Conditions: Advanced Hepatocellular Carcinoma
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 34
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of cabozantinib in Japanese participants with advanced hepatocellular carcinoma (HCC) who have received prior systemic anticancer therapy.

Detailed description:
The drug being tested in this study is called Cabozantinib. Cabozantinib is being tested to treat advanced hepatocellular carcinoma in Japanese patients. This study will look at the efficacy and safety of Cabozantinib.

The study will enroll approximately 34 patients. Participants will be assigned to Cohort A (at least 17 participants) or Cohort B (approximately 15 participants) and will receive the following treatment. Participants who have received prior sorafenib will enroll to Cohort A and participants who have not received prior sorafenib will enroll to Cohort B.

\- Cabozantinib 60 mg

All participants will be asked to take one tablet of cabozantinib once daily in the fasted state (dose at least 2 hours after meal and no more food intake for 1 hour postdose) throughout the study.

This multi-center trial will be conducted in Japan. The overall time to participate in this study is approximately at most 3 years. Participants will make multiple visits to the clinic during the treatment and posttreatment period, including a follow-up assessment after last dose of study drug.

Arms:
arm 1: Participants who have received first/second line anticancer therapy with sorafenib were assigned to Cohort A and received cabozantinib 60 milligrams (mg), tablet, orally, once daily in the fasted state, up to approximately 2 years. arm 2: Participants who did not receive first/second line anticancer therapy with sorafenib were assigned to Cohort B and received cabozantinib 60 mg, tablet orally, once daily in the fasted state, up to approximately 2 years.

Interventions: intervention 1: Cabozantinib
Intervention descriptions: intervention 1: Cabozantinib tablet

Protocol document:
Prot_000.pdf: 
 
 
Title: A Phase 2, Open-Label, Single-Arm Study of Cabozantinib in Japanese Patients 
With Advanced Hepatocellular Carcinoma Who Have Received Prior Systemic 
Anticancer Therapy 
 
NCT Number: NCT03586973 
Protocol Approve Date: 30-OCT-2018 
 
Certain information within this protocol has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable 
information or company confidential information. 
 
This may include, but is not limited to, redaction of the following: 
 
Named persons or organizations associated with the study. 
 
Patient identifiers within the text, tables, or figures or in by-patient data listings. 
 
Proprietary information, such as scales or coding systems, which are considered 
confidential information under prior agreements with license holder. 
 
Other information as needed to protect confidentiality of Takeda or partners, 
personal information, or to otherwise protect the integrity of the clinical study. 
 
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 
 


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1.0
ADMINISTRATIVE
1.1
Contacts
A separate contact information list will be provided to each site.
Serious adverse event and pregnancy reporting information is presented in Section 10.0, as is 
information on reporting product complaints.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
Contact Type/Role
Contact
SAE and pregnancy reporting
See protocol annex
Responsible Medical Officer 
(carries overall responsibility for the conduct of the study)
See protocol annex
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1.3
Protocol Amendment 01 Summary of Changes
This document describes the changes in reference to the Protocol Incorporating Amendment 
No. 01.
The primary changes of Amendment 01 are as follows:

The subject, who continued the study treatment after determination of PD per RECIST 1.1,
should discontinue study treatment after the second determination of disease progression.

If the subsequent systemic anticancer treatment is conducted within 30 days after the last dose
of study drug, 30-Day Posttreatment Followup is completed at that time.

If the subsequent systemic anticancer treatment is conducted within 30 days after the last dose
of study drug, AEs collection and recording in the eCRF are to be completed at that time.
Other changes were also made to clarify the study procedures. In addition, minor revisions 
(including grammatical and editorial changes) are included for clarification purposes. The details 
on changes of text are given in Appendix J.
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE.......................................................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 01 Summary of Changes ..........................................................4
2.0
STUDY SUMMARY ....................................................................................................11
3.0
STUDY REFERENCE INFORMATION ......................................................................18
3.1
Study-Related Responsibilities.................................................................................18
3.2
Signatory Coordinating Investigator.........................................................................18
3.3
List of Abbreviations ...............................................................................................19
4.0
INTRODUCTION.........................................................................................................22
4.1
Background .............................................................................................................22
4.1.1
Disease Under Treatment: Hepatocellular Carcinoma.........................................22
4.1.2
Study Drug.........................................................................................................23
4.1.3
Nonclinical Experience ......................................................................................24
4.1.4
Clinical Experience............................................................................................25
4.1.5
DDI Risk of Cabozantinib..................................................................................30
4.2
Rationale for the Proposed Study.............................................................................31
4.2.1
Rationale for Study Design and Primary Endpoint .............................................32
4.2.2
Rationale for Dose .............................................................................................33
4.2.3
Rationale for PK Assessments............................................................................33
4.2.4
Rationale for Biomarker Analysis ......................................................................33
4.2.5
Rationale for Pharmacogenomic Assessments....................................................33
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................35
5.1
Objectives................................................................................................................35
5.1.1
Primary Objective ..............................................................................................35
5.1.2
Secondary Objectives.........................................................................................35
5.1.3
Safety Objective.................................................................................................35
5.1.4
Additional Objectives.........................................................................................35
5.2
Endpoints.................................................................................................................36
5.2.1
Primary Endpoint...............................................................................................36
5.2.2
Secondary Endpoints..........................................................................................36
5.2.3
Safety Endpoints................................................................................................36
5.2.4
Additional Endpoints .........................................................................................36
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6.0
STUDY DESIGN..........................................................................................................38
6.1
Overview of Study Design.......................................................................................38
6.2
Number of Subjects .................................................................................................41
6.3
Duration of Study ....................................................................................................41
6.3.1
Duration of an Individual Patient’s Study Participation ......................................41
6.3.2
End of Study/Study Completion Definition and Planned Reporting....................41
6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures.........42
6.3.4
Total Study Duration..........................................................................................43
7.0
STUDY POPULATION................................................................................................44
7.1
Inclusion Criteria .....................................................................................................44
7.2
Exclusion Criteria ....................................................................................................45
8.0
STUDY DRUG .............................................................................................................49
8.1
Study Drug Administration......................................................................................49
8.1.1
Cabozantinib Administration on Week 1 Day 1..................................................49
8.1.2
Subsequent Dose Administration of Cabozantinib..............................................49
8.2
Dose Modification Guidelines..................................................................................50
8.2.1
Dose Reductions, Interruptions and Discontinuation ..........................................50
8.2.2
Dose Reinstitution and Re-escalation .................................................................51
8.3
Excluded Concomitant Medications and Procedures ................................................52
8.4
Permitted Concomitant Medications and Procedures................................................53
8.5
Precautions and Restrictions ....................................................................................54
8.5.1
Pregnancy and Contraception.............................................................................54
8.6
Management of Clinical Events ...............................................................................55
8.6.1
GI Disorders ......................................................................................................55
8.6.2
Hepatobiliary Disorders .....................................................................................57
8.6.3
Hematological Disorders....................................................................................58
8.6.4
Fatigue, Anorexia, and Weight Loss...................................................................59
8.6.5
Skin Disorders ...................................................................................................59
8.6.6
Hypertension......................................................................................................61
8.6.7
Thromboembolic Events ....................................................................................62
8.6.8
Proteinuria .........................................................................................................63
8.6.9
Corrected QT Prolongation ................................................................................64
8.6.10 Hypophosphatemia ............................................................................................65
8.6.11 Thyroid Function Disorders ...............................................................................66
8.6.12 Hemorrhagic Events...........................................................................................66
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8.6.13 GI Perforation/Fistula and Non-GI Fistula Formation.........................................67
8.6.14 Osteonecrosis of the Jaw....................................................................................67
8.6.15 RPLS .................................................................................................................68
8.7
Blinding and Unblinding..........................................................................................68
8.8
Description of Investigational Agents ......................................................................68
8.9
Preparation, Reconstitution, and Dispensation..........................................................68
8.10
Packaging and Labeling...........................................................................................68
8.11
Storage, Handling, and Accountability.....................................................................69
9.0
STUDY CONDUCT......................................................................................................70
9.1
Study Personnel and Organizations..........................................................................70
9.2
Arrangements for Recruitment of Patients................................................................70
9.3
Study Enrollment.....................................................................................................70
9.4
Study Procedures.....................................................................................................70
9.4.1
Informed Consent...............................................................................................71
9.4.2
Demographics....................................................................................................71
9.4.3
Medical History .................................................................................................71
9.4.4
Tumor Biopsy....................................................................................................71
9.4.5
Physical Examination.........................................................................................71
9.4.6
Height and Weight .............................................................................................71
9.4.7
Vital Signs .........................................................................................................71
9.4.8
ECOG PS...........................................................................................................72
9.4.9
Pregnancy Test...................................................................................................72
9.4.10 Concomitant Medications and Procedures..........................................................72
9.4.11 Adverse Events ..................................................................................................72
9.4.12 ECG...................................................................................................................72
9.4.13 Echocardiogram.................................................................................................73
9.4.14 Clinical Laboratory Evaluations .........................................................................73
9.4.15 Tumor Assessment.............................................................................................76
9.4.16 Alpha-Fetoprotein..............................................................................................78
9.4.17 PK Measurements..............................................................................................79
9.4.18 Pharmacogenomic Blood Sample Collection......................................................79
9.4.19 Biomarker Assessment.......................................................................................79
9.4.20 Health-Related Quality of Life Assessments ......................................................80
9.4.21 Child-Pugh Scoring............................................................................................81
9.4.22 Survival Status and Subsequent Anticancer Therapy ..........................................81
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9.5
Completion of Study Treatment (for Individual Subjects) ........................................81
9.6
Completion of Study (for Individual Subjects) .........................................................81
9.7
Discontinuation of Treatment With Study Drug and Subject Replacement ...............81
9.8
Withdrawal of Subjects From Study.........................................................................82
9.9
Study Compliance....................................................................................................83
9.10
Posttreatment Followup Assessments.......................................................................83
10.0
ADVERSE EVENTS ....................................................................................................84
10.1
Definitions...............................................................................................................84
10.1.1 Adverse Event Definition...................................................................................84
10.1.2 Serious Adverse Event Definition ......................................................................84
10.2
Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events........................................................................................................85
10.3
Monitoring of Adverse Events and Period of Observation........................................86
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events.........86
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) ................................................................................................................87
10.5.1 Procedures for Reporting Product Complaints....................................................87
10.5.2 Procedures for Reporting Medication Errors (Including Overdose) ....................87
10.6
Safety Reporting to Investigators, IRBs and Regulatory Authorities.........................87
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................88
11.1
Independent Radiology Committee ..........................................................................88
12.0
DATA HANDLING AND RECORDKEEPING............................................................89
12.1
eCRFs......................................................................................................................89
12.2
Record Retention .....................................................................................................89
13.0
STATISTICAL METHODS..........................................................................................91
13.1
Statistical and Analytical Plans ................................................................................91
13.1.1 Analysis Sets......................................................................................................91
13.1.2 Analysis of Demographics and Other Baseline Characteristics ...........................91
13.1.3 Efficacy Analysis...............................................................................................91
13.1.4 PK Analysis .......................................................................................................93
13.1.5 Biomarker Analysis............................................................................................93
13.1.6 Pharmacogenomic Analysis ...............................................................................93
13.1.7 Safety Analysis ..................................................................................................93
13.2
Interim Analysis and Criteria for Early Termination ................................................94
13.3
Determination of Sample Size..................................................................................94
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2.0
STUDY SUMMARY
Name of Sponsor:
Takeda Pharmaceutical Company, Ltd.
Compound:
Cabozantinib
Title of Protocol: A Phase 2, Open-Label, Single-Arm 
Study of Cabozantinib in Japanese Patients With Advanced 
Hepatocellular Carcinoma Who Have Received Prior 
Systemic Anticancer Therapy
IND No.:
Not Applicable
EudraCT No.:
Not Applicable
Study Number: Cabozantinib-2003
Phase: 2
Study Design:
This is a phase 2, open-label, single-arm study to evaluate the efficacy and safety of cabozantinib in Japanese patients 
with advanced hepatocellular carcinoma (HCC) who have received prior systemic anticancer therapy (Cohort A: 
patients who have received prior sorafenib, Cohort B: patients who have not received prior sorafenib).
Following the Screening period, patients will be enrolled and treated with cabozantinib. A subject is considered to be 
enrolled in the study when the first dose of study drug will be administered.
Screening Period: Potential subjects will be screened to determine if they meet the required eligibility criteria after 
informed consent. Qualifying screening assessments must be performed within 28 days before the first day of study 
drug administration (Week 1 Day 1) unless otherwise specified.
Treatment Period: Subjects who meet all study eligibility criteria will receive cabozantinib 60 mg orally, once daily 
(QD) in the fasted state (dose at least 2 hours after meal and no more food intake for 1 hour postdose), preferably at 
bedtime. 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, or until there are any other reasons for treatment discontinuation listed in the 
protocol. Treatment may continue after radiographic HCC progression per Response Evaluation Criteria in Solid 
Tumors Version 1.1 (RECIST 1.1) 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 risks. However 
the subject should discontinue study treatment after the second determination of disease progression.
Posttreatment Period: A 30-day posttreatment followup visit for safety will occur 30 (+14) days after the last dose of
study drug or until the start of subsequent systemic anticancer treatment, whichever occurs first. Radiographic tumor 
assessments, Child-Pugh assessments, alpha-fetoprotein (AFP) assessments, and health-related quality of life 
(HRQOL) assessments will continue, regardless of whether study treatment is given, reduced, held or discontinued 
until the day of the last tumor imaging assessment. Subjects will be contacted every 8 weeks (±7 days) after the 30-day 
posttreatment followup visit to assess survival status and document receipt of subsequent anticancer therapy. Subjects 
will be followed until death, withdrawal of consent, or the sponsor decision to discontinue collection of these data in 
the study.
Primary Objective:
The primary objective is to evaluate the efficacy of cabozantinib measured by Independent Radiology Committee 
(IRC)-assessed 24-week progression-free survival rate (PFSR) per RECIST 1.1 in Japanese patients with advanced 
HCC who have received prior sorafenib.
Secondary Objectives:
To evaluate the efficacy of cabozantinib measured by IRC-assessed progression-free survival (PFS) per RECIST 1.1
in the patient population under study.
To evaluate the efficacy of cabozantinib measured by IRC-assessed objective response rate (ORR) per RECIST 1.1
in the patient population under study.
To evaluate the efficacy of cabozantinib measured by IRC-assessed  disease control rate (DCR)  per RECIST 1.1 in
the patient population under study.
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To evaluate the efficacy of cabozantinib measured by overall survival (OS) in the patient population under study.
Safety Objective:
To evaluate the safety of cabozantinib in the patient population under study.
Subject Population: Previously treated advanced HCC
Planned Number of Subjects:
Approximately 32 subjects
Cohort A (subjects who have received prior sorafenib):
at least 17 subjects
Cohort B (subjects who have not received prior
sorafenib): approximately 15 subjects
Planned Number of Sites:
Approximately 18 sites in Japan
Dose Level:
Cabozantinib 60 mg (60 mg tablet×1), QD
Route of Administration:
Oral
Duration of Treatment:
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, or until there are 
any other reasons for treatment discontinuation listed in 
the protocol.
Study Length:
The duration of the study, including enrollment, 
treatment, and followup, will be approximately 3 years.
Main Criteria for Inclusion:
1.
Male or female Japanese patients 20 years of age or older on the day of consent.
2.
Histological or cytological diagnosis of HCC (results of a previous biopsy will be accepted).
3.
Measurable disease per RECIST 1.1 as determined by the investigator.
4.
Patients who have disease that is not amenable to a curative treatment approach (eg, transplant, surgery,
radiofrequency ablation).
5.
Patients who have received 1 or 2 prior systemic anticancer therapies for advanced HCC.
- Cohort A: patients who have received prior sorafenib.
- Cohort B: patients who have not received prior sorafenib.
Note: Additional prior systemic therapies used as adjuvant or local therapy are allowed.
6.
Radiographic progression following prior systemic anticancer therapy for advanced HCC.
7.
Recovery to ≤Grade 1 Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 from toxicities
related to any prior treatments, unless the adverse events are clinically nonsignificant and/or stable on supportive
therapy.
8.
Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1, and life expectancy of at least
3 months.
9.
Child-Pugh Score of A.
10.
Adequate organ and marrow function at Screening (within 10 days before Week 1 Day 1):
a)
Absolute neutrophil count (ANC) ≥1,200/mm3.
b)
Platelets ≥60,000/mm3.
c)
Hemoglobin ≥8 g/dL.
d)
Serum creatinine ≤1.5 upper limit of normal (ULN) or calculated creatinine clearance ≥40 mL/min using
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the Cockroft-Gault equation.
e)
Urine protein-to-creatinine ratio (UPCR) ≤1 mg/mg.
f)
Total bilirubin ≤2 mg/dL.
g)
Serum albumin ≥2.8 g/dL.
h)
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤5.0 ULN.
i)
Hemoglobin A1c (HbA1c) ≤8% (if HbA1c results are unavailable [eg, hemoglobin variant], a fasting serum
glucose ≤160 mg/dL).
11.
Antiviral therapy per local standard of care if active hepatitis B virus (HBV) infection.
12.
Female patients who:
a)
Are postmenopausal (natural amenorrhea, not due to other medical reasons) for at least 1 year before the
Screening visit, OR
b)
Are surgically sterile, OR
c)
If they are of childbearing potential, agree to practice 1 highly effective method of birth control with a
condom, which is an effective barrier method of contraception, at the same time, from the time of signing
the informed consent through 4 months after the last dose of study drug, OR
d)
Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient,
from the time of signing the informed consent through 4 months after the last dose of study drug. (Periodic
abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], condoms only, withdrawal,
spermicides only, and lactational amenorrhea are not acceptable methods of contraception.)
Male patients, even if surgically sterilized (ie, status postvasectomy), who:
e)
Agree to practice effective barrier contraception during the entire study treatment period and through
4 months after the last dose of study drug. If their partner are of childbearing potential, their female partner
should use 1 highly effective method of birth control at the same time, OR
f)
Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient,
from the time of signing the informed consent through 4 months after the last dose of study drug. (Periodic
abstinence [eg, calendar, ovulation, symptothermal, postovulation methods for the female partner],
condoms only, withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of
contraception.)
13.
Voluntary written consent must be given before performance of any study-related procedure not part of standard
medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice
to future medical care.
14.
Patient is willing and able to adhere to the study visit schedule and other protocol requirements.
Main Criteria for Exclusion:
1.
Fibrolamellar carcinoma or mixed hepatocellular cholangiocarcinoma.
2.
Any type of anticancer agent within 14 days before the first day of study drug administration (Week 1 Day 1).
3.
Radiation therapy  within 28 days (14 days for radiation for bone metastases) or radionuclide treatment (eg, I-131
or Y-90) within 42 days before Week 1 Day 1 (patient is excluded if there are any clinically relevant ongoing
complications from prior radiation therapy).
4.
Prior cabozantinib treatment.
5.
Treatment with any investigational products (excluding anticancer products approved in Japan) within 28 days
before Week 1 Day 1.
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 Week 1 Day 1. Eligible patients must be without
corticosteroid treatment at Week 1 Day 1.
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7.
Concomitant anticoagulation, with oral anticoagulants (eg, warfarin, direct thrombin and Factor Xa inhibitors) or
platelet inhibitors (eg, clopidogrel).
Note: Low-dose aspirin for prophylactic use (per local applicable guidelines) and low-dose, low molecular
weight heparins (LMWH) are permitted (LMWH has not been approved for the use for cardioprotection in
Japan). Anticoagulation with therapeutic doses of LMWH is allowed in patients without radiographic evidence
of brain metastasis, who are on a stable dose of LMWH for at least 12 weeks before Week 1 Day 1, and who have
had no complications from a thromboembolic event or the anticoagulation regimen.
8.
Patients who have 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 blood pressure >150 mm Hg systolic, or >100 mm Hg
diastolic despite optimal antihypertensive treatment.
iii.
Stroke (including transient ischemic attack [TIA]), myocardial infarction, or other ischemic event
within 6 months before Week 1 Day 1.
iv.
Thromboembolic event within 3 months before Week 1 Day 1.
v.
A left-ventricular ejection fraction ≤50%.
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
Week 1 Day 1.
Note: Complete healing of an intra-abdominal abscess must be confirmed prior to Week 1 Day 1.
c)
Major surgery within 2 months before Week 1 Day 1. Complete healing from major surgery must have
occurred 1 month before Week 1 Day 1. Complete healing from minor surgery (eg, simple excision, tooth
extraction) must have occurred at least 7 days before Week 1 Day 1. Patients 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. Patients with invasion or thromboses of portal/hepatic vasculature attributed to underlying liver
disease and/or liver tumor are eligible.
f)
Clinically significant bleeding risk including the following within 3 months before Week 1 Day 1:
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.
ii.
Known infection with human immunodeficiency virus, or known acquired immunodeficiency
syndrome -related illness.
iii.
Active hepatitis B and/or C. Patients with active hepatitis virus infection controlled with antiviral
therapy are eligible.
iv.
Serious non-healing wound/ulcer/bone fracture.
v.
Malabsorption syndrome.
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vi.
Uncompensated/symptomatic hypothyroidism.
vii. Requirement for hemodialysis or peritoneal dialysis.
viii. History of solid organ transplantation.
9.
Patients with untreated or incompletely treated varices with bleeding or high risk for bleeding.  Patients 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 before Week 1 Day 1 are eligible.
10.
Moderate or severe ascites.
11.
Corrected QT interval calculated by the Fridericia formula (QTcF) >500 msec within 14 days before Week 1 Day
1.
Note: If the QTcF is >500 msec in first electrocardiogram (ECG), a total of 3 ECGs each separated by at least 3
minutes should be performed within 30 minutes. If the average of these 3 consecutive results for QTcF is
≤500 msec, the patient meets eligibility in this regard.
12.
Inability to swallow tablets.
13.
Previously identified allergy or hypersensitivity to components of the study treatment formulations.
14.
Female patients who are lactating and breastfeeding or have a positive serum pregnancy test during the Screening
period.
Note: Female patients who are in the lactation period, even if they discontinue breastfeeding, will be excluded
from the study.
15.
Previously diagnosed with another malignancy and have any evidence of residual disease within 2 years before
Week 1 Day 1.
Note: Patients with superficial skin cancers, or localized, low-grade tumors deemed cured and not treated with
systemic therapy are not excluded.
16.
Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the
completion of treatment according to this protocol.
17.
Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of cabozantinib.
18.
Use of strong CYP3A4 inhibitors and CYP3A4 inducers within 14 days before Week 1 Day 1.
19.
Admission or evidence of illicit drug use, drug abuse, or alcohol abuse.
Main Criteria for Evaluation and Analyses:
Primary Endpoint:
24-week PFSR, per RECIST 1.1, by IRC.
Secondary Endpoints:
PFS, per RECIST 1.1, by IRC.
ORR, per RECIST 1.1, by IRC.
DCR, per RECIST 1.1, by IRC.
OS
Safety Endpoints:
Treatment-emergent adverse events (TEAEs).
Grade 3 or higher TEAEs.
Serious TEAEs.
Permanent discontinuation by TEAEs.
Dose modification (dose reduction or interruption) by TEAEs.
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Clinically significant abnormal laboratory values.
Clinically significant abnormal vital sign measurements.
Additional Endpoints
PFS, per RECIST 1.1, by investigator.
ORR, per RECIST 1.1, by investigator.
DCR, per RECIST 1.1, by investigator.
Plasma concentrations of cabozantinib.
HRQOL assessed by the EuroQol Health questionnaire instrument (EQ-5D-5L).
Efficacy biomarker(s).
- Candidate biomarkers that may include, but are not limited to, plasma biomarkers associated with study treatment
and/or clinical outcome.
Possible safety biomarker(s).
- Association of genetic polymorphisms in genes encoding drug-metabolizing enzymes and/or transporters with
study treatment and/or clinical outcome.
Statistical Considerations:
Primary Endpoint:
24-week PFSR, per RECIST 1.1, by IRC
PFS is defined as time from the first day of study drug administration to the earlier of progressive disease (PD) per
RECIST 1.1 or death due to any cause. 24-week PFSR is defined as PFS proportion at Study Day of Week 25 Day 1
+ 7 days.
Primary Analysis
For 24-week PFSR by IRC, Kaplan-Meier estimate will be provided and the corresponding 2-sided 90% CI will be 
calculated for Cohort A using the Greenwood's formula and the complementary log-log transformation.
Other Analysis
The same analysis as that in the primary analysis will be conducted for Cohort B and overall (ie, Cohort A + Cohort 
B)
Secondary Endpoints:
PFS, per RECIST 1.1, by IRC
For PFS by IRC, median PFS will be estimated using the Kaplan-Meier method, and the Kaplan-Meier plot will be
presented for each Cohort and overall.
ORR, per RECIST 1.1, by IRC
ORR is defined as proportion of subjects whose best overall response is complete response (CR) or partial response
(PR) per RECIST 1.1, which is confirmed by a subsequent evaluation conducted ≥28 days later.
For ORR by IRC, point estimate and the 2-sided 95% exact CI will be calculated for each Cohort and overall.
DCR, per RECIST 1.1, by IRC
DCR is defined as proportion of subjects whose best overall response is CR, PR or stable disease (SD) per RECIST
1.1. CR and PR require confirmation by a subsequent evaluation conducted ≥28 days later, and SD have to be
maintained for at least 8 weeks (51 days) after the first day of study drug administration.
For DCR by IRC, point estimate and the 2-sided 95% exact CI will be calculated for each Cohort and overall.
OS
OS is defined as time from the first day of study drug administration to death due to any cause. The same analyses as
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those for PFS will be performed for OS.
Safety Endpoints:
For safety endpoints, summary of the results will be displayed for each Cohort and overall.
Additional Endpoints:
Summary of additional endpoints will be displayed.
Sample Size Justification:
A study with 17 subjects will provide at least 80% probability that the lower limit of the two-sided 90% CI for the 
24-week PFSR by Kaplan-Meier method results in ≥11.1% when assuming the true 24-week PFSR ≥38.4%.
In Study XL184-309 in subjects with advanced HCC who have received prior sorafenib, the 24-week PFSR by 
investigator was 38.4% (95% CI: [33.5, 43.3]%) and 11.1% (95% CI: [7.2, 15.8]%) in cabozantinib and placebo 
group, respectively. In reference to the above results, a 24-week PFSR of 38.4% is assumed and the threshold is set at 
11.1% in this study.
This study will enroll at least 17 subjects who have received prior sorafenib in Cohort A. In addition, for better 
understanding of the efficacy and safety profile of cabozantinib in Japanese patients, similar number of subjects who 
have received prior sorafenib in Cohort A and who have not received prior sorafenib in Cohort B will be enrolled, 
resulting in approximately 32 subjects in total.
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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities
The sponsor will perform all study-related activities with the exception of those identified in the 
protocol annex. The identified vendors in the protocol annex for specific study-related activities 
will perform these activities in full or in partnership with the sponsor.
3.2
Signatory Coordinating Investigator
Takeda will select a Signatory Coordinating Investigator from the investigators who participate in 
the study. Selection criteria for this investigator will include significant knowledge of the study 
protocol, the study medication, their expertise in the therapeutic area and the conduct of clinical 
research as well as study participation. The Signatory Coordinating Investigator will be required to 
review and sign the CSR and by doing so agrees that it accurately describes the results of the study.
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3.3
List of Abbreviations
AE
adverse event
AFP
alpha-fetoprotein
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
AUC
area under the plasma drug concentration time curve
BP
blood pressure
CAP
chest/abdomen/pelvis
CI
confidence interval
CL/F
oral clearance
Cmax
maximum observed concentration
CNS
central nervous system
CR
complete response
CRO
contract research organization
CRPC
castration-resistant prostate cancer
CSR
clinical study report
CT
computerized tomography
CTCAE
Common Terminology Criteria for Adverse Events
%CV
percent coefficient of variation
CYP
cytochrome P450
DCR
disease control rate
DDI
drug-drug interaction
DICOM
Digital Imaging and Communications in Medicine
DILI
drug-induced liver injury
DVT
deep vein/venous thrombosis
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EMA
European Medicines Agency
EQ-5D-5L
EuroQol Health questionnaire instrument
EU
European Union
FAS
full analysis set
FDA
Food and Drug Administration
FSH
follicle stimulating hormone
GB
glioblastoma multiforme
GCP
Good Clinical Practice
G-CSF
granulocyte colony-stimulating factor
GGT
γ-glutamyl transferase (gamma-glutamyl transferase)
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GI
gastrointestinal
HbA1c
hemoglobin A1c
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCC
hepatocellular carcinoma
HCV
hepatitis C virus
HCVAb
hepatitis C virus antibody
HDPE
high-density polyethylene
HR
hazard ratio
HRQOL
health-related quality of life
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IDMC
independent data monitoring committee
IRB
institutional review board
IRC
independent radiology committee
LDH
lactate dehydrogenase
LMWH
low molecular weight heparin
MedDRA
Medical Dictionary for Regulatory Activities
MET
hepatocyte growth factor receptor protein
MHLW
Ministry of Health, Labour and Welfare
MHRA
Medicines and Healthcare products Regulatory Agency
MRI
magnetic resonance imaging
MRP2
multidrug resistance-associated protein 2
MTC
medullary thyroid cancer
MTD
maximum tolerated dose
NCI
National Cancer Institute
ORR
objective response rate
OS
overall survival
PD
progressive disease
PE
pulmonary embolism
PET
positron emission tomography
PFS
progression-free survival
PFSR
progression-free survival rate
P-gp
P-glycoprotein
PK
pharmacokinetic(s)
PMDA
Pharmaceuticals and Medical Devices Agency of Japan
PopPK
population pharmacokinetic(s)
PPES
palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome)
PR
partial response
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PS
performance status
PT
preferred term
PT-INR
prothrombin time-international normalized ratio
QD
once daily
QT
time interval in ECG reading
QTcF
corrected QT interval calculated by the Fridericia formula
RCC
renal cell carcinoma
RECIST 1.1
Response Evaluation Criteria in Solid Tumors Version 1.1
RPLS
reversible posterior leukoencephalopathy syndrome
RP2D
recommended phase 2 dose
RTK
receptor tyrosine kinase
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
SoD
baseline sum of the diameters
SUSARs
suspected unexpected serious adverse reactions
TBS
technetium bone scans
TEAEs
treatment-emergent adverse events
TIA
transient ischemic attack
TKI
tyrosine kinase inhibitor
TSH
thyroid-stimulating hormone
ULN
upper limit of normal
UPCR
urine protein-to-creatinine ratio
US
United States
VEGF
vascular endothelial growth factor
VEGFR
vascular endothelial growth factor receptor
XL184
research name for investigational product cabozantinib
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4.0 
INTRODUCTION
4.1 
Background
4.1.1 Disease Under Treatment: Hepatocellular Carcinoma
4.1.1.1 Epidemiology
The number of individuals who developed cancer in 2012 is estimated to be 14,068,000 around the 
world. The number of individuals who developed liver cancer is estimated to be 782,000 and the 
number of deaths is estimated to be 746,000. Liver cancer is the second highest cause of 
cancer-related deaths in the world, behind only lung cancer. The incidence and mortality rates of 
liver cancer tends to increase globally. There are regional differences in the incidence rate of liver 
cancer, and most of individuals who developed hepatocellular carcinoma (HCC) are in the East 
Asia, South-Eastern Asia and North African countries. The incidence and mortality rates of liver 
cancer are similar in each country/region.
In Japan, the incidence rate of liver cancer has tended to decrease since late 1990, but has still been 
higher than that in the world [1]. According to the Center for Cancer Control and Information 
Services, National Cancer Center in Japan, the number of individuals who developed cancer in 
2013 was approximately 862,000. The number of individuals who developed liver cancer is 
estimated to be 40,938 and the number of deaths is estimated to be 30,173 [2].
4.1.1.2 Receptor Tyrosine Kinases in HCC
The vascular endothelial growth factor (VEGF) receptors and ligands are central mediators of 
tumor neo-angiogenesis and lymphangiogenesis [3]. High tumor microvessel density appears 
predictive of poor disease-free survival after HCC resection, and tumor vascular invasion is a 
well-established negative prognostic factor [4,5]. Resistance to VEGF-targeted therapies may 
arise from the upregulation of alternative pro-angiogenic and pro-invasive signaling pathways, 
including the hepatocyte growth factor receptor protein (MET) pathway. Consistent with this, 
combined inhibition of VEGF receptor (VEGFR) and MET results in efficacy enhanced over that 
achieved via inhibition of either pathway alone in some tumor models [6-9].
The receptor tyrosine kinase (RTK) MET and its cognate ligand hepatocyte growth factor  play an 
important role in diverse aspects of tumor pathobiology, including tumor growth, survival, 
neo-angiogenesis, invasion, and dissemination [10]. 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 [11-13]. Moreover, small-molecule inhibitors of MET have been shown 
to exhibit efficacy in preclinical models of HCC [9,14] and in early-phase clinical studies [15].
Like MET, RTK AXL plays an important role in diverse aspects of tumor pathobiology, including 
angiogenesis, epithelial-to-mesenchymal transition, invasion and dissemination, as well as 
suppressing antitumor immunity in the tumor microenvironment [16,17]. AXL has been shown to 
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be frequently activated in HCC cell lines [18]. Activating mutations in the gene encoding AXL 
appear to be extremely rare, making overexpression of AXL and/or its ligand GAS6 the primary 
mechanisms of activation in a wide range of human cancers; further, expression levels often 
correlate with poor prognosis [19]. Like VEGF and MET, AXL is upregulated by hypoxia 
inducible factors in response to hypoxia in a range of tumors [20-23]. High AXL expression in 
HCC patient samples correlates with increased invasiveness and poor prognosis [24,25]. 
Downregulation of expression or inhibition of AXL has been shown to decrease the invasiveness 
of HCC cell lines and inhibited metastasis development in vivo [18,26,27]. In other settings, AXL 
signaling has been linked to resistance to VEGFR inhibitors [28].
Given the known oncogenic potential of the MET and AXL signaling pathways, targeting these 
two oncoproteins in addition to VEGFRs may provide additional anticancer effects in HCC 
patients over more selective VEGFR inhibition strategies.
4.1.1.3 Treatment Approaches
Approximately 90% of liver cancer is HCC, which is the highest incidence rate of primary liver 
cancer. Other types of liver cancer include bile duct cancer, hepatoblastoma and angiosarcoma. 
Some patients who are found to have localized disease can undergo curative resection and other 
patients with advanced HCC can also be treated with regional therapy (local ablation, 
chemoembolization or other transcatheter therapies), but patients who present with advanced, 
particularly unresectable disease or who recur after regional therapy have a poor prognosis. If 
surgical resection or regional therapy is not eligible, systemic anticancer therapy is performed 
[29].
As a systemic anticancer therapy, sorafenib has been shown to prolong the overall survival (OS) 
and progression-free survival (PFS) in patients with HCC [30] in a placebo-controlled study, and 
has been approved in the United States (US) and the European Union (EU) in 2007, and then in 
Japan in 2009. In a placebo-controlled study, regorafenib demonstrated to prolong the OS in 
patients with unresectable HCC that has progressed after prior sorafenib [31], and has been 
approved as the second-line therapy of HCC in the US in April 2017, in Japan in June 2017, and in 
the EU in August 2017. Nivolumab has already received accelerated approval from the Food and 
Drug Administration (FDA) in September 2017 based on the response rate and the sustained 
response reported in an open-label phase 1/2 study of nivolumab conducted in patients with HCC 
who have received prior sorafenib, but has not yet been approved in Japan.
4.1.2 Study Drug
Cabozantinib (research name: XL184) is a multiple RTKs inhibitor targeting 
VEGFR/MET(c-MET)/RET/AXL/KIT/TIE-2, implicated in tumor growth, metastasis, and 
angiogenesis.
Cabozantinib is provided as both capsules and tablets, but the 2 formulations are not 
interchangeable. Cometriq (cabozantinib capsules) at an oral dose of 140 mg once daily (QD) was 
approved by the US FDA on 29 November 2012 for the treatment of patients with progressive, 
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metastatic medullary thyroid cancer (MTC). On 21 March 2014, cabozantinib capsules were 
approved by the European Commission for the treatment of adult patients with progressive, 
unresectable, locally advanced or metastatic MTC. Cabometyx (cabozantinib tablets) at an oral 
dose of 60 mg QD was approved in the US for the treatment of patients with advanced renal cell 
carcinoma (RCC) following prior anti-angiogenic therapy and in the EU for the treatment of 
advanced RCC following prior VEGF-targeted therapy [32,33]. Cabometyx was also approved by 
FDA on 19 December 2017 for patients with previously untreated advanced RCC, and by 
European Commission on 17 May 2018 for the previously untreated adults patients with 
intermediate-or poor-risk advanced RCC. In the same month of 2018, an application for marketing 
approval of Cabometyx was submitted to the US and the EU for the treatment of previously treated 
patients with advanced HCC. Regulatory submissions are underway in other regions.
4.1.3 Nonclinical Experience
4.1.3.1 Pharmacology
Cabozantinib exhibits potent inhibitory activity against several RTKs that are known to influence 
tumor growth, metastasis, and angiogenesis. The primary targets of cabozantinib are 
VEGFR2/KDR, MET, AXL, and RET. Other recognized targets of cabozantinib include ROS1, 
TRKA, TRKB, TYRO3, MER, 2 additional members of the VEGFR family (VEGFR1, 
VEGFR3), and the closely related RTKs KIT and FLT 3. In vivo pharmacodynamic activity of 
cabozantinib against VEGFR2, MET, AXL, and RET has been demonstrated in preclinical studies 
and has been associated with tumor growth inhibition and tumor regression. In preclinical studies, 
cabozantinib treatment has also been shown to inhibit tumor angiogenesis and tumor invasiveness 
and metastasis.
Data from pharmacodynamic experiments have shown that cabozantinib inhibits VEGFR2 and 
MET in vivo. 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 cancer, and glioblastoma multiforme (GB) [34]. In additional preclinical studies, 
cabozantinib treatment has also been shown to inhibit tumor invasiveness and metastasis, and the 
progression of tumors in bone [34,35].
A summary of cabozantinib pharmacology can be found in the Investigator’s Brochure (IB). The 
IB should be reviewed in conjunction with this study protocol.
4.1.3.2 Toxicology
Cabozantinib nonclinical toxicology has been characterized in single- and repeat-dose studies in 
multiple species. Details can be found in the IB.
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4.1.4 Clinical Experience
In clinical studies, cabozantinib has been evaluated in multiple tumor types including MTC, 
castration-resistant prostate cancer (CRPC), ovarian cancer, breast cancer, HCC, non-small cell 
lung cancer, melanoma, differentiated thyroid cancer, RCC, and GB. To date, cabozantinib has 
demonstrated broad clinical activity in these tumor types. Refer to the IB for more detail.
A phase 2, randomized, discontinuation trial in nine different advanced tumor types including a 
cohort of subjects with HCC (Study XL184-203 RDT) was conducted [36]. The study consisted of 
a 12 week Lead in Stage in which all subjects received open-label cabozantinib at an assigned dose 
of 100 mg/day and a Randomized Stage in which subjects with stable disease (SD) at Week 12 
were randomized in a blinded manner to receive cabozantinib or placebo. Subjects who at Week 
12 had a partial response (PR) or complete response (CR) were continued on open-label 
cabozantinib. In subjects who had a progressive disease (PD), cabozantinib treatment was 
discontinued at Week 12.
Study XL184-309 (CELESTIAL) is an ongoing phase 3, double-blinded, placebo-controlled, 
randomized study in patients with advanced HCC who have received prior systemic anticancer 
therapy. The study was designed to enroll 760 patients with advanced HCC who received prior 
sorafenib and may have received up to two prior systemic cancer therapies for HCC and had 
adequate liver function. Enrollment of the study was completed in September 2017. Patients were 
randomized 2:1 to receive 60 mg of cabozantinib QD or placebo and were stratified based on 
etiology of the disease (hepatitis C, hepatitis B or other), geographic region (Asia versus other 
regions) and presence of extrahepatic spread and/or macrovascular invasion (yes or no). No 
cross-over was allowed between the study arms during the blinded treatment phase of the study. 
The primary endpoint is OS, and the secondary endpoints include the investigator-assessed PFS 
and objective response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors 
version 1.1 (RECIST 1.1).
In Japan, a phase 1 study of cabozantinib in Japanese patients with advanced or metastatic solid 
tumors (Study XL184-014) has already been completed. In addition, a phase 2 study of 
cabozantinib in Japanese patients with advanced RCC who had progressed after prior 
VEGFR-tyrosine kinase inhibitor (TKI) (Study Cabozantinib-2001) is ongoing.
4.1.4.1 Clinical Safety of Cabozantinib
Safety in HCC Patients
In Study XL184-203 RDT, 41 subjects with advanced HCC treated with cabozantinib received an 
assigned dose of 100 mg/day. Fifty-nine percent of subjects required at least 1 dose reduction 
throughout both the Lead-in and Randomized Stages.
The most frequently reported adverse events (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  syndrome (PPES) (54%), vomiting 
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(42%), and nausea (39%). Common Grade 3 or higher AEs included diarrhea (22%), 
thrombocytopenia (17%), PPES (15%), aspartate aminotransferase (AST) increased (12%).
In Study XL184-309, the results of safety population (467 in the cabozantinib arm, 237 in the 
placebo arm) as of database cutoff date (1 June 2017) are summarized below.
Grade 3 or 4 AEs were reported for 68% of subjects in the cabozantinib arm and 36% in the 
placebo arm. Grade 3 or 4 AEs reported for ≥ 5% of subjects in either arm were PPES 
(cabozantinib 17%, placebo 0%), hypertension (16%, 2%), AST increased (12%, 7%), fatigue 
(10%, 4%), diarrhea (10%, 2%), asthenia (7%, 2%), decreased appetite (6%, < 1%), and anemia 
(4%, 5%). The incidence of Grade 5 AEs was similar for both treatment arms (12% for each arm). 
Most Grade 5 AEs were related to disease progression. Six Grade 5 AEs were assessed as 
treatment-related in the cabozantinib arm (hepatic failure, hepatorenal syndrome, 
esophagobronchial fistula, portal vein thrombosis, pulmonary embolism [PE], and upper 
gastrointestinal [GI] hemorrhage), and one Grade 5 AE was assessed as treatment-related in the 
placebo arm (hepatic failure).
Study treatment discontinuation due to treatment-related AEs was reported for 16% of 
cabozantinib subjects and 3% of placebo subjects.
Safety in Japanese Patients
Study XL184-014 was an open-label, multiple dose-escalation phase 1 study of cabozantinib 
administered orally to Japanese subjects with advanced or metastatic solid tumors for 
determination of maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D).
1. Dose-Escalation Phase
Study treatment for the capsule cohorts in the Dose-Escalation Phase was administered as a
single-agent at dose levels of 40 mg QD (Cohort 1; n=3), 60 mg QD (Cohort 2, n=6), and
80 mg QD (Cohort 3; n=5). One of the last 2 subjects enrolled in the 80 mg QD cohort were
dose-reduced to 60 mg QD during the dose limiting toxicity (DLT) Evaluation Period, and
experienced a DLT of Grade 3 hypertension on Day 20. One subject enrolled in Cohort 2
(60 mg) also experienced a DLT of Grade 3 hypertension during the DLT Evaluation Period.
As 1 out of 6 subjects enrolled in Cohort 2 (60 mg) experienced a DLT, 60 mg daily was
determined to be the MTD for the capsule formulation in Japanese subjects. Subsequently, the
tablet formulation was also evaluated in the Dose-Escalation Phase at dose levels of 40 mg QD
(Cohort 1T; n=3) and 60 mg QD (Cohort 2T; n=6). One of 6 subjects experienced DLTs at the
60 mg QD tablet dose level; the subject experienced 2 DLTs of Grade 2 protein in urine and
Grade 3 venous embolism. A dose level above 60 mg was not assessed in the tablet
formulation; therefore, the 60 mg dose level was designated the RP2D and an MTD was not
established.
All subjects (across all dose levels and both formulations) in the Dose-Escalation Cohorts
experienced at least one AE on study. The most frequent AEs (≥50%) reported were PPES
(100.0%), alanine aminotransferase (ALT) increased (95.7%), AST increased (95.7%),
hypertension (87.0%), blood thyroid-stimulating hormone (TSH) increased (82.6%), diarrhea
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(78.3%), blood lactate dehydrogenase (LDH) increased (69.6%), leukopenia (60.9%), weight 
decreased (56.5%), dysphonia (52.2%), and protein urine present (52.2%). A total of 70% of 
subjects experienced an AE of ≥Grade 3. The ≥Grade 3 AEs reported for 2 or more subjects 
(≥8.7%) were γ-glutamyltransferase (GGT) increased (17.4%), hypertension (13.0%), 
lymphopenia (13.0%), PPES (8.7%), weight decreased (8.7%), lipase increased (8.7%), 
neutropenia (8.7%), hypokalemia (8.7%), hypophosphatemia (8.7%), and hyponatremia 
(8.7%). The majority of laboratory abnormalities and associated AEs were <Grade 3.
Among all subjects in the Dose-Escalation Cohorts, 6 subjects (26.1%) experienced 9 serious 
AEs (SAEs). The reported SAEs were anemia, bile duct stone, dyspnea, venous embolism, 
hematemesis, intestinal obstruction, melena, pleural effusion, and protein urine. No SAE 
preferred term (PT) was experienced by more than one subject in the Dose-Escalation Cohorts.
In the Dose-Escalation Cohorts, there were no deaths reported through 30 days after last dose 
and no treatment-related deaths >30 days after last dose.
2. Subjects Treated with RP2D 60 mg Tablet
The most frequent AEs (≥50%) were ALT increased (92.3%), AST increased (92.3%), PPES
(84.6%), hypertension (73.1%), diarrhea (65.4%), blood TSH increased (53.8%), decreased
appetite (53.8%), proteinuria (50.0%), and stomatitis (50.0%). The ≥Grade 3 AEs reported for
2 or more subjects (≥7.7%) who received the 60 mg tablet starting dose were hypertension
(23.1%), neutropenia (19.2%), GGT increased (15.4%), dyspnea (15.4%), ALT increased
(11.5%), PPES (11.5%), hypophosphatemia (11.5%), hyponatremia (11.5%), lymphopenia
(11.5%), hypokalemia (11.5%), lipase increased (7.7%), amylase increased (7.7%), and
performance status (PS) decreased (7.7%). The majority of laboratory abnormalities and
associated AEs were <Grade 3.
Among subjects who received the 60 mg tablet starting dose, 10 subjects experienced 23
SAEs. Three SAE PTs were reported for more than 1 subject: dyspnea was reported for
3 subjects (11.5%), and PS decreased and pleural effusion were reported for 2 subjects each
(7.7%).
One subject who received the 60 mg tablet starting dose died through 30 days after the last
dose of treatment with a primary cause of death reported as respiratory failure. The death was
reported as related to study treatment due to possible heart strain from study treatment-induced
hypertension. However, the investigator also noted other possible reasons for respiratory
failure, including worsening of underlying disease or potential ischemic disease. There were
no treatment-related deaths >30 days after last dose. Further details are provided in the most
recent version of the IB.
The most frequently reported AEs were similar among subjects treated in the Dose-Escalation 
Phase and all subjects treated at the tablet RP2D of 60 mg. PPES, hypertension, and selected 
laboratory abnormalities, specifically increases in ALT and AST, were among the most frequent 
AEs reported for both of these groups of subjects. There were no hepatic AEs that led to treatment 
discontinuation, and there were no confirmed cases of drug-induced liver injury (DILI) assessed 
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by using the laboratory screening conditions defined by Hy’s Law. There were no cases of PPES 
that led to treatment discontinuation. One case of hypertension led to treatment discontinuation, 
but no hypertensive crisis (Grade 4) or death due to hypertension (Grade 5) was reported.
4.1.4.2 Clinical Efficacy of Cabozantinib in HCC
Phase 2: Study XL184-203 (HCC Cohort)
In Study XL184-203 RDT, 2 subjects (5%) had a confirmed PR during the 12-week Lead-in Stage 
(at any time through Week 12) and 31 subjects (76%) had SD; the disease control rate (PR+SD) at 
Week 12 was 66%. One subject with SD at Week 12 was subsequently randomized to receive 
placebo (see below) and achieved a PR. Twenty-eight (78%) of 36 subjects with a post-baseline 
scan had at least 1 scan demonstrating a reduction in measurable disease.
Twenty-two of the 41 subjects enrolled in the Lead-in Stage were randomized at Week 12 to 
receive either placebo or continuing cabozantinib after demonstrating SD. The 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 pretreated 
subjects [n=22] and 4.2 months for sorafenib naïve subjects [n=19]). No statistically significant 
difference in the 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) [36].
Phase 3:Study XL184-309
In Study XL184-309, a total of 707 subjects were randomized in a 2:1 ratio to receive cabozantinib 
(470 subjects) or placebo (237 subjects) (intent-to-treat population) at the time of data cutoff for 
the second prespecified interim analysis (1 June 2017). The second prespecified interim analysis 
results showed that Study XL184-309 met its primary endpoint of OS in the cabozantinib arm, 
providing a statistically significant improvement in OS compared to placebo. The independent 
data monitoring committee (IDMC) for the study recommended that the study should be stopped 
for efficacy.
This study has subsequently fully enrolled (773 subjects as of 18 September 2017, planned total 
760) and closed to enrollment. Subjects continued to receive blinded study treatment as of the data 
cutoff date.
Cabozantinib provided a statistically significant and clinically meaningful improvement versus 
placebo in OS, the trial’s primary endpoint, at the planned second interim analysis (pre-specified 
critical p-value ≤0.021): the hazard ratio (HR), adjusted for stratification factors (per interactive 
voice/web response system [IxRS]), was 0.76 (95% CI: 0.63, 0.92; stratified logrank p-value = 
0.0049 [met the critical p-value ≤0.021]). The Kaplan-Meier estimates for median duration of OS 
were 10.2 months in the cabozantinib arm versus 8.0 months in the placebo arm.
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The median PFS was more than doubled in the cabozantinib arm (5.2 months) compared to the  
placebo arm (1.9 months) (HR 0.44 [95% CI: 0.36, 0.52], p<0.0001). The ORR per RECIST 1.1 
were 4% in the cabozantinib arm and 0.4% in the placebo arm (p=0.0086).
4.1.4.3 Pharmacokinetics of Cabozantinib
An integrated population pharmacokinetic (PopPK) analysis of cabozantinib in healthy subjects 
and cancer patients with different types of malignancies was performed that included 
pharmacokinetic (PK) data from 10 clinical studies (three phase 1, two phase 2 and five phase 3) 
for a total of 9510 cabozantinib concentration records from 2023 subjects. The PopPK analysis 
included 489 HCC subjects from Study XL184-309 in addition to patients with RCC, CRPC, 
MTC, GB and other malignancies. The current analysis included data from a 2-compartment 
model with first order elimination and a dual absorption (first order + zero-order) process 
adequately described the observed cabozantinib PK data. Results from the PopPK analysis 
indicated that for a white male subject the predicted terminal plasma half-life of cabozantinib was 
approximately 99 hours; the terminal phase volume of distribution for the central compartment 
was approximately 212 L; and the oral clearance (CL/F) at steady-state was estimated to be 
approximately 2.48 L/h. Inter-individual variability in clearance (percent coefficient of variation 
[%CV] of CL/F) was estimated to be 46%. Compared to healthy subjects, the MTC population was 
the only cancer type to have a notable difference in cabozantinib PK, with an approximately 90% 
increase in CL/F. HCC patients showed a small but significant difference in CL/F (12% lower) and 
not likely to be clinically meaningful. Female gender had a significant effect on CL/F (24% lower 
than in males) which resulted in moderately increased exposure also not considered to be clinically 
meaningful. Covariates showing no statistically significant effect on CL/F included race 
(including Asian race), age and weight. Patients with mild or moderate/severe liver dysfunction 
were predicted to have minimal differences (12% or less) in CL/F and Vc/F relative to subjects 
with normal liver function.
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. Results from a PK study of cabozantinib in subjects with renal impairment (Study 
XL184-017) indicated that the ratios of geometric least square mean for plasma cabozantinib 
maximum observed concentration (Cmax) and area under the plasma drug concentration time curve 
(AUC) were 19% and 30% higher, respectively, for subjects with mild renal impairment compared 
to subjects with normal renal function. For subjects with moderate renal impairment, both Cmax 
and AUC appeared to be similar when compared to subjects with normal renal function 
(differences: <3% and <7%, respectively). Results from a PK evaluation of cabozantinib in 
subjects with hepatic impairment (Study XL184-003) indicated that AUC of cabozantinib was 
increased by about 81% and 63% in subjects with mild and moderate hepatic impairment, 
respectively.
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 (Study 
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XL184-004). Concomitant administration of the proton pump inhibitor esomeprazole resulted in 
no clinically relevant effect on cabozantinib plasma PK in healthy subjects (Study XL184-018).
Exposure (Cmax and AUC) of cabozantinib in capsule and tablet formulations was assessed in 
Japanese subjects (Study XL184-014, n=43). At steady-state exposure, AUC increased 
approximately dose proportionally from 40 mg to 80 mg capsule doses and from 40 mg to 60 mg 
tablet doses. Exposure between capsule and tablet formulations appeared to be similar. Mean 
trough concentration at steady-state was about 30% higher in Japanese subjects when compared 
with non-Japanese subjects; this is not considered clinically relevant since it is within the 
inter-subject variability.
Additional results from clinical PK trials may be found in the IB.
4.1.5 DDI Risk of Cabozantinib
Cytochrome P450
Cabozantinib is a CYP3A4 substrate and a weak substrate for CYP2C9 (but not a CYP2D6, 
CYP2C8, CYP2C19, CYP2B6, or CYP1A2 substrate). Co-administration of cabozantinib with 
strong inducers of the CYP3A4 family (eg, phenytoin, carbamazepine, rifampicin, 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.
Co-administration of cabozantinib with strong inhibitors of the CYP3A4 family (eg, ketoconazole, 
itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, and ritonavir) may increase 
cabozantinib plasma concentrations. Grapefruit and Seville oranges may also increase plasma 
concentrations of cabozantinib. Strong CYP3A4 inhibitors and other drugs that inhibit CYP3A4 
should be avoided.
Protein Binding
Cabozantinib is highly bound (approximately 99.9%) to human plasma proteins. Therefore, highly 
protein-bound drugs (eg, diazepam, furosemide, dicloxacillin, and propranolol) 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. A single case of a drug-drug interaction 
(DDI) between cabozantinib and warfarin has been reported in the literature [37], which is 
consistent with a protein-displacement interaction. Because warfarin is a highly protein-bound
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drug with a low therapeutic index, administration of warfarin is not allowed in subjects receiving 
cabozantinib due to the potential for a protein-binding displacement interaction.
Other Interactions
In vitro data suggest that cabozantinib is unlikely to be a substrate for P-glycoprotein (P-gp), but it 
does appear to have the potential to inhibit the P-gp transport activity. Therefore, cabozantinib 
may have the potential to increase plasma concentrations of co-administered substrates of P-gp. 
Subjects should be cautioned regarding taking a P-gp substrate (eg, fexofenadine, aliskiren, 
ambrisentan, dabigatran etexilate, digoxin, colchicine, maraviroc, posaconazole, ranolazine, 
saxagliptin, sitagliptin, talinolol, tolvaptan) while receiving cabozantinib.
Cabozantinib was shown to be a substrate of drug transporter multidrug resistance-associated 
protein 2 (MRP2) in an in vitro assay. Administration of MRP2 inhibitors to subjects may result in 
increases in cabozantinib plasma concentrations. Therefore, concomitant use of MRP2 inhibitors 
(eg, cyclosporine, delaviridine, efavirenz, emtricitabine) should be approached with caution, and 
subjects taking MRP2 inhibitors should be monitored for AEs.
Additional details regarding potential drug interactions with cabozantinib can be found in the IB.
4.2 
Rationale for the Proposed Study
Cabozantinib is a multiple RTKs inhibitor targeting VEGFR, MET, and AXL, implicated in tumor 
growth, metastasis, and angiogenesis. In the US and the EU, cabozantinib has already been 
approved for the treatment of progressive metastatic MTC and for the treatment of advanced RCC.
HCC is usually resistant to systemic anticancer therapy. Sorafenib, a small-molecule inhibitor of 
VEGFR and other protein kinases, has been shown to improve PFS and OS in patients with HCC, 
who eventually progress and succumb to their disease despite treatment [30]. At the time of 
initiation of Study XL184-309, a randomized, global phase 3 trial of cabozantinib versus placebo 
in patients with advanced HCC who have been previously treated with sorafenib, no drug had 
demonstrated efficacy in patients with unresectable or metastatic HCC that had progressed after 
treatment with sorafenib. Study XL184-309 met its primary endpoint of OS, with cabozantinib 
providing a statistically significant and clinically meaningful improvement in the median OS 
compared to placebo. The IDMC for the study recommended that the study should be stopped for 
efficacy following review of the second planned interim analysis. Based on results from Study 
XL184-309, an application for marketing approval of Cabometyx was submitted to the US and the 
EU for the treatment of previously treated patients with advanced HCC in March 2018.
Recently, regorafenib has been approved for the treatment of unresectable HCC that progressed 
after anticancer therapy in Japan, the EU and the US. This is only one systemic treatment option 
currently available for the patients who have already received systemic anticancer therapy in 
Japan. However, in a pivotal phase 3 study of regorafenib (RESORCE study), actual target 
population was limited to patients who have received only 1 systemic anticancer therapy with 
sorafenib, excluding those who were intolerant to sorafenib. On the other hand, Study XL184-309 
included patients with prior 2 lines of treatment for advanced HCC and did not exclude those who 
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were intolerant to sorafenib. According to the positive result of OS in broader targeting population 
in the Study XL184-309 and wider target receptors of cabozantinib including MET and AXL 
compared to regorafenib, the anticancer effect of cabozantinib is highly expected in the Japanese 
patients with previously treated advanced HCC.
The safety and tolerability of cabozantinib at same dosing regimen as Study XL184-309 has been 
shown in the completed phase 1 study conducted in Japan (Study XL184-014).
We will conduct this study to evaluate the efficacy and safety of cabozantinib in the Japanese 
patients with advanced HCC who have received prior sorafenib comparing the Study XL184-309 
as a primary objective of this study. Furthermore, we will also evaluate the safety and efficacy of 
cabozantinib in Japanese patients with previously treated advanced HCC who have not received 
prior sorafenib, for better understanding of the efficacy and safety profile of cabozantinib in 
Japanese patients, considering the change of standard of care for HCC in the future in Japan.
This study consists of 2 cohorts: Cohort A and Cohort B. Patients who have received prior 
sorafenib for advanced HCC will be enrolled in Cohort A, and patients who have not received 
sorafenib treatment for advanced HCC prior to this study will be enrolled in Cohort B. To evaluate 
the safety and efficacy in Cohorts A and B, the sample size of Cohort B will be similar to that of 
Cohort A.
4.2.1 Rationale for Study Design and Primary Endpoint
This is an open-label, single-arm study. Since regorafenib has been already approved in Japan, it is 
unfeasible from ethical point of view to conduct 2-arm study with placebo arm as a comparator. 
Additionally, it is inappropriate to conduct the head-to-head study with regorafenib arm as a 
comparator since Japanese HCC guideline [29] recommend regorafenib as second line therapy 
ONLY for patients who were tolerate with sorafenib meanwhile cabozantinib showed its efficacy 
in Study XL184-309 in population which did not exclude those who were intolerant to sorafenib. 
For these reasons, we selected single-arm study design.
The primary endpoint of this study is independent radiology committee (IRC)-assessed 
progression-free survival rate at 24 weeks from the start of study drug treatment (24-week PFSR) 
per RECIST 1.1. In a clinical study of a cytotoxic anticancer agent, especially in a phase 2, 
single-arm study, ORR has generally been used as the primary endpoint based on a concept that a 
reduction of tumor size should be considered a certain clinical benefit. Molecularly targeted 
agents, including cabozantinib, demonstrate the inhibition of tumor cell proliferation, invasion and 
distant metastasis but do not demonstrate a drastic tumor shrinkage in some malignancies such as 
HCC, even if tumor necrosis is seen[30,31]. Therefore, the selection of ORR as the primary 
endpoint is not always appropriate. PFSR (ClinicalTrials.gov Identifier: NCT00639509, 
NCT00427973, NCT00605722, NCT00639509, NCT01180959, NCT01281943, NCT01545804, 
NCT01180959, NCT01545804) has also been selected as the primary endpoint in phase 2, 
single-arm studies in patients with advanced HCC so far.
Study XL184-309 demonstrated a significant prolongation of OS and PFS in the cabozantinib arm, 
but ORR (RECIST 1.1) was 4% in the cabozantinib arm and 0.4% in the placebo arm. It means that 
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longer SD contributed to prolongation of PFS and OS. Therefore, PFSR was selected as the 
primary endpoint in this study. The duration of 24 weeks for PFSR was determined referring to the 
median PFS (5.2 months) in the cabozantinib arm (95% CI: 4.0, 5.5, HR: 0.44, 95% CI: 0.36, 0.52) 
in Study XL184-309. This duration of 24 weeks means that approximately 90 % of patients 
without active treatment reach disease progression or death, according to the PFS in the placebo 
arm in Study XL184-309.
Based on the above, the 24-week PFSR is selected as the primary endpoint of this study. Thus, it is 
supposed that 24-week PFSR to be assessed in this study will be a clinically significant indicator.
4.2.2 Rationale for Dose
The same dose regimen as Study XL184-309 (60 mg orally QD) is selected in this study. The 
safety and tolerability of Japanese patients were confirmed at 60 mg orally QD in Study 
XL184-014. No clinically meaningful difference in steady-state plasma exposures was observed 
between Japanese subjects (Study XL184-014) and non-Japanese subjects (Study XL184-309); the 
mean trough concentration was 1,628 ng/mL (%CV=37) in Japanese subjects (n=26) and 
1,180 ng/mL (%CV=47) in non-Japanese subjects (n=181).
4.2.3 Rationale for PK Assessments
Blood samples will be obtained from all subjects at specified time points to measure the plasma 
concentration of cabozantinib. The results will be used to confirm the exposure to cabozantinib. 
The PopPK may be further characterized in this population.
4.2.4 Rationale for Biomarker Analysis
Correlative studies will be conducted to identify potential candidate biomarkers (protein 
expression in signal pathway, metabolic signature, etc) that are significantly associated with 
observed clinical response to cabozantinib in Japanese patients with advanced HCC who have 
received prior systemic anticancer therapy. These candidate biomarkers may include, but are not 
limited to, soluble-VEGFR2/MET/AXL/VEGF/HGF/GAS6-signaling protein expression profiles 
and metabolic profiles. The candidate biomarkers will be prospectively validated in an 
independent patient population.
4.2.5 Rationale for Pharmacogenomic Assessments
Genetic variation in drug-metabolizing enzymes and/or transporters potentially involved in the 
disposition of cabozantinib could contribute to interindividual variability in cabozantinib plasma 
exposures, and subsequently, safety and efficacy. Somatic DNA will be obtained from whole 
blood samples and be genotyped for clinically relevant germline mutations including 
polymorphisms in genes encoding drug-metabolizing enzymes and/or transporters. Additional 
pharmacogenomic analyses may be conducted in the future to further investigate the contribution 
of genetic variance on drug response. 
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As pharmacogenomics is an evolving science, currently many genes and their function are not yet 
fully understood. Future data may suggest a role of some of these genes in drug response or 
diseases, which may lead to additional hypothesis-generating exploratory research on stored 
samples. Pharmacogenomic analyses will be conducted in accordance with Ethical Guidelines for 
Human Genome/Gene Analysis Research.
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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective
The primary objective is to evaluate the efficacy of cabozantinib measured by IRC-assessed 
24-week PFSR per RECIST 1.1 in Japanese patients with advanced HCC who have received prior
sorafenib.
5.1.2
Secondary Objectives
The secondary objectives are:

