Clinical trial NCT03339219
Conditions: Advanced Renal Cell Carcinoma
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2017-12-13; Completion date: 2020-08-25
Enrollment: 35 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the efficacy of cabozantinib measured by Independent Radiology Committee (IRC)-assessed objective response rate (ORR) in Japanese participants with advanced renal cell carcinoma (RCC) that has progressed after prior vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) therapy.

Detailed description:
The drug being tested in this study is called cabozantinib. Cabozantinib is being tested to treat people who have advanced renal cell carcinoma. This study will look at the efficacy of cabozantinib.

The study will enroll approximately 35 patients. Participants will be enrolled in one treatment group in non-randomized and opened manner:

• Cabozantinib 60 mg

All participants will be asked to take tablets of cabozantinib at once daily in the fasted state 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 in treatment period, and posttreatment period including a follow-up assessment after last dose of study drug.

Arms: arm 1: Cabozantinib 60 mg, tablet, orally, once daily (QD) in the fasted state until unacceptable toxicity or need for subsequent systemic anticancer treatment up to 2.5 years.
Interventions: intervention 1: Cabozantinib
Intervention descriptions: intervention 1: Cabozantinib tablets

Protocol documents:
Prot_000.pdf: 
Title: A Phase 2, Open-Label, Single-Arm Study of Cabozantinib in Japanese Patients 
With Advanced Renal Cell Carcinoma That Has Progressed After Prior VEGFR 
Tyrosine Kinase Inhibitor Therapy 
NCT Number: NCT03339219 
Protocol Approve Date: 30-JUL-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). 


PROTOCOL
A Phase 2, Open-Label, Single-Arm Study of Cabozantinib in Japanese Patients With 
Advanced Renal Cell Carcinoma That Has Progressed After Prior VEGFR Tyrosine Kinase 
Inhibitor Therapy
A Phase 2 Study of Cabozantinib in Japanese Patients with Advanced Renal Cell Carcinoma
Sponsor:
Takeda Pharmaceutical Company, Ltd
1-1 Doshomachi 4-chome, Chuo-ku, Osaka 540-8645
Study Number:
Cabozantinib-2001
IND Number:
Not Applicable
EudraCT Number:
Not Applicable
Compound:
Cabozantinib
Date:
30 July 2018
Amendment Number:
All sites
Amendment History:
Date
Amendment Number
Region
31 July 2017
Initial Protocol
All sites
13 October 2017
01
All sites
23 March 2018
02
All sites
30 July 2018
03
All sites
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Takeda except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study.
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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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1.2
Approval
REPRESENTATIVES OF TAKEDA
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this clinical study protocol and also in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations.
SIGNATURES
The signature of the responsible Takeda medical officer (and other signatories, as applicable) can 
be found on the signature page.
Electronic Signatures may be found on the last page of this document.
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y and subject to the applicable Terms of Use
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1.3
Protocol Amendment 03 Summary of Changes
This document describes the changes in reference to the Protocol Incorporating Amendment 
No. 03.
The primary changes of Amendment 03 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. Full details 
on changes of text are given in Appendix K.
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE.......................................................................................................2
1.1
Contacts.................................................................................................................... 2
1.2
Approval............................................................................................................... ....3
1.3
Protocol Amendment 03 Summary of Changes .......................................... . . ..........4
2.0
STUDY SUMMARY ................................................................................... .. ............11
3.0
STUDY REFERENCE INFORMATION ................................................ .. ..................15
3.1
Study-Related Responsibilities......................................................... .......................15
3.2
Signatory Coordinating Investigator....................................... .. ..............................15
3.3
List of Abbreviations ......................................................... .. ..................................16
4.0
INTRODUCTION............................................................. ... .......................................19
4.1
Background ............................................................ . ..............................................19
4.1.1
Disease Under Treatment: Renal Cell Carcinoma........................................19
4.1.2
Study Drug........................................ . .......................................................21
4.1.3
Nonclinical Experience ................ ..............................................................21
4.1.4
Clinical Experience.................... ................................................................22
4.1.5
DDI Risk of Cabozantinib ..........................................................................28
4.2
Rationale for the Proposed Study.............................................................................29
4.2.1
Rationale for Dose . ...................................................................................29
4.2.2
Rationale for PK Assessments.....................................................................30
4.2.3
Rationale for Biomarker Analysis ...............................................................30
4.2.4
Rationale for Pharmacogenomic Assessments.............................................30
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................31
5.1
Objectives.. .............................................................................................................31
5.1.1
Primary Objective .......................................................................................31
5.1.2
Secondary Objectives..................................................................................31
5.1 3
Additional Objectives..................................................................................31
5 1.4
Exploratory Objectives................................................................................31
5.2
Endpoints.................................................................................................................31
5.2.1
Primary Endpoints.......................................................................................31
5.2.2
Secondary Endpoints...................................................................................32
5.2.3
Additional Endpoints ..................................................................................32
5.2.4
Exploratory Endpoints.................................................................................32
6.0
STUDY DESIGN..........................................................................................................34
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6.1
Overview of Study Design.......................................................................................34
6.2
Number of Patients ..................................................................................................36
6.3
Duration of Study ....................................................................................................36
6.3.1
Duration of an Individual Patient’s Study Participation .......................... .. 36
6.3.2
End of Study/Study Completion Definition and Planned Reporting.... . ......37
6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures..37
6.3.4
Total Study Duration................................................................ . ................39
7.0
STUDY POPULATION........................................................................ .......................40
7.1
Inclusion Criteria ....................................................................... . ...........................40
7.2
Exclusion Criteria ....................................................................................................41
8.0
STUDY DRUG .................................................................. .... ....................................45
8.1
Study Drug Administration....................................... . ............................................45
8.1.1
Cabozantinib Administration on Week 1 Day 1...........................................45
8.1.2
Subsequent Dose Administration of Cabozantinib.......................................45
8.2
Dose Modification Guidelines..................... ............................................................46
8.2.1
Dose Reductions, Interruptions and Discontinuation ...................................46
8.2.2
Dose Reinstitution and Re-escalation ..........................................................47
8.3
Excluded Concomitant Medications and Procedures ................................................48
8.4
Permitted Concomitant Medications and Procedures................................................49
8.5
Precautions and Restrictions ....................................................................................50
8.5.1
Pregnancy and Contraception......................................................................50
8.6
Management of Clinical Events ...............................................................................51
8.6.1
GI Disorders ...............................................................................................51
8.6.2
Hepatobiliary Disorders ..............................................................................53
8.6.3
Hematological Disorders.............................................................................53
8.6.4
Fatigue, Anorexia, and Weight Loss............................................................54
8.6.5
Skin Disorders ............................................................................................55
8 6 6
Hypertension...............................................................................................56
8.6.7
Thromboembolic Events .............................................................................57
8.6.8
Proteinuria ..................................................................................................58
8.6.9
Corrected QT Prolongation .........................................................................59
8.6.10
Hypophosphatemia......................................................................................60
8.6.11
Thyroid Function Disorders.........................................................................61
8.6.12
Hemorrhagic Events....................................................................................61
8.6.13
GI Perforation/Fistula and Non-GI Fistula Formation..................................62
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8.6.14
Osteonecrosis of the Jaw .............................................................................62
8.6.15
RPLS ..........................................................................................................63
8.7
Blinding and Unblinding..........................................................................................63
8.8
Description of Investigational Agents ................................................................. .. 63
8.9
Preparation, Reconstitution, and Dispensation................................................. . ......63
8.10
Packaging and Labeling............................................................................. .. .........63
8.11
Storage, Handling, and Accountability.................................................. . ................64
9.0
STUDY CONDUCT.............................................................................. .......................65
9.1
Study Personnel and Organizations............................................ . ...........................65
9.2
Arrangements for Recruitment of Patients................................................................65
9.3
Study Enrollments ........................................................ .... ....................................65
9.4
Study Procedures...................................................... . ............................................65
9.4.1
Informed Consent..................................... . ...............................................66
9.4.2
Demographics................................... ... ....................................................66
9.4.3
Medical History ............................. ............................................................66
9.4.4
Physical Examination............. . ................................................................66
9.4.5
Height and Weight ............... . ....................................................................66
9.4.6
Vital Signs ................... .. ..........................................................................66
9.4.7
Performance Status ... ...............................................................................66
9.4.8
Pregnancy Test..... ......................................................................................67
9.4.9
Concomitant Medications and Procedures...................................................67
9.4.10
Adverse Events ...........................................................................................67
9.4.11
ECG.. . .....................................................................................................67
9.4.12
Echocardiogram..........................................................................................68
9.4.13
Clinical Laboratory Evaluations ..................................................................68
9.4.14
Tumor Assessments ....................................................................................71
9.4.15
PK Measurements .......................................................................................74
9 4 16
Pharmacogenomic Blood Sample Collection...............................................74
9.4.17
Biomarker Assessment................................................................................74
9.4.18
Health-Related Quality of Life Assessments................................................75
9.4.19
Survival Status and Subsequent Anticancer Therapy ...................................76
9.5
Completion of Study Treatment (for Individual Subjects) ........................................76
9.6
Completion of Study (for Individual Subjects) .........................................................76
9.7
Discontinuation of Treatment With Study Drug and Subject Replacement ...............76
9.8
Withdrawal of Subjects From Study.........................................................................77
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9.9
Study Compliance....................................................................................................78
9.10
Posttreatment Followup Assessments.......................................................................78
10.0
ADVERSE EVENTS ....................................................................................................79
10.1
Definitions.......................................................................................................... .. 79
10.1.1
Adverse Event Definition................................................................... . ......79
10.1.2
Serious Adverse Event Definition ................................................. .. .........79
10.2
Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events................................................................................ . . ...................80
10.3
Monitoring of Adverse Events and Period of Observation........................................81
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events.........81
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) .................................................................... ...........................................82
10.5.1
Procedures for Reporting Product Complaints.............................................82
10.5.2
Procedures for Reporting Medication Errors (Including Overdose)..............82
10.6
Safety Reporting to Investigators, IRBs and Regulatory Authorities.........................82
11.0
STUDY-SPECIFIC COMMITTEES ........... ... .............................................................83
11.1
Independent Radiology Committee ... .. ...................................................................83
12.0
DATA HANDLING AND RECORDKEEPING............................................................84
12.1
eCRFs.................................... .................................................................................84
12.2
Record Retention .............. . ...................................................................................84
13.0
STATISTICAL METHODS .........................................................................................86
13.1
Statistical and Analytical Plans ................................................................................86
13.1.1
Analysis Sets...............................................................................................86
13.1.2
Analysis of Demographics and Other Baseline Characteristics ....................86
13.1.3
Efficacy Analysis........................................................................................86
13.1.4
PK Analysis ................................................................................................88
13.1.5
Biomarker Analysis.....................................................................................88
13.1.6
Pharmacogenomic Analysis ........................................................................88
13.1.7
Safety Analysis ...........................................................................................89
13.2
Interim Analysis and Criteria for Early Termination ................................................89
13.3
Determination of Sample Size..................................................................................89
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................90
14.1
Study-Site Monitoring Visits ...................................................................................90
14.2
Protocol Deviations..................................................................................................90
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................90
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Appendix K
Detailed Description of Amendments to Text...................................................116
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2.0
STUDY SUMMARY
Clinical Study Sponsor:
Takeda Pharmaceutical Company, Ltd.
Compound:
Cabozantinib
Study Title: A Phase 2, Open-Label, Single-Arm Study of 
Cabozantinib in Japanese Patients With Advanced Renal 
Cell Carcinoma That Has Progressed After Prior VEGFR 
Tyrosine Kinase Inhibitor Therapy
IND No.:
Not Applicable
EudraCT No.:
Not Applicable
Study Identifier: Cabozantinib-2001
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 renal cell carcinoma (RCC) that has progressed after prior vascular endothelial growth factor receptor
(VEGFR) tyrosine kinase inhibitor (TKI) therapy. Following the Screening period, patients will be enrolled and 
treated with cabozantinib. A patient is considered to be enrolled in the study when the first dose of cabozantinib has 
been administered.
Screening Period: Potential subjects will be screened to determine whether 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 (at least 2 hours after meal), 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 until there are any other reasons for treatment 
discontinuation listed in the protocol. 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.
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 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 evaluat e the efficacy of cabozantinib measured by Independent Radiology Committee 
(IRC)-assessed objective response rate (ORR) in Japanese patients with advanced RCC that has progressed after prior 
VEGFR-TKI therapy.
Secondary Objectives:

To evaluate the efficacy of cabozantinib measured by IRC-assessed clinical benefit rate (CBR) in the patient 
population under study.

