
7.6 
Subgroups ........................................................................................................38 
8 
SAFETY SUMMARIES ...........................................................................................40 
8.1 
Adverse Events ................................................................................................41 
8.2 
Deaths ..............................................................................................................44 
8.3 
Laboratory Assessments ..................................................................................45 
8.3.1 
Variables ..............................................................................................45 
8.3.2 
Analysis................................................................................................46 
8.4 
Vital Signs ........................................................................................................47 
8.4.1 
Variables ..............................................................................................47 


 
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8.4.2 
Analysis................................................................................................47 
8.5 
ECOG Performance Status ..............................................................................48 
8.6 
Electrocardiogram (ECG) ................................................................................48 
9 
IDENTIFICATION AND SUMMARY OF PROTOCOL DEVIATIONS ..............49 
10 
DATA QUALITY ASSURANCE ............................................................................49 
11 
REFERENCES .........................................................................................................50 
 
LIST OF APPENDICES 
Appendix A: Date Imputation Rules................................................................................. 51 
Appendix B: Rounding Rules for Reported Percentages .................................................. 54 
Appendix C: Imputation Rules for Laboratory Values Outside of Quantification 
Range ........................................................................................................ 55 
Appendix D: EQ-5D-5L Index Value Conversion Guidelines ......................................... 56 
 


 
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LIST OF ABBREVIATIONS 
AE 
Adverse event 
AFP 
Alpha fetoprotein 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATA 
Adequate tumor assessment 
ATC 
Anatomical Therapeutic Chemical 
BLQ 
Below limit of quantitation 
BMI 
Body mass index 
BSAP 
Bone-specific alkaline phosphatase 
BUN 
Blood urea nitrogen 
CI 
Confidence interval 
CMH 
Cochran-Mantel-Haenszel 
CRF 
Case report form 
CT 
Computerized tomography 
CTC 
Circulating tumor cell 
CTCAE 
Common terminology criteria for adverse events 
CTMS 
Clinical trial management system 
CTx 
C-terminal cross-linked telopeptides of type I collagen 
DBP 
Diastolic blood pressure 
EBRT 
External beam radiation therapy 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
ER 
Emergency room visit 
FDA 
Food and Drug Administration 
GGT 
Gamma-glutamyltransferase 
HBCAB 
Hepatitis B core antibody 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCC 
Hepatocellular carcinoma 
HCRU 
Health care resource utilization 
HCV 
Hepatitis C virus 


 
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HGB 
Hemoglobin 
HbA1c 
Glycated hemoglobin 
HR 
Hazard ratio 
HRQOL 
Health Related Quality of Life 
ICH 
International Conference on Harmonization 
ICU 
Intensive care unit 
IDMC 
Independent Data Monitoring Committee 
INR 
Prothrombin International normalized ratio 
ITT 
Intent-To-Treat 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
LDH 
Lactate dehydrogenase 
LLN 
Lower limit of normal 
LLQ 
Lower limit of quantitation 
MRI 
Magnetic resonance imaging 
MedDRA 
Medical Dictionary for Regulatory Activities 
NPACT 
Non-protocol anti-cancer therapy 
NTx 
N-terminal cross-linked telopeptides of type I collagen 
OS 
Overall survival 
ORR 
Objective response rate 
PD 
Progressive Disease 
PFS 
Progression-free survival 
PK 
Pharmacokinetic 
PP 
Per-protocol 
qd 
Once daily 
QOL 
Quality of Life 
SAE 
Serious adverse event 
SBP 
Systolic blood pressure 
SAP 
Statistical analysis plan 
SD 
Stable Disease 
TEAE 
Treatment emergent-adverse event 
TSH 
Thyroid-stimulating hormone 


 
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UE 
Unable to evaluate 
ULN 
Upper limit of normal 
ULQ 
Upper limit of quantitation 
UPCR 
Urine protein/creatinine ratio 
VAS 
Visual analogue scale 
WHO-DD 
World Health Organization drug dictionary 
 


 
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1 
ADMINISTRATIVE STRUCTURE AND VERSION HISTORY 
This study is being conducted under the sponsorship of Exelixis, Inc. Statistical 
programming and analyses are being conducted under contract by PPD in conjunction with 
Exelixis, Inc.  
This version of the Statistical Analysis Plan (SAP) is based on amendment 1.0 of the 
protocol dated 23, April 2014. 
Table 1:  Protocol Version History 
Date 
Version 
Primary Reason(s) for Amendment 
12 March 2013 
Original Protocol  Not Applicable 
23 April 2014 
Amendment 1.0 
Provides additional clarification to 3 inclusion 
criteria and 4 exclusion criteria. 
Additional Child-Pugh testing time-points have 
been added. 
Specifies that all subjects will have hepatitis virus 
testing via central laboratory prior to enrollment but 
those results will not be required for randomization. 
Introduces the Maintenance Phase, which subjects 
will enter when sufficient data have been collected 
to evaluate all study endpoints. 
 
Table 2:  SAP Version History 
Date 
Version 
Primary Reason(s) for Amendment 
2015NOV02 
Original 
 
2016JUN08 
Version 2.0 
All efficacy analyses will be w.r.t  IxRS stratification 
factors instead of stratification factors based on CRF 
 
Per protocol population deleted as analyses by ITT 
population is deemed more robust 
 
Baseline for biomarkers defined w.r.t first dose date as 


 
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Date 
Version 
Primary Reason(s) for Amendment 
samples were collected prior to first dose date and not 
prior to randomization 
 
Surgical history summarization deleted as all fields 
collected on the CRF are free text intended to support 
subject narratives as needed 
 
Progression for a subject updated to accept new lesions 
identified on bone scan as evidence of progression. 
Adequate tumor assessments will include unscheduled 
tumor assessments 
 
Refined PFS sensitivity analyses (PFS2 and PFS3) 
algorithm to exclude treatment discontinuation due to 
adverse event  
 
Repeated measures analysis added for EQ-VAS and EQ-
Index parameters. Per patient reported outcome experts,  
revised the definition of potentially clinically meaningful 
effect size from 0.3 – 0.5 to ≥ 0.3 
 
Health care resource utilization section was added for 
summarizing hospitalizations, emergency room visits, 
intensive care unit visits 
 
Subgroup categories refined to include only relevant 
prognostic factors  
 
Safety observation period refined to better reflect a 
subject’s time on study treatment 
 
Exposure summary will be in months instead of weeks 
 
Blood pressure summary revised to consider treatment 


 
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Date 
Version 
Primary Reason(s) for Amendment 
emergent adverse finding 
 
2 
STUDY DESCRIPTION 
2.1 
Study Design 
This is a Phase 3 multicenter, randomized, double-blinded, controlled trial of cabozantinib 
vs. placebo, both with best supportive care, in subjects with advanced hepatocellular 
carcinoma (HCC) who were previously treated with sorafenib. The primary efficacy 
endpoint for the study is overall survival (OS). Approximately 760 subjects will be 
randomized in a 2:1 ratio to receive either cabozantinib or placebo.  
Each subject’s course of treatment will consist of the following periods: 
Pre-treatment Period: Potential subjects will be screened to determine if they meet the 
required eligibility criteria. Qualifying screening assessments must be performed within 28 
days before randomization unless otherwise specified. 
Treatment Period: Subjects who meet all study eligibility criteria, in addition to receiving 
best supportive care, will be randomly assigned in a 2:1 ratio to the cabozantinib and 
placebo arms respectively. Crossover between treatment arms will not be allowed. 
Subjects will receive blinded study treatment and best supportive care as long as they 
continue to experience clinical benefit in the opinion of the investigator or until there is 
unacceptable toxicity or the need for subsequent systemic anti-cancer treatment or liver-
directed local anti-cancer therapy. Study treatment may even continue after radiographic 
progression as long as the investigator believes that the subject is still receiving clinical 
benefit and that the potential benefit of continuing study treatment outweighs potential risk.  
When sufficient data have been collected to evaluate all study endpoints and upon site 
notification from the Sponsor, subjects remaining on study treatment will enter the study 
Maintenance Phase. In this phase subjects will continue to receive study treatment until a 
criterion for protocol-defined discontinuation has been met. Subjects will undergo safety 
assessments and tumor assessments per standard of care.  


 
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Post-Treatment Period:  The final safety assessment will occur at the post-treatment 
follow-up visit 30 (+14) days after the date of the decision to discontinue treatment unless a 
Grade 3/4 AE or an SAE is determined to be ongoing. 
Radiographic tumor assessments and EQ-5D-5L quality of life (QOL) assessments will 
continue per the protocol-defined schedule, regardless of whether study treatment is given, 
reduced, interrupted, or discontinued until the later of 8 weeks after radiographic 
progression per RECIST 1.1 as determined by the investigator or the date of the decision to 
permanently discontinue study treatment.  
Subjects will additionally be contacted approximately every 8 weeks after the post-treatment 
follow-up visit to assess survival status and to document receipt of subsequent anti-cancer 
therapy. Every effort will be made to collect these protocol-specific evaluations unless 
consent to participate in the study is withdrawn. 
The study design, schedule of the visits, assessments and conduct are described in the study 
protocol. 
2.2 
Study Treatment 
Eligible subjects will be randomized in a 2:1 ratio to the following treatment arms: 
• Cabozantinib arm: Oral cabozantinib (60 mg) qd  
• Placebo arm: Oral cabozantinib-matched placebo qd  
In addition, all subjects will also receive best supportive care. 
2.3 
Study Objectives and Endpoints 
The primary objective of this study is to evaluate the effect of cabozantinib compared with 
placebo on overall survival in subjects with advanced HCC previously treated with 
sorafenib. 
2.3.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is overall survival (OS) (see section 7.1.1for definition).  
2.3.2 
Secondary Efficacy Endpoint 
The secondary efficacy endpoints are: 


 
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• Objective response rate (ORR) per RECIST 1.1 (see section 7.1.1) 
• Progression-free survival (PFS) per RECIST 1.1 (see section 7.1.1) 
2.3.3 
Additional Endpoints 
The following endpoints are discussed in their respective sections: 
• Safety and tolerability (see section 8) 
• Relationship of baseline and changes in biomarkers with treatment and/or clinical 
outcome (see section 7.5) 
• Health-related quality of life (HRQOL) as assessed by the EuroQol Health 
questionnaire instrument (EQ-5D-5L) (see section 7.5.1) 
• Pharmacokinetics (PK) (see section 7.5.7) 
2.4 
Power and Sample Size Justification 
For the primary OS endpoint, up to three event-driven analyses are planned at 50%, 75%, 
and 100% information fraction (311, 466, and 621 deaths, respectively).  A sample size of 
760 subjects with a total of 621 events (and two interim analyses) provides the study with 
90% power for a 2-sided log-rank test at 5% level of significance to detect a 31.6% increase 
in OS (HR = 0.76). Assuming a median OS of 8.2 months in the placebo arm (based upon 
the BRISK trial; Llovet 2012) and exponential distribution, this corresponds to median OS 
of 10.8 months in the cabozantinib arm.  
In the current design, the minimum observed effect that would result in statistical 
significance for OS at the two interim and final analyses are 42.1% improvement (HR = 
0.70, from 8.2 to 11.7 months), 25.7% improvement (HR = 0.80, from 8.2 to 10.3 months) 
and 18.4% improvement (HR = 0.84, from 8.2 to 9.7 months), respectively. 
With an average accrual rate of 31.5 subjects per month and using a 2:1 treatment allocation 
ratio, an approximate total of 760 subjects (507 subjects in cabozantinib arm and 253 
subjects in placebo arm) are required to observe the minimum number of events within the 
planned study duration (25 months accrual and approximately 38 months to observe the 
required events for OS). Currently since the average accrual rate is less than 31.5 subjects 
per month this will also prolong the study duration and time required to observe the required 
events for OS. 
Power and sample size estimates were calculated using EAST v5 by Cytel Software. 