To evaluate the efficacy of cabozantinib measured by IRC-assessed PFS per RECIST 1.1 in
the patient population under study.

To evaluate the efficacy of cabozantinib measured by IRC-assessed ORR per RECIST 1.1 in
the patient population under study.

To evaluate the efficacy of cabozantinib measured by IRC-assessed disease control rate
(DCR) per RECIST 1.1 in the patient population under study.

To evaluate the efficacy of cabozantinib measured by OS in the patient population under
study.
5.1.3
Safety Objective
The safety objective is:

To evaluate the safety of cabozantinib in the patient population under study.
5.1.4
Additional Objectives
The additional objectives are:

To evaluate the efficacy of cabozantinib measured by investigator-assessed PFS, ORR, and
DCR per RECIST 1.1 in the patient population under study.

To characterize the plasma PK of cabozantinib in the patient population under study.

To assess health-related quality of life (HRQOL) by the EuroQol Health questionnaire
instrument (EQ-5D-5L) in the patient population under study.

To explore candidate biomarkers predictive of response to cabozantinib.

To explore possible candidate biomarkers predictive of safety of treatment with cabozantinib.
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5.2
Endpoints
5.2.1
Primary Endpoint
The primary endpoint is:

24-week PFSR, per RECIST 1.1, by IRC.
5.2.2
Secondary Endpoints
The secondary endpoints are:

PFS, per RECIST 1.1, by IRC.

ORR, per RECIST 1.1, by IRC.

DCR, per RECIST 1.1, by IRC.

OS
5.2.3
Safety Endpoints
The safety endpoints are:

Treatment-emergent adverse events (TEAEs).

Grade 3 or higher TEAEs.

Serious TEAEs.

Permanent discontinuation by TEAEs.

Dose modification (dose reduction or interruption) by TEAEs.

Clinically significant abnormal laboratory values.

Clinically significant abnormal vital sign measurements.
5.2.4
Additional Endpoints
The additional endpoints are:

PFS, per RECIST 1.1, by investigator.

ORR, per RECIST 1.1, by investigator.

DCR, per RECIST 1.1, by investigator.

Plasma concentrations of cabozantinib.

HRQOL assessed by the EQ-5D-5L.

Efficacy biomarker(s).
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–
Candidate biomarkers that may include, but are not limited to, plasma biomarkers
associated with study treatment and/or clinical outcome.

Possible safety biomarker(s).
–
Association of genetic polymorphisms in genes encoding drug-metabolizing enzymes
and/or transporters with study treatment and/or clinical outcome.
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6.0 
STUDY DESIGN
6.1 
Overview of Study Design
This is a phase 2, open-label, single-arm study to evaluate the efficacy—as measured by 24-week 
PFSR and other efficacy variables including PFS, ORR, DCR, and OS—and safety of 
cabozantinib in Japanese patients with advanced HCC who have received prior systemic 
anticancer therapy (Cohort A: patients who have received prior sorafenib, Cohort B: patients who 
have not received prior sorafenib).
Screening Period
Potential subjects will be screened to determine if they meet the required eligibility criteria after 
informed consent. Qualifying screening assessments must be performed within 28 days before the 
first day of study drug administration (defined as Week 1 Day 1) unless otherwise specified.
Treatment Period
Subjects who meet all study eligibility criteria will receive cabozantinib 60 mg orally, QD in the 
fasted state (dose at least 2 hours after meal, and no more food intake for 1 hour postdose), 
preferably at bedtime. A subject is considered to be enrolled in the study when the first dose of 
study drug will be administered.
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, or until there are any other 
reasons for treatment discontinuation listed in the protocol (see Section 9.7). Treatment may 
continue after radiographic HCC progression per RECIST 1.1 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 risks. However the subject should discontinue 
study treatment after the second determination of disease progression.
Posttreatment Period
A 30-day posttreatment followup visit for safety will occur 30 (+14) days after the last dose of 
study drug or until the start of subsequent systemic anticancer treatment, whichever occurs first. 
Radiographic tumor assessments, Child-Pugh assessments, alpha-fetoprotein (AFP) assessments, 
and HRQOL assessments will continue, regardless of whether study treatment is given, reduced, 
held or discontinued until the day of the last tumor imaging assessment (See Appendix A
[Schedule of Events]). Subjects will be contacted every 8 weeks (±7 days) after the 30-day 
posttreatment followup visit to assess survival status and document receipt of subsequent 
anticancer therapy. Subjects will be followed until death, withdrawal of consent, or the sponsor 
decision to discontinue collection of these data in the study.
Major assessments of the study are described below.
Radiographic Tumor Assessment
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Subjects will be monitored for radiographic response and progression per RECIST 1.1. Response 
and progression will be assessed by the IRC and by the investigator. Tumor assessments should 
continue on the protocol-defined schedule regardless of whether study treatment is given, reduced, 
held or discontinued. The duration of radiographic tumor assessments for individual subjects is 
described in Section 9.4.15. The same imaging modalities used at Screening will be used for 
subsequent tumor assessments after enrollment.
Chest/Abdomen/Pelvis: Computerized tomography (CT) (or magnetic resonance imaging 
[MRI]) of chest/abdomen/pelvis (CAP) will be performed in all subjects at Screening. These 
assessments will be performed on Week 9 Day 1 and every 8 weeks (±7 days) thereafter. If MRI of 
the CAP study is performed at Screening, then a noncontrast CT of the chest should be performed 
as well.
Brain: MRI (or CT) of the brain will be performed in all subjects at Screening. After Week 1 Day 
1, MRI (or CT) scans of the brain are required only in subjects with known brain metastasis. 
Assessments will be performed on Week 9 Day 1 and every 8 weeks (±7 days) thereafter. If CT of 
the brain is performed instead of MRI, ambiguous results must be confirmed by MRI. (Note: In 
order to meet the eligibility requirements of the study, brain metastasis must have been treated and 
stable for at least 3 months before enrollment. Subjects without documented brain metastasis 
during the screening assessment are not required to undergo postenrollment brain imaging unless 
clinically indicated.)
Bone: Whole body technetium bone scans (TBS) will be performed in all subjects at Screening. 
After Week 1 Day 1, bone scans will be performed only in subjects with known bone metastasis on 
Week 9 Day 1, Week 17 Day 1, and every 16 weeks (±7 days) thereafter until last CT/MRI scan. 
(Note: Subjects without documented bone metastasis during the screening assessment are not 
required to undergo postenrollment bone scan imaging unless clinically indicated.) Lesions 
identified on bone scan are not to be recorded as target, nontarget, or new lesions. Bone scans are 
to be used to direct corroborative imaging with CT/MRI if necessary (these CT/MRI findings will 
be used for RECIST 1.1 evaluation). Bone scan findings alone cannot be used for the 
determination of progression per RECIST 1.1.
Tumor Marker Assessment
A blood sample for AFP will be obtained at the time of each radiographic tumor assessment visit 
according to the schedule in Appendix A. These assessment will continue regardless of whether 
study treatment is given, reduced, held or discontinued until last tumor assessment.
Safety Assessments
Safety will be assessed on Week 1 Day 1 and at minimum every 2 weeks up to Week 9 Day 1, and 
every 4 weeks thereafter. A 30-day posttreatment followup visit will be performed at least 30 days 
(+14 days) after the last dose of study drug, and subjects will report and will be queried on, AEs 
experienced through the 30 days. Routine safety evaluations will include physical examination, 
vital signs, Eastern Cooperative Oncology Group (ECOG) PS, 12-lead electrocardiogram (ECG), 
echocardiogram, hematology, serum chemistries, coagulation tests, urine tests (including urine 
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protein-to-creatinine ratio [UPCR]), serum or urine pregnancy tests (in females of childbearing 
potential), and thyroid function tests.
AE seriousness, severity grade, and relationship to study treatment will be assessed by the 
investigator. Severity grade will be defined by the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.03.
HRQOL Assessments
Subjects will complete the HRQOL assessments (the EQ-5D-5L questionnaire) on Week 1 Day 1 
prior to dosing. After Week 1 Day 1, the HRQOL assessments will be collected every 4 weeks (±2 
days) up to Week 9 Day 1, and every 4 weeks (±7 days) thereafter through 6 months on study. 
Upon completion of 6 months on study, the HRQOL assessments will be collected every 8 weeks 
(±7 days) thereafter until last tumor assessment. The HRQOL questionnaires should be completed 
by the patient before any other study procedures are performed or study drug is administered on 
scheduled visits. These assessments are to be conducted regardless of whether study treatment is 
given, reduced, held or discontinued until the day of the last tumor imaging assessment as 
described in Section 9.4.15. Consequently these assessments may be required in the Posttreatment 
period for some subjects.
Child-Pugh Assessments
The Child-Pugh assessments should be performed in all subjects at Screening. Assessments will be 
performed on Week 1 Day 1, Week 9 Day 1, and every 8 weeks (±7 days) thereafter. These 
assessments will continue regardless of whether study treatment is given, reduced, held, or 
discontinued until last tumor assessment. Determination of severity of ascites and encephalopathy 
will be made by clinical assessment.
PK Assessments
PK blood samples will be obtained from all subjects on Week 1 Day 1, Week 3 Day 1, Week 5 Day 
1, and Week 9 Day 1. The plasma concentration of cabozantinib will be measured, and the results 
will be used to confirm exposure to cabozantinib. The PopPK may be further characterized in this 
population. Collection of PK samples may be halted early or sampling frequency may be reduced 
at the discretion of the sponsor.
Pharmacogenomic Assessments
A pharmacogenomic blood sample will be collected from all subjects predose on Week 1 Day 1 for 
single nucleotide polymorphism variation analysis by DMETTM Plus Array to investigate the 
contribution of genetic variance on PK, safety and tolerability to study treatment. Unless failure to 
grant informed consent for this purpose, or sponsor decision, additional pharmacogenomic 
analyses (eg, the contribution of genetic variance on drug response) may be conducted in the 
future.
Biomarker Assessments
Assessment of biomarkers in plasma (protein expression in signal pathway, metabolic signature, 
etc) will be performed. Samples for these studies will be obtained on Week 1 Day 1, Week 3 Day 
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1, Week 5 Day 1, and Week 9 Day 1. After Week 9 Day 1, samples for signaling protein 
expression profile assessment will be obtained every 8 weeks (±5 days) through Week 25 Day 1.
Serum bone biomarkers (bone specific alkaline phosphatase [ALP]) will be also assessed. Samples 
for these studies will be obtained from all subjects on Week 1 Day 1, Week 3 Day 1, Week 5 Day 
1, and Week 9 Day 1.
Collection of biomarker samples may be halted early or sampling frequency may be modified at 
the discretion of the sponsor.
A schedule of assessments is listed in Appendix A.
6.2
Number of Subjects
Approximately 32 subjects will be enrolled in this study from approximately 18 study sites in 
Japan.

Cohort A (subjects who have received prior sorafenib): at least 17 subjects.