To evaluate the efficacy of cabozantinib measured by IRC-assessed progression-free survival (PFS) in the patient 
population under study.

To evaluate the efficacy of cabozantinib measured by overall survival (OS) in the patient population under study.

To evaluate the safety of cabozantinib in the patient population under study.
Subject Population: Previously treated advanced RCC
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Planned Number of Subjects:
Approximately 35 subjects
Planned Number of Sites:
Estimated total: approximately 20 in Japan
Dose Level(s):
Cabozantinib 60 mg (60 mg tablet×1), QD
Route of Administration:
Oral
Duration of Treatment:
Subjects will continue 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 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:

Male or female Japanese patients 20 years of age or older on the day of consent.

Documented histological or cytological diagnosis of RCC with a clear-cell component.

Measurable disease per RECIST 1.1 as determined by the investigator.

Must have received at least one VEGFR-targeting TKI (eg, sorafenib, sunitinib, axitinib, pazopanib or tivozanib).

For the most recently received VEGFR-targeting TKI the following criteria must apply:
–
Must have radiographically progressed during treatment, or been treated for at least 4 weeks and 
radiographically progressed within 6 months after the last dose.
Radiographic progression is defined as unequivocal progression of existing tumor lesions or developing new 
tumor lesions as assessed by the investigator on computerized tomography (CT) or magnetic resonance 
imaging (MRI) scans.
–
The last dose must have been within 6 months before the first day of study drug administration (Week 1 
Day 1).

Recovery to baseline or ≤Grade 1 Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03
from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on 
supportive therapy.

Karnofsky Performance Status (KPS) score of ≥70%.

Adequate organ and marrow function at Screening.
Main Criteria for Exclusion:

Prior treatment with everolimus, or any other specific or selective target of rapamycin complex 1 
/phosphoinositide 3-kinase/AKT inhibitor (eg, temsirolimus), or cabozantinib.

Receipt of any type of small-molecule kinase inhibitor (including investigational kinase inhibitor) within 14 days 
before Week 1 Day 1.

Receipt of any type of anticancer antibody (including investigational antibody) within 28 days before Week 1 
Day 1.

Radiation therapy for bone metastasis within 14 days, and/or any other external radiation therapy within 28 days 
before Week 1 Day 1. Systemic treatment with radionuclides within 42 days before Week 1 Day 1.
Patients with clinically relevant ongoing complications from prior radiation therapy are not eligible.
Main Criteria for Evaluation and Analyses:
Primary Endpoint:

ORR, per RECIST 1.1, by IRC.
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Secondary Endpoints:

CBR, per RECIST 1.1, by IRC.

PFS, per RECIST 1.1, by IRC.

Safety
–
Percentage of subjects with treatment-emergent adverse events (TEAEs).
–
Percentage of subjects with Grade 3 or higher TEAEs.
–
Percentage of subjects with serious TEAEs.
–
Percentage of subjects with permanent discontinuation by TEAEs.
–
Percentage of subjects with dose modification (dose reduction or interruption) by TEAEs.
–
Percentage of subjects with clinically significant abnormal laboratory values.
–
Percentage of subjects with clinically significant abnormal vital sign measurements.

OS
Additional Endpoints:

ORR, per RECIST 1.1, by investigator.

CBR, per RECIST 1.1, by investigator.

PFS, per RECIST 1.1, by investigator.

Duration of radiographic response.

Plasma concentrations of cabozantinib.

Change in kidney cancer-related symptoms as assessed by the Functional Assessment of Cancer Therapy
(FACT)-Kidney Cancer Symptom Index (FKSI-19).

Change in mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, and global health as 
assessed by the EuroQol Health questionnaire instrument (EQ-5D-5L).
Statistical Considerations:
Primary Endpoint:

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 90% exact confidence interval (CI) will be calculated.
Secondary Endpoints:

CBR, per RECIST 1.1, by IRC
CBR 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 
assessment of SD have to be made at least 8 weeks after the first day of study drug administration.
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For CBR by IRC, point estimate and the 2-sided 95% exact CI will be calculated.

PFS, 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 per 
RECIST 1.1 or death due to any cause.
For PFS by IRC, median PFS will be estimated using the Kaplan-Meier method, and Kaplan-Meier plot will be 
presented.

OS
OS is defined as time from the first day of study drug administration to death due to any cause.
For OS, the same analyses as those for PFS will be performed.