 
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2.5 
Randomization and Blinding 
This is a randomized, double-blinded, controlled trial of cabozantinib versus placebo. 
cabozantinib-matched placebo will be packaged and color-, size-, and shape-matched to be 
indistinguishable from cabozantinib. 
Study treatment assignment will be unknown to the subjects, investigators, study centers, the 
Sponsor, and any contract research organization affiliated with the study other than those 
authorized to access treatment assignment for regulatory safety reporting and submission 
processes (see Section 8.2.2 of Protocol), IVRS or IWRS system administration and drug 
supply management. 
When an individual subject has been deemed eligible at the study site, the site representative 
will use the designated interactive voice response system/interactive web response system 
(IVRS/IWRS) to enroll the subject into the study. Eligible subjects will be randomly 
assigned in a 2:1 ratio to the cabozantinib and placebo arms.  
Randomization will be stratified by the following factors: 
• 
etiology of disease (HBV [with or without HCV], HCV [without HBV], or Other),  
• 
geographic region (Asia [includes Japan, Hong Kong, South Korea, Singapore, 
Malaysia, Philippines, Taiwan, Thailand, Vietnam], Other Regions) 
• 
presence of extrahepatic spread of disease and/or macrovascular invasion (Yes, 
No).  
Note that IVRS/IWRS will be referred as IxRS in this document and HBV refers to hepatitis 
B virus and HCV refers to hepatitis C virus. 
 
3 
ANALYSIS POPULATIONS 
3.1 
Intent to Treat 
The Intent-To-Treat (ITT) population is defined as all randomized subjects regardless of 
whether any study treatment or the correct study treatment was received. This population 
will be used for efficacy analyses.  


 
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3.2 
Safety Population 
The Safety population will include all randomized subjects who receive any amount of study 
treatment (either cabozantinib or cabozantinib-matched placebo). Analyses based on the 
Safety population will be performed according to the actual treatment received. Subjects 
randomized to the placebo arm who receive any amount of cabozantinib in error will be 
summarized in the cabozantinib group.  
3.3 
Per Protocol Population 
A Per Protocol  population is not defined or planned for the study. 
 
4 
GENERAL CONVENTIONS 
The statistical principles applied in the design and planned analyses of this study are 
consistent with International Conference on Harmonization (ICH) E9 guidelines (ICH 
1998). 
Continuous data will be summarized using descriptive statistics (number of observations, 
mean, standard deviation, median, 25th and 75th percentiles, minimum, and maximum). 
Frequencies and percentages will be used for summarizing categorical (discrete) data.  
Confidence intervals, when presented, will generally be constructed at the 95% level. For 
binomial variables, the normal approximation methods will be employed unless otherwise 
specified.  
A month is operationally defined to be 30.4375 days. Six months is operationally defined to 
be 183 days. 
All summaries will be presented by treatment arm unless otherwise specified. 
4.1 
Definition of Baseline 
In general, for efficacy endpoints the last observed measurement prior to randomization will 
be considered the baseline measurement. Exception to this rule are efficacy markers such as 
pharmacogenetics blood samples, biomarker samples, bone marker samples and blood 
samples for potential circulating tumor cell (CTC) analyses. These samples per schedule of 
assessment were collected prior to the first dose date hence the baseline measurements will 
be with respect to the first dose date. For subjects who did not take any study treatment, any 


 
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biomarker sample available prior to randomization will be considered as baseline 
observation. 
For safety endpoints the last observation before first dose of study treatment will be 
considered the baseline measurement unless otherwise specified. For assessments on the day 
of first dose where time is not captured, a nominal pre-dose indicator, if available, will serve 
as sufficient evidence that the assessment occurred prior to first dose. 
Assessments on the day of first dose where neither time nor a nominal pre-dose indicator are 
captured will be considered prior to first dose if such procedures are required by the protocol 
to be conducted before first dose. 
4.2 
Definition of Study Day 
For the purpose of efficacy data summaries, study day is defined with respect to the 
randomization date. For visits (or events) that occur on or after randomization, study day is 
defined as (date of visit [event] – date of randomization + 1). For visits (or events) that occur 
prior to randomization, study day is defined as (date of visit [event] – date of 
randomization). There is no Study Day 0. 
For the purpose of safety data summary, Dose Day 1 is defined as the date of first dose of 
study treatment (referred to in the protocol as Week 1 Day 1). For visits (or events) that 
occur on or after first dose, dose day is defined as (date of visit [event] – date of first dose of 
study treatment + 1).  For visits (or events) that occur prior to first dose, dose day is defined 
as (date of visit [event] – date of first dose of study treatment). There is no Dose Day 0. 
For listings (such as for adverse events [AEs]) that include the derivation of “days since last 
dose,” this is defined as (event date – date of last dose). Events that occur on the same day as 
the last dose of study drug will therefore be described as occurring zero days from the last 
dose of study drug. 
4.3 
Visit Window Calculation 
Analyses will be according to actual visit dates and times. The planned analyses do not 
require the calculation of visit windows. However, for analyses that require a particular visit 
as planned, measurements included in that visit must have occurred during the acceptable 
window defined for the visit in the protocol, unless otherwise specified in this plan. 


 
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4.4 
Missing and Partial Data 
In general, other than for partial dates, missing data will not be imputed and will be treated 
as missing. The algorithms for imputation of partial dates vary depending upon the 
parameter. These are presented in Appendix A.  
4.5 
Safety Observation Period 
The safety observation period is defined as time from first dose date of study treatment to 
the earlier of the date of the decision to permanently discontinue study treatment+ 30 days or 
date subject withdrew consent or date of death or data cut-off date.  
Generally only the safety data (including adverse events, laboratory results, vital signs, 
ECG, ECOG PS, concomitant medications and etc.) reported during the safety observation 
period will be analyzed and summarized, unless otherwise specified in this plan.   
4.6 
Definition of Prior, Concomitant, and Subsequent Therapy 
For the purpose of inclusion in summary tables, incomplete medication or radiation start and 
stop dates will be imputed as detailed in Appendix A. Based on imputed start and stop dates: 
• Prior medications/radiation therapies are defined as medications with a start date 
occurring before the date of first dose of study treatment. 
• Concomitant medications/radiation therapies are defined as medications that stop or 
continue on or after date of first dose day through the end of safety observation 
period.  
• Subsequent medications/radiation therapies are defined as those that stop or continue 
on or after the date of randomization. 
• Medications/radiation therapies may be summarized as prior, concomitant and/or 
subsequent.  
4.7 
Software 
All analyses will be conducted using SAS Version 9.1 or higher. 


 
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4.8 
Changes to Planned Analyses 
Substantive changes to the analyses described in the protocol or in approved versions of this 
plan will be fully documented in a revised version of the plan approved by the Sponsor prior 
to unblinding the study to conduct the analyses. 
Clarifications, minor corrections, and operational considerations necessary to accurately 
conduct the analyses that do not materially change the nature of the analysis will be 
documented in an addendum to this plan that will be also be approved by the Sponsor prior 
to unblinding the study to conduct the analyses. 
 
5 
STUDY POPULATION SUMMARIES 
5.1 
Enrollment 
Subjects are defined to be enrolled at randomization. Enrollment will be summarized by 
region, country, site and protocol amendments. 
5.2 
Disposition 
Subject disposition will be summarized categorically and will include the number and 
percentage of subjects in the ITT and Safety populations.  
The reasons for study treatment discontinuation and study follow-up discontinuation will 
also be summarized categorically. 
5.3 
Demographic and Baseline Characteristics 
Summaries of demographics, stratification factors and baseline characteristics will be 
presented for subjects in the ITT and Safety populations.  
[A] The demographic characteristics include: 
o Age (continuous) 
o Age category 1 
 < 65 years 
 ≥ 65 years 
o Age category 2 
 < 75 years 
 >=75 years 


 
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o Age category 3 
 <65 years 
 65 to <75 years 
 75 to <85 years 
 ≥85 years 
o Sex 
 Male 
 Female 
 Not reported 
o Ethnicity 
 Hispanic or Latino 
 Not Hispanic or Latino 
 Not Reported 
o Race 
 American Indian or Alaska Native 
 Asian 
 Black or African American 
 Native Hawaiian or Other Pacific Islander 
 White 
 Not Reported 
 Other 
o Geographic Region 
 Australia/New Zealand 
 Asia (excluding Japan) 
 Europe  
 North America (Canada/USA) 
o Japanese decent (world-wide) 
 Japanese descent 
 Non-Japanese descent 
 Both Japanese and Non-Japanese descent 
 Not Reported 
 
Note for this study birth date is not collected but age in years is collected at informed 
consent. 