Cohort B (subjects who have not received prior sorafenib): approximately 15 subjects.
A patient is considered to be enrolled in the study when the first dose of study drug has been 
administered.
6.3 
Duration of Study
6.3.1 Duration of an Individual Patient’s Study Participation
Treatment may continue after radiographic HCC progression per RECIST 1.1 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 risks. However the subject 
should discontinue study treatment after the second determination of disease progression.
A 30-day posttreatment followup visit for safety will occur 30 (+14) days after the last dose of 
study drug or until the start of subsequent systemic anticancer treatment, whichever occurs first. 
Radiographic tumor assessments, Child-Pugh assessments, AFP assessments, and HRQOL 
assessments will continue regardless of whether study treatment is given, reduced, held or 
discontinued until the day of the last tumor imaging assessment. Subjects will be contacted every 8 
weeks (±7 days) after the 30-day posttreatment followup visit to assess survival status and 
document receipt of subsequent anticancer therapy. Subject will be followed until death, 
withdrawal of consent, or the sponsor decision to discontinue collection of these data in the study.
6.3.2 End of Study/Study Completion Definition and Planned Reporting
Primary Completion
The primary analysis for the efficacy and safety endpoints and authoring of a clinical study report 
(CSR) may be conducted after all patients enrolled in the study have had the opportunity to 
complete 24 weeks of treatment with study drug and assessments at Week 25 Day 1.
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Other Planned Analyses
A CSR efficacy and safety addendum is planned at study completion.
Study Completion
The estimated time frame for study completion is approximately 3 years. The study will end at the 
time of commercial cabozantinib placing on the market for this study indication in Japan at the 
latest.
6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures
Refer to Table 6.a for disclosures information for all primary and secondary endpoints.
Table 6.a
Primary and Secondary Endpoints for Disclosures
Endpoint
Definition
Maximum Time Frame (a)
Primary:
24-week PFSR, per RECIST 1.1, 
by IRC
The PFS proportion as assessed by the 
IRC per RECIST 1.1 at Study Day of 
Week 25 Day 1 + 7 days. 
Up to approximately 2 years after 
enrollment of the last subject.
Secondary:
ORR, per RECIST 1.1, by IRC
The proportion of subjects in the FAS 
whose best overall response is CR or PR, 
as assessed by the IRC per RECIST 1.1, 
which is confirmed by a subsequent 
evaluation conducted ≥28 days later.
Up to approximately 2 years after 
enrollment of the last subject.
PFS, per RECIST 1.1, by IRC
The time from the first day of study drug 
administration to the earlier of PD, as 
assessed by the IRC per RECIST 1.1 or 
death due to any cause.
Up to approximately 2 years after 
enrollment of the last subject.
DCR, per RECIST 1.1, by IRC
The proportion of subjects in the FAS 
whose best overall response is CR, PR or 
SD, as assessed by the IRC per RECIST 
1.1. CR and PR require confirmation by a 
subsequent evaluation conducted ≥28 
days later, and SD have to be maintained 
for at least 8 weeks (51 days) after the 
first day of study drug administration.
Up to approximately 2 years after 
enrollment of the last subject.
OS
The time from the first day of study drug 
administration to death due to any cause. 
Up to approximately 2 years after 
enrollment of the last subject.
CR=complete response, DCR=disease control rate, FAS=full analysis set, IRC=independent radiology committee, 
ORR=objective response rate, OS=overall survival, PD= progressive disease, PFS=progression-free survival, 
PFSR=progression-free survival rate, PR=partial response, RECIST=Response Evaluation Criteria In Solid Tumors, 
SD=stable disease.
(a) Time to last assessment for that endpoint for an individual patient.
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6.3.4
Total Study Duration
It is anticipated that this study will last for approximately 3 years.
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7.0
STUDY POPULATION
7.1
Inclusion Criteria
Each patient must meet all of the following inclusion criteria to be enrolled in the study:
1. Male or female Japanese patients 20 years of age or older on the day of consent.
2. Histological or cytological diagnosis of HCC (results of a previous biopsy will be accepted).
3. Measurable disease per RECIST 1.1 as determined by the investigator.
4. Patients who have disease that is not amenable to a curative treatment approach (eg, transplant,
surgery, radiofrequency ablation).
5. Patients who have received 1 or 2 prior anticancer therapies for advanced HCC.
–
Cohort A: patients who have received prior sorafenib.
–
Cohort B: patients who have not received prior sorafenib.
Note: Additional prior systemic therapies used as adjuvant or local therapy are allowed.
6. Radiographic progression following prior systemic anticancer therapy for advanced HCC.
7. Recovery to ≤Grade 1 CTCAE Version 4.03 from toxicities related to any prior treatments,
unless the AEs are clinically nonsignificant and/or stable on supportive therapy.
8. ECOG PS of 0 or 1, and life expectancy of at least 3 months.
9. Child-Pugh Score of A.
10. Adequate organ and marrow function at Screening (within 10 days before Week 1 Day 1) :
a)
Absolute neutrophil count (ANC) ≥1,200/mm3.
b)
Platelets ≥60,000/mm3.
c)
Hemoglobin ≥8 g/dL.
d)
Serum creatinine ≤1.5 × upper limit of normal (ULN) or calculated creatinine clearance
≥40 mL/min using the Cockroft-Gault equation (see Appendix H).
e)
UPCR ≤1 mg/mg Cr.
f)
Total bilirubin ≤2 mg/dL.
g)
Serum albumin ≥2.8 g/dL.
h)
ALT and AST ≤5.0 × ULN.
i)
Hemoglobin A1c (HbA1c) ≤8% (if HbA1c results are unavailable [eg, hemoglobin
variant], a fasting serum glucose ≤160 mg/dL).
11. Antiviral therapy per local standard of care if active hepatitis B virus (HBV) infection.
12. Female patients who:
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a)
Are postmenopausal (natural amenorrhea, not due to other medical reasons) for at least 1
year before the Screening visit, OR
b)
Are surgically sterile, OR
c)
If they are of childbearing potential, agree to practice 1 highly effective method of birth
control with a condom, which is an effective barrier method of contraception, at the same
time, from the time of signing the informed consent through 4 months after the last dose
of study drug, OR
d)
Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle
of the patient, from the time of signing the informed consent through 4 months after the
last dose of study drug. (Periodic abstinence [eg, calendar, ovulation, symptothermal,
postovulation methods], condoms only, withdrawal, spermicides only, and lactational
amenorrhea are not acceptable methods of contraception.)
Male patients, even if surgically sterilized (ie, status postvasectomy), who:
e)
Agree to practice effective barrier contraception during the entire study treatment period
and through 4 months after the last dose of study drug. If their partner are of childbearing
potential, their female partner should use 1 highly effective method of birth control at the
same time, OR
f)
Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle
of the patient, from the time of signing the informed consent through 4 months after the
last dose of study drug. (Periodic abstinence [eg, calendar, ovulation, symptothermal,
postovulation methods for the female partner], condoms only, withdrawal, spermicides
only, and lactational amenorrhea are not acceptable methods of contraception.)
13. Voluntary written consent must be given before performance of any study-related procedure
not part of standard medical care, with the understanding that consent may be withdrawn by
the patient at any time without prejudice to future medical care.
14. Patient is willing and able to adhere to the study visit schedule and other protocol
requirements.
7.2
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
1. Fibrolamellar carcinoma or mixed hepatocellular cholangiocarcinoma.
2. Any type of anticancer agent within 14 days before the first day of study drug administration
(Week 1 Day 1).
3. Radiation therapy within 28 days (14 days for radiation for bone metastases) or radionuclide
treatment  (eg, I-131 or Y-90) within 42 days before Week 1 Day 1 (patient is excluded if there
are any clinically relevant ongoing complications from prior radiation therapy).
4. Prior cabozantinib treatment.
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5. Treatment with any investigational products (excluding anticancer products approved in
Japan) within 28 days before Week 1 Day 1.
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
Week 1 Day 1. Eligible patients must be without corticosteroid treatment at Week 1 Day 1.
7. Concomitant anticoagulation, with oral anticoagulants (eg, warfarin, direct thrombin and
Factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel).
Note: Low-dose aspirin for prophylactic use (per local applicable guidelines) and low-dose,
low molecular weight heparins (LMWH) are permitted (LMWH has not been approved for the
use for cardioprotection in Japan). Anticoagulation with therapeutic doses of LMWH is
allowed in patients without radiographic evidence of brain metastasis, who are on a stable dose
of LMWH for at least 12 weeks before Week 1 Day 1, and who have had no complications
from a thromboembolic event or the anticoagulation regimen.
8. Patients who have 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 blood pressure (BP) >150 mm Hg
systolic, or >100 mm Hg diastolic despite optimal antihypertensive treatment.
iii. Stroke (including transient ischemic attack [TIA]), myocardial infarction, or other
ischemic event within 6 months before Week 1 Day 1.
iv. Thromboembolic event within 3 months before Week 1 Day 1.
v.
A left-ventricular ejection fraction ≤50%.
b)
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 Week 1 Day 1.
Note: Complete healing of an intra-abdominal abscess must be confirmed prior to 
Week 1 Day 1.
c)
Major surgery within 2 months before Week 1 Day 1. Complete healing from major
surgery must have occurred 1 month before Week 1 Day 1. Complete healing from minor
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surgery (eg, simple excision, tooth extraction) must have occurred at least 7 days before 
Week 1 Day 1. Patients 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. Patients with invasion or thromboses of portal/hepatic
vasculature attributed to underlying liver disease and/or liver tumor are eligible.
f)
Clinically significant bleeding risk including the following within 3 months before Week
1 Day 1: 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.
ii.
Known infection with human immunodeficiency virus, or known acquired
immunodeficiency syndrome -related illness.
iii. Active hepatitis B and/or C. Patients with active hepatitis virus infection controlled
with antiviral therapy are eligible.
iv. Serious non-healing wound/ulcer/bone fracture.
v.
Malabsorption syndrome.
vi. Uncompensated/symptomatic hypothyroidism.
vii. Requirement for hemodialysis or peritoneal dialysis.
viii. History of solid organ transplantation.
9. Patients with untreated or incompletely treated varices with bleeding or high risk for bleeding.
Patients 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 before Week 1 Day 1 are eligible.
10. Moderate or severe ascites.
11. Corrected QT interval calculated by the Fridericia formula (QTcF) >500 msec within 14 days
before Week 1 Day 1.
Note: If the QTcF is >500 msec in first ECG, a total of 3 ECGs each separated by at least 3
minutes should be performed within 30 minutes. If the average of these 3 consecutive results
for QTcF is ≤500 msec, the patient meets eligibility in this regard.
12. Inability to swallow tablets.
13. Previously identified allergy or hypersensitivity to components of the study treatment
formulations.
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14. Female patients who are lactating and breastfeeding or have a positive serum pregnancy test
during the Screening period.
Note: Female patients who are in the lactation period, even if they discontinue breastfeeding,
will be excluded from the study.
15. Previously diagnosed with another malignancy and have any evidence of residual disease
within 2 years before Week 1 Day 1.
Note: Patients with superficial skin cancers, or localized, low-grade tumors deemed cured and
not treated with systemic therapy are not excluded.
16. Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially
interfere with the completion of treatment according to this protocol.
17. Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of
cabozantinib.
18. Use of strong CYP3A4 inhibitors and CYP3A4 inducers within 14 days before Week 1 Day 1.
19. Admission or evidence of illicit drug use, drug abuse, or alcohol abuse.
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8.0 
STUDY DRUG
8.1 
Study Drug Administration
All protocol-specific criteria for administration of study drug must be met and recorded prior to 
drug administration. Study drug will be administered only to eligible patients under the 
supervision of the investigator or identified subinvestigator(s).
Subjects will take the cabozantinib tablet(s) orally, QD in the fasted state (dose at least 2 hours 
after meal, and no more food intake for 1 hour postdose), preferably at bedtime.
The assigned dose is 60 mg (60 mg tablet×1) cabozantinib given QD. A dose of 60 mg should be 
maintained in the absence of treatment-emergent toxicity.
8.1.1 Cabozantinib Administration on Week 1 Day 1
On Week 1 Day 1, cabozantinib will be administered in the clinic to enable a predose blood sample 
to be taken for PK evaluation. Subjects should be fasted (with the exception of water) for at least 2 
hours before receiving cabozantinib. 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 receive the 60 mg oral dose of cabozantinib with a full glass of water in the 
clinic and then continue to fast for 1 hour while under observation to monitor for potential AEs.
8.1.2 Subsequent Dose Administration of Cabozantinib
After Week 1 Day 1, cabozantinib will be self-administered at home by taking cabozantinib QD at 
the same time each day. Any unused study drug must be returned to the study site for drug 
accountability and disposal. Subjects should fast (with the exception of water) for at least 2 hours 
after eating the evening meal before taking their doses of cabozantinib. After the 2 hour fast and 
before going to bed, subjects are to take cabozantinib with a full glass of water with no more food 
intake for 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. The subject should 
take cabozantinib at approximately the same time every day and should adhere to the fasting 
requirements described in this section. On Week 3 Day 1, Week 5 Day 1, and Week 9 Day 1, 
subjects should be instructed to visit the clinic without taking cabozantinib because PK sample 
should be collected approximately 8 or more hours after the previous dose of study drug.
Subjects should be instructed not to make up vomited doses and to maintain the planned dosing 
schedule. Subjects should not make up for missed doses if more than 12 hours have elapsed after 
the time the subject would usually take cabozantinib. In the event of missed doses, subjects should 
not take 2 doses to make up for the 1 missed.
Subjects will receive 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 treatment or liver directed local anticancer therapy, or until any other reasons for 
treatment discontinuation listed in the protocol (see Section 9.7).
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8.2
Dose Modification Guidelines
8.2.1
Dose Reductions, Interruptions and Discontinuation
Subjects will be monitored for AEs from the time of signing informed consent through 30 days 
after the last dose of study drug. Subjects will be instructed to notify the investigator immediately 
of any occurring AE. Causality assessment of AEs should include at minimum confounding 
factors such as disease and concomitant medications. AE severity will be graded by the 
investigator according to CTCAE Version 4.03. Local laboratory assessments should be obtained 
and used for dose modification consideration (reductions or interruption) of cabozantinib at the 
study visit. The following parameters must be included in local laboratory assessment for dose 
modification: WBC count with differential and platelets , ALP, ALT, AST, and total bilirubin.
The following should be taken into consideration in decisions regarding dose modifications:

As a general approach, all AEs should be managed with supportive care at the earliest signs of
toxicity considered related to cabozantinib treatment. Should this be ineffective, dose
reductions or interruptions should be considered to prevent worsening of toxicity.

Dose modification criteria for cabozantinib are shown in Table 8.b. Dose reductions and/or
interruptions should be implemented for unacceptable toxicity. Doses may be modified at any
time while on study.

The assigned dose for cabozantinib is 60 mg/day. Two dose reduction levels of cabozantinib
are permitted (Table 8.a).

Dose reductions or interruptions may also occur in the setting of lower-grade toxicity than
defined in Table 8.b if the investigator feels it is in the interest of a subject’s safety and will
optimize drug tolerability.

Interruption of cabozantinib treatment for AEs may occur at any time per investigator
discretion. If treatment is interrupted due to AEs for more than 6 weeks, cabozantinib should
be discontinued.

Following cases require sponsor approval;

Keeping same level of dose despite the toxicity meet the status in the modification
guideline that require dose reduction or interruption.

Dose re-escalation or dose reinstitution at the same level after dose interruption due to the
toxicity.

Dose interruptions for reason(s) other than AEs (eg, surgical procedures) for more than
6 weeks. The acceptable length of interruption will depend on agreement between
investigator and the sponsor.
Guidelines for the management of specific AEs such as GI disorders, hepatobiliary disorders, 
hematological disorders, constitutional disorders, skin disorders, hypertension, thromboembolic 
events, proteinuria, QTc prolongation, hypophosphatemia, thyroid function disorders, 
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hemorrhagic events, GI perforation/fistula and non-GI fistula formation, osteonecrosis of the jaw, 
and reversible posterior leukoencephalopathy syndrome (RPLS) are provided in Section 8.6.
Table 8.a
Dose Reductions of Cabozantinib
Assigned Dose
First Dose-Level Reduction
Second Dose-Level Reduction
60 mg cabozantinib oral QD
(60 mg tablet×1)
40 mg cabozantinib oral QD
(20 mg tablet×2)
20 mg cabozantinib oral QD
(20 mg tablet×1)
QD=once daily.
Cabozantinib should be discontinued if a QD dose of 20 mg cabozantinib (minimum dose) is not tolerated.
Table 8.b
Dose Modifications of Cabozantinib for Treatment Related AEs
CTCAE Version 4.03 Grade
Recommended Guidelines for Managements (a)
Grade 1 AEs
Add supportive care as indicated. Continue cabozantinib treatment 
at the current dose level if AE is manageable and tolerable.
Grade 2 AEs which are tolerable and are easily 
managed
Grade 2 AEs which are intolerable and cannot 
be adequately managed
Continue cabozantinib treatment at the current dose level with 
supportive care.
At the discretion of the investigator, cabozantinib should be 
dose-reduced or interrupted.
Note: It is recommended that dose holds be as brief as possible.
Grade 3 AEs (except clinically nonrelevant 
laboratory abnormalities)
Cabozantinib should be interrupted unless the toxicity can be 
easily managed with a dose reduction and optimal medical care.
Note: It is recommended that dose holds be as brief as possible.
Grade 4 AEs (except clinically nonrelevant 
laboratory abnormalities)
Subjects should have cabozantinib interrupted immediately.
Discontinue cabozantinib 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 reduction 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 8.6. For 
retreatment criteria of study treatment after a dose hold, see Section 8.2.2.
(a) Study treatment dose adjustment is only needed if the toxicity was deemed related to cabozantinib treatment or
had an unclear relationship to cabozantinib treatment.
8.2.2 Dose Reinstitution and Re-escalation
If the subject recovers from his or her toxicities to CTCAE Version 4.03 Grade ≤1, to the baseline 
value, or to within normal range, and the toxicity was unrelated to study treatment, then study 
treatment may be restarted with no change in dose.
If the subject recovers from his or her toxicities to Grade 1, to the baseline value, or to within 
normal range, and the toxicity was deemed possibly related to study treatment, then study 
treatment may be restarted at a reduced dose (see Table 8.a for the schedule of dose reductions).
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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 should 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 for AEs which have resolved or 
recovered to Grade 1 (or baseline value) and deemed tolerable and easily managed by optimized 
supportive treatment. Dose re-escalation is not allowed for a drug-related dose reduction triggered 
by Grade 4 hematologic toxicities or by Grade 4 AEs affecting major organs (eg, central nervous 
system [CNS], cardiac, hepatic, renal).
8.3
Excluded Concomitant Medications and Procedures
The following medications and procedures are prohibited until study treatment has been 
permanently discontinued:

Any investigational agent or investigational medical device.

Oral anticoagulants (eg, coumarin-related agents or other direct thrombin or direct FXa
inhibitors, or antiplatelet agents such as clopidogrel, or chronic use of aspirin above low dose
levels for prophylactic use per local applicable guidelines).

Any nonprotocol systemic anticancer treatment (eg, chemotherapy, immunotherapy,
radionuclides, drugs or herbal products used specifically for the treatment of HCC).

Any liver-directed local anticancer 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).

interferon treatment
The following medications and procedures should be avoided until study treatment has been 
permanently discontinued or until the investigator discusses with the sponsor and receives sponsor 
approval:

Palliative external radiation to bone metastasis or skin/subcutaneous metastasis should not be
performed unless clinically unavoidable. If clinically unavoidable the investigator must seek
sponsor approval prior to the procedure. Subjects who have such an intervention may be
considered not evaluable (and may be assigned a censoring or progression date) 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 [38].
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
Concomitant medications that are known to prolong the QTc interval should be avoided in
subjects who receive cabozantinib until they have permanently discontinued cabozantinib
treatment.

Chronic co-administration of cabozantinib with strong inducers of the CYP3A4 family
(eg, phenytoin, carbamazepine, rifampicin, rifabutin, phenobarbital, and St. John’s wort)
should be avoided. Selection of alternate concomitant medications with no or minimal
CYP3A4 enzyme induction potential is recommended. Caution must be used when
discontinuing treatment with a strong CYP3A4 inducer in a subject for enrollment of this
study.

Co-administration of cabozantinib with strong inhibitors of the CYP3A4 family
(eg, boceprevir, conivaptan, posaconazole, ketoconazole, itraconazole, clarithromycin,
indinavir, nefazodone, nelfinavir, saquinavir, ritonavir, telaprevir and voriconazole) should be
avoided. Grapefruit and Seville oranges with inhibitory effect on CYP3A4 family should be
avoided.
Refer to Appendix I for a nonexhaustive list of medications, supplements, and food products
that are strong inhibitors or inducers of the CYP3A4 family based on the final draft of
Ministry of Health, Labour and Welfare (MHLW) DDI Guidance.
8.4
Permitted Concomitant Medications and Procedures

Antiemetics and antidiarrheal medications are allowed prophylactically according to standard
clinical practice if clinically indicated.

Granulocyte colony-stimulating factors (granulocyte colony-stimulating factor [G-CSF] or
granulocyte-macrophage colony-stimulating factor) are allowed while the subject is enrolled
in the study. However, these should not be administered prophylactically before initial
treatment with study drug.

Drugs used to control bone loss (eg, bisphosphonates and denosumab) can be continued if
started before Week 1 Day 1 and the benefit outweighs the risk per the investigator’s
discretion. (Note: Osteonecrosis of the jaw has been reported in subjects using
bisphosphonates and denosumab. Oral examinations are recommended before Week 1 Day 1
to determine eligibility and periodically during the study. In addition, subjects should be
advised regarding oral hygiene practice and to report symptoms quickly to the investigator.
Frequent monitoring for potentially overlapping toxicities with study treatment is
recommended.)

Transfusion should be used in accordance with institutional guidelines.

Hormone replacement, and short-term steroid treatment (above the physiologic replacement
dose) may be utilized as indicated by standard clinical practice.

Individualized anticoagulation therapy with heparin is allowed if it can be provided safely and
effectively under the following circumstances:
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–
Low-dose heparins for prophylactic use are allowed if clinically indicated and the benefit
outweighs the risk per the investigator’s discretion.
–
Therapeutic doses of LMWH at the time of Week 1 Day 1 are allowed if the subject has no
evidence of brain metastasis, has been on a stable dose of LMWH for at least 12 weeks, and
has had no complications from a thromboembolic event or the anticoagulation regimen.
(Note: LMWH has not been approved for the use for cardioprotection in Japan.)
–
Therapeutic doses of LMWH after Week 1 Day 1 are allowed if clinically indicated (eg, for
the treatment of deep vein/venous thrombosis [DVT]), and the benefit outweighs the risk
per the investigator’s discretion. For management of thromboembolic complications while
on study, refer to Section 8.6.7.
–
Accepted clinical guidelines regarding appropriate management while receiving
anticoagulation therapy with heparins must be followed. This includes, but is not limited to,
subject education regarding potential adverse drug reactions, monitoring laboratory
parameters, dose adjustments (eg, due to kidney dysfunction).
–
For restrictions on oral anticoagulants, see Section 8.3.
Potential drug interactions with cabozantinib are summarized in Section 4.1.5.
8.5
Precautions and Restrictions
8.5.1
Pregnancy and Contraception
It is not known what effects cabozantinib has on human pregnancy or development of the embryo 
or fetus. Therefore, female patients participating in this study should avoid becoming pregnant, 
and male patients should avoid impregnating a female partner. Nonsterilized female patients of 
reproductive age group and male patients should use effective methods of contraception through 
defined periods during and after study treatment as specified below.
Female subjects must meet 1 of the following:

Postmenopausal (natural amenorrhea, not due to other medical reasons) for at least 1 year
before the Screening visit, OR

Surgically sterile, OR

If they are of childbearing potential, agree to practice 1 highly effective method of birth
control (see examples below) with a condom, which is an effective barrier method of
contraception, at the same time, from the time of signing the informed consent form (ICF)
through 4 months after the last dose of study drug, OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of
the subject, from the time of signing the informed consent through 4 months after the last dose
of study drug. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation
methods], condoms only, withdrawal, spermicides only, and lactational amenorrhea are not
acceptable methods of contraception.)
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Male subjects, even if surgically sterilized (ie, status postvasectomy) must agree to 1 of the 
following:

Agree to practice effective barrier contraception during the entire study treatment period and
through 4 months after the last dose of study drug. If their partner are of childbearing potential,
their female partner should use 1 highly effective method of birth control (see examples
below) at the same time, OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of
the subject, from the time of signing the informed consent through 4 months after the last dose
of study drug. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation
methods for the female partner], condoms only, withdrawal, spermicides only, and lactational
amenorrhea are not acceptable methods of contraception.)
Women of childbearing potential is defined as any sexually active female subjects who meet both 
of the following criteria:

Those who have not undergone hysterectomy or bilateral oophorectomy, AND

Those who have not had natural menopause for 12 consecutive months or longer.
Note: A postmenopausal state is defined as no menses for 12 months without an alternative
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range
may be used to confirm a postmenopausal state in women not using hormonal contraception or
hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a single
FSH measurement is insufficient.
Examples of highly effective contraception methods are listed below:

Hormonal birth control pills.

Intrauterine device.

Intrauterine hormone-releasing system.
8.6 
Management of Clinical Events
If dose alterations are necessary as a result of the events detailed below, refer to Section 8.2.
8.6.1 GI Disorders
The most common GI AEs reported in clinical studies with cabozantinib are diarrhea, oral pain, 
dyspepsia, stomatitis, and dysphagia.
8.6.1.1 Diarrhea
Subjects should be instructed to notify their physicians immediately at the first signs of poorly 
formed or loose stool or an increased frequency of bowel movements. Guidelines for the 
evaluation and management of diarrhea are shown in Table 8.c.
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Administration of antidiarrheal/antimotility agents is recommended as initial management at the 
first sign of diarrhea. 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 8.a. 
When the diarrhea is controlled, retreatment with study treatment may be acceptable per 
investigator decision.
In addition, general supportive measures should be implemented including continuous oral 
isotonic hydration, correction of fluid and electrolyte abnormalities, small frequent meals, and 
stopping lactose-containing products, high-fat meals, and alcohol.
Recurrent or prolonged diarrhea can be associated with anal or perianal skin erosions which 
increase the risk for anal abscesses, fistulas, or proctitis. Good personal hygiene should be 
emphasized. Regular examinations of the perianal region should be performed whenever diarrhea 
has occurred during treatment with cabozantinib. Infections of the perianal region should be 
treated per local guidelines.
Table 8.c
Management of Treatment-Emergent Diarrhea
Status
Management
Tolerable Grade 1-2 
(duration <48 hr)
Continue with study treatment and consider dose reduction
Initiate treatment with an antidiarrheal agent per institutional guidelines
Dietary modifications (eg, small lactose-free meals, bananas and rice)
Intake of isotonic fluids (1-1.5 L/day)
Re-assess after 24 hr:
– Diarrhea resolving to baseline bowel habits: gradually add solid foods and discontinue or
decrease antidiarrheal treatment after 12 hr diarrhea-free interval.
– Diarrhea not resolving: Continue/resume antidiarrheal treatment.
Intolerable Grade 2, 
Grade 2 >48 hr, 
or ≥Grade 3
Interrupt study treatment.
Ask subject to attend clinic.
Rule out infection (eg, stool sample for culture).
– Administer antibiotics as needed (eg, if fever or Grade 3-4 neutropenia persists >24 hr).
Administer fluids (1-1.5 L/day orally or intravenous [IV], as appropriate) for hydration or 
to correct electrolyte abnormalities.
For Grade 3-4 or complicated lower-grade diarrhea consider hospitalization and IV 
hydration.
Re-assess after 24 hr.
– Diarrhea resolving to baseline bowel habits or Grade ≤1: consider restarting study
treatment at reduced dose.
– Diarrhea not resolving:
– Start and or continue antidiarrheal treatment per Institutional Guidelines.
– Consider starting second line antidiarrheal or referral to gastroenterologist.
AE=adverse event.
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Note: The dose delay and modification criteria for specific medical conditions are provided in Section 8.6. For 
re-treatment criteria of study treatment after a dose hold see Section 8.2.2.
8.6.1.2 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. However, the 5-HT3 receptor antagonists are recommended over chronic use 
of NK-1 receptor antagonists (ie, aprepitant and fosaprepitant) and dexamethasone (NK-1 receptor 
antagonists can inhibit CYP3A4, and glucocorticoids induce CYP3A4 and thus might affect 
cabozantinib exposure) (see Section 8.3).
8.6.1.3 Stomatitis and Mucositis
Preventive measures may include a comprehensive oral examination to identify and treat any 
potential risk of complications before study treatment is initiated. Appropriate correction of local 
factors should be instituted as indicated, such as modification of ill-fitting dentures and 
appropriate care of gingivitis.
During treatment with cabozantinib, good oral hygiene and standard local treatments such as 
nontraumatic and nonirritating cleansing and oral rinses (eg, with a weak solution of salt and 
baking soda) should be maintained. Lips should be kept well moisturized using moisturizers which 
do not contain a large amount of artificial chemicals, preservatives, colors and perfumes. 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 cabozantinib should be considered.
8.6.2 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 × ULN at Week 1 Day 1 and who develops 
≥Grade 3 elevated ALT, AST, or total bilirubin should have study treatment interrupted and the 
dose reduced as outlined in Table 8.a and Table 8.b.
Subjects on this study may enter the study with elevations of AST/ALT up to 5.0 × ULN at 
screening. Elevations of aminotransferases when hepatic tumors are present may not require dose 
modifications if there are no progressive changes in the aminotransferases (less than 2 times value 
at Week 1 Day 1) and if there are no progressive elevations in serum total bilirubin concentration 
or coagulation factors. To predict severe hepatotoxicity, monitoring of prothrombin 
time-international normalized ratio (PT-INR) is useful. Cabozantinib treatment should be 
interrupted when transaminase increases are followed by or concurrent with progressive elevations 
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of total bilirubin, and/or elevations of coagulation tests (eg, PT-INR). More frequent monitoring 
(eg, at least weekly) of transaminases should be considered and study treatment should be held 
until the etiology of the abnormalities is clarified, until the laboratory test value return to the Week 
1 Day 1 value, 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 with at least weekly monitoring until acceptable and stable level of transaminase. 
Study treatment should be discontinued if hepatic dysfunction is not reversible despite temporary 
interruption of study treatment.
Elevations >3 × ULN of ALT or AST followed by or concurrent with >2 × ULN total bilirubin 
without other explanation can indicate DILI 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 [including reactivation of hepatitis virus] 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.
8.6.3 Hematological Disorders
Hematological toxicities (ie, neutropenia and thrombocytopenia) and associated complications 
have been observed after administration of cabozantinib and may be managed with dose 
interruptions and/or dose reductions. Use of G-CSF support for neutrophil recovery is allowed per 
investigator discretion and in accordance with accepted guidelines after the first incidence of 
clinically relevant cytopenia. Guidelines for the management of neutropenia and 
thrombocytopenia are shown in Table 8.d.
Complete blood counts with differentials and platelets should be performed regularly. 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 appropriately and in a timely manner according to institutional guidelines.
Dose reductions or dose interruptions for anemia are not mandated but can be applied as clinically 
indicated. Supportive care for thrombocytopenia or anemia, such as transfusions, may be managed 
according to institutional guidelines.
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Table 8.d
Management of Treatment-Emergent Neutropenia and Thrombocytopenia
Status
Action to be Taken
Grade 3 neutropenia with documented infection, 
Grade 3 neutropenia ≥5 days, 
Grade 4 neutropenia, or 
Febrile neutropenia
Interrupt cabozantinib treatment until toxicity resolves to 
≤Grade 1, then resume cabozantinib with 1 dose-level reduction.
Grade 3 thrombocytopenia with clinically 
significant bleeding, or 
Grade 4 thrombocytopenia
Interrupt cabozantinib treatment until toxicity resolves to 
≤Grade 1, then resume cabozantinib with 1 dose-level reduction.
8.6.4 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), poor nutrition, sleep 
disturbance, and hypothyroidism should be ruled out and/or causes should be 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, which is an inducer of CYP3A4, should be 
avoided because of its potential to reduce cabozantinib exposure; see IB.)
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 
physical examination and nutritional support. Pharmacologic therapy 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 cabozantinib may be re-escalated to the previous dose.
8.6.5 Skin Disorders
8.6.5.1 Palmar-planter erythrodysesthesia syndrome (PPES)
PPES (also known as hand-foot syndrome), skin rash (including blister, erythematous rash, 
macular rash, skin exfoliation, dermatitis acneiform, and papular rash), pruritus, dry skin, 
erythema, pigmentary changes and alopecia have been reported 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 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).
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Early signs of hand-foot 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. Analgesics may be required for pain 
control.
Aggressive management of symptoms is recommended, including early dermatology referral. 
Treatment guidelines for PPES are presented in Table 8.e.
In the case of skin changes (eg, rash, hand-foot syndrome), the investigator may request that 
additional assessments be conducted with the subject’s consent. These assessments may include 
digital photographs of the skin changes and/or a biopsy of the affected skin and may be repeated 
until the skin changes resolve.
Table 8.e
Management of Treatment-Emergent PPES
CTCAE Version 4.03 
Grade
Action to be Taken
1
Cabozantinib treatment may be continued at the current dose if PPES is clinically 
insignificant and tolerable. Otherwise, cabozantinib should be reduced to the next lower 
dose level. Start urea 20% cream twice daily AND high-potency steroid cream 
(eg, clobetasol 0.05% cream) QD. Re-assess at least weekly; if PPES worsens at any time 
or does not improve after 2 weeks, proceed to the intervention guidelines for Grade 2.
2
Cabozantinib treatment may be continued if PPES is tolerated. Cabozantinib should be 
dose-reduced or interrupted if PPES is intolerable. Continue urea 20% cream twice daily 
AND high-potency steroid cream QD and add analgesics (eg, NSAIDs/GABA agonists) 
for pain control if needed. Re-assess at least weekly; if PPES does not improve within 2 
weeks or worsens or affects self-care, proceed to the intervention guidelines for Grade 3.
3
Interrupt cabozantinib treatment until severity decreases to Grade 1 or 0. Continue 
treatment of skin reaction with high-potency steroid cream twice daily AND analgesics. 
Resume cabozantinib at reduced dose if PPES recovers to Grade 0 or 1. Discontinue 
subject from study treatment if intolerable PPES recurs after dose reduction or does not 
improve within 6 weeks.
CTCAE=Common Terminology Criteria for Adverse Events, GABA=gamma-aminobutyric acid, 
NSAID=non-steroidal anti-inflammatory drug, PPES=palmar-plantar erythrodysesthesia syndrome.
8.6.5.2 Wound Healing and Surgery
Cabozantinib has the potential to cause wound healing complications and wound dehiscence 
which may even occur long after a wound has been considered healed. Therefore, surgical and 
traumatic wounds must have completely healed prior to starting cabozantinib treatment and be 
monitored for wound dehiscence or wound infection and other signs of impaired wound healing 
while the subject is being treated with cabozantinib. If dehiscence occurs, cabozantinib treatment 
should not be restarted until complete healing has taken place.
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Treatment with cabozantinib should be stopped at least 28 days prior to scheduled surgery. Shorter 
treatment holds can be acceptable based on the investigator’s medical judgment in terms of the 
subject’s potential benefit/risk balance, but will require prior notification to the sponsor.
The decision to resume treatment with cabozantinib after the surgery should be based on clinical 
judgment of adequate wound healing.
8.6.6
Hypertension
Hypertension is a common class effect of drugs that inhibit VEGF pathways and has been reported 
in subjects treated with cabozantinib.
BP should be monitored in a constant position at each visit in a relaxed setting. Treatment 
guidelines for hypertension are presented in Table 8.f. 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 8.f
Management of Treatment-Emergent Hypertension
Criteria for Dose Modification
Action to be Taken
Subjects NOT receiving optimized antihypertensive therapy
>150 mm Hg (systolic) (a) and
<160 mm Hg
OR
>100 mm Hg (diastolic) (a) and
<110 mm Hg

Optimize antihypertensive treatment by adding new or additional 
antihypertensive medications and/or increase dose of existing 
medications.

Reduce cabozantinib treatment by 1 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 cabozantinib treatment by 1 dose level or interrupt 
cabozantinib treatment per investigator discretion.

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, cabozantinib treatment should be 
dose-reduced further or interrupted.

Cabozantinib treatment should be dose-interrupted if upper limits 
of systolic BP (≥160 mm Hg systolic) are sustained and not 
adequately manageable or if systolic BP is >180 mm Hg or 
diastolic BP is >110 mm Hg or if subject is symptomatic.

Restart cabozantinib treatment at the most tolerable dose and 
re-escalate cabozantinib dose only if BP falls to and is sustained at 
<150 mm Hg systolic and <100 mm Hg diastolic.
Hypertensive emergency (b) or 
hypertensive encephalopathy

Discontinue cabozantinib treatment.
BP=blood pressure.
(a) The investigator should consider whether to initiate or adjust antihypertensive treatment at a lower threshold than
systolic BP >150 mm Hg or diastolic BP >100 mm Hg based on his/her clinical judgment and assessment of the
individual subject.
(b) Hypertensive emergency is defined as uncontrolled elevated BP with clinical evidence of progressive or
impending end-organ damage (ie, myocardial infarction/ischemia, intracranial hemorrhage, cerebral ischemia,
pulmonary edema, encephalopathy, kidney damage).
8.6.7 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 IB). Subjects who develop a PE and/or DVT should have cabozantinib treatment held 
until therapeutic anticoagulation with heparins (eg, LMWH) is established. (Note: Therapeutic 
anticoagulation with oral anticoagulants or oral platelet inhibitors such as clopidogrel is not 
allowed in this study.) Cabozantinib treatment may be resumed in subjects with PE or DVT if it is 
determined that the event is uncomplicated and that they are deriving clinical benefit from 
cabozantinib treatment. During anticoagulation treatment, subjects need to be monitored on an 
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ongoing basis for bleeding risk and signs of bleeding which may require additional or more 
frequent laboratory tests according to institutional guidelines. If there are any signs of clinically 
relevant bleedings, cabozantinib treatment should be interrupted immediately and the sponsor 
contacted to discuss further study participation. 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.
Arterial thrombotic events (eg, TIA, myocardial infarction) have been observed in studies with 
cabozantinib. Subjects should be evaluated for pre-existing risk factors for arterial thrombotic 
events such as diabetes mellitus, hyperlipidemia, hypertension, coronary artery disease, history of 
tobacco use, and cardiac and/or thromboembolic events that occurred prior to initiation of study 
treatment. Cabozantinib treatment should be discontinued in subjects who develop an acute 
myocardial infarction or any other clinically significant arterial thromboembolic complication.
For recurrent/worsening venous thromboembolic events after resumption of cabozantinib 
treatment, cabozantinib treatment should be discontinued.
8.6.8 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 UPCR 
performed by the central lab. In addition, urine dipstick analysis will be performed by the local lab 
in regular intervals (see Appendix A) and as clinically indicated. Management of proteinuria will 
be based on UPCR results provided by the central lab (see Table 8.g).
However, since 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 of proteinuria. 
For example, if the dipstick analysis shows proteinuria ≥3+ the investigator may decide to 
interrupt cabozantinib dosing until the UPCR result becomes available and treatment decisions can 
be made.
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Table 8.g
Management of Treatment-Emergent Proteinuria
Severity of Proteinuria (UPCR)
Action to be Taken
≤1 mg/mg
(≤113.1 mg/mmol)

No change in cabozantinib treatment or monitoring.
>1 and <3.5 mg/mg
(>113.1 and <395.9 mg/mmol)

Consider confirming with a 24-hr protein assessment within 7 days.