Safety
–
Percentage of subjects with TEAEs.
–
Percentage of subjects with Grade 3 or higher TEAEs.
–
Percentage of subjects with serious TEAEs.
–
Percentage of subjects with permanent discontinuation by TEAEs.
–
Percentage of subjects with dose modification (dose reduction or interruption) by TEAEs.
–
Percentage of subjects with clinically significant abnormal laboratory values.
–
Percentage of subjects with clinically significant abnormal vital sign measurements.
The frequency distribution will be provided for each summary using the Medical Dictionary for Regulatory 
Activities (MedDRA) system organ class and preferred term.
Sample Size Justification:
A study with 32 subjects will provide at least 80% power of binomial test to detect an ORR ≥17% when testing a null 
hypothesis of ORR ≤3% at 1-sided significance level of 5%.
In Study XL184-308, the ORR by IRC was 17% (95% CI: [13, 22]%) and 3% (95% CI: [2, 6]%) in cabozantinib and 
everolimus group, respectively. In reference to the above results, an ORR of 17% is assumed and the threshold is set at 
3% in this study.
Assuming a 10% dropout rate, approximately 35 subjects will be enrolled.
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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
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
CBR
clinical benefit rate
CI
confidence interval
CL/F
oral clearance
Cmax
maximum observed concentration
CNS
central nervous system
CR
complete response
CRO
contract research organization
CSR
clinical study report
CT
computerized tomography
CTCAE
Common Terminology Criteria for Adverse Events
%CV
percent coefficient of variation
CYP
cytochrome P450
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
EQ-5D-5L
EuroQol Health questionnaire instrument
FACT
Functional Assessment of Cancer Therapy
FAS
full analysis set
FDA
Food and Drug Administration
FFPE
formalin-fixed paraffin embedded
FKSI-19
Functional Assessment of Cancer Therapy-Kidney Cancer Symptom Index
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
G-CSF
granulocyte colony-stimulating factor
GGT
γ-glutamyl transferase (gamma-glutamyl transferase)
GI
gastrointestinal
HBcAb
hepatitis B core antibody
HBsAb
hepatitis B surface antibody
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HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HCVAb
hepatitis C virus antibody
HIF
hypoxia-inducible factor
HPDE
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
IFN
interferon
IL-2
interleukin 2
INR
international normalized ratio
IRB
institutional review board
IRC
independent radiology committee
ITT
intent-to-treat
KPS
Karnofsky Performance Status
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
NCCN
National Comprehensive Cancer Network
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
P-gp
P-glycoprotein
PK
pharmacokinetic(s)
PMDA
Pharmaceuticals and Medical Devices Agency (of Japan)
PopPK
population PK
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PPES
palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome)
PR
partial response
PT
prothrombin time
QD
once daily
QT
time interval in ECG reading
QTcF
corrected QT interval 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
RTKs
receptor tyrosine kinases
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
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
VHL
Von Hippel-Lindau (gene)
XL184
research name for investigational product cabozantinib
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4.0
INTRODUCTION
4.1
Background
4.1.1
Disease Under Treatment: Renal Cell Carcinoma
4.1.1.1
Epidemiology
In the United States (US), the number of individuals in 2016 who developed renal cancer is 
estimated to be 62,700 and the number of deaths is estimated to be 14,240. Renal cell carcinoma 
(RCC) accounts for approximately 3.8% of all newly diagnosed cancers, and the median age at the 
time of diagnosis was 64. The incidence rate of RCC has been increasing by 1.1% annually, while 
the mortality rate declined by 0.7% from 2004 to 2013. In recent years, molecularly targeted 
agents and immune checkpoint inhibitors have been approved for the treatment of RCC, 
contributing to the prolongation of survival. Although the 5-year survival rate improved from 
88.4% (1992-1995) to 92.5% (2006-2012) in patients with limited-stage RCC, it only improved 
from 7.3% (1992-1995) to 11.6% (2006-2012) in patients with advanced-stage RCC [1].
In the European Union, the number of individuals in 2012 who newly developed RCC was 
approximately 84,400 and the number of renal cancer-related deaths was approximately 34,700. 
The number of deaths from RCC in Europe tended to increase until the early 1990s, then became 
constant, and now, tended to decrease conversely. However, in some European countries, the 
number of deaths from RCC has still been increasing [2].
In Japan, the number of individuals in 2016 who developed renal cancer and those who developed 
urinary tract cancer (excluding bladder cancer) is estimated to be 29,400 (2.9% of all cancer 
patients) and the number of deaths is estimated to be 9,400 (2.5% of all cancer patients). The 
incidence rate and the mortality rate of RCC in Japan have been increasing. The 5-year survival 
rate is 93.3% (2006-2008) in patients with limited-stage RCC, and only 12.9% (2006-2008) in 
patients with advanced-stage RCC [3].
The incidence rate of RCC becomes higher as individuals become older, especially in the 50s to 
70s age group. There is a higher incidence and mortality in men than women. The comparison of 
the incidence rate of RCC between countries showed that the incidence rate of RCC seemed to be 
lower in Japan than in Western countries, and that the incidence rate of RCC in black people was 
higher than other races. Established risk factors for RCC are smoking and obesity. Von 
Hippel-Lindau (VHL) disease and acquired cystic kidney disease are known as underlying 
diseases associated with RCC [4].
4.1.1.2
Hepatocyte Growth Factor Receptor Protein and Vascular Endothelial Growth Factor 
Receptor 2 in Renal Cell Carcinoma
Approximately 90% of renal cancer is RCC, and 80% of RCC is clear cell carcinoma. Other 
histological types of RCC include papillary RCC, chromophobe RCC, translocation RCC and 
collecting duct carcinoma (Bellini duct carcinoma). Clear cell RCC commonly exhibits mutations 
in the tumor suppressor VHL gene, which triggers a decrease in the degradation of 
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hypoxia-inducible factor (HIF), resulting in increased vascular endothelial growth factor (VEGF)
transcription and tumor angiogenesis. VEGF receptor 2 (VEGFR2), expressed on endothelial 
cells, is a well established key mediator of VEGF signaling in the process of tumor angiogenesis.
Hepatocyte growth factor receptor protein (MET) and AXL are receptor tyrosine kinases (RTKs)
that play key roles in the promotion of tumor cell proliferation, invasion, metastasis, and/or tumor 
angiogenesis in multiple cancers including RCC. Like VEGF, the expressions of both MET and 
AXL are controlled by HIFs.
4.1.1.3
Treatment Approaches
There are no substantial differences in histological type and staging system of RCC among Japan, 
Europe and the US. Also, there are no substantial differences in treatment strategy among these 
countries. Postoperative multidisciplinary therapy, regardless of the presence of metastasis, is 
recommended to use for patients with metastatic RCC who are candidates for surgery [1,2,5].
In the US, the multidisciplinary therapy for RCC had been limited to cytokine therapy until 2005. 
The objective response rate (ORR) in interferon (IFN) -alpha or interleukin 2 (IL-2) therapy is 
reportedly 5% to 27%, indicating that the effectiveness of these therapies was limited. In recent 
years, molecularly targeted agents such as tyrosine kinase inhibitor (TKI) and anti-VEGF antibody 
were approved for the treatment of RCC, contributing to an improvement in the response to
treatment. According to the National Comprehensive Cancer Network (NCCN) guidelines, in 
addition to the high-dose IL-2 therapy, the use of sunitinib, sorafenib, pazopanib, axitinib, 
temsirolimus, and a combination therapy of bevacizumab+IFN are recommended as the frontline 
therapy for advanced RCC. As the second- and subsequent-line therapy for RCC, the use of 
cabozantinib, nivolumab, axitinib, a combination therapy of lenvatinib+everolimus, everolimus 
alone, pazopanib, sorafenib, sunitinib, bevacizumab and temsirolimus are recommended in 
addition to the high-dose IL-2 therapy.
In Europe, the use of bevacizumab, sunitinib, pazopanib, sorafenib, high-dose IL-2 therapy, and a 
combination therapy of bevacizumab+low-dose IFN are recommended as the frontline therapy for 
advanced RCC. For patients with poor prognosis, the use of temsirolimus, sunitinib, sorafenib and 
pazopanib is recommended. As the second-line therapy for RCC, the use of axitinib, sorafenib, 
pazopanib and sunitinib is recommended. After prior VEGF-targeted therapy, the use of 
cabozantinib and nivolumab is recommended [6].
In Japan, since sorafenib and sunitinib were approved for the treatment of RCC in 2008, 
everolimus, temsirolimus, pazopanib, axitinib and nivolumab were additionally approved, so that 
almost the same treatments are now available in Japan as in Western countries.
Resistance to VEGF-targeted therapies may arise from the upregulation of alternative 
pro-angiogenic and pro-invasive signaling pathways, including the MET pathway [7].
Based on the molecular pathophysiology of RCC, there is a strong mechanistic rationale for the 
evaluation of cabozantinib, with its potent dual inhibition of MET and VEGFR2, in the treatment 
of RCC.
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4.1.2
Study Drug
Cabozantinib (research name: XL184) is a multiple RTKs inhibitor targeting MET 
(c-MET)/VEGFR2/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; recommended dose of 140 mg) was approved 
by the US Food and Drug Administration (FDA) on 29 November 2012 for the treatment of 
patients with progressive, 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; recommended dose of 60 mg) was approved by FDA on 25 April 2016 for 
patients with advanced RCC who have received prior anti-angiogenic therapy and by European 
Commission on 09 September 2016 for patients with advanced RCC who have received prior 
VEGF-targeted therapy. 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.
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 MET, 
VEGFR2/KDR, 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 
MET, VEGFR2, 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 MET and 
VEGFR2 in vivo. Oral administration of cabozantinib resulted in the blockade of MET 
phosphorylation in human lung tumor xenografts grown in nude mice, blockade of MET 
phosphorylation in livers of mice, and blockade of VEGFR2 phosphorylation in mouse lung tissue. 
In addition, oral administration of cabozantinib resulted in the blockade of phosphorylation of 
mutationally activated RET in human MTC xenografts grown in nude mice [8].
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 [9]. In additional preclinical studies, cabozantinib treatment has also 
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been shown to inhibit tumor invasiveness and metastasis, and the progression of tumors in bone 
[9,10].
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.
4.1.4
Clinical Experience
In clinical studies, cabozantinib has been evaluated in multiple tumor types including MTC, 
castration-resistant prostate cancer, ovarian cancer, breast cancer, hepatocellular carcinoma, 
non-small cell lung cancer, melanoma, differentiated thyroid cancer, RCC, and glioblastoma 
multiforme. To date, cabozantinib has demonstrated broad clinical activity in these tumor types 
and has been approved by the US FDA for the treatment of progressive, metastatic medullary 
thyroid carcinoma and, as a capsule formulation, has been approved in the US and Europe, for a 
MTC indication. Refer to the IB for more detail.
For the clinical development of cabozantinib for RCC in countries other than Japan, a phase 3, 
randomized, active-controlled study of cabozantinib to compare with everolimus in patients with 
metastatic RCC whose disease had progressed after prior VEGFR-TKI therapy (Study XL184-308 
[Study METEOR]) was conducted. Based on the results of efficacy and safety evaluations in this 
study, cabozantinib tablet (60 mg once daily [QD]) was approved as the second-line therapy for 
RCC in Europe and the US.
Also, a phase 2, randomized, open-label study of cabozantinib to compare with sunitinib in 
patients with locally advanced or metastatic RCC who had not received prior systemic therapy 
(Study A031203 [Study CABOSUN]) was conducted. Based on the results of efficacy and safety 
evaluations in this study, cabozantinib tablet was approved as the first-line therapy for RCC in 
Europe and the US.
In Japan, a phase 1 study of cabozantinib in Japanese patients with advanced or metastatic solid 
tumors (Study XL184-014) has already been completed.
4.1.4.1
Clinical Safety of Cabozantinib
Safety in RCC Patients
Study XL184-308 is an ongoing global, phase 3 randomized, open-label study of cabozantinib 
versus everolimus in subjects with metastatic RCC that has progressed after prior VEGFR-TKI. 
The results of the Safety population (331 cabozantinib, 322 everolimus) through database cutoff 
date of 02 October 2016 are summarized below.
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The median duration of exposure was 36 weeks in the cabozantinib arm and 19 weeks in the 
everolimus arm. A total of 63.7% of subjects in the cabozantinib arm and 24.8% of subjects in the 
everolimus arm had a dose reduction due to an adverse event (AE); the median time to first dose 
reduction was 57.0 days and 62.5 days, respectively. A second dose-level reduction due to an AE 
occurred in 24.5% and 1.9% of subjects in the respective treatment arms. Dose interruptions due to 
an AE were reported for 74% and 61% of subjects on the cabozantinib and everolimus arms, 
respectively. The median time to first dose interruption was 42.0 days and 50.0 days, respectively. 
Dose modifications (dose reductions or interruptions) due to an AE were reported for 80% and 
63% of subjects, respectively. Treatment discontinuation due to an AE was reported for 13% of 
subjects in the cabozantinib arm and 11% of subjects in the everolimus arm. This does not include 
subjects who discontinued study treatment for AEs related to disease progression.
All subjects in each treatment arm had an AE.
Adverse events reported for ≥20% of subjects in the cabozantinib arm were diarrhea (75%), 
fatigue (60%), nausea (53%), decreased appetite (49%), palmar-plantar erythrodysesthesia
syndrome (PPES) (44%), hypertension (37%), vomiting (35%), weight decreased (35%), 
constipation (29%), dysgeusia (24%), hypothyroidism (23%), cough (22%), stomatitis 
(22%),dysphonia (22%), back pain (21%), dyspnea (21%), anemia (20%) and mucosal 
inflammation (20%).
Grade 3 or 4 events were reported for 71% of subjects in the cabozantinib arm and 61% in the 
everolimus arm; the higher incidence in the cabozantinib arm was primarily due to a higher rate of 
hypertension, diarrhea, and PPES. Grade 3 or 4 AEs reported for ≥5% of subjects in the 
cabozantinib arm were hypertension (15%), diarrhea (13%), fatigue (11%), PPES (8.5%), and 
anemia (6.6%). The overall incidence of Grade 4 AEs was 8.2% in the cabozantinib arm and 8.7% 
in the everolimus arm.
The number of deaths observed through the 02 October 2016 data cutoff was 199 (60%) in the 
cabozantinib arm and 227 (70%) in the everolimus arm. Deaths through 30 days after the last dose 
occurred in 21 subjects (6.3%) in the cabozantinib arm and 23 (7.1%) in the everolimus arm. The 
causes of death in the cabozantinib arm were attributed to progressive disease (PD) for 12 subjects 
(3.6%) and to other reasons for 9 subjects (2.7%). Deaths more than 30 days after last dose of study 
treatment occurred in 178 subjects (54%) in the cabozantinib arm and were primarily attributed to 
PD (149 subjects [45%]).
The subject incidence of serious adverse events (SAEs) was 49% in the cabozantinib arm and 48% 
in the everolimus arm. SAEs reported for ≥1.5% of subjects in the cabozantinib arm were pleural 
effusion (3.9%), RCC (3.9%), abdominal pain (3.6%), dyspnea (2.7%), pneumonia (2.7%), 
anemia (2.4%), nausea (2.4%), back pain (2.1%), diarrhea (2.1%), pulmonary embolism (PE) 
(2.1%), fatigue (1.8%), general physical health deterioration (1.8%), hyponatremia (1.8%), 
vomiting (1.8%), asthenia (1.5%), and pain (1.5%).
The most frequent AEs (≥10% incidence) that led to dose modifications (ie, reductions or 
interruptions) for subjects in the cabozantinib arm were consistent with the most frequent AEs of 
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any grade reported in the study and comprised diarrhea (29%), PPES (17%), fatigue (17%), and 
nausea (11%).
The most frequent (≥1%) AEs that led to treatment discontinuation in the cabozantinib arm were 
decreased appetite (2.1%), diarrhea (2.1%), fatigue (1.8%), asthenia (1.2%) and proteinuria 
(1.2%).
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 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 cohort) 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 in the Dose-Escalation Cohorts experienced at least one AE on study. A total of 
70% of subjects experienced an AE of ≥Grade 3. The most frequent AEs (≥50%) reported were 
PPES (100.0%), alanine aminotransferase (ALT) increased (95.7%), aspartate 
aminotransferase (AST) increased (95.7%), hypertension (87.0%), blood thyroid-stimulating 
hormone (TSH) increased (82.6%), diarrhea (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%). 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 SAEs. 
The reported SAEs were anemia, bile duct stone, dyspnea, venous embolism, hematemesis, 
intestinal obstruction, melena, pleural effusion, and protein urine. No SAE PT was experienced 
by more than one subject in the Dose-Escalation Cohorts.
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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 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 performance status 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 
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
Efficacy in RCC Patients
In Study XL184-308, the primary analysis of the progression-free survival (PFS) primary endpoint 
was based on the first 375 randomized subjects (defined to Primary Endpoint Intent-to-Treat 
(PITT) population). The analysis was conducted after 247 events had occurred as of the data cutoff 
date (22 May 2015). The results of the analysis demonstrated a statistically significant 
improvement in PFS per independent radiology committee (IRC) for subjects in the cabozantinib 
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arm (n=187) compared with the everolimus arm (n=188): the hazard ratio (HR) adjusted for 
stratification factors was 0.58 (95% confidence interval [CI]: 0.45, 0.74; stratified log-rank 
p-value <0.0001). The Kaplan-Meier estimates for median duration of PFS were 7.4 months in the 
cabozantinib arm versus 3.8 months in the everolimus arm. Kaplan-Meier estimates of the percent 
of subjects event-free at 6- and 12-month landmarks after treatment randomization were higher for 
the cabozantinib arm than for the everolimus arm (6 months: 55% cabozantinib, 34% everolimus; 
12 months: 29%, 15%).The PFS analysis was repeated in the Intent-to-Treat (ITT) population 
(658 subjects), and results were similar to those obtained for the PITT population. The HR 
adjusted for stratification factors was 0.51 (95% CI: 0.41, 0.62).
A pre-specified interim analysis of overall survival (OS) was conducted for the ITT population as 
of the 22 May 2015 database cutoff, at the time of the primary analysis of PFS. There were a total 
of 202 deaths (89 cabozantinib, 113 everolimus) by this date, representing 49% (202/408) of the 
total required for the pre-specified primary analysis of OS. The minimum time of followup (from 
randomization of the last subject through 22 May 2015) was 5.9 months. The interim analysis 
demonstrated a strong trend for improvement in duration of OS for subjects in the cabozantinib 
arm compared with the everolimus arm: the HR, adjusted for stratification factors was 0.68 (95% 
CI: 0.51, 0.90; stratified log-rank p-value=0.006). The OS results nearly met the criteria required 
to reject the null hypothesis at the interim analysis; the critical p-value was ≤0.0019 (HR≤0.645).
Following these results, in August 2015 an unplanned second interim OS analysis was specified, 
with a prospectively defined cutoff date of 31 December 2015 to provide at least 12 months of 
followup from the last subject randomized. The second interim OS analysis with 13 months of 
followup demonstrated a highly statistically significant prolongation of OS for subjects in the 
cabozantinib arm compared with the everolimus arm: the HR, adjusted for stratification factors, 
was 0.66 (95% CI: 0.53, 0.83; stratified log-rank p-value=0.0003). The critical value for rejecting 
the null hypothesis at the current analysis was p<0.0163. Kaplan-Meier estimates for median 
duration of OS were 21.4 months in the cabozantinib arm and 16.5 months in the everolimus arm. 
The proportion of subjects estimated to be alive by Kaplan-Meier analysis was greater among 
subjects in the cabozantinib arm compared with everolimus at each time point. The respective 
landmark estimates of survival were 73% and 63% at 12 months and 58% and 47% at 18 months.
The followup analysis of OS with a cutoff date of 02 October 2016 included 430 deaths 
(198 cabozantinib, 232 everolimus). The followup OS analysis confirmed the statistically 
significant prolongation of OS for subjects in the cabozantinib arm compared with the everolimus 
arm: the HR, adjusted for stratification factors, was 0.70 (95% CI: 0.58, 0.85; stratified log-rank 
p-value = 0.0002). Kaplan-Meier estimates for median duration of OS were 21.4 months in the 
cabozantinib arm and 17.1 months in the everolimus arm. The respective landmark estimates of 
survival were 73% and 64% at 12 months, 44% and 34% at 24 months, and 35% and 25% at 
30 months.
The primary analysis of ORR per IRC based on Response Evaluation Criteria In Solid Tumors 
Version 1.1 (RECIST 1.1) was conducted in the ITT population at the time of the primary analysis 
of PFS. The same data cutoff date was used as for the PFS analysis. Tumor assessments that 
occurred after the individual subject PFS-censoring dates were excluded from this analysis. The 
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ORR in the ITT population for the cabozantinib and everolimus arms, respectively, was 17% (95% 
CI: 13, 22) and 3% (95% CI: 2, 6) (unstratified p-value <0.0001). All responses were partial
responses (PRs). Of note was a low incidence in the cabozantinib arm of PD as best response (12% 
vs 27%), which indicates a low incidence of primary refractory disease with cabozantinib in this 
study population.
4.1.4.3
Pharmacokinetics of Cabozantinib
Population pharmacokinetic (PopPK) analysis was conducted using plasma concentrations of 
cabozantinib from 318 subjects with RCC in Study XL184-308 and 63 healthy subjects in Study 
XL184-020. The RCC subjects received a 60 mg cabozantinib tablet dose QD and the healthy 
subjects received a single cabozantinib dose at a tablet strength of 20 mg, 40 mg, or 60 mg. 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 
was approximately 319 L; and the oral clearance (CL/F) at steady-state was estimated to be 
approximately 2.2 L/h. Inter-individual variability in clearance (percent coefficient of variation
[%CV] of CL/F) was estimated to be 46%. Female gender and Asian race were significant 
covariates on CL/F, where female subjects had 21% lower CL/F compared with male subjects and 
Asian subjects had 27% lower CL/F compared with white subjects. While the attributes of Asian 
race and female gender were statistically significant, they were not deemed clinically meaningful 
given the magnitude of the effects. Covariates determined to have a nonsignificant effect on CL/F 
were age, baseline body mass index, baseline hemoglobin, baseline total bilirubin, baseline ALT, 
baseline serum albumin, baseline calculated creatinine clearance, and population (healthy subjects 
or subjects with RCC).
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 pharmacokinetic (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 
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 
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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 this and other 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 CYP3A family (eg, phenytoin, carbamazepine, rifampicin, rifabutin, 
rifapentin, phenobarbital, and St. John’s wort) may significantly decrease cabozantinib 
concentrations. The chronic use of strong CYP3A inducers should be avoided. Other drugs that 
induce CYP3A 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 CYP3A enzyme induction potential is recommended. Caution must be used when 
discontinuing treatment with a strong CYP3A 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 CYP3A 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 CYP3A inhibitors and other drugs that inhibit CYP3A 
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 [11], which is 
consistent with a protein-displacement interaction. Because warfarin is a highly protein-bound 
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 
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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
Current first-line therapies for RCC include vascular endothelial growth factor (VEGF)-TKI such 
as sunitinib, sorafenib and pazopanib. These agents have resulted in marked gains in PFS, and 
trends towards improvements in OS. However, patients treated with these agents generally have 
disease progression within 6 to 11 months [12,13,14]. Therefore, effective therapies after these 
VEGF-targeted TKI therapies are clearly required. Since MET and VEGF receptor cooperate to 
promote tumor growth through angiogenesis, invasion, motility, proliferation and survival, the 
inhibition of both MET and VEGF receptor by cabozantinib is expected to show strong efficacy in 
patients with advanced RCC.
An extensive range of clinical studies with cabozantinib has already been completed. A phase 3 
Study XL184-308 (Study METEOR), a randomized open-label study in patients with metastatic 
RCC that has progressed after treatment with a prior VEGFR-TKI, showed a statistically 
significant benefit compared to everolimus arm in median PFS; primary endpoint (7.4 months vs 
3.8 months in cabozantinib arm vs everolimus arm) and in OS; secondary endpoint (21.4 months 
vs 16.5 months). Based on the result of Study XL184-308, cabozantinib was approved by FDA and 
European Medicines Agency in 2016 for the treatment of patients with previously treated 
advanced RCC. Previously, a phase 1 study (Study XL184-014) was conducted in Japan in 
patients with advanced solid tumors (predominantly non-small cell lung cancer). Clinical activity 
was demonstrated in this study in Japanese subjects with a comparable safety profile to that seen in 
Western subjects.
These results support the initiation of a phase 2 study to evaluate the efficacy and safety of 
cabozantinib in Japanese patients with advanced RCC that has progressed after treatment with a 
prior VEGFR-TKI.
4.2.1
Rationale for Dose
The same dose regimen as Study XL184-308 (60 mg orally QD) is selected for 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 indicated 
between Japanese subjects (Study XL184-014) and Western subjects (Study XL184-308); the
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mean trough concentration was 1628 ng/mL (%CV=37) in Japanese subjects (n=26) and 
1220 ng/mL (%CV=46) in non-Japanese subjects (n=134).
4.2.2
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 exposure to cabozantinib. The 
PopPK may be further characterized in this population.
4.2.3
Rationale for Biomarker Analysis
Correlative studies will be conducted to identify potential candidate biomarkers (genetic 
alterations, gene and protein expression, gene expression signature, pathway signature, metabolic 
signature, etc) that are significantly associated with observed clinical response to cabozantinib in 
Japanese patients with advanced RCC that has progressed after prior therapy with a VEGFR-TKI. 
These candidate biomarkers may include, but are not limited to, signaling protein expression 
profiles, cancer-specific somatic gene alterations, micro RNA expression profiles, metabolic 
profiles, RCC disease biomarkers relevant to diagnosis and prognosis. The candidate biomarkers 
will be prospectively validated in an independent patient population.
4.2.4
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. While participation of sites may be required, participation of 
study subjects in pharmacogenomic sample collection is optional.
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.
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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 ORR 
in Japanese patients with advanced RCC that has progressed after prior VEGFR-TKI therapy.
5.1.2
Secondary Objectives
The secondary objectives are:

To evaluate the efficacy of cabozantinib measured by IRC-assessed clinical benefit rate (CBR) 
in the patient population under study.

To evaluate the efficacy of cabozantinib measured by IRC-assessed PFS in the patient 
population under study.

To evaluate the efficacy of cabozantinib measured by OS in the patient population under study.

To evaluate the safety of cabozantinib in the patient population under study.
5.1.3
Additional Objectives
The additional objectives are:

To evaluate the efficacy of cabozantinib measured by investigator-assessed ORR, CBR and 
PFS, and by duration of radiographic response 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 NCCN-Functional Assessment of 
Cancer Therapy (FACT)-Kidney Cancer Symptom Index (FKSI-19) and the EuroQol Health 
questionnaire instrument (EQ-5D-5L) in the patient population under study.
5.1.4
Exploratory Objectives
5.2
Endpoints
5.2.1
Primary Endpoints
The primary endpoint is:

ORR, per RECIST 1.1, by IRC.
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5.2.2
Secondary Endpoints
The secondary endpoints are:

CBR, per RECIST 1.1, by IRC.

PFS, per RECIST 1.1, by IRC.

Safety
–
Percentage of subjects with treatment-emergent adverse events (TEAEs).
–
Percentage of subjects with Grade 3 or higher TEAEs.
–
Percentage of subjects with serious TEAEs.
–
Percentage of subjects with permanent discontinuation by TEAEs.
–
Percentage of subjects with dose modification (dose reduction or interruption) by TEAEs.
–
Percentage of subjects with clinically significant abnormal laboratory values.
–
Percentage of subjects with clinically significant abnormal vital sign measurements.

OS.
5.2.3
Additional Endpoints
The additional endpoints are:

ORR, per RECIST 1.1, by investigator.

CBR, per RECIST 1.1, by investigator.

PFS, per RECIST 1.1, by investigator.

Duration of radiographic response.

Plasma concentrations of cabozantinib.

Changes in kidney cancer-related symptoms as assessed by the NCCN-FKSI-19.