 
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[B] Categorical summaries of the following stratification factors will be presented as 
recorded (a) in the IxRS during randomization (b) on the CRF (c) cross tabulation of all 
3  stratification factors per IxRS (d) cross tabulation of all 3 stratification factors per 
CRF (e) cross-tabulation of geographic region and etiology of disease per CRF:  
o etiology of disease  
 HBV [with or without HCV] 
 HCV [without HBV]  
 Other  
o geographic region (Asia, Other Regions) 
o presence of extrahepatic spread of disease and/or macrovascular invasion (Yes, 
No) 
[C] Baseline characteristics include: 
o Height in inches– descriptive statistics 
o Weight in kg – descriptive statistics 
o Body mass index (BMI) in kg/meter2, calculated as (weight in kg*1000)/(Height in 
cm)2 –descriptive summary: 
o ECOG PS: 0, 1, Missing 
o Smoking history 
 Current  
 Former 
 Never  
o Alcohol use – Categorical summary for subjects classified as current user, former 
user or never will be presented 
[D] Descriptive statistics and or categorical summaries for the following baseline laboratory 
characteristics : 
o Alpha fetoprotein [AFP] ( < 400 ng/ml,  ≥ 400 ng/ml) 
o Prothrombin International normalized ratio [INR] (≤ 2.3, >2.3) 
o Albumin (< 35 g/L, ≥ 35 g/L) 
o Total bilirubin in umol/L (< 22.23,  ≥ 22.23 – 29.07,  ≥ 29.07)  
o Neutrophil/Lymphocyte ratio (< 3, ≥ 3) 


 
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o Albumin and total bilirubin (ALBI) grade derived from calculated ALBI score = 
[log(Bilirubin in umol/L)*0.66 – (Albumin in g/L)*0.085] 
 Grade 1: ALBI score ≤ -2.60  
 Grade 2:  -2.60 < ALBI score ≤ -1.39 
 Grade 3:  ALBI score > -1.39 
 
For laboratory parameters summarized as baseline characteristics, the most-recent non-
missing central or local sample available before the date and time of randomization will be 
employed. This differs from definition of baseline laboratory values used in safety 
summaries. 
5.4 
Medical History 
General medical history data will be coded per MedDRA. 
5.5 
Cancer History and Current Disease Status 
Cancer history and current disease characteristics data collected on the cancer history CRF 
will be summarized categorically or with descriptive statistics as appropriate. The following 
summaries are planned:  
• Diagnosis of carcinoma of HCC by histology or cytology (Yes, No) 
• Current etiology: 
o Hepatitis B virus (without HCV) 
o Hepatitis C virus (without HBV) 
o Hepatitis B and C virus 
o Hepatitis B virus (regardless of HCV) 
o Hepatitis C virus(regardless of HBV) 
o Alcoholism 
o Nonalcoholic Steatohepatitis (NASH) 
o Other 
• Hepatitis B virus surface antigen (HBsAg), Hepatitis B virus core antibody 
(HBCAB) and HCV laboratory results summary 
o HBsAg(+) , HBCAB(+) 
o HBsAg(+) , HBCAB(-)   
o HBsAg(-) , HBCAB(+) 
o HBsAg(-) , HBCAB(-) 


 
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o HCV(+) 
o HCV(-) 
• Child-Pugh Grade 
o A (score 5 - 6) 
o B (score 7 – 9) 
o C (score 10 – 15) 
• Hepatic Encephalopathy 
o None 
o Grade I-II 
o Grade III-IV 
o Missing or unknown 
• Ascites 
o Absent 
o Slight 
o Moderate 
o Missing or unknown 
• Time in years to randomization since diagnosis of HCC as identified by histology or 
cytology (Note: Incomplete diagnosis dates will be imputed as detailed in Appendix 
A) 
• Currently has locally advanced disease  (Yes, No, Unknown)  
• Currently has metastatic disease (Yes, No) 
• Extent of disease at baseline per target/non-target sites identified by the investigator 
on the tumor assessment CRFs (liver, lymph node, brain, bone, other, peritoneum , 
visceral sites other than liver , etc.) 
• Number of target/non-target sites at baseline identified on tumor assessment CRFs 
per investigator (1, 2, ≥ 3) 
• Has bone metastasis at baseline per history of bone lesion CRF or as identified by 
target and non-target lesion CRFs (Yes, No) 
• Has measurable disease at baseline identified by the investigator on tumor 
assessment CRFs (Yes, No) 
• Current Extent of HCC Disease : 
o Portal Vein Invasion (Yes, No, Unknown) 
o Bile Duct Invasion  (Yes, No, Unknown) 
o Macrovascular Invasion  (Yes, No, Unknown) 


 
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o Extrahepatic Spread  (Yes, No, Unknown) 
o Other (Yes, No) 
• MET immunohistochemistry status (High, Low/Negative, Unknown). The status of 
high and low/negative will be based on cutoff of ≥50% of tumor tissue stained with 
an intensity of 2+ or 3+).  The cut-off  is based on historical NSCLC and HCC data, 
may be adjusted if warranted based on results in initial XL184-309 data transfers 
• VEGF-A amplification in circulating tumor cells  (Yes, No, Unknown) 
 
6 
TREATMENTS AND MEDICATIONS 
6.1 
Prior Anti-Cancer and Radiation Therapy 
Prior anti-cancer therapies will be coded per World Health Organization drug dictionary 
(WHO-DD).   
The following will be summarized categorically or with descriptive statistics as appropriate 
for all subjects in the ITT and Safety population: 
• Received prior sorafenib for HCC (Yes, No) 
• Descriptive summary for duration of treatment in months on prior sorafenib for HCC 
• Categorical summaries for duration of treatment in months on prior Sorafenib for 
HCC as follows: 
o < 1 month, ≥ 1 month 
o < median,  ≥ median  
• Number and percent of subjects who progressed on the most recent prior systemic 
non-radiation anti-cancer therapy for HCC (Yes, No) 
• Number and percent of subjects who got prior sorafenib as the most recent prior anti-
cancer therapy for HCC and progressed (Yes, No) 
• Cross tabulation of type of non-radiation therapy (Local, Systemic and Unknown) 
with indication (for HCC [Local-Liver directed, Local-Other locations, Adjuvant, 
Advanced, Other], Other than HCC) 
• Number of prior systemic non-radiation anti-cancer regimens for advanced HCC per 
subject (1, 2, ≥3) and descriptive statistics 


 
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• Number of prior systemic non-radiation anti-cancer agents for advanced HCC per 
subject (1, 2, ≥3) and descriptive statistics 
• The time from the end of most-recent non-radiation prior systemic anti-cancer 
treatment for HCC to randomization will be summarized descriptively Number of 
prior radiation therapies for HCC per subject (1, 2, ≥3) and descriptive statistics 
• Subject incidence of radiation therapy by indication from history of radiation therapy 
(Disease under study and Other) 
• Subject incidence of radiation therapy type (External beam radiation therapy 
[EBRT], Internal radiation therapy [brachytherapy], Radioisotope therapy, 
Radioembolization, Radiofrequency ablation and Other) from history of radiation 
therapy received for HCC or Other indications  
• Subject incidence of site (Bone, Soft-tissue, Systemic, Unknown) of radiation from 
history of radiation therapy received for HCC or Other indications  
All prior non-radiation anti-cancer agents will be summarized categorically by Anatomical 
Therapeutic Chemical (ATC) Class Text and WHO-DD base substance preferred name by 
treatment arm and type of therapy (Local-liver directed, Local-non-liver directed, Systemic,  
Unknown) for all subjects in the ITT population. 
6.2 
Prior and Concomitant Medications 
Medications recorded on the CRFs will be coded using the WHO-DD. Prior and 
concomitant medications, other than prior and subsequent anticancer therapies will be 
summarized by treatment group in the Safety population by ATC and WHO-DD base 
substance preferred name. In addition, prior medication will also be summarized in the ITT 
population by ATC and WHO-DD base substance preferred name. Anticancer therapies are 
addressed in sections 6.6 and 6.7 of this plan. 
6.3 
Study Treatment Exposure 
Study treatment exposure will be summarized with descriptive statistics in the Safety 
population. 
The following will be derived for each subject and will be summarized: 
• Duration (in months) of exposure per subject, calculated as (date of decision to 
discontinue study treatment – date of first dose + 1) /30.4375  


 
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• Average daily dose per subject (mg/day) of cabozantinib (or cabozantinib-matched 
placebo), calculated as (total dose received / duration of exposure) 
• Percent dose intensity for cabozantinib (or cabozantinib-matched placebo) calculated as 
100*(average daily dose mg/day) / (60 mg/day) 
• Duration of treatment in months defined as (date of decision to discontinue study 
treatment – date of first dose – total duration  of dose holds + 1) /30.4375 
6.4 
Study Treatment Modifications 
Treatment modifications (holds and reductions) for cabozantinib (or cabozantinib-matched 
placebo) will be summarized in the Safety population. Only modifications due to AE will be 
summarized. 
A. The following summaries will be presented for the cabozantinib (or matched placebo) 
component of study treatment:  
i. For dose reductions due to AE     
Categorical summaries for: 
• Subjects with any dose reduction 
• Dose levels received by a subject 
• Lowest non-zero dose level received   
• Last non-zero dose level received  
• Last dose level received (including dose holds)  
Descriptive statistics for: 
• Duration of treatment in months for each dose level (60 mg, 40 mg, 20 mg, 0 
mg) 
• Time to first dose level reduction (first receipt of 40mg) (days) 
• Time to second dose level reduction (first receipt of 20mg) (days) 
ii. Summaries for dose holds due to AE:  
• Descriptive statistics for number of dose holds due to an AE 
• Descriptive statistics for duration of dose holds per dose hold and per subject 
due to an AE, calculated as (stop date of hold – start date of hold + 1)  
• Categorical summary for subjects with duration of  holds due to an AE that 
can be classified as any number of days,  ≥ 7 days,  ≥ 14 days, and  ≥ 21  days 


 
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• Descriptive statistics for time to first dose hold, time to first dose hold that 
was   ≥ 7 days, ≥ 14 days, and ≥ 21 days. The time to dose hold is calculated 
as (start date of the hold – first dose date + 1)   
• Descriptive statistics for time to second dose hold, time to second dose hold 
that was ≥ 7 days, ≥ 14 days, and  ≥ 21  days 
iii. Summaries for dose modifications (defined as a reduction or hold) due to AE:  
• Frequency counts and percentages for subjects with any dose modifications 
• Descriptive statistics for number of dose modifications (0-3) 
• Descriptive statistics for time to the first dose modification  
• Descriptive statistics for time to the second dose modification 
 