No change in cabozantinib treatment required if UPCR ≤2 mg/mg on repeat 
UPCR testing or urine protein ≤2 g/24 hr on 24-hr urine collection.

Dose-reduce or interrupt cabozantinib treatment if UPCR >2 mg/mg on 
repeat UPCR testing or urine protein >2 g/24 hr on 24-hr urine collection. 
Continue cabozantinib on a reduced dose if UPCR decreases to ≤2 mg/mg. 
Consider holding cabozantinib treatment if UPCR remains >2 mg/mg 
despite a dose reduction until UPCR decreases to ≤2 mg/mg. Restart 
cabozantinib treatment at a reduced dose after a dose hold unless otherwise 
approved by sponsor.

Repeat UPCR within 7 days and once per week. If UPCR ≤1 mg/mg on 2 
consecutive readings, UPCR monitoring can revert to protocol-specific 
times. (Second reading is confirmatory and can be done within 1 week of 
first reading.) If UPCR remains >1 mg/mg and ≤2 mg/mg for 1 month or is 
determined to be stable (<20% change) for 1 month, check urine 
protein/creatinine per protocol or as clinically indicated.
≥3.5 mg/mg
(≥395.9 mg/mmol)

Hold cabozantinib treatment pending repeat UPCR within 7 days and/or 
24-hr urine protein.

If ≥3.5 mg/mg on repeat UPCR, continue to hold cabozantinib treatment 
and check UPCR every 7 days. If UPCR <3.5 mg/mg and >2 mg/mg, 
continue to hold cabozantinib treatment. If UPCR decreases to ≤2 mg/mg, 
restart cabozantinib treatment at a reduced dose and monitoring of urine 
protein/creatinine should continue weekly until the UPCR decreases to 
≤1 mg/mg. If UPCR remains >1 mg/mg and ≤2 mg/mg for 1 month or is 
determined to be stable (<20% change) for 1 month, check urine 
protein/creatinine per protocol or as clinically indicated.
Nephrotic syndrome

Discontinue cabozantinib treatment.
UPCR=urine protein-to-creatinine ratio.
8.6.9
Corrected QT Prolongation
Only subjects with a baseline QTcF ≤500 msec (single measurement or an average of 
3 consecutive results) within 14 days before Week 1 Day 1 are eligible for this study (Exclusion 
Criterion 11). Subjects will have ECGs performed at times designated by the protocol (see 
Section 9.4.12 and Schedule of Events [Appendix A]).
If at any time on study after Week 1 Day 1 there is an increase in QTcF interval to an absolute 
value >500 msec, 2 additional ECGs must be performed with intervals at least 3 minutes apart 
within 30 minutes after the initial ECG.
If the average QTcF is >500 msec, the following actions must be taken:

Withhold study treatment.
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
Notify the sponsor immediately.

Hospitalize symptomatic subjects (eg, with palpitations, dizziness, syncope, orthostatic
hypotension, a significant ventricular arrhythmia on ECG) for a prompt cardiology evaluation
and management until the average QTcF is ≤500 msec and symptoms have resolved.

Monitor QTcF closely (approximately every hour or at a frequency deemed clinically
indicated by consultation with a cardiologist) until the average QTcF is ≤500 msec on
2 consecutive ECGs at least 1 hour apart or otherwise determined by a cardiologist.

Check electrolytes, especially magnesium, calcium, 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.
Cabozantinib treatment may be restarted at a reduced dose level if all of the following conditions 
are met:

Symptoms are determined to be unrelated to the QT interval prolongation.

QTcF value >500 msec is not confirmed or a QTcF >500 msec returns to ≤500 msec.

Study treatment has been interrupted through a minimum of 1 week following the return of the
QTcF to ≤500 msec.

QT prolongation can be unequivocally associated with an event other than cabozantinib
administration and is treatable/has been resolved.

Sponsor has reviewed all available information and has agreed to the continuation of study
treatment.
Following re-initiation 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 after re-initiation of study treatment at a reduced dose.
8.6.10 Hypophosphatemia
Hypophosphatemia has been reported during treatment with cabozantinib. Serum phosphorus 
should be monitored frequently while receiving cabozantinib. Mild hypophosphatemia is usually 
asymptomatic or symptoms can be nonspecific such as weakness, bone pain, rhabdomyolysis, or 
altered mental status. Other causes of hypophosphatemia such as poor nutrition, chronic 
alcoholism, malabsorption, excessive antacid use, glucocorticoids use, kidney dysfunction, 
respiratory alkalosis, and vitamin D deficiency should be ruled out and/or these causes treated 
according to standard of care. Mild to moderate hypophosphatemia should be managed by oral 
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replacement including foods that are high in phosphate (dairy items, meats, beans) and/or oral 
phosphate supplements according to standard clinical practice guidelines.
Clinically relevant hypophosphatemia should be managed according to the dose modification 
guidelines as outlined in Table 8.b or as clinically indicated.
8.6.11 Thyroid Function Disorders
Treatment-emergent elevation of TSH has been observed with cabozantinib treatment. Currently 
available data are insufficient to determine the mechanism of thyroid function test alterations and 
its clinical relevance. Routine monitoring of thyroid function and assessments for signs and 
symptoms associated with thyroid dysfunction is recommended before initiation and during 
treatment with cabozantinib. Management of thyroid dysfunction (eg, symptomatic 
hypothyroidism) should follow accepted clinical practice guidelines and dose modification 
guidelines as outlined in Table 8.b.
8.6.12 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 cabozantinib treatment and should be 
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:

Lung metastasis that invades, encases, or abuts major blood vessels.

Recent or concurrent radiation to the thoracic cavity.

Active peptic ulcer disease, inflammatory GI diseases including Crohn’s disease, and
ulcerative colitis.

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, hematemesis or hematuria.
The risk of hemorrhage in cabozantinib-treated subjects with brain metastasis has not been 
thoroughly analyzed. Currently, brain metastasis of carcinomas are not contraindications to the use 
of cabozantinib, but subjects with brain metastasis should be monitored with a high index of 
suspicion if symptoms occur that could be due to a CNS hemorrhage.
Discontinue cabozantinib treatment in subjects who have been diagnosed with severe bleeding 
complications (ie, Grade 2 CNS or pulmonary hemorrhage, or any Grade 3 or 4 hemorrhage).
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8.6.13 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, those 
listed below.
8.6.13.1 GI perforation/fistula

Intra-abdominal tumor/metastases invading GI mucosa.

Active peptic ulcer disease, inflammatory bowel disease (eg, ulcerative colitis, Crohn’s
disease), diverticulitis, cholecystitis or symptomatic cholangitis, or appendicitis.

History of abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess.

Ongoing visceral complications from prior radiation therapy.

Prior GI surgery (particularly when associated with delayed or incomplete healing).
Complete healing following abdominal surgery and/or resolution of intra-abdominal abscess must 
be confirmed prior to initiating treatment with cabozantinib.
Additional risk factors include concurrent chronic use of steroid treatment or nonsteroidal 
anti-inflammatory drugs. Constipation indicative of bowel obstruction should be monitored and 
effectively managed.
Discontinue cabozantinib treatment in subjects who have been diagnosed with GI 
perforation/fistula.
8.6.13.2 Non-GI fistula
Complications from radiation therapy have been identified as possible predisposing risk factors for 
non-GI fistula formation in subjects undergoing treatment with VEGF pathway inhibitors 
(eg, bevacizumab).
Discontinue cabozantinib treatment in subjects who have been diagnosed with non-GI fistula.
8.6.14 Osteonecrosis of the Jaw
Osteonecrosis of the jaw has been reported in subjects treated with cabozantinib. Additional risk 
factors include use of bisphosphonates and denosumab, use of corticosteroids, anticancer agents, 
local radiotherapy, poor oral hygiene, smoking, dental or orofacial surgery procedures, and cancer 
itself. Osteonecrosis has been reported in subjects treated with cabozantinib, the details of which 
are provided in the current version of the IB. As a preventive measure, invasive dental procedures 
should be avoided if possible in subjects who have previously been treated with or concomitantly 
receive bisphosphonates or denosumab.
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In cases where dental procedures are unavoidable, the risks and benefits of a dental procedure and 
the extent of the procedure as well as the risk of developing osteonecrosis of the jaw need to be 
considered when deciding on the duration of a temporary treatment interruption of cabozantinib. If 
clinically possible, treatment with cabozantinib should be held for approximately 4 weeks prior to 
a dental procedure and resumed after complete healing has occurred. Bone healing may often 
require a protracted time.
Subjects with any documented case of osteonecrosis should have study treatment interrupted, and 
appropriate clinical management should be initiated. Re-initiation of study treatment must be 
discussed with and approved by the sponsor on a case-by-case basis.
8.6.15 RPLS
For signs and symptoms suggestive of RPLS (eg, confusion, headache, seizures, cortical 
blindness) of any grade, interrupt cabozantinib treatment. Suspected RPLS should be investigated 
with MRI. If RPLS is confirmed, discontinue cabozantinib treatment.

If RPLS is ruled out via MRI, the decision to resume cabozantinib should be based on the
signs and symptoms: for Grade 4 events considered at least possibly related to cabozantinib,
discontinue cabozantinib treatment.

For Grade 3 events, cabozantinib may be resumed if events improve to ≤Grade 1 with 1
dose-level reduction.
8.7 
Blinding and Unblinding
This is an open-label study.
8.8 
Description of Investigational Agents
Cabozantinib will be supplied as 20 mg or 60 mg (expressed as the free base equivalent weight), 
yellow film-coated tablets. The 20 mg tablets are round and the 60 mg tablets are oval.
For additional details, refer to the IB and Pharmacy Manual.
8.9 
Preparation, Reconstitution, and Dispensation
Detailed instructions for dispensing cabozantinib tablets are provided in the Pharmacy Manual.
Cabozantinib is an anticancer drug, and as with other potentially toxic compounds, caution should 
be exercised when handling cabozantinib.
8.10 
Packaging and Labeling
The cabozantinib 20 mg tablets and 60 mg tablets will be provided by the sponsor. The study drug 
will be provided in 60 cc round high-density polyethylene (HDPE) bottles. Each HDPE bottle 
contains a total of 30 tablets, sealed with induction seal and a plastic cap with child-resistant 
closure, labeled in an open fashion with a single panel label. The study drug labels will fulfill all 
requirements specified by governing regulations.
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8.11
Storage, Handling, and Accountability
Cabozantinib tablets should be stored in the original dispensing bottles at 1°C to 30°C. All 
temperature excursions for the tablets must be reported back to the sponsor for assessment and 
determination for continued use. Refer to the Pharmacy Manual for additional information. Study 
medication is to remain in the HDPE bottle until time of dosing. All clinical trial material must be 
kept in an appropriate, limited-access, secure place until it is used or returned to the sponsor or 
designee for destruction. All study medication must be stored under the conditions specified on the 
label and remain in the original container until dispensed. A daily temperature log of the drug 
storage area must be maintained each working day. Temperature excursion must be reported to the 
sponsor or designee.
Cabozantinib tablets are meant to be taken orally only and are not to be crushed for dissolving in 
liquid or administered through other routes including percutaneous endoscopic gastrostomy tubes. 
Cabozantinib tablets should not be administered to subjects who do not have adequate swallowing 
capacity; they must be stored at controlled room temperature, and inventoried according to 
applicable governing regulations.
A drug dispensing log, including records of drug received from the sponsor and drug dispensed to 
the subjects, will be provided and kept at the study site.
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9.0 
STUDY CONDUCT
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP), 
applicable regulatory requirements, and International Conference on Harmonisation (ICH) 
guidelines.
9.1 
Study Personnel and Organizations
The contact information for the Takeda clinician, the central laboratory, any additional clinical 
laboratories or vendors participating on the study as well as the list of investigators can be found in 
the protocol annex.
9.2 
Arrangements for Recruitment of Patients
Recruitment and enrollment strategies for this study may include recruitment from the 
investigator’s local practice or referrals from other physicians. If advertisements become part of 
the recruitment strategy, they will be reviewed by the institutional review board (IRB).
9.3 
Study Enrollment
After written informed consent has been obtained, the patient will be assigned a subject 
identification code.
Patient eligibility will be confirmed by a Takeda clinician before enrollment by the investigator 
into the study. Re-enrollment of the same patient will not be permitted. If a subject discontinues 
from the study, that subject identification code will not be reused.
A patient is considered to be enrolled in the study when the first dose of study drug has been 
administered.
Procedures for completing the enrollment information are described in the subjects' 
enrollment/discontinuation manual.
9.4 
Study Procedures
Subjects will be evaluated at scheduled visits over the following study periods: Screening, 
Treatment and Posttreatment. This protocol generally presents scheduled timelines for study 
procedures by references to week (W) and day (D) (eg, Week 1 Day 1, Week 3 Day 1, etc). Each 
timeline will be relative to the date of Week 1 Day 1.
Screening assessments must be performed within 28 days before Week 1 Day 1.
All assessments for efficacy, safety and HRQOL assessments will be scheduled based on Week 1 
Day 1. Unscheduled visits for radiographic evaluations and safety evaluations are allowed at any 
time.
Refer to the Schedule of Events (Appendix A) for timing of assessments.
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9.4.1 Informed Consent
Each patient must provide written informed consent before any study-required procedures are 
conducted, unless those procedures are performed as part of the patient’s standard care.
9.4.2 Demographics
The date of birth, race, and sex of the subject are to be recorded during Screening.
9.4.3 Medical History
At Screening and Week 1 Day 1, a complete medical history will be compiled for each subject, 
including medical and cancer history, surgical history, radiation therapy history, and systemic 
anticancer treatment history including names and administration dates of all VEGFR-targeting 
TKI.
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.
9.4.4 Tumor Biopsy
For subjects who have not had previous histological or cytological diagnosis of HCC, biopsy will 
be required to establish eligibility at Screening. Healing from biopsy must be complete at least 
7 days before Week 1 Day 1.
9.4.5 Physical Examination
A physical examination will be completed per standard of care at the times specified in the 
Schedule of Events (Appendix A). Physical examinations will include an assessment of the 
following systems: skin, head, eyes, ears, nose, throat, respiratory system, cardiovascular system, 
GI system, neurological condition, blood and lymphatic systems, and the musculoskeletal system. 
A symptom-directed physical examination will be conducted on Week 1 Day 1 before first dose of 
study drug.
9.4.6 Height and Weight
Height will be measured during Screening only (within 28 days before Week 1 Day 1).
Weight will be measured as specified in the Schedule of Events (Appendix A).
9.4.7 Vital Signs
Vital sign measurements include seated position (after the subject has been sitting quietly for 
approximately 5 minutes in this position) measurements of diastolic and systolic BP, pulse, 
respiratory rate and temperature will be assessed as specified in the Schedule of Events (Appendix 
A).
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9.4.8 ECOG PS
The ECOG PS of the subject will be assessed at Screening to establish eligibility and also assessed 
at each scheduled visit for safety assessment starting on Week 1 Day 1 (Appendix A).
Refer to Appendix D for the ECOG scale criteria.
9.4.9 Pregnancy Test
A serum pregnancy test will be performed for women of childbearing potential at Screening (after 
the subject signs the ICF and 7 or more days before Week 1 Day 1). A urine or serum pregnancy 
test will also be performed predose on Week 1 Day 1 (Note: Considering that there are false 
negative periods [approximately 7 days for serum test and approximately 10 days for urine test] in 
early pregnancy, the test methods and the duration between the tests performed at Screening and 
the predose tests performed on Week 1 Day 1 should be determined.) Negative results must be 
obtained before the first dose of study drug. Subsequently, urine or serum pregnancy tests will be 
performed predose every 12 weeks (±5 days) and will also be performed at the 30-day 
posttreatment followup visit.
9.4.10 Concomitant Medications and Procedures
Medications used by the subject (including prescription and over-the-counter medications, 
transfusions, vitamins, herbal remedies, and nutritional supplements) and therapeutic procedures 
completed by the subject and their outcomes will be recorded in the electronic case report form 
(eCRF) from the time of the signing of the ICF through 30 days after the last dose of study drug or 
the start of subsequent systemic anticancer treatment, whichever occurs first. See Section 8.3 and 
Section 8.4 for information on excluded and/or permitted concomitant medications and procedures 
during the study.
9.4.11 Adverse Events
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as specified in 
the Schedule of Events (Appendix A). Refer to Section 10.0 for details regarding definitions, 
documentation, and reporting of AEs and SAEs.
9.4.12 ECG
Single ECG assessments with standard 12-lead ECG equipment according to standard procedures 
will be performed and interpreted locally at the time points specified in the Schedule of Events 
(Appendix A). The QTcF should be determined by the investigator at all time points. ECGs to 
establish eligibility at Screening must be done within 14 days before Week 1 Day 1 (Appendix A).
All scheduled ECGs should be performed predose and after the subject has rested quietly for at 
least 5 minutes in a supine position. When the timing of a PK, biomarker or safety laboratory blood 
sampling coincides with the timing of ECG measurements, the ECG will be completed before the 
blood sample collection. In some cases, it may be appropriate to repeat an ECG to rule out 
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improper lead placement contributing to the ECG abnormality. ECGs should be reviewed by the 
investigator or delegate before the subject leaves the clinic on visit days.
If the result for QTcF is ≤500 msec at Screening, the subject meets eligibility in this regard 
(Exclusion Criterion 11).
If indicated due to any cardiac abnormalities (see Section 8.6.9), 2 additional ECGs must be 
performed within 30 minutes after the initial ECG, each with intervals at least 3 minutes apart.
Abnormalities in the ECG that lead to a change in subject management (eg, dose reduced or 
withheld, treatment discontinued, requirement for additional medication or monitoring) or result in 
clinical signs and symptoms will be considered clinically significant for the purposes of this study 
and will be deemed AEs. If values meet the criteria defining them as serious, they must be reported 
as SAEs (see Section 10.2).
9.4.13 Echocardiogram
Echocardiogram will be performed at Screening and every 24 weeks (±7 days) thereafter. 
Additional cardiac function tests are required if any signs or symptoms of cardiac dysfunction 
occur. Echocardiogram should be performed for determination of left ventricle ejection fraction.
9.4.14 Clinical Laboratory Evaluations
Blood and urine samples for analysis of the parameters shown in Table 9.a will be obtained as 
specified in the Schedule of Events (Appendix A). Handling and shipment of clinical laboratory 
samples will be outlined in the laboratory manual.
Hematology, serum chemistry, coagulation, UPCR including components (urine protein and 
creatinine), AFP, bone specific ALP, and thyroid function tests are to be performed by a central 
laboratory, including labs obtained at unscheduled visits whenever possible. All central laboratory 
results will be provided to the investigator. Local laboratory tests for dose modification 
consideration will be performed at each study visit as well as central laboratory tests. On Week 1 
Day 1, the results of local laboratory tests at the most recent or Week 1 Day 1 that consideration 
will be used to start of treatment. WBC count with differential and platelets , ALP, ALT, AST, and 
total bilirubin must be included in local laboratory assessment for dose modification. Local 
laboratory assessments for other than the above parameters may be obtained and used if the results 
are required by the investigator in a rapid timeframe (eg, monitoring for AEs, SAEs). However, the 
results of local laboratory tests may not be used to establish eligibility. In rare, exceptional 
circumstances and with approval of the sponsor, local laboratory results may be allowed to use for 
the purpose of determining eligibility in the event that the results of individual tests performed at 
the central laboratory are unavailable at the time of subject enrollment or the accuracy of test 
results is questioned. Qualitative urinalysis (dipstick or routine), microscopic urine examination, 
and urine or serum pregnancy tests are to be done by local laboratory. These results or the status 
will be recorded on eCRFs.
A blood sample for AFP (see Section 9.4.16) and a serum sample for bone specific ALP (see 
Section 9.4.19) will be obtained.
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Laboratory tests to establish eligibility must be done within 10 days before Week 1 Day 1 
(Appendix A). A serum pregnancy test must be performed after informed consent and 7 or more 
days before Week 1 Day 1.
HbA1c will only be tested at Screening to confirm eligibility and must be done within 10 days 
before Week 1 Day 1. For subjects whose HbA1c results are unavailable (eg, hemoglobin variant), 
a fasting serum glucose test result can be used to confirm eligibility after sponsor approval.
Throughout the study fasted glucose will be monitored. On days when the blood sample is drawn, 
subjects must fast (no caloric intake for at least 8 hours; consumption of water is allowed) 
overnight.
Serum virus tests will be performed by central laboratory during the Screening period. Hepatitis B 
virus (HBV) testing will include hepatitis B surface antigen (HBsAg) and hepatitis B viral load 
(HBV-DNA). Hepatitis C virus (HCV) testing will include HCV antibody (HCVAb) and hepatitis 
C viral load (HCV-RNA).
If transaminase increases are followed by or concurrent with progressive elevations of total 
bilirubin, and/or elevations of coagulation tests (eg, PT-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 return to the baseline values or are stabilized
to the clinically acceptable levels.
To estimate creatinine clearance, the Cockcroft-Gault equation will be employed (Appendix H).
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9.4.15
Tumor Assessment
9.4.15.1 General
Radiographic response and disease progression will be determined using RECIST 1.1 (Appendix 
F). For the purpose of determination of the study endpoints of PFSR, PFS, ORR and DCR, central 
review of radiographic images will be conducted by an IRC (see Section 9.4.15.2 and Section 
11.1). All radiographic tumor assessments (both scheduled and unscheduled) must be sent to the 
IRC, which also will review prior radiation history data for the purpose of selection of target 
lesions.
Radiographic tumor assessments will include the following:
1. Chest/Abdomen/Pelvis: CT (or MRI) of CAP will be performed in all subjects at Screening.
CT (or MRI) will be performed on Week 9 Day 1 and every 8 weeks (±7 days) thereafter. If
MRI of the CAP study is used at Screening, MRI of abdomen and pelvis will be required and
noncontrast CT of the chest should be performed as well.
2. Brain: MRI (or CT) of the brain will be performed in all subjects at Screening. After Week 1
Day 1, MRI (or CT) scans of the brain are only required in subjects with known brain
metastasis. Assessments will be performed on Week 9 Day 1 and every 8 weeks (±7 days)
thereafter. If CT of the brain is performed instead of MRI, ambiguous results must be
confirmed by MRI. (Note: In order to meet the eligibility requirements of the study, brain
metastasis must have been treated and stable for at least 3 months before enrollment. Subjects
without documented brain metastasis during the screening assessment are not required to
undergo postenrollment brain imaging unless clinically indicated.)
3. Bone: Whole body TBS will be performed in all subjects at Screening. After Week 1 Day 1,
bone scans will be performed only in subjects with known bone metastasis on Week 9 Day 1,
Week 17 Day 1 (±7 days), and every 16 weeks (±7 days) thereafter until last CT/MRI scan.
(Note: Subjects without documented bone metastasis during the screening assessment are not
required to undergo postenrollment bone scan imaging unless clinically indicated.) Lesions
identified on bone scans are not to be recorded as target, nontarget, or new lesions. Bone scans
are to be used to direct corroborative imaging with CT/MRI if necessary (these CT/MRI
findings will be used for RECIST 1.1 evaluation). Bone scan findings alone cannot be used for
the determination of progression per RECIST 1.1.
Imaging Guidelines
All CT/MRI (CAP, brain) and TBS imaging studies are recommended to be performed using the 
study-specified imaging protocol (refer to the imaging manual). To ensure image consistency, the 
same imaging modalities and acquisition protocols used at Screening should be used for 
subsequent tumor assessments. All imaging must be acquired and transmitted for central review in 
original Digital Imaging and Communications in Medicine (DICOM) format (not a secondary 
capture).
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CT/MRI
For screening period and all scheduled followup imaging examinations, CT or MRI of CAP 
should be obtained. CT of CAP should include contrast with triphasic (arterial, portal and 
delayed venous phase) imaging of the liver. For imaging of the liver, MRI with gadolinium 
enhanced imaging may be substituted for the contrast enhanced triphasic CT scan. A 
noncontrast liver study must be acquired (at least at screening). If MRI is used for CAP study,
MRI of abdomen and pelvis will be required and noncontrast CT of the chest should be 
performed as well. For enrolled subjects with treated and stable brain metastasis, the same 
postcontrast MRI (or postcontrast CT) of the brain as performed at Screening should be 
performed during subsequent assessments while on study. Volume acquisition CT 
reconstructed every 3 mm to 5 mm contiguously with a soft tissue filter should be performed. 
MRI scans should be performed using a body coil and reconstruction every 3 mm to 5 mm 
without gap. For all followup CT (or MRI) examinations, the same imaging modalities used at 
Screening will be used. If at a followup imaging time point there is a contraindication to use of 
contrast (eg, impaired renal function) then a noncontrast CT or MRI should be performed.
TBS
Whole body TBS images must be acquired 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.
Lesions identified on TBS are not to be recorded as target, nontarget, or new lesions. Bone 
scans are to be used to direct corroborative imaging with CT/MRI if necessary (these CT/MRI 
findings will be used for RECIST 1.1 evaluation). Bone scan findings alone cannot be used for 
the determination of progression per RECIST 1.1.
Duration of Radiographic Tumor Assessments
Tumor assessments are to be performed per the protocol-defined schedule regardless of whether 
study treatment is given, reduced, held, or discontinued.
End of radiographic tumor assessments by CT/MRI:

For subjects who discontinue study treatment before radiographic disease progression or
within 8 weeks after radiographic disease progression, final radiographic tumor assessments
are to be performed 8 weeks after radiographic disease progression. For subjects who
discontinued study treatment and commenced a subsequent anticancer therapy (other than
radiation therapy to bone), radiographic tumor assessments should be performed prior to the
subsequent therapy. No further radiographic tumor assessments are necessary to be
performed.

For subjects who continue to receive study treatment for more than 8 weeks after radiographic
disease progression, tumor assessments are to continue per the protocol-defined schedule until
study treatment is permanently discontinued.
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Bone scan evaluations will end on the day of last CT/MRI scan. If the bone scan schedule does not 
coincide with the last CT/MRI scan, no additional bone scan is needed after the last CT/MRI has 
been performed.
Tumor assessment by investigator
For the purpose of subject management and treatment decisions, radiographic response and 
disease progression will be assessed by investigators using RECIST 1.1 (Appendix F). The 
sponsor should be notified of all disease progression as soon as possible. If any doubt or 
ambiguities exist about radiographic progression, investigators are encouraged to continue study 
therapy if the subject is tolerating it acceptably, repeat radiographic studies at the next scheduled 
time, and delay determination of progression until the findings indicating radiographic progression 
are unequivocal. Radiographic progression determined by the investigator does not warrant 
discontinuation of tumor assessments or study treatment (see Section 9.7). If the study treatment is 
continued even after determination of disease progression, the time of disease progression 
determined by the investigator will be considered "baseline" and tumor assessment will be 
continued based on the RECIST 1.1 criteria. If a new lesion is identified and determined to be 
disease progression by the investigator, this lesion will be assessed as a nontarget lesion and tumor 
assessment will be continued. No radiographic assessment is necessary after the second 
determination of disease progression.
9.4.15.2 Central Independent Radiology Committee
All radiological studies acquired at all scheduled time points and any additional (unscheduled) 
radiological images acquired to evaluate for potential metastatic disease must be sent to the IRC in 
original DICOM format (as detailed in the imaging manual). The IRC will evaluate prior radiation 
history for the purpose of valid identification of target lesions and all images in a central and 
independent fashion as further described in Section 11.1. Electronic transfer of scan files (via AG 
Mednet, sFTP, or similar means) is preferred, although transfer on physical media (such as DVDs 
or CDs) is acceptable. For digital media, each disk should contain one time point for one subject. 
For this study no paper or film will be acceptable. The site is expected to maintain a copy of digital 
data for the retention period applicable to the protocol and GCP. The sponsor and or designee will 
retain the media for the life of the study.
9.4.16 Alpha-Fetoprotein
A blood sample for AFP will be obtained at the time of each radiographic tumor assessment visit 
according to the schedule in Appendix A.
Samples for AFP measurement should be collected at Screening. Assessments will be performed 
on Week 9 Day 1, and every 8 weeks (±7 days) thereafter. Assessments will continue regardless of 
whether study treatment is given, reduced, held, or discontinued until last tumor assessment.
Detailed instructions for sample preparation will be provided in the laboratory manual.
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9.4.17 PK Measurements
PK blood samples will be obtained from all subjects as described in Appendix A unless otherwise 
approved by the sponsor.
The Week 1 Day 1 PK sample should be taken prior to dosing of study drug and at 3 hours after the 
dosing. The scheduled Week 3 Day 1, Week 5 Day 1 and Week 9 Day 1 on-treatment PK samples 
should be obtained whether or not study drug is administered on that day. For each on-treatment 
visit for subjects, the PK sample should be collected approximately 8 or more hours after the 
previous dose of study drug, and if the study drug will be administered on that day, should be 
collected prior to the administration. The investigator will ask the subject for the date and time of 
the most recent prior dose of study drug, and this information will be recorded in the eCRF. 
Subjects should be encouraged to take the study drug at the same time every day. Collection of 
these blood samples may be halted early or sampling frequency may be reduced at the discretion of 
the sponsor.
Detailed instructions for sample preparation will be provided in the laboratory manual.
9.4.18 Pharmacogenomic Blood Sample Collection
A pharmacogenomic blood sample will be collected from all subjects predose on Week 1 Day 1 for 
single nucleotide polymorphism variation analysis by
to investigate the 
contribution of genetic variance on PK, safety and tole
ment. Somatic DNA 
will be obtained from blood samples and be genotyped for clinically relevant germline mutations 
including polymorphisms in genes encoding drug-metabolizing enzymes and/or transporters. 
Unless failure to grant informed consent for this purpose, or sponsor decision, additional 
pharmacogenomic analyses (eg, the contribution of genetic variance on drug response) may be 
conducted in the future. This additional analyses are limited to analyses of study drug and/or 
diseases.
The analysis performed with somatic DNA is not intended to make determinations about a 
subject’s health or the likelihood that a subject will develop any disease. In the analytical method 
used for the study, there are no possibilities that genetic mutation involved in developing any 
disease will be incidentally discovered. Therefore, no test results will be provided to the 
investigators and subject, or put into a subject’s medical record.
Somatic DNA will be stored at LSI Medience Corporation for up to 15 years after the date of study 
completion as identified in the CSR and will be degraded and discarded. If subjects withdraw 
consent, the samples will be degraded and discarded. Details regarding the preparation, 
processing, and shipping of samples can be found in the laboratory manual.
9.4.19 Biomarker Assessment
Samples for biomarker assessment are for research purposes only and biomarker researches may 
be conducted when necessary even after the study completion.
CCI
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Assessment of biomarkers in plasma (candidate biomarkers: 
soluble-VEGFR2/MET/AXL/VEGF/HGF/GAS6-signaling protein expression profiles and 
metabolic profiles) will be performed. Samples for these studies will be collected from all subjects 
according to the schedule outlined in Appendix A. The candidate biomarkers will be prospectively 
validated in an independent patient population.
Serum bone biomarker (bone specific ALP) will also be assessed. Samples for these studies will be 
collected according to the schedule outlined in Appendix A.
Collection of these samples may be halted early or sampling frequency may be reduced at the 
discretion of the sponsor. Details regarding the preparation, processing, and shipping of samples 
can be found in the laboratory manual.
9.4.20 Health-Related Quality of Life Assessments
Subjects will self-report information on HRQOL utilizing the Japanese versions of the EQ-5D-5L 
(Appendix G) questionnaire. 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 [39].
EQ-5D-5L has two pages (Appendix G): a descriptive page with 5 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 first assessments will be performed on Week 1 Day 1 prior to dosing. After Week 1 Day 1, the 
HRQOL assessments will be collected every 4 weeks (±2 days) up to Week 9 Day 1, and every 4 
weeks (±7 days) thereafter through 6 months on study. Upon completion of 6 months on study, the 
HRQOL assessments will be collected every 8 weeks (±7 days) thereafter until last tumor 
assessment. The HRQOL questionnaires should be completed by the patient before any other 
study procedures are performed or study drug is administered on scheduled visits. Subjects will 
continue completing questionnaires regardless of whether study treatment is given, reduced, held, 
or discontinued until the day of the last tumor imaging assessment as described in Section 9.4.15.
Every effort should be made by the study site to retrieve all completed HRQOL questionnaires 
including the assessment following radiographic progression or discontinuation of study 
treatment, and kept at the site as source documentation.
The Japanese versions of the EQ-5D-5L questionnaire and instructions for filling them out will be 
provided to each study site.
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9.4.21 Child-Pugh Scoring
Child-Pugh score will be based on the Modified Child-Pugh classification of severity of liver 
disease [40,41] 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 within 10 days 
before Week 1 Day 1. Laboratory parameters required for the scoring must be evaluated within 10 
days before Week 1 Day 1. If possible, the results of central laboratory tests to establish eligibility 
may be used for Child-Pugh assessment. Child-Pugh assessments should be performed on Week 1 
Day 1, Week 9 Day 1, and every 8 weeks (±7 days) thereafter. These assessments will continue 
regardless of whether study treatment is given, reduced, held, or discontinued until last tumor 
assessment. Determination of severity of ascites and encephalopathy will be made by clinical 
assessment.
9.4.22 Survival Status and Subsequent Anticancer Therapy
Overall survival will be assessed every 8 weeks (±7 days) after the 30-day posttreatment followup 
visit. Subjects will be followed until death, consent withdrawn, or the sponsor decision to no 
longer collect these data. Receipt of subsequent nonprotocol anticancer therapy will also be 
collected during followup contacts.
9.5
Completion of Study Treatment (for Individual Subjects)
Not applicable for this study.
9.6
Completion of Study (for Individual Subjects)
Not applicable for this study.
9.7
Discontinuation of Treatment With Study Drug and Subject Replacement
Treatment with study drug may be discontinued for any of the following reasons. However, 
subjects may discontinue study treatment at any time without prejudice. If treatment is interrupted 
for more than 6 weeks for study treatment-related TEAEs it should be permanently discontinued, 
unless continuation of treatment is approved by the sponsor for interruptions which are not due to 
AEs (see Section 8.2.1).

AE (excluding AEs of disease progression).

Clinical deterioration (AEs or SAEs related to disease progression).

Protocol deviation.

PD.

Lack of efficacy.
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Subject no longer experiences clinical benefit as determined by the investigator. If study 
treatment is discontinued for this reason, the date of this decision is to be recorded and every 
effort should be made to continue safety evaluations, tumor assessments, and collection of 
subsequent anticancer treatment information and followup information for survival.

Death

Study terminated by sponsor.

Pregnancy.

Withdrawal by subject (with or without concurrent withdrawal of informed consent).

Lost to followup.

Physician decision.
The investigator feels it is not in the best interest of the subject to continue on study.

Other.
The sponsor should be notified of all discontinuations of study treatment as soon as possible (see 
the subjects' enrollment/discontinuation manual). The reason for treatment discontinuation and the 
date of the last known dose of study treatment will be recorded in the eCRF. Subjects who 
discontinue treatment with study drug will not be replaced.
Once study drug has been discontinued, all study procedures outlined for the 30-day posttreatment 
followup visit will be completed as specified in the Schedule of Events (Appendix A). For subjects 
who withdraw or are withdrawn from study treatment, every effort must be made to continue 
protocol-specified evaluations and procedures 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.
If a subject withdraws from study treatment, AEs are to be documented and/or followed as 
described in Section 10.2 and Section 10.3.
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.
9.8
Withdrawal of Subjects From Study
A subject may be withdrawn from the study for any of the following reasons. However, subjects 
may withdraw their consent to participate in the study at any time without prejudice.

Study terminated by sponsor.

Withdrawal by subject (with or without concurrent withdrawal of informed consent).

Lost to followup.
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
Death.

Other.
The sponsor should be notified of all subject withdrawals from the study as soon as possible. No 
further study procedures or assessments will be performed or study data collected for this subject. 
The consequence of study withdrawal is that no new information will be collected from the 
withdrawn subject and added to the existing data or any database. However, every effort will be 
made to follow all subjects for safety.
9.9 
Study Compliance
Study drug will be administered or dispensed only to eligible patients under the supervision of the 
investigator or identified subinvestigator(s).
9.10 
Posttreatment Followup Assessments 
A 30-day posttreatment followup visit for safety will occur 30 (+14) days after the last dose of 
study drug or until the start of subsequent systemic anticancer treatment, whichever occurs first. 
Radiographic tumor assessments, Child-Pugh assessments, AFP assessments, and HRQOL 
assessments will continue regardless of whether study treatment is given, reduced, held, or 
discontinued until the date of the last tumor imaging assessment as described in Section 9.4.15. 
Consequently these assessments may be required in the Posttreatment period for some subjects. 
All subsequent antineoplastic therapies will be recorded, regardless if they are initiated before or 
after PD. 
In addition, subjects will be contacted every 8 weeks (±7 days) after the 30-day posttreatment 
followup visit to assess survival status and document receipt of subsequent anticancer therapy. 
Subjects will be followed until death, withdrawal of consent, or the sponsor decision to 
discontinue collection of these data in the study. Survivor information and death details may be 
collected by methods that include, but are not limited to, telephone, e-mail, or mail. In addition, the 
start of another anticancer therapy for the disease under study will be collected. Every effort must 
be made to collect these protocol-specific evaluations unless consent to participate in the study and 
data collection is withdrawn.
Note: Related SAEs must be reported to the Global Pharmacovigilance department or designee. 
This includes deaths that the investigator considers related to study treatment that occur during the 
posttreatment followup. Refer to Section 10.0 for details regarding definitions, documentation, 
and reporting of SAEs.
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10.0
ADVERSE EVENTS
10.1
Definitions
10.1.1 Adverse Event Definition
An AE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study; it does not necessarily have to have a causal 
relationship with this treatment or study participation.
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a drug whether or 
not it is considered related to the drug.
This includes any newly occurring event, or a previous condition that has increased in severity or 
frequency after signing the ICF.
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is considered 
by the investigator to be a clinically significant change from baseline.
10.1.2 Serious Adverse Event Definition
An SAE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study that at any dose:

Results in death.