Changes in mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, and 
global health as assessed by the EQ-5D-5L.
5.2.4
Exploratory Endpoints
Propert
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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 ORR and 
other efficacy variables including CBR, PFS and OS—and safety, of cabozantinib in Japanese 
patients with advanced RCC that has progressed after prior VEGFR-TKI therapy.
Screening Period
Potential subjects will be screened to determine whether 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 (at least 2 hours after meal), preferably at bedtime. A patient is considered to be 
enrolled in the study when the first dose of cabozantinib has been 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 need for subsequent systemic 
anticancer treatment, or until there are any other reasons for treatment discontinuation listed in the 
protocol (see Section 9.7). Treatment may continue after radiographic RCC 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 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, and 
will continue until death, withdrawal of consent, or the sponsor decision to discontinue data 
collection.
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.
Computerized tomography (CT) (or magnetic resonance imaging [MRI]) of chest/abdomen/pelvis 
(CAP) will be performed in all subjects at Screening and every 8 weeks (±7 days) after Week 1 
Day 1 throughout the first 12 months on study. Upon completion of 12 months on study, these 
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assessments will be performed every 12 weeks (±7 days). If MRI of the abdomen and pelvis is 
performed at Screening, then a CT of the chest should be performed as well.
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 every 8 weeks (±7 days) throughout the first 12 months on study. Upon 
completion of 12 months on study, these assessments will be performed every 12 weeks (±7 days). 
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.)
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 every 16 weeks 
(±7 days) throughout the first 12 months on study. Upon completion of 12 months on study, these 
assessments will be performed every 24 weeks (±14 days). (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 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 9.4.14. The same imaging modalities used at 
Screening will be used for subsequent tumor assessments after enrollment.
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 or until the start of subsequent systemic anticancer 
treatment, whichever occurs first, and subjects will report and will be queried on, AEs experienced 
through the 30 days. Routine safety evaluations will include physical examination, vital signs, 
performance status, 12-lead electrocardiogram (ECG), echocardiogram, hematology, serum 
chemistries, coagulation tests, urine tests (including urine protein-to-creatinine ratio [UPCR]), 
serum or urine pregnancy tests (in females of childbearing potential), and thyroid function tests.
Adverse event 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. A Safety Management Team
will be established to monitor safety of the study on a regular basis.
Subjects will complete the HRQOL assessments (NCCN-FKSI-19 Version 2 questionnaire and the 
EQ-5D-5L) 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 
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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 9.4.14. Consequently these 
assessments may be required in the Posttreatment period for some subjects.
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.
Unless there is failure to grant informed consent for this purpose, or sponsor decision, a 
pharmacogenomic blood sample will be collected on Week 1 Day 1 for genotyping/single 
nucleotide polymorphism/copy number variation analysis to correlate genetic variation with PK, 
safety, tolerability, and response to study treatment.
Assessment of biomarkers in plasma (signaling protein expression profiles, micro RNA 
expression profiles and metobolic profiles) will be performed. Samples for these studies will be 
obtained on Week 1 Day 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.
In addition, tumor tissue (archival or recently biopsied) will be obtained at Screening whenever 
available for exploratory analysis of MET, and potentially other signaling pathway components or 
modulators associated with RCC or the mechanism(s) of action of study treatment, as predictive 
biomarkers.
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 Patients
Approximately 35 patients will be enrolled in this study from approximately 20 study centers in 
Japan. A patient is considered to be enrolled in the study when the first dose of cabozantinib has 
been administered.
6.3
Duration of Study
6.3.1
Duration of an Individual Patient’s Study Participation
Treatment may continue after radiographic RCC 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.
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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 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, and 
will continue until death, withdrawal of consent, or the sponsor decision to discontinue data in 
collection.
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 12 weeks of treatment with study drug.
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.
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Table 6.a
Primary and Secondary Endpoints for Disclosures
Endpoint
Definition
Maximum Time Frame (a)
Primary:

ORR, per RECIST 1.1, by IRC
The proportion of subjects in the full 
analysis set (FAS) whose best overall 
response is either 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.
Secondary:

CBR, per RECIST 1.1, by IRC
The proportion of subjects in the FAS 
whose best overall response is CR, PR or 
stable disease (SD), as assessed by the 
IRC per RECIST 1.1. CR and PR require 
confirmation by a subsequent evaluation 
conducted ≥28 days later, and assessment 
of SD have to be made at least 8 weeks 
after the first day of study drug 
administration.
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 
progressive disease, 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.

Safety
–
Percentage of subjects with 
TEAEs (b)
Percentage of subjects in the safety 
analysis set with TEAEs.
Up to approximately 2 years after 
enrollment of the last subject.
–
Percentage of subjects with 
Grade 3 or higher TEAEs
Percentage of subjects in the safety 
analysis set with Grade 3 or higher 
TEAEs.
Up to approximately 2 years after 
enrollment of the last subject.
–
Percentage of subjects with 
serious TEAEs
Percentage of subjects in the safety 
analysis set with serious TEAEs.
Up to approximately 2 years after 
enrollment of the last subject.
–
Percentage of subjects with 
permanent discontinuation 
by TEAEs
Percentage of subjects in the safety 
analysis set with permanent 
discontinuation by TEAEs.
Up to approximately 2 years after 
enrollment of the last subject.
–
Percentage of subjects with
dose modification (dose 
reduction or interruption) by 
TEAEs
Percentage of subjects in the safety 
analysis set with dose modification (dose 
reduction or interruption) by TEAEs.
Up to approximately 2 years after 
enrollment of the last subject.
–
Percentage of subjects with 
clinically significant 
abnormal laboratory values.
Percentage of subjects in the safety 
analysis set with clinically significant 
abnormal laboratory values.
Up to approximately 2 years after 
enrollment of the last subject.
–
Percentage of subjects with 
clinically significant 
abnormal vital sign 
measurements.
Percentage of subjects in the safety 
analysis set with clinically significant 
abnormal vital sign measurements.
Up to approximately 2 years after 
enrollment of the last subject.
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Table 6.a
Primary and Secondary Endpoints for Disclosures (continued)
Endpoint
Definition
Maximum Time Frame (a)

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.
CBR=clinical benefit rate, CR=complete response, FAS=full analysis set, IRC=independent radiology committee, 
ORR=objective response rate, OS=overall survival, PFS=progression-free survival, PR=partial response, 
RECIST=Response Evaluation Criteria In Solid Tumors, SD=stable disease, TEAE=treatment-emergent adverse 
events.
(a) Time to last assessment for that endpoint for an individual patient.
(b) TEAEs are defined as AEs whose date of onset occurs on or after the start of study drug and within 30 days after the 
last dose of study treatment.
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. Documented histological or cytological diagnosis of RCC with a clear-cell component.
3. Measurable disease per RECIST 1.1 as determined by the investigator.
4. Must have received at least one VEGFR-targeting TKI (eg, sorafenib, sunitinib, axitinib, 
pazopanib or tivozanib).
Prior treatment with other anticancer therapies including cytokines (eg, interleukin-2, 
interferon-alfa), monoclonal antibodies, (eg, bevacizumab), and cytotoxic chemotherapy is 
allowed (except for drugs stated in Exclusion Criterion 1).
5. For the most recently received VEGFR-targeting TKI the following criteria must apply:
a) Must have radiographically progressed during treatment, or been treated for at least 4 
weeks and radiographically progressed within 6 months after the last dose.
Radiographic progression is defined as unequivocal progression of existing tumor lesions 
or developing new tumor lesions as assessed by the investigator on CT or MRI scans.
b) The last dose must have been within 6 months before Week 1 Day 1.
6. Recovery to baseline or ≤Grade 1 CTCAE Version 4.03 from toxicities related to any prior 
treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy.
7. Karnofsky Performance Status (KPS) score of ≥70%.
8. Adequate organ and marrow function at Screening.
a) Absolute neutrophil count (ANC) ≥1500 mm3.
b) Platelets ≥100,000/mm3.
c) Hemoglobin ≥9 g/dL.
d) ALT and AST <3.0upper limit of normal (ULN).
e) Total bilirubin ≤1.5ULN. For subjects with Gilbert’s disease ≤3 mg/dL.
f)
Serum creatinine ≤2.0ULN or calculated creatinine clearance ≥30 mL/min using the 
Cockcroft-Gault equation (see Appendix H for Cockcroft-Gault equation).
g) UPCR ≤1 mg/mg creatinine.
9. Female patients who:
a) Are postmenopausal (natural amenorrhea, not due to other medical reasons) for at least 1 
year before the screening visit, OR
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b) Are surgically sterile, OR
c) If they are of childbearing potential, agree to practice 1 highly effective method (see 
examples in Section 8.5.1) 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 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.)
Male patients, even if surgically sterilized (ie, status postvasectomy), who:
a) 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 (see examples in 
Section 8.5.1) at the same time, OR
b) 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.)
10. 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.
11. 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. Prior treatment with everolimus, or any other specific or selective target of rapamycin complex 
1/phosphoinositide 3-kinase/AKT inhibitor (eg, temsirolimus), or cabozantinib.
2. Receipt of any type of small-molecule kinase inhibitor (including investigational kinase 
inhibitor) within 14 days before Week 1 Day 1.
3. Receipt of any type of anticancer antibody (including investigational antibody) within 28 days 
before Week 1 Day 1.
4. Treatment with any investigational products within 28 days before Week 1 Day 1.
5. Radiation therapy for bone metastasis within 14 days, and/or any other external radiation 
therapy within 28 days before Week 1 Day 1. Systemic treatment with radionuclides within 
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42 days before Week 1 Day 1. Patients with clinically relevant ongoing complications from 
prior radiation therapy are not eligible.
6. Known brain metastasis 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 subjects must be neurologically asymptomatic and without corticosteroid treatment at 
the time of 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 subjects 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. The subject has uncontrolled, significant intercurrent or recent illness including, but not 
limited to, the following conditions:
a) Cardiovascular disorders:
i.
Congestive heart failure New York Heart Association class III or IV (Appendix I), 
unstable angina pectoris, 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), myocardial infarction, or other ischemic 
event, or thromboembolic event (eg, DVT, PE) within 6 months before Week 1 Day 1.
iv. 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, 
diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute 
pancreatitis or acute obstruction of the pancreatic or biliary duct, or gastric outlet 
obstruction.
ii.
Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess 
within 6 months before Week 1 Day 1.
Note: Complete healing of an intra-abdominal abscess must be confirmed before 
Week 1 Day 1.
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c) Clinically significant hematuria, hematemesis, or hemoptysis of >2.5 ml of red blood, or 
other history of significant bleeding (eg, pulmonary hemorrhage) within 3 months before 
Week 1 Day 1.
d) Cavitating pulmonary lesion(s) or known endobronchial disease manifestation.
e) Lesions invading major pulmonary blood vessels.
f)
Known human immunodeficiency virus seropositive (testing not required) or acquired 
immunodeficiency syndrome-related illness.
g) Active hepatitis B or C (refer to Section 9.4.13).
h) Other clinically significant disorders such as:
i.
Active infection requiring systemic treatment.
ii.
Serious nonhealing wound/ulcer/bone fracture.
iii. Malabsorption syndrome.
iv. Uncompensated/symptomatic hypothyroidism.
v.
Moderate to severe hepatic impairment (Child-Pugh B or C).
vi. Requirement for hemodialysis or peritoneal dialysis.
vii. History of organ transplantation.
9. Major surgery (eg, GI surgery, removal or biopsy of brain metastasis) within 2 months before 
Week 1 Day 1. Complete wound healing from major surgery must have occurred 1 month 
before Week 1 Day 1, and from minor surgery (eg, simple excision, tooth extraction) at least 
10 days before Week 1 Day 1  Subjects with clinically relevant ongoing complications from 
prior surgery are not eligible.
10. Corrected QT interval calculated by the Fridericia formula (QTcF) >500 msec within 14 days 
before Week 1 Day 1.
Note: If initial QTcF is found to be >500 msec, 2 additional ECGs separated by at least 3 
minutes should be performed. If the average of these 3 consecutive results for QTcF is 
≤500 msec, the subject meets eligibility in this regard.
11. 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.
12. Inability to swallow tablets or capsules.
13. Previously identified allergy or hypersensitivity to components of the study treatment 
formulations.
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14. 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.
15. Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially 
interfere with the completion of treatment according to this protocol.
16. Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of 
cabozantinib.
17. Use of strong CYP3A inhibitors and CYP3A inducers within 14 days before Week 1 Day 1.
18. 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 documented 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 (at least 2 hours after 
meal), 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 conduct PK blood sampling 
predose. 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 
approximately the same time each day. Any unused study drug must be returned to the study site 
for drug accountability and disposal Subjects should be fasted (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.
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 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. Adverse event 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: complete blood count with differential leukocyte count, ALP, ALT, AST, and 
bilirubin (total bilirubin, conjugated and unconjugated 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 (see Table 8.a).