6.5 
Study Treatment Non-Compliance and Dosing Errors 
Treatment non-compliance and dosing errors for reasons other than AE will be summarized 
in the Safety population. Frequency counts and percentages will be presented by treatment 
groups for: 
• Subjects with dose hold (0 mg) due to non-compliance 
• Subjects who received dose > maximum allowed dose level at any time 
• Subjects who received wrong dose (≤ maximum allowed dose level) at any time due 
to non-compliance 
• Subjects who received wrong dose (≤ maximum allowed dose level) at any time due 
to site/logistic error or other reason 
6.6 
Non-Protocol Anti-cancer Therapy 
For the purpose of supporting safety evaluation: 
Non-radiation concomitant (see definition in section 4.6.) NPACT will be summarized by 
ATC text and WHO Drug base substance preferred name in the Safety population.  
For the purpose of supporting efficacy evaluation: 
All subsequent (see definition in section 4.6.) NPACT, including radiation therapy, will be 
summarized by treatment group in the ITT population as follows: 


 
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• Based on the non-radiation therapy received subjects will be categorized into one or 
more of the following categories:  systemic, local, or unknown and all NPACTs 
falling under these categories will be summarized by ATC text and WHO Drug 
based substance preferred name  
• Time to first systemic NPACT will be summarized by descriptive statistics 
• Frequency counts and percentages will be presented for radiation therapy indication, 
type and site  
6.7 
 Post-randomization Surgery/Procedure 
Post-randomization surgery/procedures that impacted the tumor lesion(s) (Yes, No, 
Unknown) will be summarized by treatment group for subjects in the ITT and Safety 
populations. 
6.8 
Concomitant Transfusions 
Concomitant transfusions will be summarized by transfusion type and treatment group for 
subjects in the safety population. 
7 
EFFICACY ANALYSES 
Primary efficacy analyses will be performed on all subjects in the ITT population.  
7.1 
Primary Efficacy Endpoint (OS) 
7.1.1 
Definition  
The primary efficacy endpoint is overall survival. Duration of OS is defined as the time 
from randomization to death due to any cause. For subjects who are alive at the time of data 
cutoff but are permanently lost to follow-up, duration of OS will be right censored at the 
date the subject was last known to be alive. Those who withdraw consent from survival  
follow-up and are alive will be right censored at the date the subject withdrew consent from 
survival follow-up. Subjects alive on or after the data cutoff or those who died after the data 
cutoff will be right censored at the date of data cutoff.  
OS (months) = (earliest date of death or censoring – date of randomization + 1)/30.4375   


 
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7.1.2 
Hypothesis  
The hypotheses to be evaluated in the analysis of the primary efficacy endpoint are:  
H0: S(t)cabozantinb = S(t)placebo  
HA: S(t)cabozantinb ≠ S(t)placebo  
 
where S(t)𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 and S(t)𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 are the survivor functions for the cabozantinib and 
placebo arms, respectively. 
7.1.3 
Primary Analysis 
The primary analysis of OS will include all subjects in the ITT population.  
The hypothesis testing between the two treatment arms will be performed using the stratified 
log-rank test with a 2-sided α=0.05 level of significance. The stratification factors are as 
described in Section 2.5 and the values used for analysis will be those recorded in the 
(IxRS). 
The median duration of OS and the associated 95% confidence interval (CI) for each 
treatment arm will be estimated using the Kaplan-Meier method. The stratified hazard ratio 
(HR) and its 95% CI will be estimated using a Cox proportional-hazard model with 
treatment group as the independent variable and stratified by the same randomization 
stratification factors as were used for the log-rank test.  
The analysis of OS is event-based. Up to three analyses of OS are planned: two interim 
analyses and a final analysis that will occur when 311, 466 and 621 deaths (i.e. 50%, 75% 
and 100% deaths) have been observed respectively. Inflation of Type I error associated with 
interim analyses will be controlled using a Lan-DeMets O’Brien-Fleming alpha-spending 
function. The critical p-values (and observed HR) for rejecting the null hypothesis will be 
0.0031 (HR≤ 0.70), 0.0183 (HR≤ .80) and 0.044 (HR≤ .84) at the time when 311, 466 and 
621 deaths (50%, 75% and 100% information) are observed respectively. The actual critical 
values will depend upon the true number of events observed at each analysis. The interim 
analyses of OS are also described in section 7.4. 
At an analysis time point, if the p-value for the stratified log-rank test is less than the critical 
value for rejecting the null hypothesis and the HR is < 1, the null hypothesis will be rejected 


 
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and it will be inferred that OS is superior in the cabozantinib arm compared to the placebo 
arm. 
7.1.4 
Exploratory Analyses 
Overall survival analyses as described in section 7.1.3 will be conducted by censoring for 
subjects who receive a systemic NPACT or a local liver directed therapy after 
randomization.  
7.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints for this study are duration of PFS and ORR. Formal 
hypothesis tests are planned for the secondary efficacy endpoints. 
7.2.1 
Progression-Free Survival (PFS) 
7.2.1.1 
Definition 
Duration of PFS is defined as the time from randomization to the earlier of the date of 
radiographic progression or date of death due to any cause.  
PFS (months) =(earliest date of progression, death, censoring – date of randomization  + 
1)/30.4375 
The primary analysis of PFS will include all subjects in the ITT population and will include 
radiographic progression events as determined by the investigator per RECIST 1.1 and 
deaths.  
The recorded date of radiographic progression is the date of the tumor assessment visit at 
which progression is declared.  If multiple scan dates are associated with a tumor assessment 
visit, the earliest assessment date within the set will be chosen as the progression date. 
Only adequate tumor assessments (ATAs) will be considered in the determination of 
radiographic progression and censoring dates. For the purpose of this study, ATA is defined 
as one that results in a time point assignment of: response (complete or partial), stable 
disease/(non-CR, non-PD), or progression. For PFS, ATA is based on soft tissue evaluation 
by CT/MRI and/or new lesions identified by bone scan.  
General censoring rules for the primary analysis of PFS are described below: 
• 
Subjects who receive systemic or liver directed local NPACT or non-protocol radiation 
therapy (other than to bone) or surgery to resect tumor lesions before experiencing an 


 
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event will be right censored at the date of the last ATA on or prior to the date of 
initiation of subsequent therapy/surgery. If there is no such tumor assessment after 
randomization, the subject will be right censored on the date of randomization. 
• 
Subjects who have not experienced an event (and are not otherwise censored) at the 
time of data cutoff will be right censored on the date of their last tumor assessment 
after randomization that is on or prior to the data cutoff. If there is no such tumor 
assessment after randomization, the subject will be right censored on the date of 
randomization.   
• 
Subjects who miss two or more ATAs (operationally defined as 126 days without an 
ATA) followed by an event (progression or death) will be right censored on the date of 
their most-recent ATA prior to the missing assessments. If there is no such tumor 
assessment after randomization, the subject will be right censored on the date of 
randomization.   
7.2.1.2 
Hypothesis  
The hypotheses to be evaluated in the analysis of the PFS are:  
H0: S(t)cabozantinb = S(t)placebo  
HA: S(t)cabozantinb ≠ S(t)placebo  
 
where S(t)𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 and S(t)𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 are the survivor functions for PFS for the 
cabozantinib and placebo arms, respectively. 
7.2.1.3 
Primary Analysis 
The hypothesis testing of PFS between the two treatment arms will occur only if the result 
of either an interim analysis or the final analysis of OS achieves statistical significance. The 
primary analysis of PFS will include all subjects in the ITT population.  
The summaries (median and 95% CI, stratified and unstratified log-rank p-values, stratified 
and unstratified HRs and their 95% CI) and graphs described in section 7.1.3 will be 
generated for PFS using a 2-sided level of significance, α=0.04. 


 
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If the p-value for the stratified log-rank test for PFS is less than 0.04 and the HR is < 1, the 
null hypothesis will be rejected and it will be inferred that PFS is superior in the 
cabozantinib arm compared with the placebo arm. 
7.2.1.4 
Sensitivity Analyses 
The primary analysis (PFS1) and 2 types of sensitivity analyses (PFS2 and PFS3) are 
outlined in Table 3. These analyses will include all subjects in the ITT population. 
Summaries and graphs as described in section 7.1.3 will be presented.  
The sensitivity analyses (PFS2 and PFS3) define additional clinical outcomes as events and 
also evaluate the impact of informative censoring.   
For PFS2 analysis, the following are considered as events: 
• Radiographic progression per RECIST 1.1 
• Death due to any reason 
• Treatment discontinuation due to clinical deterioration 
• Receipt of systemic non-protocol anti-cancer therapy (NPACT) 
• Receipt of local liver-directed NPACT 
• Radiation (other than to bone) 
• Surgery to resect tumor lesions  
For PFS3 analysis, the following are considered as events: 
• Radiographic progression per RECIST 1.1 
• Death due to any reason 
• Treatment discontinuation due to clinical deterioration 
 
 


 
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Table 3:   Event and censoring rules for primary and sensitivity analyses of PFS 
Count as censored 
or event at earliest 
outcome criterion 
met 
PFS1 
PFS2 
PFS3 
Purpose 
Primary 
Sensitivity 
Sensitivity 
Situation 
Outcome 
Date 
Outcome 
Date 
Outcome 
Date 
No post baseline 
assessment 
Censored 
Date of 
randomization 
Censored 
Date of 
randomization 
Censored 
Date of 
randomization 
Radiographic PD 
Event 
Date of PD  
Event 
Date of PD  
Event 
Date of PD  
Death 
Event 
Date of death  Event 
Date of death  
Event 
Date of death  
Subsequent 
systemic or local 
liver directed non-
protocol anti-
cancer therapy 
(NPACT)  
 
Censored 
Date of last 
ATA on or 
prior to 
NPACT  
Event 
Date of NPACT Censored 
Date of last 
ATA on or 
prior to 
NPACT 
Radiation (other 
than to bone) 
Censored 
Date of last 
ATA on or 
prior to 
Radiation 
Event 
Date of 
radiation 
Censored 
Date of last 
ATA on or 
prior to 
Radiation 
Surgery to resect 
tumor lesions 
Censored 
Date of last 
ATA on or 
prior surgery 
Event 
Date of surgery 
Censored 
Date of last 
ATA on or 
prior surgery 
Event after more 
than two missed 
ATAs (>126 days) 
Censored 
Date of last 
ATA prior to 
the missing 
visits  
Censored 
Date of last 
ATA prior to the 
missing visits  
Censored 
Date of last 
ATA prior to 
the missing 
visits  
Treatment 
Discontinuation 
due to Clinical 
deterioration 
NA 
NA 
Event 
Date of 
determination 
Event 
Date of 
determination 
No Event by last 
ATA  
Censored 
Date of last 
ATA  
Censored 
Date of last 
ATA 
Censored 
Date of last 
ATA 
 ATA:Adequate tumor assessment; PD=Progressive Disease; NA=Not Applicable 
 
7.2.2 
Objective Response Rate (ORR) 
7.2.2.1 
Definition 
For each subject, best overall response (BOR) is defined as the best tumor assessment 
category as determined by the investigator per RECIST 1.1 that occurs prior to any of the 
censoring events defined for the primary analysis of PFS as described in section 7.2.1.1. 
Tumor assessment categories are ranked as: confirmed complete response (CR), confirmed 
partial response (PR), stable disease (SD), progressive disease (PD) and not evaluable (NE). 
To be classified as confirmed CR or confirmed PR, confirmation must have occurred on a 
subsequent visit that is ≥ 28 days after the response was first observed. 