Is life-threatening (refers to an AE in which the subject was at risk of death at the time of the
event. It does not refer to an event which hypothetically might have caused death if it were
more severe).

Requires inpatient hospitalization or prolongation of an existing hospitalization (see
clarification in the paragraph in Section 10.2 on planned hospitalizations).

Results in persistent or significant disability or incapacity. (Disability is defined as a
substantial disruption of a person’s ability to conduct normal life functions).

Is a congenital anomaly/birth defect.

Is a medically important event. This refers to an AE that may not result in death, be
immediately life threatening, or require hospitalization, but may be considered serious when,
based on appropriate medical judgment, may jeopardize the subject, require medical or
surgical intervention to prevent 1 of the outcomes listed above, or involves suspected
transmission via a medicinal product of an infectious agent. Examples of such medical events
include allergic bronchospasm requiring intensive treatment in an emergency room or at home,
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the
development of drug dependency or drug abuse; any organism, virus, or infectious particle
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(eg, prion protein transmitting transmissible spongiform encephalopathy), pathogenic or 
nonpathogenic, is considered an infectious agent.
In this study, intensity for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, Version 4.03, effective date 14 June 2010 [42]. Clarification should be made 
between an SAE and an AE that is considered severe in intensity (Grade 3 or 4), because the terms 
serious and severe are NOT synonymous. The general term severe is often used to describe the 
intensity (severity) of a specific event; the event itself, however, may be of relatively minor 
medical significance (such as a Grade 3 headache). This is NOT the same as serious, which is 
based on subject/event outcome or action criteria described above, and is usually associated with 
events that pose a threat to a subject’s life or ability to function. A severe AE (Grade 3 or 4) does 
not necessarily need to be considered serious. For example, a white blood cell count of 1000/mm3 
to less than 2000 is considered Grade 3 (severe) but may not be considered serious. Seriousness 
(not intensity) serves as a guide for defining regulatory reporting obligations.
10.2 
Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events
All AEs spontaneously reported by the subject and/or in response to an open question from study 
personnel or revealed by observation, physical examination, or other diagnostic procedures will be 
recorded on the appropriate page of the eCRF (see Section 10.3 for the period of observation). Any 
clinically relevant deterioration in laboratory assessments or other clinical finding is considered an 
AE. When possible, signs and symptoms indicating a common underlying pathology should be 
noted as 1 comprehensive event.
Regardless of causality, SAEs (as defined in Section 10.1) must be reported (see Section 10.3 for 
the period of observation) by the investigator to the Takeda Global Pharmacovigilance department 
or designee (contact information provided in the protocol annex). This should be done by faxing an 
SAE form, by telephone or by e-mail within 24 hours after becoming aware of the event. Followup 
information on the SAE may be requested by Takeda. SAE report information must be consistent 
with the data provided on the eCRF.
Planned hospital admissions or surgical procedures for an illness or disease that existed before the 
subject was enrolled in the trial are not to be considered AEs unless the condition deteriorated in an 
unexpected manner during the trial (eg, surgery was performed earlier or later than planned).
For both serious and nonserious AEs, the investigator must determine both the severity (toxicity 
grade) of the event and the causality of the event to study drug administration.
Severity (toxicity grade) for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, Version 4.03, effective date 14 June 2010 [42].
If a subject is noted to have ALT and/or AST elevated >3 ×ULN and total bilirubin >2 ×ULN, the 
abnormality should be recorded as an SAE. The SAE form should be completed and reported as 
described above. The investigator must contact the monitor or the sponsor’s designee for 
discussion of the relevant subject details and possible alternative etiologies, such as acute viral 
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hepatitis A or B or other acute liver disease or medical history/concurrent medical conditions. 
Followup laboratory tests as described in Section 9.4.14 must also be performed.
Causality of the event to study drug administration will be determined by the investigator 
responding yes (related) or no (unrelated) to this question: “Is there a reasonable possibility that 
the AE is associated with the study drug?”
10.3
Monitoring of Adverse Events and Period of Observation
AEs, both nonserious and serious, will be monitored throughout the study as follows:

AEs will be reported from the signing of ICF through 30 days after the last dose of study drug
or the start of subsequent systemic anticancer treatment whichever occurs first, and recorded
in the eCRFs.

SAEs (related and unrelated) will be reported to the Takeda Global Pharmacovigilance
department or designee from the time of the signing of the ICF through 30 days after
administration of the last dose of study drug or the start of subsequent systemic anticancer
treatment whichever occurs first, and recorded in the eCRF. After this period, only related
SAEs must be reported to the Takeda Global Pharmacovigilance department or designee.
SAEs should be monitored until they are resolved or are clearly determined to be due to a
subject’s stable or chronic condition or intercurrent illness(es).
All SAEs that are ongoing 30 days after the last dose of study drug, and AEs assessed Grade 3 or 4 
that led to study treatment discontinuation that are ongoing 30 days after the last dose of study 
drug, 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 day of the last dose of 
study drug.
The status of all other AEs that are ongoing at the 30-day posttreatment followup visit will be 
documented as of the 30-day posttreatment followup visit.
10.4 
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
If a woman becomes pregnant or suspects that she is pregnant while participating in this study, she 
must inform the investigator immediately and permanently discontinue study drug. The sponsor 
must also be contacted immediately by faxing a completed Pregnancy Form to the Takeda Global 
Pharmacovigilance department or designee (see Section 10.2). The pregnancy must be followed 
for the final pregnancy outcome.
If a female partner of a male subject becomes pregnant during the male subject’s participation in 
this study, the sponsor must also be contacted immediately by faxing a completed Pregnancy 
Form 
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to the Takeda Global Pharmacovigilance department or designee (see Section 10.2). Every effort 
should be made to follow the pregnancy for the final pregnancy outcome.
10.5 
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose)
10.5.1 Procedures for Reporting Product Complaints
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product. Investigators who 
identify a potential product complaint situation should immediately report this to the study 
monitors.
If a product complaint results in an SAE, an SAE form should be completed and sent to BI 
Medical, Inc (contact information is provided in the protocol annex).
10.5.2 Procedures for Reporting Medication Errors (Including Overdose)
A medication error is a preventable event that involves an identifiable subject and that leads to 
inappropriate medication use, which may result in subject harm. Whereas overdoses and 
underdoses constitute medication errors, doses missed inadvertently by a subject do not.
All cases of overdose (with or without associated AEs) will be documented on an Overdose page 
of the eCRF, in order to capture this important safety information consistently in the database. 
Cases of overdose without manifested signs or symptoms are not considered AEs. AEs associated 
with an overdose will be documented on the AE page of the eCRF.
If a medication error results in an SAE, an SAE form should be completed and sent to BI Medical, 
Inc (contact information is provided in the protocol annex).
10.6 
Safety Reporting to Investigators, IRBs and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators, IRBs and/or the 
head of each study site. Relative to the first awareness of the event by/or further provision to the 
sponsor or sponsor’s designee, SUSARs will be submitted to the regulatory authorities as an 
expedited report within 7 days for fatal and life-threatening events and 15 days for other serious 
events, unless otherwise required by national regulations. The sponsor will also prepare an 
expedited report for other safety issues where these might materially alter the current benefit-risk 
assessment of an investigational medicinal product or that would be sufficient to consider changes 
in the investigational medicinal product’s administration or in the overall conduct of the trial.
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11.0
STUDY-SPECIFIC COMMITTEES
11.1
Independent Radiology Committee
An IRC will be established to evaluate tumor scans and prior radiation history data of trial subjects 
in a central, blinded, and independent fashion (see also Section 9.4.15.2). The IRC will be 
comprised of board certified radiologists who will determine radiographic response and 
progression following enrollment. Additional imaging results may be requested by the sponsor for 
IRC review.
Additional details regarding IRC member qualification, training, methods, procedures, and other 
issues relevant to committee operations will be described in the IRC Charter.
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12.0 
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
If selected for coding, AEs, medical history including concurrent conditions will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the 
World Health Organization Drug Dictionary.
12.1 
eCRFs
Completed eCRFs are required for each subject who signs an ICF.
The sponsor or its designee will allow the study sites to have access to eCRFs and will make 
arrangements to train appropriate site staff in the use of the eCRF. These forms are used to transmit 
the information collected in the performance of this study to the sponsor, contract research 
organization (CRO) partners, and regulatory authorities. Investigative sites must complete eCRFs 
in English.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site.
Any change of, modification of, or addition to the data on the eCRFs should be made by the 
investigator or appropriate site personnel. Corrections to eCRFs are recorded in an audit trail that 
captures the old information, the new information, identification of the person making the 
correction, the date the correction was made, and the reason for change.
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the principal investigator must retain 
full responsibility for the accuracy and authenticity of all data entered on the eCRFs.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
12.2 
Record Retention
The investigator and the head of the institution agree to keep the records stipulated in Section 12.1 
and those documents that include (but are not limited to) the study-specific documents, the 
identification log of all participating subjects, medical records, temporary media such as thermal 
sensitive paper, source worksheets, all original signed and dated ICFs, subject authorization forms 
regarding the use of personal health information (if separate from the ICFs), electronic copies of 
eCRFs, including the audit trails, and detailed records of drug disposition to enable evaluations or 
audits from regulatory authorities, the sponsor or its designees. Any source documentation printed 
on degradable thermal sensitive paper should be photocopied by the site and filed with the original 
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in the subject’s chart to ensure long term legibility. Furthermore, ICH E6 Section 4.9.5 requires the 
investigator and the head of the institution to retain essential documents specified in ICH E6 
(Section 8) until at least 3 years after the last approval of a marketing application for a specified 
drug indication being investigated or, if an application is not approved, until at least 3 years after 
the investigation is discontinued and regulatory authorities are notified. In addition, ICH E6 
Section 4.9.5 states that the study records should be retained until an amount of time specified by 
applicable regulatory requirements or for a time specified in the Clinical Study Site Agreement 
between the investigator and/or the head of the institution and sponsor.
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. The 
investigator and the head of the institution should contact and receive written approval from the 
sponsor before disposing of any such documents.
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13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) for the CSR and for the CSR efficacy and safety addendum will 
be prepared separately, and finalized prior to database lock for each analysis. These documents 
will provide further details regarding the definition of analysis variables and analysis methodology 
to address all study objectives.
A data review will be conducted prior to database lock for each analysis. This review will assess 
the accuracy and completeness of the study database, subject evaluability, and appropriateness of 
the planned statistical methods.
13.1.1 Analysis Sets
In this study, 2 kinds of analysis sets are defined: full analysis set (FAS) and safety analysis set. 
Both FAS and safety analysis set will be defined as “all subjects who received at least one dose of 
study drug.”
13.1.2 Analysis of Demographics and Other Baseline Characteristics
Demographics and other baseline characteristics will be summarized for each Cohort and overall 
using the FAS.
13.1.3 Efficacy Analysis
Efficacy analyses will be performed using the FAS unless otherwise specified.
13.1.3.1 Primary Endpoint and Analytical Methods
The primary endpoint is 24-week PFSR, per RECIST 1.1 by IRC. PFS is defined as time from the 
first day of study drug administration to the earlier of PD per RECIST 1.1 or death due to any 
cause. 24-week PFSR is defined as PFS proportion at Study Day of Week 25 Day 1 + 7 days.
Only adequate tumor assessments will be considered in the determination of progression and 
censoring date. General censoring rules for the analysis of PFS will be as follows:

Subjects who have not experienced an event at the time of data cutoff will be censored at the
date of the last adequate tumor assessment.

Subjects who receive subsequent systemic or liver directed local anticancer therapy or
radiation therapy (other than to bone) before experiencing an event will be censored at the date
of the last adequate tumor assessment on or prior to the date of initiation of the subsequent
treatment.

Subjects who receive tumor resection surgery after enrollment before experiencing an event
will be censored at the date of the last adequate tumor assessment on or prior to the date of the
surgery.
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
Subjects who miss 2 or more consecutive adequate scheduled tumor assessments immediately
followed by an event will be censored at the date of the last adequate tumor assessment prior
to the missing/inadequate assessments.
–
If the 2 or more consecutive missing adequate assessments are immediately followed by an
adequate assessment with an overall response assignment of SD, PR, or CR, this will be
deemed sufficient clinical evidence that progression did not occur during the period of
missing data and the missing evaluations will be ignored.
Primary Analysis
For 24-week PFSR by IRC, Kaplan-Meier estimate will be provided and the corresponding 
2-sided 90% CI will be calculated for Cohort A using the Greenwood's formula and the 
complementary log-log transformation.
Other Analysis
The same analysis as that in the primary analysis will be conducted for Cohort B and overall (ie, 
Cohort A + Cohort B).
13.1.3.2 Secondary Endpoints and Analytical Methods
PFS, per RECIST 1.1, by IRC
For PFS by IRC, median PFS will be estimated using the Kaplan-Meier method, and the 
Kaplan-Meier plot will be presented for each Cohort and overall.
ORR, per RECIST 1.1, by IRC
ORR is defined as proportion of subjects whose best overall response is CR or PR per RECIST 1.1, 
which is confirmed by a subsequent evaluation conducted ≥28 days later.
Only the results of tumor assessment conducted on or prior to the earlier of the date of PFS event or 
date of censoring for PFS, described in the analytical method for 24-week PFSR above, will be 
used in order to determine the best overall response.
For ORR by IRC, point estimate and the 2-sided 95% exact CI will be calculated for each Cohort 
and overall.
DCR, per RECIST 1.1, by IRC
DCR is defined as proportion of subjects whose best overall response is CR, PR or SD per RECIST 
1.1. CR and PR require confirmation by a subsequent evaluation conducted ≥28 days later, and SD 
have to be maintained for at least 8 weeks (51 days) after the first day of study drug administration.
DCR will be determined using the same data as those used in the determination of ORR.
For DCR by IRC, point estimate and the 2-sided 95% exact CI will be calculated for each Cohort 
and overall.
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OS
OS is defined as time from the first day of study drug administration to death due to any cause.
Subjects who have not experienced an event at the time of data cutoff will be censored at the earlier 
of the data cutoff or the last date when the subjects are known to be alive.
For OS, the same analyses as those for PFS will be performed.
13.1.3.3 Additional Endpoints
Analytical methods for the additional endpoints will be described in the SAP.
13.1.3.4 Confidence Coefficient

Analyses for primary endpoint: 90% (2-sided).

Other analyses: 95% (2-sided).
13.1.4 PK Analysis
The plasma concentration of cabozantinib will be analyzed by the designee using a validated 
bioanalytical method. Descriptive statistics (eg, number, mean and/or median, standard deviation, 
and coefficient of variation) will be used to describe the concentration-time data. Where 
appropriate, these data may be analyzed using PopPK models and/or combined with data from 
other studies as part of a meta-analysis. The influence of exposure on biomarkers, clinical safety 
parameters (eg, selected AEs) or clinical response may also be explored.
13.1.5 Biomarker Analysis
A retrospective correlative study of candidate biomarkers (protein expression in signal pathway, 
metabolic signature, etc) in relation to clinical response to cabozantinib in patients with advanced 
HCC may be performed using descriptive statistics, graphical methods, and statistical modeling as 
appropriate. Biomarker analysis data from this study may be combined with data from other 
studies. Results of pooled analyses may be summarized in a separate report.
13.1.6 Pharmacogenomic Analysis
Genotyping of polymorphisms in genes encoding drug-metabolizing enzymes and/or transporters 
will be performed. Individual germline genotype will be listed for each of the polymorphisms 
evaluated, if applicable. Descriptive and graphical methods may be used to explore the 
relationship between genotype and PK, safety, tolerability, and/or response to study treatment. 
Pharmacogenomic data from this study may be combined with data from other studies. Results of 
pooled analyses may be summarized in a separate report.
13.1.7 Safety Analysis
Safety analyses will be performed using the safety analysis set.
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13.1.7.1 Safety Endpoints and Analytical Methods
TEAEs

TEAEs.

Grade 3 or higher TEAEs.

Serious TEAEs.

Permanent discontinuation by TEAEs.

Dose modification (dose reduction or interruption) by TEAEs.
TEAE is defined as an AE whose date of onset occurs on or after the start of study drug and within 
30 days after the last dose of study drug. TEAEs will be coded using the MedDRA dictionary.
The frequency distribution will be provided for each Cohort and overall for each summary using 
the system organ class and the PT. The same analyses will be provided including only TEAEs 
which are considered related to the study drug.
Laboratory Values and Vital Sign Measurements

Clinically significant abnormal laboratory values.

Clinically significant abnormal vital sign measurements.
The frequency distribution of maximum grade for laboratory abnormalities, and the frequency 
distribution of clinically significant abnormal vital sign measurements will be provided for each 
Cohort and overall.
13.2 
Interim Analysis and Criteria for Early Termination
No interim analysis is planned.
13.3 
Determination of Sample Size
A study with 17 subjects will provide at least 80% probability that the lower limit of the two-sided 
90% CI for the 24-week PFSR by Kaplan-Meier method results in ≥11.1% when assuming the true 
24-week PFSR ≥38.4%.
In Study XL184-309 in subjects with advanced HCC who have received prior sorafenib, the 
24-week PFSR by investigator was 38.4% (95% CI: [33.5, 43.3]%) and 11.1% (95% CI: [7.2, 
15.8]%) in cabozantinib and placebo group, respectively. In reference to the above results, a 
24-week PFSR of 38.4% is assumed and the threshold is set at 11.1% in this study.
This study will enroll at least 17 subjects who have received prior sorafenib in Cohort A. In 
addition, for better understanding of the efficacy and safety profile of cabozantinib in Japanese 
patients, similar number of subjects who have received prior sorafenib in Cohort A and who have 
not received prior sorafenib in Cohort B will be enrolled, resulting in approximately 32 subjects in 
total.
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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE
14.1 
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and the head of the study site guarantee access to source documents by the 
sponsor or its designee (CRO) and by the IRB.
All aspects of the study and its documentation will be subject to review by the sponsor or designee, 
including the Investigator’s Binder, study medication, subject medical records, informed consent 
documentation, and review of eCRFs and associated source documents. It is important that the 
investigator and other study personnel are available during the monitoring visits and that sufficient 
time is devoted to the process.
14.2 
Protocol Deviations
The investigator can deviate and change from the protocol for any medically unavoidable reason, 
for example, to eliminate an immediate hazard to study subjects, without a prior written agreement 
with the sponsor or a prior approval from IRB. In the event of a deviation or change, the principal 
investigator should notify the sponsor and the head of the site of the deviation or change as well as 
its reason in a written form, and then retain a copy of the written form. When necessary, the 
principal investigator may consult and agree with the sponsor on a protocol amendment. If the 
protocol amendment is appropriate, the amendment proposal should be submitted to the head of 
the site as soon as possible and an approval from IRB should be obtained.
The investigator should document all protocol deviations. In the event of a significant deviation, 
the site should notify the sponsor or its designee (and IRB, as required).
14.3 
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments (eg, the FDA, the United Kingdom Medicines and Healthcare 
products Regulatory Agency [MHRA], the Pharmaceuticals and Medical Devices Agency of 
Japan [PMDA]). If the study site is contacted for an inspection by a regulatory body, the sponsor 
should be notified immediately. The investigator and the head of the study site guarantee access 
for quality assurance auditors to all study documents as described in Section 14.1.
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15.0 
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in Appendix B. 
The principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
15.1 
IRB Approval
IRBs must be constituted according to the applicable local requirements of each participating 
region. The sponsor or designee will require documentation noting all names and titles of members 
who make up the respective IRB. If any member of the IRB has direct participation in this study, 
written notification regarding his or her abstinence from voting must also be obtained.
The sponsor or designee will supply relevant documents for submission to the respective IRB for 
the protocol’s review and approval. This protocol, the IB, a copy of the ICF, and, if applicable, 
subject recruitment materials and/or advertisements and other documents required by all 
applicable laws and regulations, must be submitted to a central or local IRB for approval. The 
IRB’s written approval of the protocol and subject informed consent must be obtained and 
submitted to the sponsor or designee before commencement of the study (ie, before signing a 
contract for the clinical study). The IRB approval must refer to the study by exact protocol title, 
number, and version date; identify versions of other documents (eg, ICF) reviewed; and state the 
approval date. The sponsor will notify site once the sponsor has confirmed the adequacy of site 
regulatory documentation. Until the site receives notification, no protocol activities including 
assignment of patients may occur.
Study sites must adhere to all requirements stipulated by their respective IRBs. This may include 
notification to the IRB regarding protocol amendments, updates to the ICF, recruitment materials 
intended for viewing by subjects, local safety reporting requirements, reports and updates 
regarding the ongoing review of the study at intervals specified by the respective IRB, and 
submission of the investigator’s final status report to IRB. All IRB approvals and relevant 
documentation for these items must be provided to the sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB and sponsor.
15.2 
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The ICF describes the planned and permitted uses, transfers, and 
disclosures of the subject’s personal and personal health information for purposes of conducting 
the study. The ICF further explains the nature of the study, its objectives, and potential risks and 
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benefits, as well as the date that informed consent is given. The ICF will detail the requirements of 
the participant and the fact that he or she is free to withdraw at any time without giving a reason 
and without prejudice to his or her further medical care.
The principal investigator is responsible for the preparation, content, and IRB approval of the ICF. 
The ICF must be approved by both the IRB and the sponsor prior to use.
The ICF must be written in a language fully comprehensible to the prospective subject. It is the 
responsibility of the investigator to explain the detailed elements of the ICF to the subject. 
Information should be given in both oral and written form whenever possible and in the manner 
deemed appropriate by the IRB.
The subject must be given ample opportunity to: (1) inquire about details of the study and 
(2) decide whether or not to participate in the study. If the subject determines he or she will 
participate in the study, then the ICF must be signed and dated by the subject, at the time of consent 
and prior to the subject entering into the study. The subject should be instructed to sign using their 
legal names, not nicknames, using blue or black ballpoint ink. The investigator must also sign and 
date the ICF at the time of consent and prior to subject entering into the study.
Once signed, the original ICF will be stored in the investigator’s site file. The investigator must 
document the date the subject signs the informed consent in the subject’s medical record. Copies 
of the signed ICF shall be given to the subject.
All revised ICFs must be reviewed and signed by relevant subjects in the same manner as the 
original informed consent. The date the revised consent was obtained should be recorded in the 
subject’s medical record, and the subject should receive a copy of the revised ICF.
15.3 
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth may be used to verify the subject and accuracy of the subject’s unique identification 
number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, the FDA, MHRA, PMDA), the sponsor’s designated auditors, and the 
appropriate IRBs to review the subject’s original medical records (source data or documents), 
including, but not limited to, laboratory test result reports, ECG reports, admission and discharge 
summaries for hospital admissions occurring during a subject’s study participation, and autopsy 
reports. Access to a subject’s original medical records requires the specific authorization of the 
subject as part of the informed consent process (see Section 15.2).
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Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1 Publication
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator.
The investigator needs to obtain a prior written approval from the sponsor to publish any 
information from the study externally such as to a professional association.
15.4.2 Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum, register 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with facility name, investigator’s city, country, and recruiting status 
will be registered and available for public viewing.
15.4.3 Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites (including the Takeda corporate site) and registries, as required by Takeda 
Policy/Standard, applicable laws and/or regulations.
15.5 
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study subjects. 
Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this policy, he or 
she should contact the sponsor or sponsor’s designee.
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16.0
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Study No. Cabozantinib-2003
Page 122 of 130
Protocol Incorporating Amendment No.01
30 October 2018
Appendix J 
Detailed Description of Amendments to Text
This document describes changes in reference to Protocol Incorporating Amendment No. 01.
The text that was deleted or revised in Amendment No. 01 is indicated using italics and underline 
font. New or revised text adopted in Amendment No.01 is shown in bold font.
Page 11, Section 2.0 STUDY SUMMARY (Treatment Period) / Page 38, Section 6.1 
Overview of Study Design (Treatment Period) / Page 41, Section 6.3.1 Duration of an 
Individual Patient’s Study Participation
Existing Text
Treatment may continue after radiographic RCC progression per Response Evaluation Criteria In 
Solid Tumors Version 1.1 (RECIST 1.1) 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 risks.
Revised Text
Treatment may continue after radiographic RCC progression per Response Evaluation Criteria In 
Solid Tumors Version 1.1 (RECIST 1.1) 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 risks. However the subject should discontinue study treatment 
after the second determination of disease progression.
Rationale for Amendment
Revised to clarify the duration of the study treatment tolerable in subjects with disease progression. 
The subject should discontinue study treatment after the second determination of disease 
progression to consider any other treatment opportunity.
Page 11, Section 2.0 STUDY SUMMARY (Posttreatment Period) / Page 38, Section 6.1 
Overview of Study Design (Posttreatment Period) / Page 41, Section 6.3.1 Duration of an 
Individual Patient’s Study Participation / Page 83, Section 9.10 Posttreatment Followup 
Assessments
Existing Text
A 30-day posttreatment followup visit for safety will occur 30 (+14) days after the last dose of 
study drug.
Revised Text
A 30-day posttreatment followup visit for safety will occur 30 (+14) days after the last dose of 
study drug or until the start of subsequent systemic anticancer treatment, whichever occurs 
first.
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Cabozantinib
Study No. Cabozantinib-2003
Page 123 of 130
Protocol Incorporating Amendment No.01
30 October 2018
Rationale for Amendment
Revised the posttreatment followup period. Considering that the subsequent systemic anticancer 
treatment may modify the safety profile of Cabozantinib, if the subsequent systemic anticancer 
treatment is conducted within 30 days after the last dose of study drug, posttreatment followup is 
to be completed at that time.
Page 24, Section 4.1.2 Study Drug
Existing Text
Cabometyx is also currently under review by the European Medicines Agency (EMA)  for 
previously untreated patients with advanced RCC, and the Committee for Medicinal Products for 
Human Use adopted a positive opinion recommending a change to the terms of the marketing 
authorization on 22 March 2018.
Revised Text
Cabometyx was also approved by FDA on 19 December 2017 for patients with previously 
untreated advanced RCC, and by European Commission on 17 May 2018 for the previously 
untreated adults patients with intermediate-or poor-risk advanced RCC.
Rationale for Amendment
Updated information. This information is also reflected in Section 4.2 Rationale for the Proposed 
Study.
Page 50, Section 8.2.1 Dose Reductions, Interruptions and Discontinuation / Page 73 Section 
9.4.14 Clinical Laboratory Evaluations / Page 75 Table 9.a.
Existing Text
The following parameters must be included in local laboratory assessment for dose modification: 
complete blood count with differential leucocyte count, ALP, ALT, AST, and bilirubin (total 
bilirubin, conjugated and unconjugated bilirubin) .
Revised Text
The following parameters must be included in local laboratory assessment for dose modification: 
WBC count with differential and platelets , ALP, ALT, AST, and total bilirubin.
Rationale for Amendment
Modified to clarify that local laboratory assessment for dose modification.
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Study No. Cabozantinib-2003
Page 124 of 130
Protocol Incorporating Amendment No.01
30 October 2018
Page 50, Section 8.2.1 Concomitant Medications and Procedures
Existing Text

Dose interruptions for reason(s) other than AEs (eg, surgical procedures) can be longer than 6
weeks but require sponsor approval. The acceptable length of interruption will depend on
agreement between investigator and the sponsor.
Revised Text

Following cases require sponsor approval;

Keeping same level of dose despite the toxicity meet the status in the modification
guideline that require dose reduction or interruption.

Dose re-escalation or dose reinstitution at the same level after dose interruption due
to the toxicity.

Dose interruptions for reason(s) other than AEs (eg, surgical procedures) for more than
6 weeks. The acceptable length of interruption will depend on agreement between
investigator and the sponsor.
Rationale for Amendment
Added the cases that require sponsor approval in dose modifications.
Page 72, Section 9.4.10 Concomitant Medications and Procedures
Existing Text
Medications used by the subject (including prescription and over-the-counter medications, 
transfusions, vitamins, herbal remedies, and nutritional supplements) and therapeutic procedures 
completed by the subject and their outcomes will be recorded in the electronic case report form 
(eCRF) from the time of the signing of the ICF through 30 days after the last dose of study drug.
Revised Text
Medications used by the subject (including prescription and over-the-counter medications, 
transfusions, vitamins, herbal remedies, and nutritional supplements) and therapeutic procedures 
completed by the subject and their outcomes will be recorded in the electronic case report form 
(eCRF) from the time of the signing of the ICF through 30 days after the last dose of study drug or 
the start of subsequent systemic anticancer treatment, whichever occurs first.
Rationale for Amendment
Revised the collection period of concomitant medications and procedures to adapt it to the revised 
posttreatment followup period.
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Study No. Cabozantinib-2003
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Protocol Incorporating Amendment No.01
30 October 2018
Page 73, Section 9.4.14 Clinical Laboratory Evaluations
Existing Text
Local laboratory tests for dose modification consideration will be performed at each study visit as 
well as central laboratory tests.
Revised Text
Local laboratory tests for dose modification consideration will be performed at each study visit as 
well as central laboratory tests. On Week 1 Day 1, the  results of local laboratory tests at the 
most recent or Week 1 Day 1 that consideration will be used to start of treatment.
Rationale for Amendment
Added the results of local laboratory tests at the most recent or Week 1 Day 1 that consideration 
will be used to start of treatment on Week 1 Day 1.
Page 76, Section 9.4.15.1General
Existing Text
1. Chest/Abdomen/Pelvis: CT (or MRI) of CAP will be performed in all subjects at Screening.
CT (or MRI) will be performed on Week 9 Day 1 and every 8 weeks (±7 days) thereafter. If
MRI of the CAP study is performed at Screening, then a noncontrast CT of the chest should be
performed as well.
…
Duration of Radiographic Tumor Assessments

For subjects who discontinue study treatment before radiographic disease progression or
within 8 weeks after radiographic disease progression, final radiographic tumor assessments
are to be performed 8 weeks after radiographic disease progression. For subjects who
discontinued study treatment and commenced a subsequent anticancer therapy (other than
radiation therapy to bone), radiographic tumor assessments are no longer necessary to be
performed.
…
Tumor assessment by investigator
…
For the purpose of subject management and treatment decisions, radiographic response and 
disease progression will be assessed by investigators using RECIST 1.1 (Appendix F). The 
sponsor should be notified of all disease progression as soon as possible. If any doubt or 
ambiguities exist about radiographic progression, investigators are encouraged to continue study 
therapy if the subject is tolerating it acceptably, repeat radiographic studies at the next scheduled 
time, and delay determination of progression until the findings indicating radiographic progression 
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Study No. Cabozantinib-2003
Page 126 of 130
Protocol Incorporating Amendment No.01
30 October 2018
are unequivocal. Radiographic progression determined by the investigator does not warrant 
discontinuation of tumor assessments or study treatment (see Section 9.7).
Revised Text
1. Chest/Abdomen/Pelvis: CT (or MRI) of CAP will be performed in all subjects at Screening.
CT (or MRI) will be performed on Week 9 Day 1 and every 8 weeks (±7 days) thereafter. If
MRI of the CAP study is used at Screening, MRI of abdomen and pelvis will be required
and noncontrast CT of the chest should be performed as well.
…
Duration of Radiographic Tumor Assessments

For subjects who discontinue study treatment before radiographic disease progression or
within 8 weeks after radiographic disease progression, final radiographic tumor assessments
are to be performed 8 weeks after radiographic disease progression. For subjects who
discontinued study treatment and commenced a subsequent anticancer therapy (other than
radiation therapy to bone), radiographic tumor assessments should be performed prior to
the subsequent therapy. No further radiographic tumor assessments are necessary to be
performed.
…
Tumor assessment by investigator
…
For the purpose of subject management and treatment decisions, radiographic response and 
disease progression will be assessed by investigators using RECIST 1.1 (Appendix F). The 
sponsor should be notified of all disease progression as soon as possible. If any doubt or 
ambiguities exist about radiographic progression, investigators are encouraged to continue study 
therapy if the subject is tolerating it acceptably, repeat radiographic studies at the next scheduled 
time, and delay determination of progression until the findings indicating radiographic progression 
are unequivocal. Radiographic progression determined by the investigator does not warrant 
discontinuation of tumor assessments or study treatment (see Section 9.7). If the study treatment 
is continued even after determination of disease progression, the time of disease progression 
determined by the investigator will be considered "baseline" and tumor assessment will be 
continued based on the RECIST 1.1 criteria. If a new lesion is identified and determined to 
be disease progression by the investigator, this lesion will be assessed as a nontarget lesion 
and tumor assessment will be continued. No radiographic assessment is necessary after the 
second determination of disease progression.
Rationale for Amendment
Added the requirements of the MRI. This change is also included in the same section Imaging 
Guidelines. Clarified the radiographic tumor assessments period of the subjects who commenced a 
subsequent anticancer therapy. Clarified the study treatment continued procedures of after 
determination of disease progression.
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Study No. Cabozantinib-2003
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Protocol Incorporating Amendment No.01
30 October 2018
Page 84, Section 10.1.1 Adverse Event Definition
Existing Text
This includes any newly occurring event, or a previous condition that has increased in severity or 
frequency since the administration of study drug.
Revised Text
This includes any newly occurring event, or a previous condition that has increased in severity or 
frequency after signing the ICF.
Rationale for Amendment
Modified to make consistent with the collection period of adverse event.
Page 86, Section 10.3 Monitoring of Adverse Events and Period of Observation
Existing Text

AEs will be reported from the signing of ICF through 30 days after the last dose of study drug
and recorded in the eCRFs.

SAEs (related and unrelated) will be reported to the Takeda Global Pharmacovigilance
department or designee from the time of the signing of the ICF through 30 days after
administration of the last dose of study drug and recorded in the eCRF. After this period, only
related SAEs must be reported to the Takeda Global Pharmacovigilance department or
designee. SAEs should be monitored until they are resolved or are clearly determined to be
due to a subject’s stable or chronic condition or intercurrent illness(es).
All SAEs that are ongoing 30 days after the last dose of study drug, and AEs assessed Grade 3 or 4 
that led to study treatment discontinuation that are ongoing 30 days after the last dose of study 
drug, 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 day of the last dose of 
study drug.
The status of all other AEs that are ongoing 30 days after the day of the last dose of study drug will 
be documented as of the 30-day posttreatment followup visit.
Revised Text

AEs will be reported from the signing of ICF through 30 days after the last dose of study drug
or the start of subsequent systemic anticancer treatment whichever occurs first, and
recorded in the eCRFs.
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Study No. Cabozantinib-2003
Page 128 of 130
Protocol Incorporating Amendment No.01
30 October 2018

SAEs (related and unrelated) will be reported to the Takeda Global Pharmacovigilance
department or designee from the time of the signing of the ICF through 30 days after
administration of the last dose of study drug or the start of subsequent systemic anticancer
treatment whichever occurs first, and recorded in the eCRF. After this period, only related
SAEs must be reported to the Takeda Global Pharmacovigilance department or designee.
SAEs should be monitored until they are resolved or are clearly determined to be due to a
subject’s stable or chronic condition or intercurrent illness(es).
All SAEs that are ongoing 30 days after the last dose of study drug, and AEs assessed Grade 3 or 4 
that led to study treatment discontinuation that are ongoing 30 days after the last dose of study 
drug, 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 day of the last dose of 
study drug.
The status of all other AEs that are ongoing at the 30-day posttreatment followup visit will be 
documented as of the 30-day posttreatment followup visit.
Rationale for Amendment
Revised the posttreatment AEs followup period. Considering that the subsequent systemic 
anticancer treatment may modify the safety profile of Cabozantinib, if the subsequent systemic 
anticancer treatment is conducted within 30 days after the last dose of study drug, AEs collection 
and recording in the eCRF are to be completed at that time.
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SAP_001.pdf: 
Title: A Phase 2, Open-Label, Single-Arm Study of Cabozantinib in Japanese Patients 
With Advanced Hepatocellular Carcinoma Who Have Received Prior Systemic 
Anticancer Therapy 
NCT Number: NCT03586973 
Statistical analysis plan Approve Date: 05-SEP-2019 
Certain information within this Statistical analysis plan has been redacted (ie, specific 
content is masked irreversibly from view with a black/blue bar) to protect either 
personally identifiable information or company confidential information. 
This may include, but is not limited to, redaction of the following: 

Named persons or organizations associated with the study.

Patient identifiers within the text, tables, or figures or in by-patient data listings.

Proprietary information, such as scales or coding systems, which are considered
confidential information under prior agreements with license holder.