Dose modifications 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.

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.
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, 
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.
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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 RCC).
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:

Local anticancer treatment including palliative radiation, ablation, embolization, or surgery 
with impact on tumor lesions should not be performed until radiographic tumor assessments 
have been discontinued per protocol-defined criteria. 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 [15].

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 CYP3A family 
(eg, phenytoin, carbamazepine, rifampicin, rifabutin, phenobarbital, and St. John’s wort) 
should be avoided. Selection of alternate concomitant medications with no or minimal CYP3A 
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enzyme induction potential is recommended. Caution must be used when discontinuing 
treatment with a strong CYP3A inducer in a subject for enrollment of this study.

Co-administration of cabozantinib with strong inhibitors of the CYP3A 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 CYP3A family should be avoided.
Refer to Appendix J for a nonexhaustive list of medications, supplements, and food products 
that are strong inhibitors or inducers of the CYP3A 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 if used per clinical guidelines 
(eg, American Society of Clinical Oncology or European Society of Medical Oncology 
guidelines).

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.)

Transfusions, hormone replacement, and short-term higher doses of corticosteroids (above the 
physiologic replacement dose) should 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:
–
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 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.
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–
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 subjects participating in this study should avoid becoming pregnant, 
and male subjects should avoid impregnating a female partner. Nonsterilized female subjects of 
reproductive age group and male subjects 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 (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 (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.)
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 (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 
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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.
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.
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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.
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. The 5-HT3 receptor antagonists are recommended over chronic use of NK-1 
receptor antagonists (ie, aprepitant and fosaprepitant) and dexamethasone (NK-1 receptor 
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antagonists can induce or inhibit CYP3A4, and glucocorticoids induce CYP3A4 and thus could 
lower 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 bilirubin have been observed during treatment with cabozantinib. It 
is recommended that subjects with elevation of ALT, AST and/or bilirubin have more frequent 
laboratory monitoring of these parameters (see Section 9.4.13). If possible, hepatotoxic 
concomitant medications should be discontinued in subjects who develop increased values of 
ALT, AST or bilirubin.
Subjects on this study may enter with increased ALT/AST serum levels up to 3ULN. Dose 
reductions of study treatment should be considered in any subject who develops Grade 2 elevated 
ALT, AST or bilirubin lasting longer than 1 week. A subject who develops ≥Grade 3 elevated 
ALT, AST, or bilirubin should have study treatment held and restarted at a reduced dose (see 
Table 8.a) after ALT, AST, and bilirubin levels resolve to at least ≤Grade 1 or baseline. In subjects 
with recurrence of ≥Grade 3 elevated ALT, AST, or bilirubin at the lowest dose level, study 
treatment should be discontinued. In subjects who develop ALT/AST elevations >3ULN in 
combination with a bilirubin elevation >2ULN without reasonable other explanation, DILI 
should be suspected and cabozantinib treatment interrupted. Reinstitution of study treatment after 
recovery of ALT, AST, and bilirubin to Grade 1 or baseline level must be discussed and approved 
with the sponsor.
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 
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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.
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, or
Grade 4 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.
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8.6.5
Skin Disorders
Palmar-plantar erythrodysesthesia syndrome (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).
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.
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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 erythrodysethesia syndrome.
8.6.5.1
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.
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.
Blood pressure 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 
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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.
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 or diastolic BP >100 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. Deep 
vein/venous thrombosis (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 
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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 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, transient ischemic attack, 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 ratio 
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 10). Subjects will have ECGs performed at times designated by the protocol (see 
Section 9.4.11 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 approximately 3 minutes 
apart within 30 minutes after the initial ECG.
If the average QTcF is >500 msec, the following actions must be taken:
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
Withhold study treatment.

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 
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according to standard of care. Mild to moderate hypophosphatemia should be managed by oral 
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:

Tumor of the lung (with cavitary lesions or tumor lesions) that invades, encases, or abuts major 
blood vessels. Non-small cell lung cancer with squamous cell differentiation is known for 
significant lung cavitations and centrally located tumors that may invade major blood vessels. 
Thus, the anatomic location and characteristics of tumor as well as the medical history must be 
carefully reviewed in the selection of subjects for treatment with cabozantinib.

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.
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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).
8.6.13 GI Perforation/Fistula and Non-GI Fistula Formation
Gastrointestinal 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, chemotherapy, 
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 
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should be avoided if possible in subjects who have previously been treated with or concomitantly 
receive bisphosphonates or denosumab.
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 (HPDE) bottles. Each HPDE bottle 
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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.
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 HPDE 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 Enrollments
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 cabozantinib has been 
administered.
Procedures for completing the enrollment information are described in the Study 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 abbreviated references to week (W) and day (D) (eg, Week 1 Day 1, Week 3 Day 1 
etc) 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.
A Safety Management Team will be established to monitor safety of the study on a regular basis.
Refer to the Schedule of Events (Appendix A) for schedule of assessments.
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9.4.1
Informed Consent
Each subject must provide written informed consent before any study-required procedures are 
conducted, unless those procedures are performed as part of the subject’s standard care. The 
investigator or appropriate site personnel will contact the sponcer after obtaing the informed 
consent form from each subject (see the Study Manual).
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 (including history of skeletal-related events), surgical 
history, radiation therapy history, and systemic anticancer treatment history including names and 
administration dates of all VEGFR-targeting TKI.
9.4.4
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.
Symptom-directed physical examination will be conducted on Week 1 Day 1 before first dose of 
study treatment.
9.4.5
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).
9.4.6
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).
9.4.7
Performance Status
The KPS will be assessed during Screening to determine the eligibility and the prognostic risk 
score of the subject according to the Memorial Sloan-Kettering Cancer Center prognostic criteria.
The Eastern Cooperative Oncology Group (ECOG) performance status of the subject will be 
assessed at each scheduled safety assessment starting on Week 1 Day 1.
Refer to Appendix D for the ECOG scale and Karnofsky scale criteria.
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9.4.8
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) and predose on Week 1 Day 1. 
Negative results must be obtained before the first dose of cabozantinib may be administered  
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.
9.4.9
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.
9.4.10 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.
9.4.11
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 prior to 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 
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 10).
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 approximately 3 minutes 
apart.
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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 are considered clinically significant for the purposes of this study and 
will be deemed AEs. If values meet criteria defining them as serious, they must be reported as 
SAEs (see Section 10.2).
9.4.12 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.
9.4.13
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 Study Manual.
Hematology, serum chemistry, coagulation, UPCR including components, 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 assessments for these panels may be obtained and used if the results are required by the 
investigator in a rapid timeframe (eg, monitoring for AEs, SAEs), but may not be used to establish 
eligibility. In rare, exceptional circumstances and with approval of the sponsor, local laboratory 
results may be allowed 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 enrollment or the 
accuracy of test results is questioned
Qualitative (dipstick or routine) analysis, microscopic urine examination, and urine or serum 
pregnancy tests are to be done by local laboratory. Results or status from these tests will be 
recorded on eCRFs.
Laboratory tests to establish eligibility must be done within 14 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.
Serum virus tests will be performed during the Screening period. Hepatitis B virus (HBV) testing 
will include hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), and 
hepatitis B core antibody (HBcAb). For patients who are HBsAg negative but HBsAb and/or 
HBcAb positive, hepatitis B viral load (HBV DNA) will also be assessed at Screening. HCV 
testing will include hepatitis C virus (HCV) antibody (HCVAb). Patients who test positive for 
HCVAb will also be tested for hepatitis C viral load (HCV RNA) at Screening.
Patients who have isolated positive HBcAb and/or positive HBsAb (in the setting of negative 
HBsAg) may be included if they have an undetectable HBV-DNA. In this case, patients should be 
monitored for HBV-DNA every 4 weeks during the treatment period up to the 30-day 
posttreatment followup. Patients who develop detectable HBV-DNA, the patient will be 
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withdrawn from the study and will be treated per institutional guidelines; a consultation with a 
hepatologist should be considered.
Patients who have positive HCVAb may be included if they have an undetectable HCV-RNA.
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.
If subjects experience an upward trend in ALT and/or AST at 2 consecutive measurements, 
additional testing (at least serum alkaline phosphatase (ALP), ALT, AST, total bilirubin, and 
PT/international normalized ratio [INR]) should be performed per medical monitor’s request 
(eg, more than once a week).
If subjects experience ALT or AST >3×ULN, followup laboratory tests (at least serum ALP, ALT, 
AST, total bilirubin, and PT/INR) should be performed within a maximum of 7 days and 
preferably within 48 to 72 hours after the abnormality was noted. (Refer to Section 8.6.2 for dose 
modification guidelines of hepatobiliary disorders and Section 10.2 for the appropriate guidance 
on reporting abnormal liver function tests).
To estimate creatinine clearance, the Cockcroft-Gault equation will be employed (Appendix H).
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ALP=alkaline phosphatase, ALT=alanine amino transferase, ANC=absolute neutrophil count, APTT=activated 
partial thromboplastin time, AST=aspartate amino transferase, HCG=human chorionic gonadotropin, BUN=blood 
urea nitrogen, GGT=gamma glutamyl transferase, HBcAb=hepatitis B core antibody, HBsAb=hepatitis B surface 
antibody, HBsAg=hepatitis B surface antigen, HBV=hepatitis B virus, HCV=hepatitis C virus, HCVAb=hepatitis C 
virus antibody, INR=international normalized ratio, LDH=lactate dehydrogenase, PCR=polymerase chain reaction, 
PT=prothrombin time, TSH=thyroid-stimulating hormone, UPCR=urine protein to creatinine ratio, WBC=white 
blood cell.
(a) The results of local laboratory tests will be used for consideration of dose modification. At least, parameters 
described in the table must be evaluated.
9.4.14
Tumor Assessments
9.4.14.1 General
Radiographic response and disease progression will be determined using RECIST 1.1 
(Appendix E). For the purpose of determination of the study endpoints of ORR, CBR and PFS, 
central review of radiographic images will be conducted by an IRC (see Section 9.4.14.2 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 
and every 8 weeks (±7 days) after Week 1 Day 1 throughout the first 12 months on study. Upon 
completion of 12 months on study, these assessments will be performed every 12 weeks 
(±7 days). If MRI of the abdomen and pelvis is performed at screening, then a 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 every 8 weeks (±7 days) throughout the first 
12 months on study  Upon completion of 12 months on study, these assessments will be 
performed every 12 weeks (±7 days). 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: 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 every 16 weeks (±7 days) 
throughout the first 12 months on study. Upon completion of 12 months on study, these 
assessments will be performed every 24 weeks (±14 days). (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 
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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 Study 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).