 
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The ORR is defined as the proportion of subjects with a BOR of confirmed CR or confirmed 
PR. 
7.2.2.2 
Hypothesis  
The hypotheses to be evaluated in the analysis of the ORR are as follows: 
H0:  ORRCabozantinib ≤ ORRPlacebo 
HA:  ORRCabozantinib > ORRPlacebo 
where ORRCabozantinib and ORRPlacebo are the ORRs for the cabozantinib and placebo arms, 
respectively. 
7.2.2.3 
Primary Analysis 
Hypothesis testing for ORR will be performed using the Fisher’s exact test at the 2-sided 
α=0.01 level of significance. If a sufficient number of responders are observed, analysis 
using the Cochran-Mantel-Haenszel (CMH) method to adjust for stratification factors per 
IxRS may also be conducted. The testing of ORR will occur only if the result of either an 
interim analysis or the final analysis of OS achieves statistical significance. The primary 
analysis of ORR will include all subjects in the ITT population. 
Point estimates of ORR for each treatment arm, the difference in ORR between the two 
treatment arms, and associated confidence intervals will be provided. The odds ratio and its 
confidence intervals will also be shown. The 95% CIs for the point estimate will be 
calculated using exact methods. The 95% CIs for the difference in ORR between the two 
treatment arms and for the odds ratio will be calculated by asymptotic methods. 
If the p-value for the two-sided Fisher’s exact test is less than 0.01 and the point estimate for 
ORR in the cabozantinib arm is higher than that in the placebo arm, the null hypothesis of 
no difference in ORR will be rejected and it will be inferred that ORR is superior in the 
cabozantinib arm compared with the placebo arm. 
7.2.2.4 
Supportive Analyses 
To provide a more detailed understanding of anti-tumor activity, the maximum tumor 
reduction since baseline in target lesions will be derived for those subjects who have 
baseline and at least one post-baseline measure. The maximum percent tumor reduction 
from baseline in target lesions for each arm will be displayed graphically using waterfall 


 
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plots. For each subject, data from time points after the first date of any of the censoring 
events defined for the primary analysis of PFS as described in section 7.2.1.1. will be 
excluded from the waterfall plots. 
7.3 
Control of Type I Error 
The multiplicity issue resulting from analysis of one primary endpoint (OS), two secondary 
efficacy endpoints (PFS and ORR), and planning two interim analyses for testing OS will be 
addressed by employing a fixed-sequence testing procedure, applying a modified Bonferroni 
procedure (dividing the alpha between the secondary endpoints), and implementing an 
alpha-spending function. 
Up to three event-driven analyses of OS are planned: two interim analyses and a final 
analysis (see details in section 7.1.3). Inflation of Type 1 error associated with interim 
analyses will be controlled using a Lan-DeMets O’Brien-Fleming alpha-spending function.  
Interim analysis of PFS and ORR are not planned. The testing of these two secondary 
endpoints will occur only if the result of either an interim analysis or the final analysis of OS 
achieves statistical significance. The hypothesis for PFS and ORR will be tested in parallel. 
PFS will be tested at the 2-sided α=0.04 level of significance and ORR will be tested at the 
2-sided α=0.01 level of significance. 
All other statistical evaluations of efficacy will be considered exploratory. 
7.4 
Interim Analyses 
The size of the trial is based upon the assumptions currently available and provides high 
power to detect what the Sponsor believes is the smallest clinically meaningful difference in 
OS under these assumptions. However, as there is uncertainty in the assumptions, interim 
analyses provides an opportunity to stop the trial early if the treatment benefit of 
cabozantinib is larger than expected, potentially allowing cabozantinib to become available 
sooner to this patient population. 
Two interim analyses for primary endpoint of OS are planned. The interim analyses will be 
conducted at the time when approximately 311 and 466 deaths have been observed 
respectively. It is anticipated that this will be at approximately the 50% and 75% 
information fraction respectively for OS. Type I error for the interim analysis will be 
controlled by a Lan-DeMets O’Brien-Fleming alpha spending function as described in 


 
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Section 7.3. The actual critical values employed at the interim and final analyses of OS will 
depend upon the actual information fraction at the time of the interim analyses. 
If the planned first or second interim OS analysis achieves overwhelming evidence of 
efficacy (p-value = 0.0031 or 0.0183, respectively, under trial design assumptions) in favor 
of cabozantinib, analyses of the secondary endpoints will be performed as planned. Interim 
analyses will be evaluated by the IDMC. Monitoring guidance will be provided to allow the 
study to be stopped early if the null hypothesis for OS is rejected in favor of cabozantinib. A 
nonbinding boundary for harm will be used by the IDMC to help evaluate subject safety. 
Stopping for futility is not planned. 
7.5 
Exploratory Efficacy Endpoints 
Each exploratory endpoint will be analyzed using an appropriate two-sided statistical test 
without adjustment for multiplicity unless specified otherwise. Statistical results for 
exploratory endpoints will be considered descriptive. Exploratory analyses will be 
performed using all subjects in the ITT population unless specified otherwise. 
7.5.1 
Health-Related Quality of Life (HRQOL) 
Health-related quality of life (HRQOL) will be assessed by the EuroQol Health 
questionnaire instrument (EQ-5D-5L). The questionnaire will be self-completed by the 
subjects at various time points until disease progression and will provide a generic measure 
of health for clinical appraisal (see protocol Section 5.5.8). The EQ-5D-5L questionnaire has 
two pages: a descriptive page which assesses on an increasing severity scale of 1-5 changes 
in the following five questions (dimensions): mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. The second page has a 0-100 visual analogue scale 
(VAS) which records the subjects self-rated health between 100 (best health you can 
imagine) and  0 (worst health you can imagine) and serves as quantitative measure of health 
by the subject (see protocol Appendix F and EQ-5D-5L User Guide 2015).  
To compare the two treatment arms the following summaries are planned at each time point 
for each of the 6 questions: 
Within each treatment arm:   
• Descriptive statistics (number of observations, mean and standard deviation)  
• Rate of completion for the questionnaire at each time point. This is defined as total 
number of subjects who answered all questions on the EQ-5D-5L questionnaire / the 
expected total number of subjects still on study at the visit 


 
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• Mean change from baseline at each time point and the corresponding 95% CI and p-
value from one-sample t-test   
• Effect size for change from baseline within arm, calculated as (mean of change in 
score/pooled standard deviation for baseline scores).  An effect size greater than ≥ 
0.3 will be considered potentially clinically meaningful  
• Shift in the severity scale since baseline  
Across treatment arms   
• The difference in the effect sizes will be presented  
• Difference in mean change from baseline for the questions at the time point will be 
evaluated by a two sample t-test  
• Line plots for mean±standard error and the corresponding mean for change from 
baseline over time. Data from both treatment arms will be displayed on the same 
plot. In addition, these plots will also show the average state of the subjects at 3 
landmark points, namely, around end of treatment, around progression and around 30 
days post treatment  follow-up for the two treatment arms 
• Percentage of subjects in Level 1 (no problem) vs. Levels 2-5 (any problems) will be 
summarized over time  
• Percentage of subjects with any problems (Level 2-5) will be compared between the 
treatment arms using a bar chart 
 
The EQ-5D-5L may be converted into a single index (EQ-Index) value normalized across 
different countries where the index is validated. See Appendix D for conversion details. For 
EQ-VAS and EQ-Index, descriptive statistics for change from baseline at each time will be 
presented. Plots for mean±standard error and mean change from baseline±standard error 
over all time points for the two treatment arms will be generated. In addition, repeated-
measures mixed-effects models will be used to explore treatment differences over time.  
These analyses will include the outcome variable of QOL score change from baseline.  The 
predictors (fixed effects) will be the baseline scores, treatment arms, visit, and 
randomization strata described in Section 2.5.  The individual subject nested within the 
planned treatment arm will be the random effect.  All available data will be included for the 
analysis.  The estimated least squares means for the two treatment arm and their difference, 
the p-values comparing the 2 treatment arms and the effect size will be presented. No 
adjustment will be made for multiple comparisons. An effect size of differences in the ≥ 0.3 
range will be considered potentially clinically meaningful. 


 
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7.5.2 
Duration of Objective Response  
Duration of objective response is defined as the time from the first documentation of 
objective response by the investigator that is subsequently confirmed at a visit that is 
≥ 28 days later to disease progression or death due to any cause.  
 
Duration of response (months) = (earliest date of progressive disease or death due to any 
cause or censoring – date of first objective response + 1)/30.4375  
  
Duration of objective response will be computed only among subjects who experience an 
objective response (confirmed CR or confirmed PR). Dates of progression and censoring 
will be determined as described for the secondary endpoint analysis of PFS (see section 
7.2.1). 
 
Duration of objective response will be analyzed using the same analysis method (Kaplan-
Meier) as for the analysis on PFS (see Section 7.2.1.3).  
The analyses for duration of response will be performed only if ORR >10%.  
 
7.5.3 
Time to Objective Response  
Time to objective response is defined as the time from randomization to the first 
documentation of objective response by the investigator that is subsequently confirmed at a 
visit that is ≥ 28 days later to disease progression or death due to any cause.  
 