Other information as needed to protect confidentiality of Takeda or partners,
personal information, or to otherwise protect the integrity of the clinical study.
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 


STATISTICAL ANALYSIS PLAN
STUDY NUMBER: Cabozantinib-2003
A Phase 2, Open-Label, Single-Arm Study of Cabozantinib in Japanese Patients With Advanced 
Hepatocellular Carcinoma Who Have Received Prior Systemic Anticancer Therapy
PHASE 2
Version: 2
Date: 5 September 2019
Prepared by:
Biostatistics, Takeda Development Center Japan
Based on:
Protocol Version: Amendment 01
Protocol Date: 30 October 2018
PPD
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Cabozantinib-2003
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Statistical Analysis Plan Version 2
5 September 2019
1.1
Approval Signatures
Electronic signatures can be found on the last page of this document.
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Page 3 of 64
Statistical Analysis Plan Version 2
5 September 2019
2.0
TABLE OF CONTENTS
1.0
TITLE PAGE.................................................................................................................. 1
1.1
Approval Signatures.................................................................................................. 2
2.0
TABLE OF CONTENTS ................................................................................................ 3
List of In-Text Tables ........................................................................................................... 4
3.0
LIST OF ABBREVIATIONS.......................................................................................... 5
4.0
OBJECTIVES................................................................................................................. 7
4.1
Primary Objective ..................................................................................................... 7
4.2
Secondary Objectives ................................................................................................ 7
4.3
Safety Objective........................................................................................................ 7
4.4
Additional Objectives................................................................................................ 7
4.5
Study Design............................................................................................................. 7
5.0
ANALYSIS ENDPOINTS .............................................................................................. 9
6.0
DETERMINATION OF SAMPLE SIZE....................................................................... 10
7.0
METHODS OF ANALYSIS AND PRESENTATION .................................................. 11
7.1
General Principles ................................................................................................... 11
7.1.1
Study Definitions............................................................................................... 11
7.1.2
Definition of Study Days ................................................................................... 12
7.1.3
Definition of Study Visit Windows.................................................................... 12
7.1.4
Significance Level and Confidence Coefficient.................................................. 13
7.1.5
Conventions for Missing Adverse Event Dates .................................................. 14
7.1.6
Conventions for Missing Concomitant Medication Dates................................... 14
7.1.7
Imputation of Other Incomplete Dates ............................................................... 14
7.2
Analysis Sets........................................................................................................... 14
7.3
Disposition of Subjects............................................................................................ 15
7.3.1
Study Information.............................................................................................. 15
7.3.2
Screen Failures .................................................................................................. 15
7.3.3
Subject Eligibility.............................................................................................. 15
7.3.4
Number of Subjects Enrolled into the Treatment Period by Site......................... 16
7.3.5
Disposition of Subjects ...................................................................................... 16
7.3.6
Protocol Deviations and Analysis Sets............................................................... 17
7.4
Demographic and Other Baseline Characteristics..................................................... 18
7.5
Medical History and Concurrent Medical Conditions............................................... 20
7.6
Medication History and Concomitant Medications .................................................. 21
7.7
Prior Surgery and Procedure.................................................................................... 21
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Statistical Analysis Plan Version 2
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7.8
Prior Non-Surgical Anticancer Therapy................................................................... 22
7.9
Concomitant and Subsequent Anticancer Therapy................................................... 25
7.10
Study Drug Exposure and Compliance .................................................................... 27
7.11
Dose Modification................................................................................................... 27
7.12
Efficacy Analysis .................................................................................................... 29
7.12.1 Primary Endpoint............................................................................................... 29
7.12.2 Secondary Endpoints ......................................................................................... 30
7.12.3 Additional Endpoints......................................................................................... 32
7.12.4 Statistical/Analytical Issues ............................................................................... 36
7.13
Safety Analysis........................................................................................................ 38
7.13.1 Adverse Events.................................................................................................. 38
7.13.2 Clinical Laboratory Evaluations......................................................................... 44
7.13.3 Vital Signs and Weight...................................................................................... 46
7.13.4 12-Lead ECGs................................................................................................... 47
7.13.5 Other Observations Related to Safety................................................................. 48
7.14
Interim Analysis...................................................................................................... 49
7.15
Changes in the Statistical Analysis Plan................................................................... 50
8.0
REFERENCES ............................................................................................................. 51
9.0
APPENDIX................................................................................................................... 52
9.1
Criteria for Clinically Significant Abnormal Values ................................................ 52
9.2
Criteria for Elevated Liver Enzyme and Elevated Serum Creatinine ........................ 53
9.3
Definition of Treatment-Emergent Adverse Events to Monitor................................ 55
9.4
Statistical Analysis Plan Version 2 Summary of Changes........................................ 63
LIST OF IN-TEXT TABLES
Table 7.a
Visit Window for Endpoints Other Than AFP, Bone Specific ALP and Plasma 
Concentrations of Cabozantinib ......................................................................... 13
Table 7.b
Visit Window for AFP and Bone Specific ALP ................................................. 13
Table 7.c
Visit Window for Plasma Concentrations of Cabozantinib................................. 13
Table 9.a
Clinically Significant Abnormal Value Criteria for Laboratory Parameters........ 52
Table 9.b
Clinically Significant Abnormal Value Criteria for Vital Sign Parameters ......... 53
Table 9.c
Clinically Significant Abnormal Value Criteria for ECG Parameters ................. 53
Table 9.d
Criteria for Elevated Liver Enzyme.................................................................... 53
Table 9.e
Criteria for Elevated Serum Creatinine .............................................................. 55
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Statistical Analysis Plan Version 2
5 September 2019
3.0
LIST OF ABBREVIATIONS
AE
adverse event
AFP
alpha-fetoprotein
ALBI Grade
albumin-bilirubin grade
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
APTT
activated partial thromboplastin time
AST
aspartate aminotransferase
BMI
body mass index
BUN
blood urea nitrogen
CI
confidence interval
CR
complete response
CT
computerized tomography
CTCAE
Common Terminology Criteria for Adverse Events
CV
coefficient of variation
DBP
diastolic blood pressure
DCR
disease control rate
EBRT
external beam radiation therapy
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EQ-5D-5L
EuroQol Health questionnaire instrument
EQ VAS
EuroQol visual analogue scale
FAS
full analysis set
GCP
Good Clinical Practice
GGT
γ-glutamyl transferase (gamma-glutamyl transferase)
GI
gastrointestinal
HBsAg
hepatitis B surface antigen
HCC
hepatocellular carcinoma
HCVAb
hepatitis C virus antibody
HRQOL
health-related quality of life
ICF
informed consent form
IGRT
image-guided radiation therapy
IMRT
intensity-modulated radiation therapy
IRC
independent radiology committee
LDH
lactate dehydrogenase
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
NASH
nonalcoholic steatohepatitis
ORR
objective response rate
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Statistical Analysis Plan Version 2
5 September 2019
OS
overall survival
PD
progressive disease
PD-1
programmed death-1
PD-L1/L2
programmed death ligand 1/ ligand 2
PFS
progression-free survival
PFSR
progression-free survival rate
PK
pharmacokinetic(s)
PPES
palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome)
PR
partial response
PS
performance status
PT
preferred term
PT-INR
prothrombin time international normalized ratio
PTE
pretreatment event
QD
once daily
QT
time interval in ECG reading
QTcF
corrected QT interval by the Fridericia formula
RBC
red blood cell
RECIST 1.1
Response Evaluation Criteria In Solid Tumors Version 1.1
RPLS
reversible posterior leukoencephalopathy syndrome
SBP
systolic blood pressure
SD
stable disease
SOC
system organ class
SRS
stereotactic radiosurgery
TEAEs
treatment-emergent adverse events
TSH
thyroid-stimulating hormone
ULN
upper limit of normal
UPCR
urine protein-to-creatinine ratio
WBC
white blood cell
WHO
world health organization
XL184
research name for investigational product cabozantinib
2DXRT
conventional external beam radiation therapy
3DCRT
3-dimensional conformal radiation therapy
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Statistical Analysis Plan Version 2
5 September 2019
4.0
OBJECTIVES
4.1
Primary Objective
The primary objective is to evaluate the efficacy of cabozantinib measured by IRC-assessed 
24-week PFSR per RECIST 1.1 in Japanese patients with advanced HCC who have received
prior sorafenib.
4.2
Secondary Objectives
The secondary objectives are:

To evaluate the efficacy of cabozantinib measured by IRC-assessed PFS per RECIST 1.1 in
the patient population under study.

To evaluate the efficacy of cabozantinib measured by IRC-assessed ORR per RECIST 1.1 in
the patient population under study.

To evaluate the efficacy of cabozantinib measured by IRC-assessed DCR per RECIST 1.1 in
the patient population under study.

To evaluate the efficacy of cabozantinib measured by OS in the patient population under
study.
4.3
Safety Objective
The safety objective is:

To evaluate the safety of cabozantinib in the patient population under study.
4.4
Additional Objectives
The additional objectives are:

To evaluate the efficacy of cabozantinib measured by investigator-assessed PFS, ORR, and
DCR per RECIST 1.1 in the patient population under study.

To characterize the plasma PK of cabozantinib in the patient population under study.

To assess HRQOL by the EQ-5D-5L in the patient population under study.

To explore candidate biomarkers predictive of response to cabozantinib.

To explore possible candidate biomarkers predictive of safety of treatment with cabozantinib.
4.5 
Study Design
This is a phase 2, open-label, single-arm study to evaluate the efficacy—as measured by 24-week 
PFSR and other efficacy variables including PFS, ORR, DCR, and OS—and safety of 
cabozantinib in Japanese patients with advanced HCC who have received prior systemic 
anticancer therapy (Cohort A: patients who have received prior sorafenib, Cohort B: patients 
who have not received prior sorafenib).
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Cabozantinib-2003
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Statistical Analysis Plan Version 2
5 September 2019
Screening Period
Potential subjects will be screened to determine if they meet the required eligibility criteria after 
informed consent. Qualifying screening assessments must be performed within 28 days before 
the first day of study drug administration (defined as Week 1 Day 1) unless otherwise specified.
Treatment Period
Subjects who meet all study eligibility criteria will receive cabozantinib 60 mg orally, QD in the 
fasted state (dose at least 2 hours after meal, and no more food intake for 1 hour postdose), 
preferably at bedtime. A subject is considered to be enrolled in the study when the first dose of 
study drug will be administered.
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, or until there are any 
other reasons for treatment discontinuation listed in the protocol. Treatment may continue after 
radiographic HCC progression per RECIST 1.1 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 risks. However the subject should discontinue 
study treatment after the second determination of disease progression.
Posttreatment Period
A 30-day posttreatment followup visit for safety will occur 30 (+14) days after the last dose of 
study drug or until the start of subsequent systemic anticancer treatment, whichever occurs first. 
Radiographic tumor assessments, Child-Pugh assessments, AFP assessments, and HRQOL 
assessments will continue, regardless of whether study treatment is given, reduced, held or 
discontinued until the day of the last tumor imaging assessment. Subjects will be contacted every 
8 weeks (±7 days) after the 30-day posttreatment followup visit to assess survival status and 
document receipt of subsequent anticancer therapy. Subjects will be followed until death, 
withdrawal of consent, or the sponsor decision to discontinue collection of these data in the 
study.
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Cabozantinib-2003
Page 9 of 64
Statistical Analysis Plan Version 2
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5.0
ANALYSIS ENDPOINTS
Primary Endpoint

24-week PFSR, per RECIST 1.1, by IRC.
Secondary Endpoints

PFS, per RECIST 1.1, by IRC.

ORR, per RECIST 1.1, by IRC.

DCR, per RECIST 1.1, by IRC.

OS.
Safety Endpoints

TEAEs.

Grade 3 or higher TEAEs.

Serious TEAEs.

Permanent discontinuation by TEAEs.

Dose modification (dose reduction or interruption) by TEAEs.

Clinically significant abnormal laboratory values.

Clinically significant abnormal vital sign measurements.
Additional Endpoints

PFS, per RECIST 1.1, by investigator.

ORR, per RECIST 1.1, by investigator.

DCR, per RECIST 1.1, by investigator.

Plasma concentrations of cabozantinib.

HRQOL assessed by the EQ-5D-5L.

Efficacy biomarker(s).
–
Candidate biomarkers that may include, but are not limited to, plasma biomarkers
associated with study treatment and/or clinical outcome.

Possible safety biomarker(s).
–
Association of genetic polymorphisms in genes encoding drug-metabolizing enzymes
and/or transporters with study treatment and/or clinical outcome.
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Statistical Analysis Plan Version 2
5 September 2019
6.0
DETERMINATION OF SAMPLE SIZE
A study with 17 subjects will provide at least 80% probability that the lower limit of the 
two-sided 90% CI for the 24-week PFSR by Kaplan-Meier method results in ≥11.1% when 
assuming the true 24-week PFSR ≥38.4%.
In Study XL184-309 in subjects with advanced HCC who have received prior sorafenib, the 
24-week PFSR by investigator was 38.4% (95% CI: [33.5, 43.3]%) and 11.1% (95% CI: [7.2,
15.8]%) in cabozantinib and placebo group, respectively. In reference to the above results, a
24-week PFSR of 38.4% is assumed and the threshold is set at 11.1% in this study.
This study will enroll at least 17 subjects who have received prior sorafenib in Cohort A. In 
addition, for better understanding of the efficacy and safety profile of cabozantinib in Japanese 
patients, similar number of subjects who have received prior sorafenib in Cohort A and who have 
not received prior sorafenib in Cohort B will be enrolled, resulting in approximately 32 subjects 
in total.
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Statistical Analysis Plan Version 2
5 September 2019
7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
7.1.1
Study Definitions
The following definitions and calculation formulas will be used.

Descriptive statistics: Number of subjects, mean, standard deviation, maximum, minimum,
and quartiles.

Cohort: Cohort A (subjects who have received prior sorafenib) and cohort B (subjects who
have not received prior sorafenib).

BMI (kg/m2): Weight (kg) / height (m)2.

Visceral (excluding Liver): Gastrointestinal tract, kidney, lung, spleen, adrenal gland and
pancreas.

Neutrophil-Lymphocyte Ratio: ANC (/μL) / lymphocytes (/μL).

ALBI Grade: Derived from ALBI score [log10(total bilirubin (μmol/L))*0.66 – albumin
(g/L)*0.085)] as the following:
–
Grade 1: ALBI score ≤-2.60.
–
Grade 2: -2.60 < ALBI score ≤-1.39.
–
Grade 3: ALBI score > -1.39.

Medical History: Any disease recorded on the eCRF "Medical History/Medical Conditions"
page whose status at informed consent is "Resolved."

Concurrent Medical Conditions: Any disease recorded on the eCRF "Medical
History/Medical Conditions" page whose status at informed consent is "Ongoing."

Concomitant Medication: Concomitant medication is defined as medication used during the
period from the time of the signing of ICF through 30 days after the last dose of study drug.

Agent Targeting PD-1, PD-L1/L2: Medications whose preferred name coded by WHO Drug
dictionary is ATEZOLIZUMAB, AVELUMAB, DURVALUMAB, NIVOLUMAB,
PEMBROLIZUMAB or BGB A317.

Duration of Exposure to Study Drug (months): (Date of decision to discontinue study drug –
date of the first dose of study drug + 1) / 30.4375 if date of decision to discontinue study drug
is non-missing; otherwise (Date of data cutoff – date of the first dose of study drug + 1) /
30.4375.

Average Daily Dose (mg): Total dose received (mg) / duration of exposure to study drug
(days).

Dose Intensity (%): 100 * average daily dose (mg) / 60 mg.
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Statistical Analysis Plan Version 2
5 September 2019

Duration of Treatment (months): (Date of decision to discontinue study drug – date of the
first dose of study drug – total duration of dose interruptions + 1) / 30.4375 if date of
decision to discontinue study drug is non-missing; otherwise (Date of data cutoff – date of
the first dose of study drug – total duration of dose interruptions + 1) / 30.4375.

Dose Modification: Dose reduction or interruption.

CV (%): Standard deviation / mean * 100.

TEAE: An AE whose date of onset occurs on or after the start of study drug and within 30
days after the last dose of study drug.

PTE: Any untoward medical occurrence in a clinical investigation subject who has signed
informed consent to participate in a study but prior to administration of study drug.

Thrombotic Events: Arterial thrombotic events, and venous and mixed/unspecified
thrombotic events.

Toxicity Grade of 0 for Laboratory Parameters: Grade 0 will be assigned to non-missing
values that do not meet the criteria for Grade 1 or higher in the direction of interest.
7.1.2
Definition of Study Days
The following definitions and calculation formulas will be used.

Study Day: The day before the first dose of the study drug will be defined as Study Day -1
and the day of the first dose will be defined as Study Day 1. When calculating Study Day
relative to a reference date (ie, date of first dose [Study Day 1]), if the date of the observation
is on the same date or after the reference date, it will be calculated as: date of observation -
reference date + 1; otherwise, it will be calculated as: date of observation - reference date.
There is no Study Day 0. Month and year are operationally defined to be 30.4375 days and
365.25 days, respectively.

Followup Day: The day after the last dose of study drug will be defined as Followup Day 1.
When calculating Followup Day relative to a reference date (ie, date of last dose [Followup
Day 0]), it will be calculated as: date of observation - reference date.
7.1.3 Definition of Study Visit Windows
All evaluable data will be handled according to the following rules.
For each visit, observation obtained in the corresponding time interval will be used. If more than 
one observation lies within the same visit window, the observation with the closest Study Day to 
the scheduled Study Day will be used. If there are two observations equidistant to the scheduled 
Study Day, the later observation will be used.
Specifically, the last observation before the first dose of the study drug will be considered the 
baseline measurement.
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Statistical Analysis Plan Version 2 
Page 13 of64 
5 September 2019 
Table 7.a 
Visit Window for Endpoints Other Than AFP, Bone Specific ALP and 
Plasma Concentrations of Cabozantinib 
Time Interval 
Visit 
Scheduled Study Day 
Study Day 
Follow-up Day 
Baseline 
Study Day: 1 
<= 1 
WeekXDay 1
Study Day: 7 * (X- 1) + 1
•
Week 3 - Week 9:
<30 
Scheduled Study Day ±5
•
Week 9 Beyond:
Scheduled Study Day± 7
30-Day Posttreatment
Followup Day: 30 
30 - 44 
Followup 
Table 7.b 
Visit Window for AFP and Bone Specific ALP 
Time Interval 
Visit 
Scheduled Study Day 
Study Day 
Follow-up Day 
Baseline 
Study Day: 1 
<= 1 
WeekXDay 1
Study Day: 7 * (X- 1) + 1
•
Week 3 - Week 9:
Scheduled Study Day ±5
•
Week 9 Beyond:
Scheduled Study Day± 7
Table 7.c 
Visit Window for Plasma Concentrations of Cabozantinib 
Time Interval 
Visit/Time point 
Scheduled Study Day 
Study Day 
Week 1 Day 1 
Study Day: 1 
1 
Predose 
Week 1 Day 1 
Study Day: 1 
1 
3 Homs Postdose 
Week 3 Day 1 
Study Day: 15 
Scheduled Study Day ±2 
Week 5 Day 1 
Study Day: 29 
Scheduled Study Day ±2 
Week 9 Day 1 
Study Day: 57 
Scheduled Study Day ±2 
7.1.4 
Significance Level and Confidence Coefficient 
•
Confidence coefficient:
Analyses for 24-week PFSR: 90% (two-sided). 
Analyses for other endpoints: 95% (two-sided). 
 
Time from Previous 
Dose of Study Drug 
Before the First Dose 
2.5 - 3.5 Homs 
>7Homs
>7Homs
>7Homs
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Statistical Analysis Plan Version 2
5 September 2019
7.1.5
Conventions for Missing Adverse Event Dates
Not applicable.
7.1.6
Conventions for Missing Concomitant Medication Dates
Not applicable.
7.1.7
Imputation of Other Incomplete Dates

Incomplete initial diagnosis date of HCC.
–
If day and month are missing, set to July 1st.
–
If only day is missing, set to 15th of the month.
–
If either imputation rule above results in diagnosis date ≥date of informed consent, set to
date of informed consent – 1.

Incomplete start date of prior anticancer therapy.
–
If month and day are missing, set to January 1st.
–
If only day is missing, set to 1st day of the month.

Incomplete end date of prior anticancer therapy.
–
If month and day are missing, set to December 31st.
–
If only day is missing, set to last day of the month.
–
If either imputation rule above results in end date ≥date of informed consent, set to date
of informed consent – 1.

Incomplete start date of concomitant and subsequent anticancer therapy.
–
If month and day are missing, set to January 1st if year of the start date of the anticancer
therapy > year of the last dose of study drug; set to date of the last dose + 1 if year of the
start date of the anticancer therapy = year of the last dose of study drug.
–
If only day is missing, set to 1st day of the month if the resulting imputed date > date of
the last dose of study drug; otherwise set to date of the last dose + 1.
* If PD date per RECIST 1.1 is available and after the last dose of study drug, replace the
date of the last dose of study drug with the PD date for the above imputation algorithm.
7.2
Analysis Sets

FAS:
All subjects who received at least one dose of study drug.

Safety analysis set:
All subjects who received at least one dose of study drug.
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Statistical Analysis Plan Version 2
5 September 2019
7.3
Disposition of Subjects
7.3.1
Study Information
Analysis Set:
All Subjects Who Signed the Informed Consent Form.
Analysis Variables:
Date First Subject Signed Informed Consent Form
Date of Data Cutoff
MedDRA Version
WHO Drug Version
SAS Version Used for Creating the Datasets
Analytical Methods:
(1) Study Information
Study information shown in the analysis variables section will be provided.
7.3.2
Screen Failures
Analysis Set:
All Subjects Not Enrolled into the Treatment Period
Analysis Variables:
Age (years)
Gender
[Male, Female]
Analytical Methods:
(1) Screen Failures
Frequency distributions for categorical variables and descriptive statistics for
continuous variables will be provided.
7.3.3
Subject Eligibility
Analysis Set:
All Subjects Who Signed the Informed Consent Form
Analysis Variables:
Enrollment Status
[Enrolled into the Treatment Period, Not Enrolled into the Treatment Period]
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Statistical Analysis Plan Version 2
5 September 2019
Primary Reason for Subject Not Being Enrolled
[Death, AE, Clinical Deterioration, Protocol Deviation, Study Terminated by 
Sponsor, Pregnancy, Withdrawal by Subject, Lost to Follow-up, Physician 
Decision, Screen Failure, Other]
Analytical Methods:
(1) Enrollment into the Treatment Period
Frequency distributions will be provided. When calculating percentages for the
primary reasons for subject not being enrolled, the total number of not enrolled
subjects will be used as the denominator.
7.3.4
Number of Subjects Enrolled into the Treatment Period by Site
Analysis Set:
All Subjects Enrolled into the Treatment Period
Analysis Variables:
Status of Enrollment into the Treatment Period
[Enrolled]
Stratum:
Site
[Site numbers will be used as categories]
Analytical Methods:
(1) Number of Subjects Enrolled into the Treatment Period by Site
Frequency distributions will be provided for each stratum by cohort and overall.
7.3.5
Disposition of Subjects
Analysis Set:
All Subjects Enrolled into the Treatment Period
Analysis Variables:
Study Drug Administration Status
[Receiving Study Drug, Discontinued Study Drug]
Reason for Discontinuation of Study Drug
[Death, AE, Clinical Deterioration, Protocol Deviation, PD, Lack of Efficacy, 
Study Terminated by Sponsor, Pregnancy, Withdrawal by Subject, Lost to 
Follow-up, Physician Decision, Other]
Status of the Posttreatment Period
[Remaining in Posttreatment Period, Discontinued Posttreatment Period]
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Statistical Analysis Plan Version 2
5 September 2019
Reason for Discontinuation of the Posttreatment Period
[Death, Study Terminated by Sponsor, Withdrawal by Subject, Lost to Follow-up, 
Other]
Analytical Methods:
(1) Disposition of Subjects
Frequency distributions will be provided for each cohort and overall. When
calculating percentages for the reasons for discontinuation, the total number of
subjects who discontinued will be used as the denominator.
7.3.6
Protocol Deviations and Analysis Sets
7.3.6.1
Protocol Deviations
Analysis Set:
All Subjects Enrolled into the Treatment Period
Analysis Variables:
Significant Protocol Deviation
[Entry Criteria, Concomitant Medication, Procedure Not Performed Per Protocol, 
Study Medication, Withdrawal Criteria, Major GCP Violations]
Analytical Methods:
(1) Protocol Deviations
Frequency distributions will be provided by cohort and overall for each deviation
category. A subject who has several deviations will be counted once in each
appropriate category. A subject who has several deviations that can be classified into
the same category will be counted only once.
7.3.6.2
Analysis Sets
Analysis Set:
All Subjects Enrolled into the Treatment Period
Analysis Variables:
Analysis Sets
Full Analysis Set
[Included]
Safety Analysis Set
[Included]
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Statistical Analysis Plan Version 2
5 September 2019
Analytical Methods:
(1) Analysis Sets
Frequency distributions will be provided by cohort and overall.
7.4
Demographic and Other Baseline Characteristics
Analysis Set:
FAS
Analysis Variables:
Age (years)
[Min<= - <65, 65<= - <=Max]
[Min<= - <75, 75<= - <=Max]
[Min<= - <65, 65<= - <75, 75<= - <85, 85<= - <=Max]
Gender
[Male, Female]
Height (cm)
Weight (kg) at Baseline
[Min<= - <60, 60<= - <=80, 80< - <=Max]
BMI (kg/m2) at Baseline
[Min<= - <18.5, 18.5<= - <25.0, 25.0<= - <30.0, 30.0<= - <=Max]
History of Drinking Alcohol
[Current, Former, Never]
Current Etiology of Disease
Hepatitis B (Without Hepatitis C)
[Yes]
Hepatitis C (Without Hepatitis B)
[Yes]
Hepatitis B and C
[Yes]
Hepatitis B (Regardless of Hepatitis C)
[Yes]
Hepatitis C (Regardless of Hepatitis B)
[Yes]
Without Hepatitis B and C
[Yes]
Alcoholism
[Yes]
NASH
[Yes]
Other
[Yes]
HBsAg at Baseline
[Positive, Negative]
HBV-DNA at Baseline
[Positive, Negative]
HCVAb at Baseline
[Positive, Negative]
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Statistical Analysis Plan Version 2
5 September 2019
HCV-RNA at Baseline
[Positive, Negative]
ALBI Grade at Baseline
[Grade 1, Grade 2, Grade 3]
Child-Pugh Score at Baseline
[A, B, C]
Hepatic Encephalopathy at Baseline
[None, Grade I-II, Grade III-IV]
Ascites at Baseline
[Absent, Slight, Moderate]
Time from Histological/Cytological Diagnosis of HCC to Enrollment (years)
Current Disease Evaluation
Locally Advanced Disease
[Yes, No, Unknown]
Metastatic Disease
[Yes, No, Unknown]
Current Extent of Disease
Portal Vein Invasion
[Yes, No, Unknown]
Bile Duct Invasion
[Yes, No, Unknown]
Macrovascular Invasion
[Yes, No, Unknown]
Extrahepatic Spread
[Yes, No, Unknown]
Extrahepatic Spread and/or Macrovascular Invasion
[Yes, No]
Other
[Yes, No]
Extent of Baseline Disease per IRC
Liver
[Yes]
Lung
[Yes]
Adrenal Grand
[Yes]
Spleen
[Yes]
Kidney
[Yes]
Pancreas
[Yes]
Gastrointestinal Tract
[Yes]
Visceral (Excluding Liver)
[Yes]
Bone (CT or MRI)
[Yes]
Bone (CT or MRI) and Visceral (Excluding Liver)
[Yes]
Brain
[Yes]
Peritoneum
[Yes]
Lymph Node
[Yes]
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Statistical Analysis Plan Version 2
5 September 2019
Other
[Yes]
Number of Involved Organs per IRC at Baseline
[0, 1, 2, 3<= - <=Max]
Sum of Diameters of Target Lesions (mm) per IRC at Baseline
ECOG PS at Baseline
[0, 1]
AFP (ng/mL) at Baseline
[Min<= - <400.0, 400.0<= - <=Max]
PT-INR at Baseline
[Min<= - <=2.30, 2.30< - <=Max]
Albumin (g/dL) at Baseline
[Min<= - <3.5, 3.5<= - <=Max]
Total Bilirubin (mg/dL) at Baseline
[Min<= - <1.3, 1.3<= - <1.7, 1.7<= - <=Max]
Neutrophil-Lymphocyte Ratio at Baseline
[Min<= - <3.0, 3.0<= - <=Max]
Analytical Methods:
(1) Summary of Demographics and Baseline Characteristics
Frequency distributions for categorical variables and descriptive statistics for
continuous variables will be provided by cohort and overall.
7.5
Medical History and Concurrent Medical Conditions
Analysis Set:
Safety Analysis Set
Analysis Variables:
Medical History
Concurrent Medical Conditions
Analytical Methods:
(1) Medical History by System Organ Class and Preferred Term
(2) Concurrent Medical Conditions by System Organ Class and Preferred Term
Frequency distributions will be provided for each cohort and overall. MedDRA
dictionary will be used for coding. Summaries will be provided using SOC and PT,
where SOC will be sorted alphabetically and PT will be sorted in decreasing
frequency.
A subject with multiple occurrences of medical history or concurrent medical
condition within a SOC will be counted only once in that SOC. A subject with
multiple occurrences of medical history or concurrent medical condition within a PT
will be counted only once in that PT.
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Statistical Analysis Plan Version 2
5 September 2019
7.6
Medication History and Concomitant Medications
Analysis Set:
Safety Analysis Set
Analysis Variables:
Prior Non-Radiation Anticancer Therapy
Concomitant Medications
Concomitant and Subsequent Non-Radiation Anticancer Therapy
Analytical Methods:
(1) Prior Non-Radiation Anticancer Therapy by Preferred Medication Name
(2) Concomitant Medications That Started Prior to and Were Ongoing at Baseline as
well as Those That Started After Baseline by Preferred Medication Name
(3) Concomitant and Subsequent Non-Radiation Anticancer Therapy That Started After
Baseline by Preferred Medication Name
(4) Concomitant and Subsequent Non-Radiation Anticancer Therapy That Started Prior
to and Were Ongoing at Baseline as well as Those That Started After Baseline by
Preferred Medication Name
Frequency distributions will be provided for each cohort and overall. WHO Drug
dictionary will be used for coding. Summaries will be provided using preferred
medication names and sorted in decreasing frequency based on the number of
reports.
A subject who has been administered several medications with the same preferred
medication name will be counted only once for that medication name.
7.7
Prior Surgery and Procedure
Analysis Set:
Safety Analysis Set
Analysis Variables:
Prior Surgery/Procedure
[Yes, No]
Prior Surgery Type
Enucleation
[Yes]
Partial Hepatectomy
[Yes]
Hepatic Subsegmentectomy
[Yes]
Hepatic Segmentectomy
[Yes]
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Statistical Analysis Plan Version 2
5 September 2019
Right Hepatic Lobectomy
[Yes]
Left Hepatic Lobectomy
[Yes]
Extended Right Hepatic Lobectomy
[Yes]
Extended Left Hepatic Lobectomy
[Yes]
Liver Transplantation
[Yes]
Other
[Yes]
History of Surgical/Procedural Wound Healing Complications
[Yes, No]
Analytical Methods:
(1) Prior Surgery and Procedure
Frequency distributions will be provided by cohort and overall.
7.8
Prior Non-Surgical Anticancer Therapy
Analysis Set:
Safety Analysis Set
Analysis Variables:
Non-Radiation Anticancer Therapy Type for HCC
Systemic
[Yes]
Local Liver-Directed
[Yes]
Local (Other Than Liver)
[Yes]
Number of Prior Systemic Non-Radiation Anticancer Regimens for HCC-Advanced
[1, 2]
Number of Prior Systemic Non-Radiation Anticancer Agents for HCC
[1, 2, 3<= - <=Max]
Number of Prior Systemic Non-Radiation Anticancer Agents for HCC-Advanced
[1, 2, 3<= - <=Max]
Number of Prior Systemic Non-Radiation Anticancer Agents for HCC-Adjuvant
[0, 1, 2, 3<= - <=Max]
Progression after Most Recent Prior Systemic Non-Radiation Anticancer Agent for HCC
[Yes, No, Unknown]
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Statistical Analysis Plan Version 2
5 September 2019
Time (months) from Progression after Most Recent Prior Systemic Non-Radiation 
Anticancer Agent for HCC to Enrollment
Time (months) from the End of Most Recent Prior Systemic Non-Radiation Anticancer 
Agent for HCC to Enrollment
Prior Sorafenib for HCC
[Yes, No]
Stop Taking Prior Sorafenib for Intolerance Reasons
[Yes, No, Not Applicable]
Prior Sorafenib as the Most Recent Prior Systemic Non-Radiation Anticancer Agent for 
HCC
[Yes, No]
Indication of Prior Sorafenib for HCC
For HCC-Advanced
[Yes]
For HCC-Advanced as First-Line
[Yes]
For HCC-Advanced as Second-Line
[Yes]
For HCC-Adjuvant
[Yes]
For HCC-Local
[Yes]
For HCC-Other
[Yes]
Progression after Prior Sorafenib for HCC
[Yes, No, Unknown]
Progression after Prior Sorafenib as the Most Recent Prior Systemic Non-Radiation 
Anticancer Agent for HCC
[Yes, No, Unknown]
Time (months) from Progression after Prior Sorafenib as the Most Recent Prior Systemic 
Non-Radiation Anticancer Agent for HCC to Enrollment
Total Duration (months) of Prior Sorafenib Treatment for HCC
[Min<= - <1, 1<= - <3, 3<= - <6, 6<= - <=Max]
Prior Lenvatinib for HCC
[Yes, No]
Prior Lenvatinib as the Most Recent Prior Systemic Non-Radiation Anticancer Agent for 
HCC
[Yes, No]
Indication of Prior Lenvatinib for HCC
For HCC-Advanced
[Yes]
For HCC-Advanced as First-Line
[Yes]
For HCC-Advanced as Second-Line
[Yes]
For HCC-Adjuvant
[Yes]
For HCC-Local
[Yes]
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Statistical Analysis Plan Version 2
5 September 2019
For HCC-Other
[Yes]
Progression after Prior Lenvatinib for HCC [Yes, No, Unknown]
Progression after Prior Lenvatinib as the Most Recent Prior Systemic Non-Radiation 
Anticancer Agent for HCC
[Yes, No, Unknown]
Time (months) from Progression after Prior Lenvatinib as the Most Recent Prior 
Systemic Non-Radiation Anticancer Agent for HCC to Enrollment
Total Duration (months) of Prior Lenvatinib Treatment for HCC
[Min<= - <1, 1<= - <3, 3<= - <6, 6<= - <=Max]
Prior Treatment with Agent Targeting PD-1, PD-L1/L2
[Yes, No]
Prior Chemoembolization for HCC
[Yes, No]
Number of Prior Chemoembolization for HCC
[0, 1, 2, 3<= - <=Max]
Prior Radiation Therapy
[Yes, No]
Indication of Prior Radiation Therapy
Disease under Study
[Yes]
Other
[Yes]
Number of Prior Radiation Therapy Types for HCC
[0, 1, 2, 3<= - <=Max]
Type of Prior Radiation Therapy for HCC
EBRT
[Yes]
SRS
[Yes]
2DXRT
[Yes]
3DCRT
[Yes]
IGRT
[Yes]
IMRT
[Yes]
Proton-Therapy
[Yes]
TomoTherapy Hi-ART
[Yes]
CyberKnife VSI
[Yes]
Other
[Yes]
Brachytherapy
[Yes]
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Statistical Analysis Plan Version 2
5 September 2019
Radioisotope Therapy
[Yes]
Radioembolization
[Yes]
Radiofrequency Ablation
[Yes]
Other
[Yes]
Site Type of Prior Radiation Therapy for HCC
Bone
[Yes]
Soft Tissue
[Yes]
Systemic
[Yes]
Unknown
[Yes]
Analytical Methods:
(1) Prior Non-Surgical Anticancer Therapy
Frequency distributions for categorical variables and descriptive statistics for
continuous variables will be provided by cohort and overall.
7.9
Concomitant and Subsequent Anticancer Therapy
Analysis Set:
Safety Analysis Set
Analysis Variables:
Concomitant and Subsequent Non-Surgical Non-Radiation Anticancer Therapy
[Yes, No]
Systemic
[Yes]
Local Liver-Directed
[Yes]
Systemic or Local Liver-Directed
[Yes]
Agent Targeting PD-1, PD-L1/L2
[Yes]
Time (days) to First Non-Surgical Non-Radiation Systemic Anticancer Therapy from 
the First Dose of Study Drug
Concomitant and Subsequent Radiation Therapy
[Yes, No]
Indication
Disease under Study
[Yes]
Other
[Yes]
Type of Radiation Therapy for HCC
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Statistical Analysis Plan Version 2
5 September 2019
EBRT
[Yes]
SRS
[Yes]
2DXRT
[Yes]
3DCRT
[Yes]
IGRT
[Yes]
IMRT
[Yes]
Proton-Therapy
[Yes]
TomoTherapy Hi-ART
[Yes]
CyberKnife VSI
[Yes]
Other
[Yes]
Brachytherapy
[Yes]
Radioisotope Therapy
[Yes]
Radioembolization
[Yes]
Radiofrequency Ablation
[Yes]
Other
[Yes]
Site Type of Radiation Therapy for HCC
Bone
[Yes]
Soft Tissue
[Yes]
Systemic
[Yes]
Unknown
[Yes]
Concomitant and Subsequent Radiation Therapy Other Than to Bone
[Yes]
Concomitant and Subsequent Surgery/Procedure
[Yes, No]
Surgery that Impacted Tumor Lesions
[Yes]
Analytical Methods:
(1) Concomitant and Subsequent Anticancer Therapy After Enrollment
For concomitant and subsequent anticancer therapies taken/performed after
enrollment, frequency distributions will be provided by cohort and overall.
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Statistical Analysis Plan Version 2
5 September 2019
7.10
Study Drug Exposure and Compliance
Analysis Set:
Safety Analysis Set
Analysis Variables:
Duration of Exposure to Study Drug (months)
Average Daily Dose (mg)
Dose Intensity (%)
Duration of Treatment (months)
Analytical Methods:
(1) Study Drug Exposure and Compliance
Descriptive statistics for continuous variables will be provided by cohort and overall.
7.11
Dose Modification
Analysis Set:
Safety Analysis Set
Analysis Variables:
Dose Reduction
Any Dose Reduction Due to AE
[Yes, No]
Dose Level Received
60 mg
[Yes]
40 mg Due to AE
[Yes]
20 mg Due to AE
[Yes]
Lowest Dose Level Received Due to AE (Excluding Dose Interruption) (mg)
[60, 40, 20]
Last Dose Level Received (Excluding Dose Interruption) (mg)
[60, 40, 20]
Last Dose Level Received (Including Dose Interruption) (mg)
[60, 40, 20, 0]
Total Duration of Treatment (days) at:
More than 0 mg
60 mg
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40 mg
20 mg
0 mg
Time to 1st Dose Reduction Due to AE from the First Dose of Study Drug (days)
Time to 2nd Dose Reduction Due to AE from the First Dose of Study Drug (days)
Dose Interruption
Any Dose Interruption Due to AE
[Yes, No]
Dose Interruption ≥7 days Due to AE
[Yes]
Dose Interruption ≥14 days Due to AE
[Yes]
Dose Interruption ≥21 days Due to AE
[Yes]
Number of Dose Interruption Due to AE [0, 1, 2, 3, 4<= - <=Max]
Total Duration of Dose Interruption Due to AE (days)
[0, 1<= - <7, 7<= - <14, 14<= - <21, 21<= - <= Max]
Time to 1st Dose Interruption Due to AE from the First Dose of Study Drug (days)
Time to 1st Dose Interruption ≥7 days Due to AE from the First Dose of Study Drug 
(days)
Time to 1st Dose Interruption ≥14 days Due to AE from the First Dose of Study Drug 
(days)
Time to 1st Dose Interruption ≥21 days Due to AE from the First Dose of Study Drug 
(days)
Time to 2nd Dose Interruption Due to AE from the First Dose of Study Drug (days)
Time to 2nd Dose Interruption ≥7 days Due to AE from the First Dose of Study Drug 
(days)
Time to 2nd Dose Interruption ≥14 days Due to AE from the First Dose of Study Drug 
(days)
Time to 2nd Dose Interruption ≥21 days Due to AE from the First Dose of Study Drug 
(days)
Dose Modification
Any Dose Modification Due to AE
[Yes, No]
Number of Dose Modification Due to AE
Time to 1st Dose Modification Due to AE from the First Dose of Study Drug (days)
Time to 2nd Dose Modification Due to AE from the First Dose of Study Drug (days)
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Analytical Methods:
(1) Dose Modification
Frequency distributions for categorical variables and descriptive statistics for
continuous variables will be provided by cohort and overall.
7.12
Efficacy Analysis
7.12.1 Primary Endpoint
Analysis Set:
FAS
Analysis Variables:
24-week PFSR, per RECIST 1.1 by IRC
PFS is defined as time from the first day of study drug administration to the earlier of
PD per RECIST 1.1 or death due to any cause. PFS will be expressed in months,
ie, PFS = (earliest date of progression or death – date of the first day of study drug
administration + 1) / 30.4375.
24-week PFSR is defined as PFS proportion at Study Day of Week 25 Day 1 + 7 days.
Only adequate tumor assessments (overall response of CR, PR, SD, Non-CR/Non-PD 
or PD) will be considered in the determination of progression and censoring date. 
General censoring rules for the analysis of PFS will be as follows:
•
Subjects who have not experienced an event at the time of data cutoff will be
censored at the date of the last adequate tumor assessment.
•
Subjects who receive subsequent systemic or liver directed local anticancer
therapy or radiation therapy (other than to bone) before experiencing an event will
be censored at the date of the last adequate tumor assessment on or prior to the
date of initiation of the subsequent treatment.
•
Subjects who receive tumor resection surgery after enrollment before experiencing
an event will be censored at the date of the last adequate tumor assessment on or
prior to the date of the surgery.
•
Subjects who miss 2 or more consecutive adequate scheduled tumor assessments
(operationally defined as an interval of >18 weeks without an adequate
assessment) immediately followed by an event will be censored at the date of the
last adequate tumor assessment prior to the missing/inadequate assessments.
−
If the 2 or more consecutive missing adequate assessments are immediately
followed by an adequate assessment with an overall response assignment of
SD, Non-CR/Non-PD, PR, or CR, this will be deemed sufficient clinical
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evidence that progression did not occur during the period of missing data and 
the missing evaluations will be ignored.
Analytical Methods:
(1) Primary Analysis
The following analyses will be conducted for cohort A.
For 24-week PFSR by IRC, Kaplan-Meier estimate will be provided and the
corresponding 2-sided 90% CI will be calculated using the Greenwood's formula and
the complementary log-log transformation.
(2) Other Analysis
The same analysis as those in the primary analysis will be conducted for Cohort B
and overall.
7.12.2 Secondary Endpoints
Analysis Set:
FAS
Analysis Variables:
PFS, per RECIST 1.1 by IRC
ORR, per RECIST 1.1, by IRC
ORR is defined as proportion of subjects whose best overall response is CR or PR per 
RECIST 1.1, which is confirmed by a subsequent evaluation conducted ≥28 days later.
Only the results of tumor assessment conducted on or prior to the earlier of the date of 
PFS event or date of censoring for PFS by IRC, described in 7.12.1 Primary Endpoint, 
will be used in order to determine the best overall response. Assessments performed 
<51 days after the first day of study drug administration will not be considered in the 
determination of best overall response unless i) PD is identified or ii) CR or PR is 
identified and subsequently confirmed ≥28 days later.
The response results are ranked as: confirmed CR, confirmed PR, SD (including 
Non-CR/Non-PD), PD and not evaluable. If a subject has multiple response results, 
then use the best response results according to this ranking as the subject’s best overall 
response.
DCR, per RECIST 1.1 by IRC
DCR is defined as proportion of subjects whose best overall response is CR, PR or SD 
(including Non-CR/Non-PD) per RECIST 1.1. CR and PR require confirmation by a 
subsequent evaluation conducted ≥28 days later, and SD (including Non-CR/Non-PD) 
have to be maintained for at least 8 weeks (51 days) after the first day of study drug
administration.
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DCR will be determined using the same data as those used in the determination of 
ORR.
OS
OS is defined as time from the first day of study drug administration to death due to 
any cause. OS will be expressed in months, ie, OS = (date of death – date of the first 
day of study drug administration + 1) / 30.4375.
Subjects who have not experienced an event at the time of data cutoff will be censored 
at the earlier of the data cutoff or the last date when the subjects are known to be alive.
Analytical Methods:
The following analyses will be conducted for each cohort and overall.
(1) PFS, per RECIST 1.1 by IRC
For PFS, per RECIST 1.1, by IRC, breakdown of the number of subjects who were
censored and who experienced an event will be summarized. Quartiles of PFS will be
estimated using the Kaplan-Meier method. Kaplan-Meier estimate of PFS proportion
at 3, 6, 12, 18 and 24 months will also be provided.
The Kaplan-Meier plot of PFS will be presented.
The PFS analysis results will be displayed in conjunction with the analyses for 7.12.1
Primary Endpoint.
(2) ORR, per RECIST 1.1, by IRC
Best overall response, per RECIST 1.1, by IRC will be summarized using the
categories of Confirmed CR, Confirmed PR, SD (including Non-CR/Non-PD), PD,
Not Evaluable and Missing. The result of Missing means that the subject has no
qualifying post baseline assessment for overall response.
For ORR, per RECIST 1.1, by IRC, point estimate and the 2-sided 95% exact CI will
be provided.
A waterfall plot of best percent change in target lesion size by IRC will be presented.
(3) DCR, per RECIST 1.1, by IRC
For DCR, per RECIST 1.1, by IRC, point estimate and the 2-sided 95% exact CI will
be provided.
(4) OS
For OS, the same analyses as those for PFS will be conducted.
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7.12.3 Additional Endpoints
7.12.3.1 PFS, ORR and CBR by Investigator
Analysis Set:
FAS
Analysis Variables:
PFS, per RECIST 1.1, by Investigator
ORR, per RECIST 1.1, by Investigator
DCR, per RECIST 1.1 by Investigator
Analytical Methods:
(1) PFS, per RECIST 1.1, by Investigator
The same analyses as those for 24-week PFSR and PFS, per RECIST 1.1, by IRC in
7.12.1 and 7.12.2 (1) will be conducted.
(2) ORR, per RECIST 1.1 by Investigator
The same analyses as those for ORR, per RECIST 1.1, by IRC in 7.12.2 (2) will be
conducted.
(3) DCR, per RECIST 1.1, by Investigator
The same analyses as those for DCR, per RECIST 1.1, by IRC in 7.12.2 (3) will be
conducted.
7.12.3.2 Concordance of Tumor Assessment Result
Analysis Set:
FAS
Analysis Variables:
Concordance between IRC and Investigator Tumor Assessment Results
Disease Progression Status
[IRC: Yes and Investigator: Yes, IRC: Yes and Investigator: No,
IRC: No and Investigator: Yes, IRC: No and Investigator: No]
[Concordant, Discordant]
Disease Progression Date
[Concordant, Discordant]
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Response Status
[IRC: Yes and Investigator: Yes, IRC: Yes and Investigator: No,
IRC: No and Investigator: Yes, IRC: No and Investigator: No]
[Concordant, Discordant]
Response Date
[Concordant, Discordant]
Analytical Methods:
(1) Concordance between IRC and Investigator Tumor Assessment Results
The following analyses will be conducted for overall subjects.
For disease progression status and response status, frequency distributions will be
provided, where response status of Yes means that a subject had at least one overall
response assignment of CR or PR (confirmation is not necessary).
For disease progression date and response date, frequency distributions will be
provided for subjects in the FAS whose disease progression/response status by both
IRC and investigator is Yes.
7.12.3.3 Plasma Concentrations of Cabozantinib
Analysis Set:
FAS
Analysis Variables:
Plasma Concentrations of Cabozantinib
Visit/Timepoint:
Week 1 Day 1 (Predose), Week 1 Day 1 (3 hr Postdose), Week 3 Day 1, Week 5 Day 1, 
Week 9 Day 1
Analytical Methods:
(1) Plasma Concentrations of Cabozantinib
Descriptive statistics and CV will be provided by cohort and overall for each
visit/timepoint.
The same analysis will be provided for subjects in the FAS who received
cabozantinib 60 mg for at least 14 of 15 days immediately prior to the visit for Week
3 Day 1, Week 5 Day 1 and Week 9 Day 1.
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7.12.3.4 Health-Related Quality of Life Assessment
Analysis Set:
FAS
Analysis Variables:
EQ-5D-5L
Mobility
[No Problem, Slight Problems, Moderate Problems, Severe Problems, Extreme 
Problems]
[No Problem, Slight Problems - Extreme Problems]
Self-Care
[No Problem, Slight Problems, Moderate Problems, Severe Problems, Extreme 
Problems]
[No Problem, Slight Problems - Extreme Problems]
Usual Activities
[No Problem, Slight Problems, Moderate Problems, Severe Problems, Extreme 
Problems]
[No Problem, Slight Problems - Extreme Problems]
Pain/Discomfort
[No Problem, Slight Problems, Moderate Problems, Severe Problems, Extreme 
Problems]
[No Problem, Slight Problems - Extreme Problems]
Anxiety/Depression
[No Problem, Slight Problems, Moderate Problems, Severe Problems, Extreme 
Problems]
[No Problem, Slight Problems - Extreme Problems]
EQ VAS Value for Your Health Today
EQ-5D-5L Index Value
EQ-5D-5L index values will be calculated using the value sets in Ikeda et al[1] if 
and only if all the 5 health state (mobility, self-care, usual activities, 
pain/discomfort, anxiety/depression) are completed and non-missing
Visit:
Baseline, Week 5 Day 1, Week 9 Day 1, Every 4 weeks through Week 25, Every 8 
Weeks Thereafter
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Analytical Methods:
The following analyses will be conducted for each cohort and overall.
(1) Frequency Distributions for EQ-5D-5L Descriptive System
Frequency distributions will be provided for each of the 5-dimention descriptive
system for each visit.
(2) Summary of EQ VAS and EQ-5D-5L Index Value by Visit
Descriptive statistics and the two-sided 95% CI of the mean will be provided for
each visit.
(3) Summary of Change from Baseline in EQ VAS and EQ-5D-5L Index Value by Visit
Descriptive statistics and the two-sided 95% CI of the mean will be provided for
each visit.
Mean changes from baseline will be plotted for each visit with standard deviation
bars.
7.12.3.5 AFP and Bone Specific ALP
Analysis Set:
FAS
Analysis Variables:
AFP
Bone Specific ALP
Visit:
AFP
Baseline, Week 9 Day 1, Every 8 Weeks Thereafter
Bone Specific ALP
Baseline, Week 3 Day 1, Week 5 Day 1, Week 9 Day 1
Analytical Methods:
The following analyses will be conducted for each cohort and overall.
(1) Summary of AFP and Bone Specific ALP, and Percent Change from Baseline by
Visit
Descriptive statistics for observed values for each visit and percent changes from
baseline will be provided.
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(2) Summary of Best and Worst Percent Change from Baseline in AFP and Bone
Specific ALP
Descriptive statistics for best (defined as the largest reduction) and worst (defined as
the largest increase) percent change from baseline will be provided using all
available data, respectively.
A waterfall plot of best percent change from baseline will be presented using all
available data.
(3) Number and Percentage of Subjects with ≥50% Reduction from Baseline in AFP
and Bone Specific ALP
Frequency distributions of subjects with ≥50% reduction from baseline and the
two-sided 95% exact CI for the proportion will be provided using all available data.
7.12.4 Statistical/Analytical Issues
7.12.4.1 Adjustments for Covariates
Not applicable.
7.12.4.2 Handling of Dropouts or Missing Data
Missing test results will not be used for the analyses unless otherwise specified.
Values below the lower limit of quantification will be treated as zero when calculating the 
descriptive statistics. Values greater than or equal to the upper limit of quantification will be 
treated as the upper limit value when calculating the descriptive statistics.
7.12.4.3 Multicenter Studies
Not applicable.
7.12.4.4 Multiple Comparison/Multiplicity
Not applicable.
7.12.4.5 Use of an “Efficacy Subset” of Subjects
Not applicable.
7.12.4.6 Active-Control Studies Intended to Show Equivalence or Non-Inferiority
Not applicable.
7.12.4.7 Examination of Subgroups
Analysis Set:
FAS
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Statistical Analysis Plan Version 2
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Analysis Variables:
24-week PFSR, per RECIST 1.1 by IRC
Subgroups:
Age (years)
[Min<= - <65, 65<= - <=Max]
Gender
[Male, Female]
Current Etiology of Disease
Hepatitis B (Without Hepatitis C)
[Yes, No]
Hepatitis C (Without Hepatitis B)
[Yes, No]
Hepatitis B and C
[Yes, No]
Hepatitis B (Regardless of Hepatitis C)
[Yes, No]
Hepatitis C (Regardless of Hepatitis B)
[Yes, No]
Without Hepatitis B and C
[Yes, No]
Alcoholism
[Yes, No]
NASH
[Yes, No]
Other
[Yes, No]
Extrahepatic Spread and/or Macrovascular Invasion
[Yes, No]
Visceral (Excluding Liver) Metastases per IRC at Baseline
[Yes, No]
Bone Metastases (CT or MRI) per IRC at Baseline
[Yes, No]
Bone (CT or MRI) and Visceral (Excluding Liver) Metastases per IRC at Baseline
[Yes, No]
ECOG PS at Baseline
[0, 1]
AFP (ng/mL) at Baseline
[Min<= - <400.0, 400.0<= - <=Max]
Number of Prior Systemic Non-Radiation Anticancer Regimens for HCC-Advanced
[1, 2]
Prior Treatment with Agent Targeting PD-1, PD-L1/L2
[Yes, No]
Prior Regorafenib
[Yes, No]
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Prior Lenvatinib
[Yes, No]
Prior Tivantinib
[Yes, No]
Prior Ramucirumab
[Yes, No]
Stop Taking Prior Sorafenib for Intolerance Reasons
[Yes, No]
Analytical Methods:
(1) Subgroup Analysis for 24-week PFSR, per RECIST 1.1 by IRC
Kaplan-Meier estimate of 24-week PFSR, per RECIST 1.1 by IRC will be provided
and the corresponding 2-sided 90% CI will be calculated for each cohort and overall
using the Greenwood's formula and the complementary log-log transformation.
7.13
Safety Analysis
7.13.1 Adverse Events
7.13.1.1 Overview of Treatment-Emergent Adverse Events
Analysis Set:
Safety Analysis Set
Analysis Variables:
TEAE
Categories:
Relationship to Study Drug
[Related, Not Related]
Toxicity Grade
[Grade 1, Grade 2, Grade 3, Grade 4, Grade 5]
Analytical Methods:
The following summaries will be provided for each cohort and overall.
(1) Overview of Treatment-Emergent Adverse Events
1)
All Treatment-Emergent Adverse Events (Number of Events, Number and
Percentage of Subjects)
2)
Relationship of Treatment-Emergent Adverse Events to Study Drug (Number of
Events, Number and Percentage of Subjects)
3)
Toxicity Grade of Treatment-Emergent Adverse Events (Number of Events,
Number and Percentage of Subjects)
4)
Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation
(Number of Events, Number and Percentage of Subjects)
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5)
Serious Treatment-Emergent Adverse Events (Number of Events, Number and
Percentage of Subjects)
6)
Relationship of Serious Treatment-Emergent Adverse Events to Study Drug
(Number of Events, Number and Percentage of Subjects)
7)
Serious Treatment-Emergent Adverse Events Leading to Study Drug
Discontinuation (Number of Events, Number and Percentage of Subjects)
8)
Treatment-Emergent Adverse Events Resulting in Death (Number of Events,
Number and Percentage of Subjects)
TEAEs will be counted according to the rules below.
Number of subjects