CT/MRI
For baseline and all scheduled followup imaging examinations by CT or MRI at least a 
postcontrast CT of the chest, and a postcontrast CT (or postcontrast MRI) of the abdomen and 
pelvis should be obtained. For subjects enrolled with treated and stable brain metastasis, the 
same postcontrast MRI (or postcontrast CT) of the brain as performed during screening should 
be performed during subsequent assessments while on study. Ideally, at the baseline imaging 
examination, a precontrast CT (or MRI) scans of the abdomen (liver at minimum) should be 
obtained. For the abdomen and pelvis, at least single-phase (equilibrium or IVC [venous] 
phase) should be obtained. Volume acquisition CT 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. Whenever possible, the same imaging 
modality, acquisition and contrast protocol should be used at all followup time points as was 
used at baseline.
For subjects with impaired renal function a postcontrast CT study with a lower dose of contrast 
and care to ensure good hydration should be considered. Alternately an MRI with contrast may 
also be performed. If there is clinical concern regarding the administration of any contrast then 
a noncontrast CAP study may be acceptable as a screening assessment if it clearly 
demonstrates measurable disease per RECIST 1.1 that can be followed without the need for 
contrast. In these subjects a postcontrast MRI (or postcontrast CT) of the brain must still be 
performed to exclude new metastasis during screening. If at a followup imaging time point the 
use of contrast is prohibited (eg, acquired impaired renal function) then the same modality 
should be used without contrast.

Technetium Bone Scans
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.
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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 are no longer necessary to be 
performed.

For subjects who continue to receive study drug 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.
* 12 weeks for subjects remaining on study treatment for more than 1 year.
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 E). The 
sponsor should be notified of all disease progression as soon as possible (see the Study Manual). 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.
9.4.14.2 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 Study Manual). The IRC will evaluate prior radiation 
history for the purpose of valid identification of target lesions and all images in a central and 
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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.
9.4.15
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 study treatment 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 Study Manual.
9.4.16 Pharmacogenomic Blood Sample Collection
Unless failure to grant informed consent for this purpose, or sponsor decision, a blood sample will 
be collected predose on Week 1 Day 1 to investigate the contribution of genetic variance on drug 
response. 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. Additional pharmacogenomic analyses may be conducted in the 
future to further investigate the contribution of genetic variance on drug response.
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, so no test results will be 
provided to the investigator 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 destroyed. If subjects withdraw consent, the 
samples will be discarded. Details regarding the preparation, processing, and shipping of samples 
can be found in the Study Manual.
9.4.17 Biomarker Assessment
Samples for biomarker assessment are for research purposes only and biomarker researches may 
be conducted when necessary even after the study completion.
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9.4.17.1 Biomarker Assessment in Plasma
Assessment of biomarkers in plasma will be performed. Samples for these studies will be collected 
according to the schedule outlined in Appendix A. Molecular markers potentially related to RCC 
and/or study treatment mechanism(s) of action may also be assessed in these samples.
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 Study Manual.
9.4.17.2 Biomarker Assessment in Tumor Tissues
Tumor tissue (archival or recently biopsied) will be obtained at Screening whenever available for 
exploratory analysis of MET (including genomic mutation and protein expression), and potentially 
other signaling pathway components or modulators associated with RCC or the mechanism(s) of 
action of study treatment, as predictive biomarkers. Somatic DNA obtained from blood sample 
(see Section 9.4.16) may also be used as a comparator for analysis of tumor mutations and genetic 
changes.
Details regarding the preparation, processing, and shipping of samples can be found in the Study 
Manual.
9.4.18 Health-Related Quality of Life Assessments
Subjects will self-report information on HRQOL utilizing the Japanese versions of the 
NCCN-FKSI-19 version 2 (Appendix F) and EQ-5D-5L (Appendix G) questionnaires. The 
objective will be to assess a possible improvement and/or delay in worsening of symptoms and 
quality of life.
The FKSI-19 instrument assesses quality of life, including 19 symptoms related to renal cell 
cancer, interference in daily activity caused by pain, and general health [16]. Each symptom can be 
reported on 5 levels: ‘not at all’, ‘a little bit’, ‘somewhat’, ‘quite a bit’, and ‘very much’.
The EQ-5D-5L instrument has 2 pages: a descriptive page with 5 dimensions which assesses 
changes in mobility, self-care, usual activities, pain/discomfort, 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 visual 
analogue scale and records the respondent’s self-rated health with endpoints ‘the best health you 
can imagine’ and ‘the worst health you can imagine’ and serves as a quantitative measure of health 
by the individual respondents.
Both HRQOL assessments will be assessed in parallel on the same schedule. 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 
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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 9.4.14. Consequently these 
assessments may be required in the Posttreatment period for some subjects (Appendix A).
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 FKSI-19 and EQ-5D-5L questionnaires and instructions for filling 
them out will be provided to each study site in a separate Study Manual.
9.4.19 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.
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.
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
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 Study 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.

Death.

Other.
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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. 
Subjects who withdraw or are withdrawn from the study will not be replaced.
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 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 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 9.4.14. Consequently these assessments may be required in the 
Posttreatment period for some subjects. All subsequent anticancer 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 drug 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 since the administration of study drug.
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 [17]. 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 [17].
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 9.4.13 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
Adverse events, 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 (refer to Section 10.2).
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 CRF(s).
If a medication error results in an SAE, an SAE form should be completed and sent to BI Medical, 
Inc (refer to Section 10.2).
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 9.4.14.2). 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, 3 kinds of analysis sets are defined: full analysis set (FAS), response-evaluable
analysis set and safety analysis set. The FAS, the analysis set used for efficacy analysis, will be 
defined as “all subjects who received at least one dose of study drug.” The response-evaluable 
analysis set will be defined as “all FAS subjects with measurable disease at baseline, and at least 
one postbaseline tumor assessment.” The 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 using the FAS.
13.1.3 Efficacy Analysis
Efficacy analyses will be performed using the FAS.
13.1.3.1 Primary Endpoint and Analytical Methods
The primary endpoint is 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 PFS below, will be used in order
to determine the best overall response.
Primary Analysis
For ORR by IRC, point estimate and the 2-sided 90% exact CI will be calculated.
Secondary Analysis
For ORR by IRC, point estimate and the 2-sided 90% exact CI will be calculated using the 
response-evaluable analysis set.
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13.1.3.2 Secondary Endpoints and Analytical Methods
CBR, per RECIST 1.1, by IRC
CBR 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 assessment of SD have to be made at least 8 weeks after the first day of study drug 
administration.
CBR will be determined using the same data as those used in the determination of ORR.
For CBR by IRC, point estimate and the 2-sided 95% exact CI will be calculated. Similar analysis 
using the response-evaluable analysis set will also be conducted.
PFS, 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 per RECIST 1.1 or death due to any cause.
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 anticancer therapy (including radiation 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 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.
For PFS by IRC, median PFS will be estimated using the Kaplan-Meier method, and 
Kaplan-Meier plot will be presented.
OS
Overall survival is defined as time from the first day of study drug administration to death due to 
any cause.
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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/Exploratory Endpoints
Analytical methods for the additional/exploratory endpoints will be described in the SAP.
13.1.3.4 Confidence Coefficient

Primary analysis: 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 (genetic alterations, gene and protein 
expression, gene expression signature, pathway signature, metabolic signature, etc) in relation to 
clinical response to cabozantinib in patients with advanced RCC that has progressed after prior 
VEGFR-TKI therapy will be performed using descriptive statistics, graphical methods, and 
statistical modeling as appropriate. Candidate biomarkers may include, but are not limited to, 
signaling protein expression profiles, cancer-specific somatic gene alterations, micro RNA 
expression profiles, metabolic profiles, and RCC disease biomarkers relevant to diagnosis and 
prognosis. The candidate biomarkers will be prospectively validated in an independent patient 
population. 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.
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13.1.7 Safety Analysis
Safety analyses will be performed using the safety analysis set.
13.1.7.1 Secondary Endpoints and Analytical Methods
TEAEs

Percentage of subjects with TEAEs.

Percentage of subjects with Grade 3 or higher TEAEs.

Percentage of subjects with serious TEAEs.

Percentage of subjects with permanent discontinuation by TEAEs.

Percentage of subjects with 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 treatment. TEAEs will be coded using the MedDRA dictionary.
The frequency distribution will be provided for each summary using the system organ class and the 
preferred term. The same analyses will be provided including only TEAEs which are considered 
related to the study drug.
Laboratory Values and Vital Sign Measurements

Percentage of subjects with clinically significant abnormal laboratory values.