Time to objective response (months) = (date of first objective response   - date of 
randomization + 1)/30.4375  
  
Time to objective response will be computed only among subjects who experience an 
objective response (confirmed CR or confirmed PR), and arithmetic methods (not Kaplan-
Meier) will be used. 
 
The analyses for time to response will be performed only if ORR >10%.  
 


 
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7.5.4 
Alpha-fetoprotein (AFP) 
For each scheduled post-baseline visit the AFP values at baseline and change from baseline 
will be summarized with standard descriptive statistics by treatment arm. Descriptive 
statistics for best/worst percent change since baseline will also be presented per arm using 
all available data. Waterfall plot will be presented by treatment arm for best percent change 
since baseline. 
 
Best change is defined as the largest reduction (or smallest increase if no reduction) and 
worst change is defined as the largest increase (or smallest reduction if no increase). 
Appropriate transformations may be applied to normalize the data for presentation or 
analysis. 
7.5.5 
Serum Bone Markers 
Serum bone markers (CTx, and BSAP) results at baseline, Week 3, Week 5 and Week 9 will 
be summarized by descriptive statistics. In addition, percent change from baseline at Week 
3, Week 5 and Week 9, as well as best/worst percent change from baseline will be presented 
per arm using all available data. 
 
Best change is defined as the largest reduction (or smallest increase if no reduction) and 
worst change is defined as the largest increase (or smallest reduction if no increase). These 
summaries will be provided for all subjects in the ITT population.  
 
Appropriate transformations may be applied to normalize the data for presentation or 
analysis. 
 
The best percent change from baseline for CTx and BSAP will be displayed graphically for 
each arm using waterfall plots. However, for CTx, subjects with baseline values that are 
below the limit of quantification (BLQ) will not be included in summaries or figures.  
 
7.5.6 
Child-Pugh Scores 
Change from baseline in Child-Pugh categories will be summarized as a shift table at each 
time point through to end of treatment. 


 
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7.5.7 
Health Care Resource Utilization  
For this study the following health care resource utilization (HCRU) parameters collected 
during the study observation period will be summarized: 
• Days of hospitalization due to SAEs 
• Days in intensive care unit (ICU) due to SAEs 
• Number of emergency room (ER) visits due to SAEs 
• Number of surgeries 
The summaries will include: 
• Number  and percentage of subjects in each category of  HCRU  
• Descriptive statistics for each HCR category amongst those subjects who utilized  
the respective resource 
• Total number of days or visits as applicable for each HCRU 
• Per person year summary for each HCRU 
To calculate the per person year value for a subject for a HCRU parameter, the numerator is 
the sum of the days or visits for that subject for the parameter; and the denominator is 
defined as: (safety observation period – date of randomization + 1) / 365.25.  
7.5.8 
Pharmacokinetics (PK)  
Pharmacokinetics analyses are outside the scope of this plan.  A separate PK analysis plan 
and report will be provided. 
 
7.6 
Subgroups 
The following subgroups based on baseline characteristics and stratification factors will be 
explored for primary and secondary efficacy endpoints 
o Age category  
o <65 years 
o 65 to <75 years 
o 75 to <85 years 
o ≥85 years 
o Sex 


 
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 Male 
 Female 
o Race 
 Asian 
 Black or African American 
 White 
 Rest of the races reported/Not Reported 
o Geographic Regions 1 
 Asia (excluding Japan) 
 Europe/Australia/New Zealand  
 North America (Canada/USA) 
 Other 
o Geographic Regions 2 
 Asia 
 Other Region 
o ECOG Performance status at baseline:  
 0  
 1 
 Missing 
o Etiology of disease per stratification factors per IxRS:  
 HBV [with or without HCV] 
 HCV [without HBV]  
 Other  
o Current etiology of disease (per cancer history CRF):  
 HBV [without HCV] (Yes/No/Unk) 
 HCV [without HBV] (Yes/No/Unk) 
 HBV and HCV (Yes/No/Unk) 
 Alcoholism (Yes/No/Unk) 
 Nonalcoholic Steatohepatitis (NASH) (Yes/No/Unk) 
 Other (Yes/No/Unk) 
o Presence of extrahepatic spread of disease and/or macrovascular invasion (per IxRS):  
 Yes  
 No  
o Presence of extrahepatic spread of disease and/or macrovascular invasion (per cancer 
history CRF):  
 Yes  


 
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 No  
o Visceral sites other than liver, bone, bone+visceral sites other than liver per tumor 
assessment CRFs per investigator. Visceral sites other than liver will include lung 
kidney, pancreas and other sites based upon a manual review of the reported sites 
after all data has been entered in the database 
o Prior systemic  non-radiation anti-cancer therapy regimens for advanced HCC per 
subject per history of non-radiation anti-cancer therapy CRF (1 vs ≥ 2) 
o Prior receipt of PD-1/PD-L1 per history of non-radiation anti-cancer therapy CRF 
(Yes, No) 
o Prior receipt of Regorafenib per history of non-radiation anti-cancer therapy CRF 
(Yes, No) 
o Prior receipt of Lenvatinib per history of non-radiation anti-cancer therapy CRF 
(Yes, No) 
o Prior receipt of Tivantinib per history of non-radiation anti-cancer therapy CRF 
(Yes. No) 
o Prior receipt of Ramucirumab per history of non-radiation anti-cancer therapy CRF 
(Yes. No) 
o VEGF-A amplification in circulating tumor cells  (Yes, No, Unknown) 
o AFP (<400 ng/mL, ≥ 400 ng/L) at baseline 
o Tumor MET status 
 High 
 Low or Negative 
 Unknown 
8 
SAFETY SUMMARIES  
All safety analyses will be performed using all subjects in the Safety population. No formal 
statistical comparison between the two treatments arms is planned. 
 
Safety and tolerability will be assessed by the incidence of treatment emergent-adverse 
events (TEAEs), changes in laboratory parameters and vital signs from baseline, and ECOG 
PS. 
 
An Independent Data Monitoring Committee (IDMC) will monitor safety during the study 
on a regular basis. The committee will operate independently from the Sponsor and the 
clinical investigators. 


 
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The primary responsibility of the IDMC is to review the accumulating safety data on a 
regular and an ad hoc basis and make recommendations to the Sponsor regarding the 
continued conduct of the study. Safety data will be provided at regular intervals to the 
IDMC in the form of summary reports or data listings from the Sponsor (blinded) or its 
designated representative (unblinded). 
 
Details regarding IDMC membership, schedule and format of meetings, format for 
presentation of data, access to interim data, method and timing of providing interim reports 
to the IDMC, and other issues relevant to committee operations are described in the IDMC 
charter. 
 
The IDMC members will use their expertise, experience, and judgment to evaluate the safety 
data from the trial and to recommend to the Sponsor whether the trial should continue or be 
stopped early for safety. No formal statistical rules recommending early stopping for safety 
are planned. 
 
8.1 
Adverse Events  
Adverse event terms recorded on the CRF will be mapped to preferred terms and system 
organ class using the Medical Dictionary for Regulatory Activities (MedDRA). The severity 
of AEs will be measured by CTCAE (Cancer Therapy Evaluation Program 2009) version 4 
guidelines. The investigator will judge each event to be “not related” or “related” to study 
treatment. 
 
A TEAE is defined as any event with an onset date on or after the date of the first dose of 
study drug or any ongoing event on the date of the first dose of study drug that worsens in 
severity after the date of the first dose of study drug.  
 
Only TEAEs with an onset date through the end of the safety observation period (see section 
4.5) will be tabulated in summary tables.  
 
For the purpose of calculating treatment emergence and inclusion in summary tables, 
incomplete onset dates will be imputed as detailed in Appendix A. 
 
For AE reporting, percentages ≥10% will generally be presented as integers, those <10% 


 
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will be presented with 1 decimal place (e.g. X.X%). Rounding rules are provided in 
Appendix B. The calculations of percentages will be based on original unrounded values. 
 
An overall summary of adverse events will be provided with the number and percent of 
subjects who experienced the following types of events during the safety observation period 
(unless otherwise noted) in each treatment arm: 
 
• Subjects with a TEAE 
• Subjects with a Related TEAE 
• Subjects with a Serious TEAE 
• Subjects with a Serious Related TEAE at any time 
• Subjects with a Worst-Grade 3 or 4 TEAE  
• Subjects with a Worst-Grade 3 or 4 Related TEAE 
• Subjects with a Worst-Grade 4 TEAE   
• Subjects with a Worst-Grade 4 Related TEAE 
• Subjects with a Grade 5 TEAE at any time 
• Subjects with a Grade 5 TEAE 
• Subjects with a Grade 5 TEAE through 30 days after the last dose of the study 
treatment 
• Subjects with a Grade 5 AE judged not to be causally related to PD through 30 days 
of last dose of the study treatment 
• Subjects with a Grade 5 AE >30 days after the last dose of the study treatment 
• Subjects with a Grade 5 AE judged not to be causally related to PD >30 days of last 
dose of the study treatment 
• Subjects with a Related Grade 5 TEAE at any time 
• Subjects with a Related Grade 5 TEAE 
• All subjects who died   
• Subjects who died within 30 days after date of last dose of study treatment  
• Subjects with a TEAE leading to Dose Modification 
• Subjects with a TEAE leading to Dose Reduction 
• Subjects with a TEAE leading to Dose Hold 
• Subjects with TEAE leading to Treatment Discontinuation 
 TEAEs not related to disease progression 
 TEAEs related to disease progression 
 
The following summaries of AEs will be provided: 