Summaries for 2) and 6)
A subject with occurrences of TEAE in both categories (ie, Related and Not Related)
will be counted once in the Related category.

Summary for 3)
A subject with multiple occurrences of TEAE will be counted once for the TEAE with
the maximum toxicity grade.

Summaries other than 2), 3), and 6)
A subject with multiple occurrences of TEAE will be counted only once.
Number of events
For each summary, the total number of events will be calculated.
7.13.1.2 Displays of Treatment-Emergent Adverse events
Analysis Set:
Safety Analysis Set
Analysis Variables:
TEAE
Categories:
Toxicity Grade
[Grade 1, Grade 2, Grade 3, Grade 4, Grade 5]
Analytical Methods:
The following summaries will be provided using frequency distribution for each cohort 
and overall.
TEAEs will be coded using the MedDRA and will be summarized using SOC and PT.
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SOC will be sorted alphabetically and PT will be sorted in decreasing frequency for 
tables provided by SOC and PT. SOC and PT will be sorted in decreasing frequency for 
tables provided by SOC only or PT only.
The definitions of the following TEAEs to monitor are given in Appendix:
GI Perforation, Fistula, Abscess, Intra-Abdominal and Pelvic Abscess, 
Hemorrhage, Thrombotic Events, Arterial Thrombotic Events, Venous and 
Mixed/Unspecified Thrombotic Events, Wound Complication, Hypertension, 
Osteonecrosis, PPES, Proteinuria, RPLS, Diarrhea, QT Prolongation, Renal 
Failure, Hypothyroidism, Hepatotoxicity
(1) Treatment-Emergent Adverse Events by System Organ Class and Preferred Term
(Any Grade and Grade ≥3)
(2) Treatment-Emergent Adverse Events by System Organ Class
(3) Treatment-Emergent Adverse Events by Preferred Term (Any Grade and Grade ≥3)
(4) Drug-Related Treatment-Emergent Adverse Events by System Organ Class and
Preferred Term (Any Grade and Grade ≥3)
(5) Drug-Related Treatment-Emergent Adverse Events by Preferred Term (Any Grade
and Grade ≥3)
(6) Toxicity Grade of Treatment-Emergent Adverse Events by System Organ Class and
Preferred Term
(7) Toxicity Grade of Drug-Related Treatment-Emergent Adverse Events by System
Organ Class and Preferred Term
(8) Grade 5 Treatment-Emergent Adverse Events by System Organ Class and Preferred
Term
(9) Grade 5 Drug-Related Treatment-Emergent Adverse Events by System Organ Class
and Preferred Term
(10)Grade 5 Treatment-Emergent Adverse Events Judged Not Causally Related to
Disease under Study by System Organ Class and Preferred Term
(11)Serious Treatment-Emergent Adverse Events by System Organ Class and Preferred
Term (Any Grade and Grade ≥3)
(12)Serious Treatment-Emergent Adverse Events by Preferred Term (Any Grade and
Grade ≥3)
(13)Drug-Related Serious Treatment-Emergent Adverse Events by System Organ Class
and Preferred Term (Any Grade and Grade ≥3)
(14)Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation by
System Organ Class and Preferred Term (Any Grade and Grade ≥3)
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(15)Drug-Related Treatment-Emergent Adverse Events Leading to Study Drug
Discontinuation by System Organ Class and Preferred Term (Any Grade and Grade
≥3)
(16)Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation and
Judged Not Causally Related to Disease under Study by System Organ Class and
Preferred Term (Any Grade and Grade ≥3)
(17)Treatment-Emergent Adverse Events Leading to Study Drug Dose Modification by
System Organ Class and Preferred Term (Any Grade and Grade ≥3)
(18)Drug-Related Treatment-Emergent Adverse Events Leading to Study Drug Dose
Modification by System Organ Class and Preferred Term (Any Grade and Grade ≥3)
(19)Treatment-Emergent Adverse Events Leading to Study Drug Dose Reduction by
System Organ Class and Preferred Term (Any Grade and Grade ≥3)
(20)Drug-Related Treatment-Emergent Adverse Events Leading to Study Drug Dose
Reduction by System Organ Class and Preferred Term (Any Grade and Grade ≥3)
(21)Treatment-Emergent Adverse Events Leading to Study Drug Dose Interruption by
System Organ Class and Preferred Term (Any Grade and Grade ≥3)
(22)Drug-Related Treatment-Emergent Adverse Events Leading to Study Drug Dose
Interruption by System Organ Class and Preferred Term (Any Grade and Grade ≥3)
(23)Treatment-Emergent Adverse Events of GI Perforation by System Organ Class and
Preferred Term (Any Grade and Grade ≥3)
(24)Treatment-Emergent Adverse Events of Fistula by System Organ Class and Preferred
Term (Any Grade and Grade ≥3)
(25)Treatment-Emergent Adverse Events of Abscess by System Organ Class and
Preferred Term (Any Grade and Grade ≥3)
(26)Treatment-Emergent Adverse Events of Intra-Abdominal and Pelvic Abscess by
System Organ Class and Preferred Term (Any Grade and Grade ≥3)
(27)Treatment-Emergent Adverse Events of Hemorrhage by System Organ Class and
Preferred Term (Any Grade and Grade ≥3)
(28)Treatment-Emergent Thrombotic Adverse Events by System Organ Class and
Preferred Term (Any Grade and Grade ≥3)
(29)Treatment-Emergent Arterial Thrombotic Adverse Events by System Organ Class
and Preferred Term (Any Grade and Grade ≥3)
(30)Treatment-Emergent Venous and Mixed/Unspecified Thrombotic Adverse Events by
System Organ Class and Preferred Term (Any Grade and Grade ≥3)
(31)Treatment-Emergent Adverse Events of Wound Complication by System Organ
Class and Preferred Term (Any Grade and Grade ≥3)
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(32)Treatment-Emergent Adverse Events of Hypertension by System Organ Class and
Preferred Term (Any Grade and Grade ≥3)
(33)Treatment-Emergent Adverse Events of Osteonecrosis by System Organ Class and
Preferred Term (Any Grade and Grade ≥3)
(34)Treatment-Emergent Adverse Events of PPES by System Organ Class and Preferred
Term (Any Grade and Grade ≥3)
(35)Treatment-Emergent Adverse Events of Proteinuria by System Organ Class and
Preferred Term (Any Grade and Grade ≥3)
(36)Treatment-Emergent Adverse Events of RPLS by System Organ Class and Preferred
Term (Any Grade and Grade ≥3)
(37)Treatment-Emergent Adverse Events of Diarrhea by System Organ Class and
Preferred Term (Any Grade and Grade ≥3)
(38)Treatment-Emergent Adverse Events of QT Prolongation by System Organ Class
and Preferred Term (Any Grade and Grade ≥3)
(39)Treatment-Emergent Adverse Events of Renal Failure by System Organ Class and
Preferred Term (Any Grade and Grade ≥3)
(40)Treatment-Emergent Adverse Events of Hypothyroidism by System Organ Class and
Preferred Term (Any Grade and Grade ≥3)
(41)Treatment-Emergent Adverse Events of Hepatotoxicity by System Organ Class and
Preferred Term (Any Grade and Grade ≥3)
The frequency distribution will be provided according to the rules below.
Number of subjects

Summary tables other than (6) and (7)
A subject with multiple occurrences of TEAE within a SOC will be counted only once
in that SOC. A subject with multiple occurrences of TEAE within a PT will be
counted only once in that PT.

Summary tables for (6) and (7)
A subject with multiple occurrences of TEAE within a SOC or a PT will be counted
only once for the TEAE with the maximum toxicity grade.
7.13.1.3 Time to First Occurrence of TEAEs to Monitor
Analysis Set:
Safety Analysis Set
Analysis Variables:
TEAEs to Monitor
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GI Perforation, Fistula, Abscess, Intra-Abdominal and Pelvic Abscess, 
Hemorrhage (All Grade), Hemorrhage (Grade ≥3), Thrombotic Events, Arterial 
Thrombotic Events, Venous and Mixed/Unspecified Thrombotic Events, Wound 
Complication, Hypertension, Osteonecrosis, PPES, Proteinuria, RPLS, Diarrhea, 
QT Prolongation, Renal Failure, Hypothyroidism, Hepatotoxicity
Analytical Methods:
(1) Time to First Occurrence of TEAEs to Monitor
Descriptive statistics of the time from the first day of study drug administration to
first occurrence (days) will be provided by cohort and overall for each TEAEs to
monitor for subjects experienced the corresponding event in the safety analysis set.
7.13.1.4 Death
Analysis Set:
Safety Analysis Set
Analysis Variables:
Subject Status
[Alive, Expired]
Deaths ≤30 Days after the Last Dose of Study Drug
[Yes]
Primary Cause of Death
[Progression of Disease under Study, Other]
Death Causally Associated with Disease under Study
[Yes, No, Unknown]
Deaths > 30 Days after the Last Dose of Study Drug
[Yes]
Primary Reason for Death
[Progression of Disease under Study, Other]
Death Causally Associated with Disease under Study
[Yes, No, Unknown]
Analytical Methods:
(1) Summary of Death
Frequency distributions will be provided for each cohort and overall.
7.13.1.5 Displays of Pretreatment Events
Analysis Set:
All Subjects Who Signed the Informed Consent Form
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Analysis Variables:
PTE
Analytical Methods:
The following summaries will be provided using frequency distribution.
PTEs will be coded using the MedDRA and will be summarized using SOC and PT. SOC 
will be sorted alphabetically and PT will be sorted in decreasing frequency.
(1) Pretreatment Events by System Organ Class and Preferred Term
(2) Serious Pretreatment Events by System Organ Class and Preferred Term
The frequency distribution will be provided according to the rules below.
Number of subjects
A subject with multiple occurrences of PTE within a SOC will be counted only once in 
that SOC. A subject with multiple occurrences of PTE within a PT will be counted only 
once in that PT.
7.13.2 Clinical Laboratory Evaluations
Analysis Set:
Safety Analysis Set
Analysis Variables:
Hematology
WBC, Neutrophils, Neutrophils/WBC, Basophils, Basophils/WBC, Eosinophils, 
Eosinophils/WBC, Lymphocytes, Lymphocytes/WBC, Monocytes, 
Monocytes/WBC, Hematocrit, Platelets, RBC, Hemoglobin, Reticulocytes
Serum Chemistry
Albumin, ALP, ALT, Amylase, AST, BUN, Corrected Calcium, Chloride, 
Creatinine, Creatinine Clearance, GGT, Fasted Glucose, LDH, Lipase, 
Magnesium, Phosphorus, Potassium, Sodium, Total Bilirubin, Conjugated 
Bilirubin, Unconjugated Bilirubin, Total Protein
Coagulation
PT-INR, APTT
Thyroid Function
TSH
Urine Chemistry
UPCR
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Statistical Analysis Plan Version 2
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Categories:
Toxicity Grade
[Grade 0, Grade 1, Grade 2, Grade 3, Grade 4]
[Grade 0, Grade 1 – Grade 4]
[Grade 0, Grade 1 or 2, Grade 3 or 4]
Visit:
Hematology, Serum Chemistry
Baseline, Week 3 Day 1, Week 5 Day 1, Week 7 Day 1, Week 9 Day 1, Every 4 
Weeks Thereafter, 30-Day Posttreatment Followup
Coagulation
Baseline, Week 5 Day 1, Week 9 Day 1, Every 4 Weeks Thereafter, 30-Day 
Posttreatment Followup
Thyroid Function
Baseline, Week 5 Day 1, Week 9 Day 1, Every 8 Weeks Thereafter, 30-Day 
Posttreatment Followup
Urine Chemistry
Baseline, Week 3 Day 1, Week 5 Day 1, Week 9 Day 1, Every 4 Weeks 
Thereafter, 30-Day Posttreatment Followup
Analytical Methods:
For each variable, summaries (1) and (2) will be provided for each cohort.
For applicable variables, summaries (3) to (8) will be provided for each cohort and 
overall.
(1) Summary of Laboratory Test Results and Change from Baseline by Visit
Descriptive statistics for observed values for each visit and changes from baseline
will be provided.
(2) Case Plots
Plots over time for each subject will be presented.
(3) Number and Percentage of Subjects with Clinically Significant Abnormal Laboratory
Values
Frequency distributions of post-baseline maximum grade for laboratory
abnormalities will be provided. Further details are given in Appendix.
(4) Summary of Shifts of Laboratory Test Results
Shift tables showing the number of subjects in each category of baseline grade and
post-baseline maximum grade for laboratory abnormalities will be provided.
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Statistical Analysis Plan Version 2
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(5) Number and Percentage of Subjects with Elevated Liver Enzyme Laboratory
Parameters
Overall frequency distributions of post-baseline elevated hepatic parameters will be
provided. Further details are given in Appendix.
(6) Time to First Occurrence of increased ALT or AST
Descriptive statistics of the time from the first day of study drug administration to
first occurrence of "ALT or AST >5xULN" and "ALT or AST >3xULN" (days)
through 30 days after the date of the last dose will be provided for subjects
experienced ALT or AST >5xULN, and subjects experienced ALT or AST >3xULN
with both baseline ALT and AST ≤3xULN, respectively, in the safety analysis set.
(7) Number and Percentage of Subjects with Elevated Serum Creatinine
Overall frequency distributions of post-baseline elevated serum creatinine will be
provided. Further details are given in Appendix.
(8) Summary of Thyroid Function Status
For TSH, shift tables showing the number of subjects in each category of “Low”,
“Normal” or “High” relative to the normal reference range provided by the central
laboratory for baseline value and post-baseline minimum/maximum value obtained
up to 30 days after the date of the last dose will be provided.
Frequency distributions of TSH and free T4 status will be provided using the post-
baseline value obtained up to 30 days after the date of the last dose based on the
following categories:

For increased TSH:
High TSH with Low Free T4 at any post-baseline visit
High TSH with Normal Free T4 (not meet the above condition)

For decreased TSH:
Low TSH with High Free T4 at any post-baseline visit
Low TSH with Normal Free T4 (not meet the above condition)
7.13.3 Vital Signs and Weight
Analysis Set:
Safety Analysis Set
Analysis Variables:
Systolic Blood Pressure
Diastolic Blood Pressure
Pulse Rate
Respiratory Rate
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Statistical Analysis Plan Version 2
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Temperature
Weight
Visit:
Baseline, Week 3 Day 1, Week 5 Day 1, Week 7 Day 1, Week 9 Day 1, Every 4 Weeks 
Thereafter, 30-Day Posttreatment Followup
Analytical Methods:
For each variable, summaries (1) and (2) will be provided for each cohort.
For applicable variables, summaries (3) and (4) will be provided for each cohort and 
overall.
(1) Summary of Vital Signs Parameters and Change from Baseline by Visit
Descriptive statistics for observed values for each visit and changes from baseline
will be provided.
(2) Case Plots
Plots over time for each subject will be presented.
(3) Number and Percentage of Subjects with Clinically Significant Abnormal Vital Sign
Measurements
Frequency distributions of post-baseline clinically significant abnormal vital sign
measurements will be provided. Further details are given in Appendix.
(4) Time to First Occurrence of Decrease in Weight ≥10% from Baseline
Descriptive statistics of the time from the first day of study drug administration to
first occurrence of decrease in weight ≥10% (days) through 30 days after the date of
the last dose will be provided for subjects experienced the weight decrease in the
safety analysis set.
7.13.4 12-Lead ECGs
Analysis Set:
Safety Analysis Set
Analysis Variables:
QTcF Interval
Interpretation
[Normal, Abnormal but not Clinically Significant, Abnormal and Clinically 
Significant]
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Statistical Analysis Plan Version 2
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Visit:
Baseline, Week 5 Day 1, Week 9 Day 1, Every 12 Weeks Thereafter, 30-Day 
Posttreatment Followup
Analytical Methods:
For QTcF interval, summaries (1) and (2) will be provided for each cohort, and summary
(3) will be provided for each cohort and overall.
For 12-lead ECG interpretation, summary (4) will be provided for each cohort and 
overall.
(1) Summary of ECG Parameters and Change from Baseline by Visit
Descriptive statistics for observed values for each visit and changes from baseline
will be provided
(2) Case Plots
Plots over time for each subject will be presented.
(3) Number and Percentage of Subjects with Clinically Significant Abnormal QTcF
Measurements
Frequency distributions of post-baseline clinically significant abnormal QTcF
measurements will be provided. Further details are given in Appendix.
(4) Summary of Shift of 12-lead ECG Interpretation
Shift table showing the number of subjects in each category for baseline result and
the worst post-baseline result obtained up to 30 days after the date of the last dose
will be provided.
7.13.5 Other Observations Related to Safety
7.13.5.1 ECOG Performance Status
Analysis Set:
Safety Analysis Set
Analysis Variables:
ECOG PS
[0, 1, 2, 3, 4]
Analytical Methods:
The following summaries will be provided for each cohort and overall.
(1) Summary of Shift of ECOG Performance Status
Shift table showing the number of subjects in each category for baseline result and
the worst post-baseline result obtained up to 30 days after the date of the last dose
will be provided.
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Statistical Analysis Plan Version 2
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(2) Number and Percentage of Subjects with Increase in ECOG Performance Status
Frequency distributions of maximum post-baseline change in ECOG PS of ≥1 and
≥2 obtained up to 30 days after the date of the last dose will be provided.
7.13.5.2 Transfusion
Analysis Set:
Safety Analysis Set
Analysis Variables:
Concomitant Transfusion After Enrollment [Yes, No]
Transfusion Type
Packed RBC
[Yes]
Platelets
[Yes]
Plasma
[Yes]
Whole Blood
[Yes]
Other
[Yes]
(1) Transfusion After Enrollment
Frequency distributions will be provided for each cohort and overall.
7.13.5.3 Child-Pugh Score
Analysis Set:
Safety Analysis Set
Analysis Variables:
Child-Pugh Score
[A, B, C]
Visit:
Baseline, Week 9 Day 1, Every 8 Weeks Thereafter
Analytical Methods:
(1) Summary of Shift of Child-Pugh Score
Shift table showing the number of subjects in each category for baseline result and
each post-baseline visit will be provided by cohort and overall.
7.14
Interim Analysis
Not applicable.
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Statistical Analysis Plan Version 2
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7.15
Changes in the Statistical Analysis Plan 
The analyses in the statistical analysis plan do not differ from the analyses specified in the 
protocol.
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Statistical Analysis Plan Version 2
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8.0
REFERENCES
[1] Ikeda, S., Shiroiwa, T., Igarashi. A., Noto, S., Fukuda, T., Saito, S. & Shimozuma, K.
(2015). Developing a Japanese version of the EQ-5D-5L value set. Journal of the National
Institute of Public Health, 64(1), 47-55.
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Statistical Analysis Plan Version 2 
9.0 
APPENDIX 
9.1 
Criteria for Clinically Significant Abnormal Values 
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5 September 2019 
For each parameter, all evaluable data (ie, non-missing data) obtained up to 30 days after the date 
of the last dose will be classified as a clinically significant abnonnal value or not. The criteria in 
the table below will be used. 
Table 9.a 
Clinically Significant Abnormal Value Criteria for Laboratory Parameters 
Abnormality 
Criteria 
WBC Increased 
CTCAEv4.03 
WBC Decreased 
CTCAEv4.03 
ANC Decreased 
CTCAEv4.03 
Lymphocytes Increased 
CTCAEv4.03 
Lymphocytes Decreased 
CTCAEv4.03 
Platelets Decreased 
CTCAEv4.03 
Hemoglobin Increased 
CTCAEv4.03 
Hemoglobin Decreased 
CTCAEv4.03 
Alblllllin Decreased 
CTCAEv4.03 
ALP Increased 
CTCAEv4.03 
Amylase Increased 
CTCAEv4.03 
ALT Increased 
CTCAEv4.03 
AST Increased 
CTCAEv4.03 
Con-ected Calcilllll Increased 
CTCAEv4.03 
Con-ected Calcilllll Decreased 
CTCAEv4.03 
Creatinine Increased 
CTCAEv4.03 
GGT Increased 
CTCAEv4.03 
Glucose Increased 
CTCAEv4.03 
Glucose Decreased 
CTCAEv4.03 
Grade I: ULN< - <=2xULN 
LDH Increased 
Grade 2: 2xULN< -<=3xULN 
Grade 3: 3xULN< 
Lipase Increased 
CTCAEv4.03 
Magnesilllll Increased 
CTCAEv4.03 
Magnesilllll Decreased 
CTCAEv4.03 
Phosphate Decreased 
CTCAEv4.03 
Potassium Increased 
CTCAEv4.03 
Potassium Decreased 
CTCAEv4.03 
Sodium Increased 
CTCAEv4.03 
Sodium Decreased 
CTCAEv4.03 
Total Bilirubin Increased 
CTCAEv4.03 
Grade 1: 17.0<= -<=121.0 g/mol 
UPCR Increased 
Grade 2: 121.0< -<=396.0 g/mol 
Grade 3: 396.0 g/mol< 
 
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Statistical Analysis Plan Version 2 
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Table 9.b 
Clinically Significant Abnormal Value Criteria for Vital Sign Parameters 
Abnormality 
Criteria 
•
SBP 120<= -<=139 mmHg or DBP 80<= -<=89 mmHg
•
SBP 140<= - <=159 mmHg or DBP 90<= - <=99 mmHg
Blood Pressw-e Increased 
•
(SBP 160 mmHg<= and DBP <120 mmHg) or DBP 100<=
(Assign the worst category when a subject meets 
-<=119 mmHg
multiple criteria) 
•
DBP 120 mmHg<= 
* Need to me.et the criteria at 2 or more visits (need not be
consecutive)
Weight Decreased 
Weight decreased >= 10% from baseline 
Table 9.c 
Clinically Significant Abnormal Value Criteria for ECG Parameters 
Abnormality 
Criteria 
QTcF Interval Prolongation 
500msec < 
(based on observed value) 
QTcF Interval Prolongation 
30msec < 
(based on change from baseline) 
60msec < 
9.2 
Criteria for Elevated Liver Enzyme and Elevated Serum Creatinine 
All evaluable data (ie, non-missing data) obtained up to 30 days after the date of the last dose 
will be used to detennine whether each criteria for elevated liver enzyme or elevated sernm 
creatinine in the table below is met or not. If there is more than one parameter that need to be 
considered for a criteria, parameter measmements taken on the same day will be used. 
Table 9.d 
Criteria for Elevated Liver Enzyme 
Criteria for Elevated Liver Enzyme 
Label 
Elevated 
Not Elevated 
Tbili > 1. 5xULN 
Total bilirubin is greater than 1.5 times the Total bilimbin is non-missing and less 
ULN 
than or equal to 1.5 times the ULN 
Tbili >2xULN 
Total bilirubin is greater than twice the 
Total bilimbin is non-missing and less 
ULN 
than or equal to twice the ULN 
ALT>3xULN 
ALT is greater than 3 times the ULN 
ALT is non-missing and less than or equal 
to 3 times the ULN 
ALT>5xULN 
ALT is greater than 5 times the ULN 
ALT is non-missing and less than or equal 
to 5 times the ULN 
ALT>lOxULN 
ALT is greater than 10 times the ULN 
ALT is non-missing and less than or equal 
to 10 times the ULN 
ALT>20xULN 
ALT is greater than 20 times the ULN 
ALT is non-missing and less than or equal 
to 20 times the ULN 
 
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Criteria for Elevated Liver Enzyme 
Label 
Elevated 
Not Elevated 
ALT is greater than 3 times the ULN and 
Either ALT is non-missing and less than or 
ALT>3xULN 
equal to 3 times the ULN, or the total 
with Tbili >2xULN 
the total bilimbin is greater than twice the 
bilimbin is non-missing and less than or 
ULN 
equal to tv.•ice the ULN 
AST>3xULN 
AST is greater than 3 times the ULN 
AST is non-missing and less than or equal 
to 3 times the ULN 
AST>5xULN 
AST is greater than 5 times the ULN 
AST is non-missing and less than or equal 
to 5 times the ULN 
AST>IOxULN 
AST is greater than 10 times the ULN 
AST is non-missing and less than or equal 
to 10 times the ULN 
AST>20xULN 
AST is greater than 20 times the ULN 
AST is non-missing and less than or equal 
to 20 times the ULN 
AST is greater than 3 times the ULN and 
Either AST is non-missing and less than or 
AST>3xULN 
equal to 3 times the ULN, or the total 
with Tbili >2xULN 
the total bilimbin is greater than twice the 
bilimbin is non-missing and less than or 
ULN 
equal to tv.•ice the ULN 
ALT or AST>3xULN 
Either ALT or AST is greater than 3 times 
Both ALT and AST are non-missing and 
theULN 
less than or equal to 3 times the ULN 
ALT or AST >5xULN 
Either ALT or AST is greater than 5 times 
Both ALT and AST are non-missing and 
theULN 
less than or equal to 5 times the ULN 
ALT or AST>lOxULN 
Either ALT or AST is greater than IO 
Both ALT and AST are non-missing and 
times the ULN 
less than or equal to 10 times the ULN 
ALT or AST >20xULN 
Either ALT or AST is greater than 20 
Both ALT and AST are non-missing and 
times the ULN 
less than or equal to 20 times the ULN 
If any of the following conditions is met: 
ALT or AST> 1 OxULN 
Either ALT or AST is greater than IO 
- Both ALT and AST are non-missing and
with Tbili >2xULN 
times the ULN and the total bilimbin is 
less than or equal to 10 times the ULN.
greater than twice the ULN 
- Total bilimbin is non-missing and less
than or equal to twice the ULN.
If any of the following conditions is met: 
Either ALT or AST is greater than 3 times 
- Both ALT and AST are non-missing and
ALT or AST>3xULN 
less than or equal to 3 times the ULN.
with Tbili >2xULN and 
the ULN and the total bilimbin is greater 
- Total bilimbin is non-missing and less
than twice the ULN and ALP is non-
ALP<2xULN 
missing and less than twice the ULN 
than or equal to twice the ULN.
- ALP is greater than or equal to twice the
ULN.
If any of the following conditions is met: 
Either ALT or AST is greater than 3 times 
- Both ALT and AST are non-missing and
ALT or AST>3xULN 
less than or equal to 3 times the ULN.
with Tbili >2xULN and 
the ULN and the total bilimbin is greater 
- Total bilimbin is non-missing and less
than twice the ULN and ALP is greater 
ALP2::2xULN 
than or equal to tv.•ice the ULN 
than or equal to twice the ULN.
- ALP is non-missing and less than twice
theULN.
 