 
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TEAE included 
Row-levels (sorted by) 
Columns 
Subject Incidence by SOC, Preferred Term and Severity 
All 
SOC and PT 
(MedDRA standard) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
Related  
SOC and PT 
(MedDRA standard) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
Serious  
SOC and PT 
(MedDRA standard) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
Related Serious  
SOC and PT 
(MedDRA standard) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
Subject Incidence by Preferred Term and Severity 
All 
PT 
(descending frequency of Any Grade) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
Related  
PT 
(descending frequency of Any Grade) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
Leading to dose reduction 
PT 
(descending frequency of Any Grade) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
Leading to dose hold 
PT 
(descending frequency of Any Grade) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
Leading to dose modification 
PT 
(descending frequency of Any Grade) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
Not Related to Disease 
Progression and  Leading to 
Study Treatment Discontinuation  
PT 
(descending frequency of Any Grade) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
Related to Disease Progression 
and Leading to Study Treatment 
Discontinuation 
PT 
(descending frequency of Any Grade) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
All 
PT 
(descending frequency of Grade 3/4) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
Related  
PT 
(descending frequency of Grade 3/4) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
Leading to dose reduction 
PT 
(descending frequency of Grade 3/4) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
Leading to dose hold 
PT 
(descending frequency of Grade 3/4) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
Leading to dose modification 
PT 
(descending frequency of Grade 3/4) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
Through 30 days after the last 
dose of study treatment 
PT 
(descending frequency of Grade 5) 
Worst severity: 
Grade 5 
Greater than 30 days after the 
last dose of study treatment 
PT 
(descending frequency of Grade 5) 
Worst severity: 
Grade 5 
AEs  judged not to be causally 
related to PD through 30 days of 
last dose of study treatment 
PT 
(descending frequency of Grade 5) 
Worst severity: 
Grade 5 
AEs  judged not to be causally 
related to PD > 30 days of last 
dose of study treatment 
PT 
(descending frequency of Grade 5) 
Worst severity: 
Grade 5 
Subject Incidence of AEs with Odds ratio, Relative Risk  and Risk Difference  
All 
PT 
(descending frequency of difference) 
All events 
Subject Incidence by Special Criteria  
Events with an increase in the 
experimental arm of ≥5% (All 
Grades) or ≥2% (Grade 3/4) 
SOC and PT 
(SOC per MedDRA standard, PT within 
SOC by decreasing difference between 
arms for All Grades) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
Subject incidence of non-serious 
adverse event with an increase 
in the cabozantinib arm of ≥ 5% 
(Any Grade) 
SOC and PT 
(SOC per MedDRA standard, PT within 
SOC by decreasing difference between 
arms for All Grades) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
All 
PT 
(descending frequency of difference in 
percent between the two arms for All 
Grades) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
All 
PT 
(descending frequency of difference in 
percent between the two arms for  
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 


 
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TEAE included 
Row-levels (sorted by) 
Columns 
Grade 3/4) 
All AEs for Subjects with 
Macrovascular Invasion per 
Cancer History CRF 
PT 
(descending frequency of Gr3/4 in the 
cabo arm) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
All AEs for Subjects without 
Macrovascular Invasion per 
Cancer History CRF 
PT 
(descending frequency of Gr3/4 in the 
cabo arm) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
All SAEs for Subjects with 
Macrovascular Invasion per 
Cancer History CRF 
PT 
(descending frequency of Gr3/4 in the 
cabo arm) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
All SAEs for Subjects without 
Macrovascular Invasion per 
Cancer History CRF 
PT 
(descending frequency of Gr3/4 in the 
cabo arm) 
Worst severity: 
All Grades, Grade 3/4, Grade 4, Grade 5 
 
The following data listings will also be provided with indicators for grade, relationship, 
seriousness, dose day of the event start/stop, days since last dose, action taken with study 
treatment: 
• All AEs 
• Grade 5 AEs 
• Serious AEs other than death 
8.2 
Deaths 
All reported subject deaths and whether death was causally associated with the disease under 
study (HCC) will be summarized by treatment arm for all subjects in the Safety population.  
The primary cause of death recorded on the CRF will be mapped to preferred term and 
system organ class using MedDRA.  The coded terms will be merged with AE records to 
determine the relationship to study treatment.   
Deaths will be summarized in 2 main categories as follows: 
• Deaths within 30 days after the date of receipt of the last dose of study treatment  
• Deaths greater than 30 days after the date of receipt of last dose of study treatment   
 
Summary of primary cause of death will be tabulated under each category by causality to 
study disease and relationship to study drug.  
All reported subject deaths will be listed. 


 
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8.3 
Laboratory Assessments 
8.3.1 
Variables 
The following treatment-emergent laboratory abnormalities will be summarized. A 
treatment emergent laboratory abnormality is defined as any laboratory abnormality with an 
onset date on or after the date of the first dose of study drug.  
Category 
Abnormality 
SDTM 
LBTESTCD 
Grading 
System 
Hematology 
WBC increased 
WBC decreased 
WBC 
CTCAE 
 
ANC decreased 
NEUT 
CTCAE 
 
Lymphocytes increased 
Lymphocytes decreased 
LYM 
CTCAE 
 
Platelets decreased 
PLAT 
CTCAE 
 
Hemoglobin increased 
Hemoglobin decreased 
HGB 
CTCAE 
Serum chemistry 
Albumin decreased 
ALB 
CTCAE 
 
ALP increased 
ALP 
CTCAE 
 
Amylase increased 
AMYLASE 
CTCAE 
 
ALT increased 
ALT 
CTCAE 
 
AST increased 
AST 
CTCAE 
 
Calcium, corr increased 
Calcium, corr decreased 
CACORR 
 
CTCAE 
 
Calcium, ion increased 
Calcium, ion decreased 
CAION 
CTCAE 
 
Creatinine increased 
CREAT 
CTCAE 
 
GGT increased 
GGT 
CTCAE 
 
Glucose increased 
Glucose decreased 
GLUC 
CTCAE 
 
LDH increased 
LDH 
Sponsor 
 
Lipase increased 
LIPASE 
CTCAE 
 
Magnesium increased 
Magnesium decreased 
MG 
CTCAE 
 
Phosphate decrease 
PHOS 
CTCAE 
 
Potassium  increased 
Potassium decreased 
K 
CTCAE 
 
Sodium increased 
Sodium decreased 
NA 
CTCAE 
 
Total bilirubin increased 
BILI 
CTCAE 
 
Uric acid  increased2 
CYURIAC 
CTCAE 
Urine chemistry 
UPCR increased 
PROTCRT 
Sponsor 
Endocrinology1 
Thyroid Stimulating Hormone increased 
Thyroid Stimulating Hormone decreased 
TSH 
HLN 
1 TSH is held in the SDTM “chemistry” laboratory category; will use HLN = high, low, normal classification based on normal 
range 
2 Uric acid increases will be graded only as Grade 1 or Grade 4. Grade 2 is not defined per CTCAE v4 and Grade 3 cannot be 
distinguished from Grade 1 based upon the result alone. 
 
 
Sponsor-defined grades are to be applied to the following analytes: 
LDH 
o Grade 1 if >ULN to ≤ 2xULN 
o Grade 2 if >2xULN to ≤ 3xULN 
o Grade 3 if >3xULN 


 
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UPCR 
o Grade 1 if  ≥ 17.0 to ≤ 121.0 mg/mmol 
(≥0.15 to ≤1.0 mg/mg) 
o Grade 2 if  >121.0 to ≤ 396.0 mg/mmol 
(>1.0 to <3.5 mg/mg) 
o Grade 3 if  >396.0 mg/mmol  
 
(>3.5 mg/mg) 
 
8.3.2 
Analysis 
All laboratory data parameters and visits will include flags for values above or below 
laboratory reference ranges. Toxicity grades will be assigned programmatically by applying 
the CTCAE v4 guidelines. Only results with assessment dates through the end of the safety 
observation period (see section 4.5) will be tabulated in summary tables.  
 
Laboratory summaries will be presented in SI units. Continuous laboratory test results will 
be summarized by treatment group using descriptive statistics for actual values and for 
changes from baseline by scheduled visit. Box-Whiskers plots may also be presented at each 
scheduled visit (with visits shown on x-axis) for some laboratory parameters. For continuous 
laboratory test results which are below or above the quantification level, the imputed values 
as described in Appendix C will be used for deriving the grade and then summarized.  
Tables summarizing the incidence of laboratory abnormalities by maximum post-baseline 
CTCAE grade overall and by baseline grade will be presented.  In addition, the following 
summaries will also be presented: 
A]Liver function abnormalities will be assessed as follows: 
• Shift from baseline based on normal ranges  
• Summaries of subjects meeting Hy’s Law laboratory screening criteria as shown 
below: 
o >3× ULN (ALT or AST), >2× ULN Total Bilirubin, and <2× ULN ALP 
o >3× ULN (ALT or AST), >2× ULN Total Bilirubin, and ≥2× ULN ALP 
• Sponsor-defined liver function test surveillance criterion: 
o >10× ULN (ALT or AST) and  >2× ULN Total Bilirubin 
B] For renal failure surveillance, a summary of subjects meeting renal failure laboratory 
screening criteria as shown below will be provided: 
• Serum creatinine >= 3.0xULN and >= 2.0x baseline value or 
• eGFR ≤ 50% of the baseline value or 


 
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• eGFR < 30 mL/min/1.73 m2  and ≥ 25% reduction from  the baseline value 
eGFR = 186 x (Creatinine in mmol per L / 88.4)-1.154 x (Age)-0.203 x (0.742 if 
female) x (1.210 if black)  [from the UK CKD eGuide on the Renal 
Association website: http://egfrcalc.renal.org/] 
C] Categorical summaries for baseline status for TSH and Free T4 will be presented. In 
addition categorical summaries for post-baseline TSH and Free T4 status among 
subjects with TSH and Free T4 in the normal range at baseline will also be presented. 
 
For descriptive summaries for change from baseline analyses, only central lab results will be 
considered. For analyses of shift in grade from baseline or worst grade after baseline, all 
available results will be considered regardless of whether from the central or local lab. 
 
Summary Type 
Include central 
lab results? 
Include local 
lab results? 
Subject-Incidence of Treatment Emergent Laboratory 
Abnormalities in Selected Laboratory Tests by CTCAE 
Grade 
Y 
Y 
Change from Baseline in Laboratory Values 
Y 
N 
Shift from Baseline in Laboratory Values by CTCAE 
Grade 
Y 
Y 
Shift from Baseline in Laboratory Values by 
High/Low/Normal 
Y 
Y 
Shift from Baseline in Laboratory Values by Sponsor-
defined Grades 
Y 
Y 
Subject-Incidence of Laboratory Abnormalities with a 
Between-Arm Difference of ≥5% (All Grades) or ≥2% 
(Grades 3-4) 
Y 
Y 
8.4 
Vital Signs 
8.4.1 
Variables 
The following vital signs will be summarized. 
• Systolic blood pressure (mmHg) 
• Diastolic blood pressure (mmHg) 
• Weight 
8.4.2 
Analysis 
Summary tables of vital signs and change from baseline for each study visit will be 
presented. Only results with assessment dates through the end of the safety observation 
period (see section 4.5) will be considered for the summaries. 