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Criteria for Elevated Liver Enzyme 
Label 
Elevated 
Not Elevated 
ALP> 1. 5xULN 
ALP is greater than 1.5 times the ULN 
ALP is non-missing and less than or equal 
to 1. 5 times the ULN 
ALP>2xULN 
ALP is greater than twice the ULN 
ALP is non-missing and less than or equal 
to tv.1ice the ULN 
Table 9.e 
Criteria for Elevated Serum Creatinine 
Criteria for Elevated Serum Creatinine 
Label 
Elevated 
Not Elevated 
1)
Creatinine clearance <30 mL/min and
1)
Creatinine Clearance is non-missing,
and either>= 30 mL/min or <25%
>=25% reduction from baseline or
reduction from baseline, and
Elevated Sernm 
2)
Creatinine clearance<= 0.5x baseline
2)
Creatinine Clearance >0.5x baseline,
Creatinine 
or
and
3)
Sernm creatinine >= 3xULN and
3) Sernm creatinine is non-missing and
>=2x baseline
either <3x ULN or <2x baseline
9.3 
Definition of Treatment-Emergent Adverse Events to Monitor 
•
GI Perforation
Abdominal hernia perforation; Appendicitis perforated; Dive1iicular perforation; Duodenal
perforation; Duodenal ulcer perforation; Duodenal ulcer perforation, obstructive; Duodenal
ulcer repair; Gastric perforation; Gastr·ic ulcer perforation; Gastr·ic ulcer perforation,
obstructive; Gash'ointestinal perforation; Gash'ointestinal ulcer perforation; Ileal perforation;
Ileal ulcer perforation; Intestinal perforation; Intestinal ulcer perforation; Jejunal perforation;
Jejunal ulcer perforation; Large intestinal ulcer perforation; Large intestine perforation;
Neonatal intestinal perforation; Oesophageal perforation; Oesophageal mpture; Oesophageal
ulcer perforation; Peptic ulcer perforation; Peptic ulcer perforation, obstructive; Perforated
peptic ulcer oversewing; Perforated ulcer; Peritonitis; Peritonitis bacterial; Rectal
perforation; Small intestinal perforation; Small intestinal ulcer perforation
•
Fistula
Acquired tr·acheo-oesophageal fistula; Anal fistula; Anal fistula excision; Anal fistula
infection; Anastomotic fistula; Anovulvar fistula; Ao1ioenteric fistula; Ao1io-oesophageal
fistula; Alierioenteric fistula; Arteriovenous fistula; Arteriovenous fistula anemysm;
Arteriovenous fistula occlusion; Alieriovenous fistula operation; Alteriovenous fistula site
complication; AI·teriovenous fistula site infection; Alieriovenous fistula thrombosis; Biliaiy
fistula; Biliaiy fistula repair; Bladder fistula repair; Bone fistula; Bronchial fistula; Bronchial
fistula repair; Bronchopleural fistula; Cerebrospinal fistula; Colon fistula repair; Colonic
fistula; Congenital arteriovenous fistula; Congenital aural fistula; Congenital lip fistula;
Dental fistula; Dive1iiculai· fistula; Dural arteriovenous fistula; Enterocolonic fistula;
 
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Enterocutaneous fistula; Enterovesical fistula; Female genital tract fistula; Fistula; Fistula 
discharge; Fistula of small intestine; Fistula repair; Gallbladder fistula; Gallbladder fistula 
repair; Gastric fistula; Gastric fistula repair; Gastrointestinal fistula; Gastrointestinal fistula 
repair; Gastropleural fistula; Gastrosplenic fistula; Infected fistula; Intestinal fistula; 
Intestinal fistula infection; Intestinal fistula repair; Intrahepatic portal hepatic venous fistula; 
Labyrinthine fistula; Lacrimal fistula; Laryngeal fistula; Laryngeal fistula repair; Lymphatic 
fistula; Male genital tract fistula; Mammary fistula; Mammary fistula repair; Ocular fistula; 
Oesophageal fistula; Oesophageal fistula repair; Oesophagobronchial fistula; Oral cavity 
fistula; Oroantral fistula; Pancreatic fistula; Pancreatic fistula repair; Perineal fistula; 
Pharyngeal fistula; Pharyngeal fistula repair; Pleural fistula; Pleurocutaneous fistula; Post 
procedural fistula; Postauricular fistula; Pulmonary arteriovenous fistula; Pulmonary fistula; 
Rectal fistula repair; Rectoprostatic fistula; Rectourethral fistula; Renal pelvis fistula; 
Salivary gland fistula; Thyroglossal fistula; Thyroglossal fistula excision; Tracheal fistula; 
Tracheal fistula repair; Tracheo-oesophageal fistula; Ureteric fistula; Urethral fistula; 
Urethroperineal fistula; Urinary fistula; Urogenital fistula; Urogenital fistula repair; Uterine 
fistula; Vaginal fistula; Vaginal fistula repair; Vesical fistula; Vesicocutaneous fistula

Abscess
Abdominal wall abscess; Abscess; Abscess bacterial; Abscess drainage; Abscess fungal;
Abscess intestinal; Abscess jaw; Abscess limb; Abscess management; Abscess neck;
Abscess of external auditory meatus; Abscess of eyelid; Abscess of salivary gland; Abscess
oral; Abscess rupture; Abscess soft tissue; Abscess sterile; Abscess sweat gland;
Administration site abscess; Adrenal gland abscess; Amoebic brain abscess; Amoebic lung
abscess; Anal abscess; Appendiceal abscess; Application site abscess; Arteriovenous graft
site abscess; Bacterial abscess central nervous system; Bartholin's abscess; Biliary abscess;
Bone abscess; Brain abscess; Breast abscess; Cardiac valve abscess; Catheter site abscess;
Central nervous system abscess; Chest wall abscess; Clitoris abscess; Colonic abscess;
Corneal abscess; Douglas' abscess; Dural abscess; Extradural abscess; Eye abscess;
Fallopian tube abscess; Fungal abscess central nervous system; Gallbladder abscess; Genital
abscess; Gingival abscess; Groin abscess; Implant site abscess; Incision site abscess;
Infusion site abscess; Injection site abscess; Injection site abscess sterile; Instillation site
abscess; Joint abscess; Liver abscess; Lung abscess; Lymph node abscess; Mastoid abscess;
Mediastinal abscess; Mesenteric abscess; Muscle abscess; Mycobacterium abscessus
infection; Myocardiac abscess; Nasal abscess; Ovarian abscess; Pancreatic abscess;
Parametric abscess; Paraoesophageal abscess; Paraspinal abscess; Parathyroid gland abscess;
Parotid abscess; Pelvic abscess; Penile abscess; Perihepatic abscess; Perineal abscess;
Perinephric abscess; Periorbital abscess; Perirectal abscess; Peritoneal abscess; Peritonsillar
abscess; Periumbilical abscess; Pharyngeal abscess; Pharyngolaryngeal abscess;
Postoperative abscess; Prostatic abscess; Psoas abscess; Puncture site abscess; Pyloric
abscess; Rectal abscess; Rectovaginal septum abscess; Renal abscess; Retroperitoneal
abscess; Scrotal abscess; Spinal cord abscess; Splenic abscess; Staphylococcal abscess;
Stitch abscess; Stoma site abscess; Streptococcal abscess; Subarachnoid abscess;
Subcutaneous abscess; Subdiaphragmatic abscess; Testicular abscess; Thymus abscess;
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Thyroid gland abscess; Tongue abscess; Tooth abscess; Transplant abscess; Tuberculous 
abscess central nervous system; Tubo-ovarian abscess; Urachal abscess; Ureter abscess; 
Urethral abscess; Urinary bladder abscess; Urinary tract abscess; Uterine abscess; 
Vaccination site abscess; Vaccination site abscess sterile; Vaginal abscess; Vitreous abscess; 
Vulval abscess; Wound abscess

Intra-Abdominal and Pelvic Abscess
Abdominal abscess; Abdominal wall abscess; Abscess intestinal; Adrenal gland abscess;
Anal abscess; Appendiceal abscess; Biliary abscess; Clitoris abscess; Colonic abscess;
Douglas' abscess; Fallopian tube abscess; Gallbladder abscess; Genital abscess; Groin
abscess; Liver abscess; Mesenteric abscess; Ovarian abscess; Pancreatic abscess; Parametric
abscess; Pelvic abscess; Penile abscess; Perihepatic abscess; Perineal abscess; Perinephric
abscess; Perirectal abscess; Peritoneal abscess; Periumbilical abscess; Prostatic abscess;
Psoas abscess; Pyloric abscess; Rectal abscess; Rectovaginal septum abscess; Renal abscess;
Retroperitoneal abscess; Scrotal abscess; Splenic abscess; Stoma site abscess;
Subdiaphragmatic abscess; Testicular abscess; Tubo-ovarian abscess; Urachal abscess;
Ureter abscess; Urethral abscess; Urinary bladder abscess; Urinary tract abscess; Uterine
abscess; Vaginal abscess; Vulval abscess

Hemorrhage
Abdominal wall haematoma; Abdominal wall haemorrhage; Abnormal withdrawal bleeding;
Adrenal haematoma; Adrenal haemorrhage; Anal haemorrhage; Anal ulcer haemorrhage;
Anastomotic haemorrhage; Anastomotic ulcer haemorrhage; Aneurysm ruptured; Anorectal
varices haemorrhage; Aortic aneurysm rupture; Aortic dissection rupture; Aortic intramural
haematoma; Aortic rupture; Arterial haemorrhage; Arterial rupture; Arteriovenous fistula
site haematoma; Arteriovenous fistula site haemorrhage; Arteriovenous graft site
haematoma; Arteriovenous graft site haemorrhage; Atrial rupture; Auricular haematoma;
Basal ganglia haemorrhage; Bladder tamponade; Bleeding varicose vein; Blood blister;
Blood loss anaemia; Blood urine; Blood urine present; Bloody discharge; Bloody peritoneal
effluent; Bone marrow haemorrhage; Brain stem haematoma; Brain stem haemorrhage;
Breast haematoma; Breast haemorrhage; Broad ligament haematoma; Bronchial
haemorrhage; Carotid aneurysm rupture; Catheter site haemorrhage; Central nervous system
haemorrhage; Cephalhaematoma; Cerebellar haematoma; Cerebellar haemorrhage; Cerebral
arteriovenous malformation haemorrhagic; Cerebral haematoma; Cerebral haemorrhage;
Cerebral haemorrhage foetal; Cerebral haemorrhage neonatal; Cerebral microhaemorrhage;
Cervix haematoma uterine; Cervix haemorrhage uterine; Choroidal haematoma; Choroidal
haemorrhage; Chronic gastrointestinal bleeding; Ciliary body haemorrhage; Colonic
haematoma; Conjunctival haemorrhage; Corneal bleeding; Cullen's sign; Cystitis
haemorrhagic; Deep dissecting haematoma; Diarrhoea haemorrhagic; Diverticulitis intestinal
haemorrhagic; Diverticulum intestinal haemorrhagic; Duodenal ulcer haemorrhage;
Duodenitis haemorrhagic; Dysfunctional uterine bleeding; Ear haemorrhage; Encephalitis
haemorrhagic; Enterocolitis haemorrhagic; Epidural haemorrhage; Epistaxis;
Exsanguination; Extradural haematoma; Extravasation blood; Eye contusion; Eye
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haemorrhage; Eyelid bleeding; Foetal-maternal haemorrhage; Gastric haemorrhage; Gastric 
ulcer haemorrhage; Gastric ulcer haemorrhage, obstructive; Gastric varices haemorrhage; 
Gastritis haemorrhagic; Gastroduodenal haemorrhage; Gastrointestinal haemorrhage; 
Gastrointestinal polyp haemorrhage; Gastrointestinal ulcer haemorrhage; Gastrointestinal 
vascular malformation haemorrhagic; Genital haemorrhage; Gingival bleeding; Graft 
haemorrhage; Haemarthrosis; Haematemesis; Haematochezia; Haematoma; 
Haematosalpinx; Haematospermia; Haematotympanum; Haematuria; Haemobilia; 
Haemoptysis; Haemorrhage; Haemorrhage coronary artery; Haemorrhage foetal; 
Haemorrhage in pregnancy; Haemorrhage intracranial; Haemorrhage neonatal; Haemorrhage 
subcutaneous; Haemorrhage subepidermal; Haemorrhage urinary tract; Haemorrhagic 
arteriovenous malformation; Haemorrhagic ascites; Haemorrhagic cerebral infarction; 
Haemorrhagic diathesis; Haemorrhagic disease of newborn; Haemorrhagic disorder; 
Haemorrhagic erosive gastritis; Haemorrhagic hepatic cyst; Haemorrhagic infarction; 
Haemorrhagic ovarian cyst; Haemorrhagic stroke; Haemorrhagic thyroid cyst; 
Haemorrhagic transformation stroke; Haemorrhagic tumour necrosis; Haemorrhagic 
urticaria; Haemorrhagic vasculitis; Haemorrhoidal haemorrhage; Haemostasis; 
Haemothorax; Hepatic haemangioma rupture; Hepatic haematoma; Hepatic haemorrhage; 
Hyphaema; Iliac artery rupture; Implant site haemorrhage; Incision site haemorrhage; 
Infusion site haemorrhage; Injection site haemorrhage; Instillation site haemorrhage; 
Intestinal haematoma; Intestinal haemorrhage; Intra-abdominal haematoma; Intra-abdominal 
haemorrhage; Intracerebral haematoma evacuation; Intracranial haematoma; Intracranial 
tumour haemorrhage; Intraocular haematoma; Intraventricular haemorrhage; Intraventricular 
haemorrhage neonatal; Iris haemorrhage; Lacrimal haemorrhage; Large intestinal 
haemorrhage; Large intestinal ulcer haemorrhage; Laryngeal haematoma; Laryngeal 
haemorrhage; Lip haematoma; Lip haemorrhage; Lower gastrointestinal haemorrhage; 
Lymph node haemorrhage; Mallory-Weiss syndrome; Mediastinal haematoma; Mediastinal 
haemorrhage; Melaena; Melaena neonatal; Meningorrhagia; Menometrorrhagia; 
Menorrhagia; Mesenteric haematoma; Mesenteric haemorrhage; Metrorrhagia; Mouth 
haemorrhage; Mucosal haemorrhage; Muscle haemorrhage; Myocardial haemorrhage; 
Myocardial rupture; Naevus haemorrhage; Neonatal gastrointestinal haemorrhage; Nephritis 
haemorrhagic; Ocular retrobulbar haemorrhage; Oesophageal haemorrhage; Oesophageal 
ulcer haemorrhage; Oesophageal varices haemorrhage; Oesophagitis haemorrhagic; Optic 
disc haemorrhage; Optic nerve sheath haemorrhage; Oral mucosa haematoma; Osteorrhagia; 
Ovarian haematoma; Ovarian haemorrhage; Pancreatic haemorrhage; Pancreatitis 
haemorrhagic; Papillary muscle haemorrhage; Paranasal sinus haematoma; Parathyroid 
haemorrhage; Parotid gland haemorrhage; Pelvic haematoma; Pelvic haematoma obstetric; 
Pelvic haemorrhage; Penile haematoma; Penile haemorrhage; Peptic ulcer haemorrhage; 
Pericardial haemorrhage; Perineal haematoma; Periorbital haematoma; Peripartum 
haemorrhage; Perirenal haematoma; Peritoneal haematoma; Peritoneal haemorrhage; 
Pharyngeal haematoma; Pharyngeal haemorrhage; Pituitary haemorrhage; Polymenorrhagia; 
Post procedural haemorrhage; Postmenopausal haemorrhage; Premature separation of 
placenta; Procedural haemorrhage; Proctitis haemorrhagic; Prostatic haemorrhage; 
Pulmonary alveolar haemorrhage; Pulmonary haematoma; Pulmonary haemorrhage; 
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Puncture site haemorrhage; Putamen haemorrhage; Radiation associated haemorrhage; 
Rectal haemorrhage; Rectal ulcer haemorrhage; Renal cyst haemorrhage; Renal haematoma; 
Renal haemorrhage; Respiratory tract haemorrhage; Respiratory tract haemorrhage neonatal; 
Retinal haemorrhage; Retinopathy haemorrhagic; Retroperitoneal haematoma; 
Retroperitoneal haemorrhage; Retroplacental haematoma; Ruptured cerebral aneurysm; 
Scleral haemorrhage; Scrotal haematocoele; Scrotal haematoma; Shock haemorrhagic; Skin 
haemorrhage; Skin ulcer haemorrhage; Small intestinal haemorrhage; Small intestinal ulcer 
haemorrhage; Soft tissue haemorrhage; Spermatic cord haemorrhage; Spinal cord 
haematoma; Spinal cord haemorrhage; Spinal epidural haematoma; Spinal epidural 
haemorrhage; Spinal subarachnoid haemorrhage; Spinal subdural haematoma; Spinal 
subdural haemorrhage; Splenic haematoma; Splenic haemorrhage; Splenic varices 
haemorrhage; Splinter haemorrhages; Spontaneous haematoma; Spontaneous haemorrhage; 
Stoma site haemorrhage; Stomatitis haemorrhagic; Subarachnoid haemorrhage; 
Subarachnoid haemorrhage neonatal; Subchorionic haematoma; Subcutaneous haematoma;
Subdural haematoma; Subdural haematoma evacuation; Subdural haemorrhage; Subdural 
haemorrhage neonatal; Subgaleal haematoma; Subretinal haematoma; Testicular 
haemorrhage; Thalamus haemorrhage; Thoracic haemorrhage; Thrombocytopenic purpura; 
Thrombotic thrombocytopenic purpura; Thyroid haemorrhage; Tongue haematoma; Tongue 
haemorrhage; Tonsillar haemorrhage; Tooth pulp haemorrhage; Tooth socket haemorrhage; 
Tracheal haemorrhage; Tumour haemorrhage; Ulcer haemorrhage; Upper gastrointestinal 
haemorrhage; Ureteric haemorrhage; Urethral haemorrhage; Urinary bladder haemorrhage; 
Urogenital haemorrhage; Uterine haematoma; Uterine haemorrhage; Vaccination site 
haemorrhage; Vaginal haematoma; Vaginal haemorrhage; Varicose vein ruptured; Vascular 
pseudoaneurysm ruptured; Vascular purpura; Vascular rupture; Venous haemorrhage; 
Ventricle rupture; Vessel puncture site haemorrhage; Vitreous haematoma; Vitreous 
haemorrhage; Vulval haematoma; Vulval haematoma evacuation; Vulval haemorrhage; 
Wound haemorrhage

Arterial Thrombotic Events
Acute aortic syndrome; Acute myocardial infarction; Aortic embolus; Aortic thrombosis;
Arterial occlusive disease; Arterial thrombosis; Basal ganglia infarction; Basal ganglia
stroke; Basilar artery occlusion; Basilar artery thrombosis; Bone infarction; Brachiocephalic
artery occlusion; Brain stem embolism; Brain stem infarction; Brain stem stroke; Brain stem
thrombosis; Carotid arterial embolus; Carotid artery occlusion; Carotid artery thrombosis;
Cerebellar artery occlusion; Cerebellar artery thrombosis; Cerebellar embolism; Cerebellar
infarction; Cerebral artery embolism; Cerebral artery occlusion; Cerebral artery thrombosis;
Cerebral infarction; Cerebral infarction foetal; Cerebral ischaemia; Cerebral septic infarct;
Cerebral thrombosis; Cerebrovascular accident; Choroidal infarction; Coeliac artery
occlusion; Coronary artery embolism; Coronary artery occlusion; Coronary artery
reocclusion; Coronary artery thrombosis; Coronary bypass thrombosis; Embolic cerebral
infarction; Embolic stroke; Embolism arterial; Femoral artery embolism; Hepatic artery
embolism; Hepatic artery occlusion; Hepatic artery thrombosis; Hepatic infarction; Iliac
artery embolism; Iliac artery occlusion; Infarction; Inner ear infarction; Intestinal infarction;
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Ischaemic cerebral infarction; Ischaemic stroke; Lacunar infarction; Leriche syndrome; 
Mesenteric arterial occlusion; Mesenteric artery embolism; Mesenteric artery thrombosis; 
Myocardial infarction; Myocardial necrosis; Optic nerve infarction; Pancreatic infarction; 
Papillary muscle infarction; Penile artery occlusion; Peripheral arterial occlusive disease; 
Peripheral arterial reocclusion; Peripheral artery occlusion; Peripheral artery thrombosis; 
Peripheral embolism; Pituitary infarction; Placental infarction; Post procedural myocardial 
infarction; Post procedural stroke; Precerebral artery occlusion; Precerebral artery 
thrombosis; Renal artery occlusion; Renal artery thrombosis; Renal embolism; Renal infarct; 
Retinal artery embolism; Retinal artery occlusion; Retinal artery thrombosis; Retinal 
infarction; Retinal vascular thrombosis; Silent myocardial infarction; Spinal artery 
embolism; Spinal artery thrombosis; Spinal cord infarction; Splenic artery thrombosis; 
Splenic embolism; Splenic infarction; Splenic thrombosis; Stroke in evolution; Subclavian 
artery embolism; Subclavian artery occlusion; Subclavian artery thrombosis; Thalamic 
infarction; Thrombotic cerebral infarction; Thrombotic microangiopathy; Thrombotic stroke; 
Thyroid infarction; Transient ischaemic attack; Truncus coeliacus thrombosis; Vertebral 
artery occlusion; Vertebral artery thrombosis

Venous and Mixed/Unspecified Thrombotic Events
Arteriovenous fistula occlusion; Arteriovenous fistula thrombosis; Atrial thrombosis;
Axillary vein thrombosis; Budd-Chiari syndrome; Cardiac ventricular thrombosis;
Cavernous sinus thrombosis; Cerebral venous thrombosis; Cerebrospinal thrombotic
tamponade; Deep vein thrombosis; Deep vein thrombosis postoperative; Embolism venous;
Graft thrombosis; Haemorrhoids thrombosed; Hepatic vascular thrombosis; Hepatic vein
occlusion; Hepatic vein thrombosis; Homans' sign positive; Iliac vein occlusion; Implant site
thrombosis; Inferior vena cava syndrome; Inferior vena caval occlusion; Infusion site
thrombosis; Injection site thrombosis; Instillation site thrombosis; Intracardiac thrombus;
Intracranial venous sinus thrombosis; Jugular vein thrombosis; Mesenteric vascular
occlusion; Mesenteric vein thrombosis; Mesenteric venous occlusion; Microembolism;
Obstetrical pulmonary embolism; Ophthalmic vein thrombosis; Ovarian vein thrombosis;
Paget-Schroetter syndrome; Paradoxical embolism; Pelvic venous thrombosis; Penile vein
thrombosis; Portal vein occlusion; Portal vein thrombosis; Post procedural pulmonary
embolism; Post thrombotic syndrome; Postoperative thrombosis; Postpartum venous
thrombosis; Pulmonary artery thrombosis; Pulmonary embolism; Pulmonary infarction;
Pulmonary microemboli; Pulmonary thrombosis; Pulmonary vein occlusion; Pulmonary
veno-occlusive disease; Pulmonary venous thrombosis; Renal vascular thrombosis; Renal
vein embolism; Renal vein occlusion; Renal vein thrombosis; Retinal vein occlusion; Retinal
vein thrombosis; Shunt occlusion; Shunt thrombosis; Splenic vein occlusion; Splenic vein
thrombosis; Stoma site thrombosis; Subclavian vein thrombosis; Superior sagittal sinus
thrombosis; Superior vena cava occlusion; Superior vena cava syndrome; Thrombophlebitis;
Thrombophlebitis migrans; Thrombophlebitis neonatal; Thrombophlebitis superficial;
Thrombosed varicose vein; Thrombosis; Thrombosis corpora cavernosa; Thrombosis in
device; Thrombosis mesenteric vessel; Transverse sinus thrombosis; Tumour thrombosis;
Umbilical cord thrombosis; Vascular graft thrombosis; Vena cava embolism; Vena cava
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thrombosis; Venoocclusive disease; Venoocclusive liver disease; Venous occlusion; Venous 
thrombosis; Venous thrombosis in pregnancy; Venous thrombosis limb; Venous thrombosis 
neonatal; Vessel puncture site thrombosis

Wound Complication
Abdominal wound dehiscence; Ciliary zonular dehiscence; Culture wound positive;
Fungating wound; Impaired healing; Incision site cellulitis; Incision site complication;
Incision site ulcer; Incisional drainage; Incisional hernia; Incisional hernia gangrenous;
Incisional hernia repair; Incisional hernia, obstructive; Inflammation of wound;
Postoperative wound complication; Postoperative wound infection; Uterine dehiscence;
Wound complication; Wound contamination; Wound decomposition; Wound dehiscence;
Wound drainage; Wound evisceration; Wound infection; Wound infection bacterial; Wound
infection fungal; Wound infection helminthic; Wound infection pseudomonas; Wound
infection staphylococcal; Wound infection viral; Wound necrosis; Wound secretion; Wound
sepsis

Hypertension
Accelerated hypertension; Blood pressure ambulatory increased; Blood pressure diastolic
increased; Blood pressure inadequately controlled; Blood pressure increased; Blood pressure
management; Blood pressure orthostatic increased; Blood pressure systolic increased;
Cardiometabolic syndrome; Diastolic hypertension; Eclampsia; Endocrine hypertension;
Essential hypertension; Gestational hypertension; HELLP syndrome; Hyperaldosteronism;
Hypertension; Hypertension neonatal; Hypertensive angiopathy; Hypertensive
cardiomegaly; Hypertensive cardiomyopathy; Hypertensive crisis; Hypertensive emergency;
Hypertensive encephalopathy; Hypertensive heart disease; Hypertensive nephropathy;
Labile hypertension; Malignant hypertension; Malignant hypertensive heart disease;
Malignant renal hypertension; Maternal hypertension affecting foetus; Mean arterial
pressure increased; Neurogenic hypertension; Orthostatic hypertension; Pre-eclampsia;
Prehypertension; Procedural hypertension; Renal hypertension; Renal sympathetic nerve
ablation; Renovascular hypertension; Retinopathy hypertensive; Secondary aldosteronism;
Secondary hypertension; Systolic hypertension; Withdrawal hypertension

Osteonecrosis
Alveolar osteitis; Bone debridement; Bone infarction; Bone sequestrum; Dental necrosis;
Exposed bone in jaw; Osteonecrosis; Osteonecrosis of jaw; Osteoradionecrosis; Periodontal
destruction

PPES
Palmar-plantar erythrodysaesthesia syndrome

Proteinuria
Albumin urine; Albuminuria; Nephrotic syndrome; Protein urine; Proteinuria
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
RPLS
Posterior reversible encephalopathy syndrome

Diarrhea
Antidiarrhoeal supportive care; Bacterial diarrhoea; Diarrhoea; Diarrhoea haemorrhagic;
Diarrhoea infectious; Diarrhoea infectious neonatal; Diarrhoea neonatal; Post procedural
diarrhoea; Prophylaxis against diarrhoea; Viral diarrhoea

QT Prolongation
Electrocardiogram QT interval abnormal; Electrocardiogram QT prolonged; Long QT
syndrome; Torsade de pointes

Renal Failure
Anuria; Diabetic end stage renal disease; Oliguria; Renal failure; Renal failure neonatal;
Renal impairment neonatal; Neonatal anuria; Crush syndrome; Pancreatorenal syndrome;
Postrenal failure; Renal injury; Renal impairment; Scleroderma renal crisis; Chronic kidney
disease; Acute kidney injury; Prerenal failure; End stage renal disease; Foetal renal
impairment; Subacute kidney injury

Hypothyroidism
Hypothyroidism

Hepatotoxicity
Acquired hepatocerebral degeneration; Acute hepatic failure; Acute on chronic liver failure;
Acute yellow liver atrophy; Ascites; Asterixis; Bacterascites; Biliary cirrhosis; Biliary
fibrosis; Cholestatic liver injury; Chronic hepatic failure; Coma hepatic; Cryptogenic
cirrhosis; Diabetic hepatopathy; Drug-induced liver injury; Duodenal varices; Gallbladder
varices; Gastric variceal injection; Gastric variceal ligation; Gastric varices; Gastric varices
haemorrhage; Hepatectomy; Hepatic atrophy; Hepatic calcification; Hepatic cirrhosis;
Hepatic encephalopathy; Hepatic encephalopathy prophylaxis; Hepatic failure; Hepatic
fibrosis; Hepatic hydrothorax; Hepatic infiltration eosinophilic; Hepatic lesion; Hepatic
necrosis; Hepatic steato-fibrosis; Hepatic steatosis; Hepatitis fulminant; Hepatobiliary
disease; Hepatocellular foamy cell syndrome; Hepatocellular injury; Hepatopulmonary
syndrome; Hepatorenal failure; Hepatorenal syndrome; Hepatotoxicity; Intestinal varices;
Intestinal varices haemorrhage; Liver dialysis; Liver disorder; Liver injury; Liver operation;
Liver transplant; Lupoid hepatic cirrhosis; Minimal hepatic encephalopathy; Mixed liver
injury; Nodular regenerative hyperplasia; Nonalcoholic fatty liver disease; Non-alcoholic
steatohepatitis; Non-cirrhotic portal hypertension; Oedema due to hepatic disease;
Oesophageal varices haemorrhage; Peripancreatic varices; Portal fibrosis; Portal
hypertension; Portal hypertensive colopathy; Portal hypertensive enteropathy; Portal
hypertensive gastropathy; Portal vein cavernous transformation; Portal vein dilatation;
Portopulmonary hypertension; Primary biliary cholangitis; Regenerative siderotic hepatic
nodule; Renal and liver transplant; Retrograde portal vein flow; Reye's syndrome; Reynold's
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syndrome; Splenic varices; Splenic varices haemorrhage; Steatohepatitis; Subacute hepatic 
failure; Varices oesophageal; Varicose veins of abdominal wall; White nipple sign; 
Anorectal varices; Anorectal varices haemorrhage; Intrahepatic portal hepatic venous fistula; 
Peritoneovenous shunt; Portal shunt; Portal shunt procedure; Small-for-size liver syndrome; 
Spider naevus; Splenorenal shunt; Splenorenal shunt procedure; Spontaneous intrahepatic 
portosystemic venous shunt; Stomal varices; Acute graft versus host disease in liver; 
Allergic hepatitis; Alloimmune hepatitis; Autoimmune hepatitis; Chronic graft versus host 
disease in liver; Chronic hepatitis; Graft versus host disease in liver; Hepatitis; Hepatitis 
acute; Hepatitis cholestatic; Hepatitis chronic active; Hepatitis chronic persistent; Hepatitis 
toxic; Immune-mediated hepatitis; Ischaemic hepatitis; Lupus hepatitis; Radiation hepatitis; 
Granulomatous liver disease; Liver sarcoidosis; Portal tract inflammation; Benign hepatic 
neoplasm; Benign hepatobiliary neoplasm; Focal nodular hyperplasia; Haemangioma of 
liver; Haemorrhagic hepatic cyst; Hepatic adenoma; Hepatic cyst; Hepatic cyst ruptured; 
Hepatic haemangioma rupture; Hepatic hamartoma; Hepatobiliary cyst; Cholangiosarcoma; 
Hepatic angiosarcoma; Hepatic cancer; Hepatic cancer metastatic; Hepatic cancer recurrent; 
Hepatic cancer stage I; Hepatic cancer stage II; Hepatic cancer stage III; Hepatic cancer 
stage IV; Hepatobiliary cancer; Hepatobiliary cancer in situ; Hepatoblastoma; 
Hepatoblastoma recurrent; Hepatocellular carcinoma; Liver carcinoma ruptured; Mixed 
hepatocellular cholangiocarcinoma; Liver ablation; Hepatic neoplasm; Hepatobiliary 
neoplasm; Cardiohepatic syndrome; Complications of transplanted liver; Increased liver 
stiffness; Liver and pancreas transplant rejection; Liver transplant rejection; Multivisceral 
transplantation; Partial splenic embolisation
9.4
Statistical Analysis Plan Version 2 Summary of Changes
The changes of Statistical Analysis Plan Version 1 are as follows:

7.1.1 Definition of Agent Targeting PD-1, PD-L1/L2 was revised to reflect the data review 
results.
−
Added: BGB A317

7.4 Analysis category for Number of Involved Organs per IRC at Baseline was changed in 
response to the data review results.
−
Changed to [0, 1, 2, 3<= - <=Max] from [1, 2, 3<= - <=Max]

9.3 Definition of Treatment-Emergent Adverse Events to Monitor was revised in response to 
the update of MedDRA version to 22.0.
−
Hemorrhage

Added: Blood loss anaemia

Deleted: Gastroduodenitis haemorrhagic; Haemorrhagic anaemia
−
Hypertension
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
Added: Cardiometabolic syndrome

Deleted: Metabolic syndrome
−
Osteonecrosis

Added: Bone sequestrum

Deleted: Primary sequestrum; Secondary sequestrum; Tertiary sequestrum
−
Renal Failure

Added: Subacute kidney injury
−
Hepatotoxicity

Added: Nonalcoholic fatty liver disease; Cardiohepatic syndrome; Complications of
transplanted liver; Increased liver stiffness; Liver and pancreas transplant rejection;
Liver transplant rejection; Multivisceral transplantation; Partial splenic
embolisation

Deleted: Liver and small intestine transplant; Non-alcoholic fatty liver;
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Signed by 
PPD 
Cabozantinib-2003 Statistical Analysis Plan 2019-09-05 
ELECTRONIC SIGNATURES 
Meaning of Signature 
Biostatistics Approval 
 
Server Date 
dd-MMM-
, , HH:mm 'UTC' 
11-Sep-2019 00:15 UTC
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