 
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Subject-incidence of clinically meaningful vital sign results as shown below will also be 
presented: 
• Subjects who got worse since baseline and met the following blood pressure criteria 
on 2 or more visits (need not be consecutive) after first dose (JNC criteria were 
modified to include single measurement per time point when triplicate assessments 
were unavailable; JAMA 2003:289:2560): 
o Pre-hypertension: SBP 120-139 mmHg or DBP 80-89 mmHg 
o Stage 1: SBP 140-159 mmHg or DBP 90-99 mmHg 
o Stage 2: (SBP >= 160 mmHg and DBP <120) or DBP 100-119 mmHg 
o Stage 3: DBP >= 120 mmHg 
• Proportion of subjects with weight loss ≥ 10% after first dose 
 
8.5 
ECOG Performance Status 
For the purpose of evaluating safety, ECOG will be summarized as shift from baseline tables 
for, at minimum, the worst value recorded after the initiation of study treatment. Only results 
with assessment dates through the end of the safety observation period (see section 4.5) will 
be tabulated in summary tables. 
Frequencies of ECOG worsening of ≥ +1 and +2 change from baseline to worst value after 
first dose will also be summarized. 
8.6 
Electrocardiogram (ECG) 
Only results with assessment dates through the end of the safety observation period (see 
section 4.5) will be considered for summaries. The following categorical summaries will be 
presented per investigator and per independent review: 
•  number of subjects with triplicate average QTc > 500 ms after first dose 
• number of subjects with increase in triplicate average QTc from baseline of >60ms  
• number of subjects with increase in triplicate average QTc from baseline of >30ms 
after first dose  


 
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For the above summaries, the most-recent average value from triplicate measurements taken 
before first dose will be used as baseline. If no triplicate measurements were taken before 
first dose, the most-recent single value taken before first dose will be used as baseline. 
9 
IDENTIFICATION AND SUMMARY OF PROTOCOL DEVIATIONS 
In accordance with ICH E3, important eligibility deviations per the inclusion/exclusion 
criteria and important post-randomization protocol deviations tracked in CTMS (clinical 
trial management system) will be identified and listed separately by study center and 
subject. Important deviations will be summarized for the ITT population as follows: 
Deviation code: 
• DID NOT SATISFY INCLUSION OR EXCLUSION CRITERIA 
• PROHIBITED MEDICATION 
• TREATMENT DEVIATION 
• WITHDRAWAL DEVIATION 
• RANDOMIZATION IRREGULARITY 
• OTHER PROTOCOL DEVIATION 
Deviations category: 
• IMPORTANT 
• OTHER 
Deviations sub-category: 
• POTENTIALLY IMPACTING SAFETY 
• POTENTIALLY IMPACTING EFFICACY 
• POTENTIALLY IMPACTING SAFETY AND EFFICACY 
• OTHER 
 
10 
DATA QUALITY ASSURANCE 
The Clinical, Data Management, Biostatistics, and Medical Writing departments at Exelixis 
and designees will work diligently and collaboratively to ensure that the data collected and 
analyzed for this study are of the high quality. In addition to electronic evaluation of the data 
and verification of data from source documents at the respective sites, a data review meeting 
will be held to review the data and correct significant data anomalies before the study 
database is locked or data are extracted for the purpose of analysis. 


 
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11 
REFERENCES 
Chobanian AV, Bakris GL, et al. The Seventh Report of the Joint National Committee On 
Prevention, Detection, Evaluation, And Treatment of High Blood Pressure:The 
JNC 7 Report. JAMA 2003 May 21; 289(19):2560-72. 
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0, USDHHS, NIH, 
NCI; publish date May 28, 2009 (v4.03: June 14, 2010). 
International Conference on Harmonization ICH E9: Statistical principles for clinical trials 
(05 February 1998 [Europe], September 1998 [FDA]). 
Llovet JM, Decaens T, Raoul J-L, et al. Brivanib versus placebo in patients with advanced 
hepatocellular carcinoma (HCC) who failed or were intolerant to sorafenib: 
results from the Phase 3 BRISK-PS study. J Hepatol 2012;56 Suppl 2, Abstract 
1398. 
Reenen MV, Janssen B et al. EQ-5D-5L User Guide, Version 2.1, April 2015 
 


 
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Appendix A: Date Imputation Rules 
 
Incomplete Cancer Diagnosis Date 
If year is missing (or completely missing): do not impute 
If only day is missing: set to 15th of the month. 
If day and month are missing: set to July 1st. 
If either imputation rule above results in a diagnosis date > informed consent: 
 
set diagnosis date to the date of informed consent - 1. 
 
Incomplete Adverse Event Onset Date 
Assumption: For on-study Adverse Events. 
If year is missing (or completely missing): set to the date of first dose. 
If (year is present and month and day are missing) or (year and day are present and month is 
missing): 
 
If year = year of first dose: set the date to the first dose date. 
 
If year < year of first dose: set month and day to December 31st. 
 
If year > year of first dose: set month and day to January 1st. 
If month and year are present and day is missing: 
 
If year = year of first dose, and: 
If month = month of first dose: set day to day of first dose. 
 
 
If month < month of first dose: set day to last day of month. 
 
 
If month > month of first dose: set day to 1st day of month. 
 
If year < year of first dose: set day to last day of month. 
 
If year > year of first dose: set day to 1st day of month. 
For all other cases: set to date of first dose. 
 
Incomplete Concomitant Medication Start Date 
If year is missing (or completely missing): do not impute. 
If (year is present and month and day are missing) or (year and day are present and month is 
missing): 
Set month and day to January 1st. 
If year and month are present and day is missing: 
Set day to 1st day of month. 


 
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Incomplete Concomitant Medication End Date 
If year is missing (or completely missing): do not impute. 
If (year is present and month and day are missing) or (year and day are present and month is 
missing): 
Set month and day to December 31st. 
If year and month are present and day is missing: 
Set day to last day of the month.  
 
Incomplete Subsequent Anti-Cancer Therapy Start Date 
Assumption: Anti-Cancer therapies reported on the Subsequent Anti-Cancer Therapy CRF. 
If year is missing (or completely missing): set to date of last dose of study treatment + 1 
If (year is present and month and day are missing) or (year and day are present and month is 
missing): 
If year > year of the last dose: Set month and day to January 1st. 
If year = year of the last dose: Set month and day to date of last dose of study treatment + 1 
If year and month are present and day is missing: 
Set day to 1st day of month if the resulting imputed date is greater than date of last dose 
or if the month is before the month of last dose date and year is same or before the year of 
the last dose date. Otherwise set the imputed date to date of last dose + 1 
 
 
Incomplete Death Date 
Identify date of last known alive (LA) prior to death from the following: 
1. Date of decision to discontinue study treatment from End of Treatment CRF 
2. Date of last radiographic assessment from End of Radiographic Follow Up CRF 
3. Date last known alive from Survival Follow Up CRF 
4. Date of last lab assessment from the Labs dataset 
 
If year is missing (or completely missing):  set to date of LA + 1 
If only day is missing: set to the maximum of the first of month or LA + 1 
If month and day are missing: 
If year of LA = year of death 
Set death date to date of LA + 1 
If year of most-recent contact < year of death 
Set month and day to Jan 1st. 


 
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Incomplete Study Treatment Start Date  
Define previous sequential dosing “milestone” as the latest of previous dose stop date, previous 
dose hold stop date, date of first dose or randomization date. 
If year is missing (or completely missing): set to date of previous sequential dosing “milestone” + 
1 
 
If (year is present and month and day are missing) or (year and day are present and month is 
missing): set to January 1st 
If year and month are present and day is missing: set to the first day of the month 
If the imputed date is before the previous sequential dosing “milestone”: set to the date of previous 
sequential dosing “milestone” + 1 
 
Incomplete Study Treatment Stop Date  
Define next sequential dosing “milestone” as the earliest of next dose start date, next dose hold 
start date, date of last dose from EOT CRF or the cutoff date. 
If year is missing (or completely missing): set to date of next sequential dosing “milestone” - 1 
If (year is present and month and day are missing) or (year and day are present and month is 
missing): set to December 31st 
If year and month are present and day is missing: set to the last day of the month 
If the imputed date is after the next sequential dosing “milestone”: set to the date of next sequential dosing 
“milestone” - 1 
 
 


 
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Appendix B: Rounding Rules for Reported Percentages  
For percentages ≥10%: 
• Values >= X.5 or above round to X+1. 
• Values >X but <X.5 round to X. 
For percentages <10%: 
• Values >= X.Y5 or above round to X.Y+0.1. 
• Values >X.Y but <X.Y5 round to X.Y. 
 
 
 


 
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Appendix C: Imputation Rules for Laboratory Values Outside of Quantification 
Range 
• Lab values below the lower level of quantification (LLQ) that are reported as 
“<LLQ” or “≤LLQ” in the database will be imputed by LLQ x 0.99 for analysis 
purposes. However the original value will also be maintained. 
 
• Lab values above the upper level of quantification (ULQ) that are reported as 
“>ULQ” or “≥ULQ” in the database will be imputed by ULQ x 1.01 for analysis 
purposes. However the original value will also be maintained. 
  
  


 
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Appendix D: EQ-5D-5L Index Value Conversion Guidelines  
The EQ-index conversion algorithm (EQ-5D-5L User Guide 2.1, April 2015. Available 
from: http://www.euroqol.org/about-eq-5d/publications/user-guide.html): 
 
o Calculate health state 
o Each of the 5 dimensions comprising the EQ-5D descriptive system is 
divided into 5 levels of perceived problems: 
 
• Level 1: indicating no problem 
• Level 2: indicating slight problems 
• Level 3: indicating moderate problems 
• Level 4: indicating severe problems 
• Level 5: indicating extreme problems 
 
o A unique health state is defined by combining 1 level from each of the 5 
dimensions. 
For example, state 11111 indicates no problems on any of the 5 
dimensions, while state 12345 indicates no problems with mobility, slight 
problems with washing or dressing, moderate problems with doing usual 
activities, severe pain or discomfort and extreme anxiety or depression.  
Note that missing values will be coded as ‘9’.  Ambiguous values will be 
treated as missing values. 
 
o EQ-index values for each country = health state * the country specific 
conversion factors for each dimension (EQ-5D-5L Index Value Calculator, 
version 1)