Percentage of subjects with 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.
13.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned.
13.3
Determination of Sample Size
A study with 32 subjects will provide at least 80% power of binomial test to detect an ORR ≥17% 
when testing a null hypothesis of ORR ≤3% at 1-sided significance level of 5%.
In Study XL184-308, the ORR by IRC was 17% (95% CI: [13, 22]%) and 3% (95% CI: [2, 6]%) in 
cabozantinib and everolimus group, respectively. In reference to the above results, an ORR of 17% 
is assumed and the threshold is set at 3% in this study.
Assuming a 10% dropout rate, approximately 35 subjects will be enrolled.
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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
REFERENCES
1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology.
Kidney Cancer. Version 2 2017. ; October 31, 2016.
2. European Association of Urology [Internet]. c2017 Uroweb. EAU Guidelines Renal Cell 
Carcinoma 2016. Available from: https://uroweb.org/guideline/renal-cell-carcinoma/
3. Monitoring of Cancer Indication in Japan – Survival 2006-2008 Report. Center for Cancer 
Control and Information Services, National Cancer Center, 2016.
4. Japan Society of Medical Oncology. Clinical Oncology Update-Essentials for Medical 
Oncologists, 4th edition. Nankodo. 2015, p. 423-9.
5. Japanese Urological Association. Clinical Practice Guideline for Kidney cancer 2011 edition. 
KANEHARA & CO., LTD. 2011.
6. Escudier B, Porta C, Schmidinger M, Rioux-Leclercq N, Bex A, Khoo V, et al. European 
Society For Medical Oncology. Renal cell carcinoma: ESMO Clinical Practice Guidelines for 
diagnosis, treatment and followup. Ann Oncol. 2016;27(suppl 5):v58-v68. 
7. Sennino B, McDonald DM. Controlling escape from angiogenesis inhibitors. Nat Rev Cancer 
2012;12(10):699-709.
8. Bentzien F, Zuzow M, Heald N, Gibson A, Shi Y, Goon L, et al. In vitro and in vivo activity of 
cabozantinib (XL184), an inhibitor of RET, MET, and VEGFR2, in a model of medullary 
thyroid cancer. Thyroid. 2013;23(12):1569-77.
9. Yakes FM, Chen J, Tan J, Yamaguchi K, Shi Y, Yu P, et al. Cabozantinib (XL184), a novel 
MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor 
growth. Mol Cancer Ther. 2011;10(12):2298-308.
10. Dai J, Zhang H, Karatsinides A, Keller JM, Kozloff KM, Aftab DT, et al. Cabozantinib inhibits 
prostate cancer growth and prevents tumor-induced bone lesions. Clin Cancer Res. 
2014;20(3):617-30.
11. Foxx-Lupo WT, Sing S, Alwan L, Tykodi SS. A drug interaction between cabozantinib and 
warfarin in a patient with renal cell carcinoma. Clin Genitourin Cancer. 2016;14(1):e119-21.
12. Motzer RJ, Hutson TE, Tomczak P, Dror Michaelson M, Bukowski RM, Oudard S, et al. 
Overall survival and updated results for sunitinib compared with interferon alfa in patients 
with metastatic renal cell carcinoma. J Clin Oncol. 2009;27(22):3584-90.
13. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Staehler M, et al. Sorafenib for 
treatment of renal cell carcinoma: final efficacy and safety results of the phase III treatment 
approaches in renal cancer global evaluation trial. J Clin Oncol. 2009;27(20):3312-8.
14. Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, et al. Pazopanib in locally 
advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin 
Oncol. 2010;28(6):1061-8.
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15. Wright JR, Ung YC, Julian JA, Pritchard KI, Whelan TJ, Smith C, et al. Randomized, 
double-blind, placebo-controlled trial of erythropoietin in non-small-cell lung cancer with 
disease-related anemia. J Clin Oncol 2007;25:1027-32.
16. Rao D, Butt Z, Rosenbloom S, Robinson D, Von Roenn J, Kuzel TM, et al. A Comparison of 
the renal cell carcinoma symptom index (RCC-SI) and the Functional Assessment of Cancer 
Therapy –Kidney Symptom Index (FKSI). J Pain Symptom Manage 2009;38(2):291-8.
17. Common Terminology Criteria for Adverse Events (CTCAE). National Cancer Institute, 
National Institutes of Health, U.S. Department of Health and Human Services Series v4.03. 
June 14, 2010. Publication No. 09-5410.
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Appendix K
Detailed Description of Amendments to Text
This document describes changes in reference to Protocol Incorporating Amendment No. 03.
The text that was deleted or revised in Amendment No. 03 is indicated using italics and underline 
font. New or revised text adopted in Amendment No.03 is shown in bold font.
Page 11, Section 2.0 STUDY SUMMARY (Treatment Period) / Page 34, Section 6.1
Overview of Study Design (Treatment Period) / Page 36, 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 34, 35 Section 6.1 
Overview of Study Design (Posttreatment Period) / Page 37, Section 6.3.1 Duration of an 
Individual Patient’s Study Participation / Page 78, 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.
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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.
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 21, Section 4.1.2 Study Drug
Existing Text
Cabometyx was also approved by FDA on 19 December 2017 for patients with previously 
untreated advanced RCC, and is currently under review by the European Medicines Agency 
(EMA). Regulatory submissions are underway in other regions.
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.
Page 22, Section 4.1.4 Clinical Experience
Existing Text
Also, a phase 2, randomized, open-label study of cabozantinib to compare with sunitinib in 
patients with locally advanced or metastatic RCC who had not received prior systemic therapy 
(Study A031203 [Study CABOSUN]) is ongoing, and favorable results have been obtained so far. 
We, therefore, will apply for additional marketing approval for cabozantinib as the frontline 
therapy for RCC after this summer in Europe and the US.
Revised Text
Also, a phase 2, randomized, open-label study of cabozantinib to compare with sunitinib in 
patients with locally advanced or metastatic RCC who had not received prior systemic therapy 
(Study A031203 [Study CABOSUN]) was conducted. Based on the results of efficacy and 
safety evaluations in this study, cabozantinib tablet was approved as the first-line therapy 
for RCC in Europe and the US.
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Rationale for Amendment
Updated information.
Page 28, Section 4.1.5 DDI Risk of Cabozantinib
Existing Text
Cytochrome P450
Co-administration of cabozantinib with strong inducers of the CYP3A family (eg, dexamethasone, 
phenytoin, carbamazepine, rifampicin, rifabutin, rifapentin, phenobarbital, and St. John’s wort) 
may significantly decrease cabozantinib concentrations.
Revised Text
Cytochrome P450
Co-administration of cabozantinib with strong inducers of the CYP3A family (eg, phenytoin, 
carbamazepine, rifampicin, rifabutin, rifapentin, phenobarbital, and St. John’s wort) may 
significantly decrease cabozantinib concentrations.
Rationale for Amendment
Deleted to be consistet within the protocol (dexamethasone is not a strong inducer of the CYP3A 
family).
Page 67, Section 9.4.9 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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Page 81, 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.

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.
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
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.
Page 96-98 
Existing Text
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Revised Text
Rationale for Amendment
Overall
Correct typographical errors, punctuation, grammar, and formatting. These changes are not listed 
individually.
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SAP_001.pdf: 
 
 
Title: A Phase 2, Open-Label, Single-Arm Study of Cabozantinib in Japanese Patients 
With Advanced Renal Cell Carcinoma That Has Progressed After Prior VEGFR 
Tyrosine Kinase Inhibitor Therapy 
 
NCT Number: NCT03339219 
Statistical analysis plan Approve Date: 29-JUN-2018 
 
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-2001
A Phase 2, Open-Label, Single-Arm Study of Cabozantinib in Japanese Patients With Advanced 
Renal Cell Carcinoma That Has Progressed After Prior VEGFR Tyrosine Kinase Inhibitor 
Therapy
PHASE 2
Version: Final
Date: 29 June 2018
Prepared by:
Biostatistics, Takeda Development Center Japan
Based on:
Protocol Version: Amendment 2
Protocol Date: 23 March 2018
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document 
constitutes the agreement by the recipient that no information contained herein will be published 
or disclosed without written authorization from Takeda.
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1.1
Approval Signatures
Electronic signatures can be found on the last page of this document.
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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
Additional Objectives................................................................ .............................. 7
4.4
Exploratory Objectives............................................................ ................................. 7
4.5
Study Design................................................................. ........................................... 7
5.0
ANALYSIS ENDPOINTS ............................................ . .............................................. 9
6.0
DETERMINATION OF SAMPLE SIZE..................... . ............................................... 11
7.0
METHODS OF ANALYSIS AND PRESENTATION .................................................. 12
7.1
General Principles ..................................... . ........................................................... 12
7.1.1
Study Definitions.......................... .. ................................................................. 12
7.1.2
Definition of Study Days .......... ........................................................................ 13
7.1.3
Definition of Study Visit Windows.................................................................... 14
7.1.4
Significance Level and Confidence Coefficient.................................................. 15
7.1.5
Conventions for Missing Adverse Event Dates .................................................. 15
7.1.6
Conventions for Missing Concomitant Medication Dates................................... 15
7.1.7
Imputation of Other Incomplete Dates ............................................................... 15
7.2
Analysis Sets. ......................................................................................................... 16
7.3
Disposition of Subjects............................................................................................ 16
7.3.1
Study Information.............................................................................................. 16
7.3.2
Screen Failures .................................................................................................. 16
7.3.3
Subject Eligibility.............................................................................................. 17
7.3.4
Number of Subjects Enrolled into the Treatment Period by Site......................... 17
7.3.5
Disposition of Subjects ...................................................................................... 17
7.3.6
Protocol Deviations and Analysis Sets............................................................... 18
7.4
Demographic and Other Baseline Characteristics..................................................... 19
7.5
Medical History and Concurrent Medical Conditions............................................... 21
7.6
Medication History and Concomitant Medications .................................................. 22
7.7
Prior Surgery and Procedure.................................................................................... 23
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7.8
Prior Non-Surgical Anticancer Therapy................................................................... 23
7.9
Concomitant and Subsequent Anticancer Therapy................................................... 24
7.10
Study Drug Exposure and Compliance .................................................................... 26
7.11
Dose Modification................................................................................................... 26
7.12
Efficacy Analysis ................................................................................................ . 28
7.12.1 Primary Endpoint....................................................................................... . ..... 28
7.12.2 Secondary Endpoints ............................................................................ . .......... 29
7.12.3 Additional Endpoints...................................................................... . . .............. 31
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........................................ . . ......................................... 47
7.13.4 12-Lead ECGs................................................ . . .............................................. 48
7.13.5 Other Observations Related to Safety....... .... .................................................... 49
7.14
Interim Analysis......................................... .. ......................................................... 50
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 for Anemia ........................................................................ 55
9.4
Definition of Treatment-Emergent Adverse Events to Monitor................................ 56
LIST OF IN-TEXT TABLES
Table 7.a
Visit Window for Endpoints Other Than Plasma Concentrations of 
Cabozantinib ..................................................................................................... 14
Table 7.b
Visit Window for Plasma Concentrations of Cabozantinib................................. 14
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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3.0
LIST OF ABBREVIATIONS
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
BMI
body mass index
BUN
blood urea nitrogen
CBR
clinical benefit rate
CI
confidence interval
CR
complete response
CT
computerized tomography
CV
coefficient of variation
DBP
diastolic blood pressure
EBRT
external beam radiation therapy
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EPO
erythropoietin
EQ-5D-5L
EuroQol Health questionnaire instrument
EQ VAS
EuroQol visual analogue scale
ESA
erythropoiesis stimulating agent
FAS
full analysis set
FKSI-19
Functional Assessment of Cancer Therapy-Kidney Cancer Symptom Index
GCP
Good Clinical Practice
GGT
γ-glutamyl transferase (gamma-glutamyl transferase)
GI
gastrointestinal
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
LLN
lower limit of normal
MedDRA
Medical Dictionary for Regulatory Activities
MET
hepatocyte growth factor receptor protein
MRI
magnetic resonance imaging
MSKCC
Memorial Sloan-Kettering Cancer Center
NCCN
National Comprehensive Cancer Network
ORR
objective response rate
OS
overall survival
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PD
progressive disease
PD-1
programmed death-1
PD-L1/L2
programmed death ligand 1/ ligand 2
PFS
progression-free survival
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
RCC
renal cell carcinoma
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
TKI
tyrosine kinase inhibitor
TSH
thyroid-stimulating hormone
ULN
upper limit of normal
UPCR
urine protein-to-creatinine ratio
VEGFR
vascular endothelial growth factor receptor
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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4.0
OBJECTIVES
4.1
Primary Objective
The primary objective is to evaluate the efficacy of cabozantinib measured by IRC-assessed 
ORR in Japanese patients with advanced RCC that has progressed after prior VEGFR-TKI 
therapy.
4.2
Secondary Objectives
The secondary objectives are:

To evaluate the efficacy of cabozantinib measured by IRC-assessed CBR in the patient 
population under study.

To evaluate the efficacy of cabozantinib measured by IRC-assessed PFS in the patient 
population under study.

To evaluate the efficacy of cabozantinib measured by OS in the patient population under 
study.

To evaluate the safety of cabozantinib in the patient population under study.
4.3
Additional Objectives
The additional objectives are:

To evaluate the efficacy of cabozantinib measured by investigator-assessed ORR, CBR and 
PFS, and by duration of radiographic response in the patient population under study.

To characterize the plasma PK of cabozantinib in the patient population under study.

To assess HRQOL by the NCCN-FKSI-19 and the EQ-5D-5L in the patient population under 
study.
4.4
Exploratory Objectives
4.5
Study Design
This is a phase 2, open-label, single arm study to evaluate the efficacy—as measured by ORR 
and other efficacy variables including CBR, PFS and OS—and safety, of cabozantinib in 
Japanese patients with advanced RCC that has progressed after prior VEGFR-TKI therapy.
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Screening Period
Potential subjects will be screened to determine whether 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 (at least 2 hours after meal), preferably at bedtime. A patient is considered to be 
enrolled in the study when the first dose of cabozantinib has been 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 need for subsequent systemic 
anticancer treatment, or until there are any other reasons for treatment discontinuation listed in 
the protocol. Treatment may continue after radiographic RCC 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.
Posttreatment Period
A 30-day posttreatment followup visit for safety will occur 30 (+14) days after the last dose of 
study drug. Radiographic tumor 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, and will continue until death, withdrawal of consent, or the sponsor decision 
to discontinue data collection.
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5.0
ANALYSIS ENDPOINTS
Primary Endpoint

ORR, per RECIST 1.1, by IRC
Secondary Endpoints

CBR, per RECIST 1.1, by IRC

PFS, per RECIST 1.1, by IRC

Safety
–
Percentage of subjects with TEAEs
–
Percentage of subjects with Grade 3 or higher TEAEs
–
Percentage of subjects with serious TEAEs
–
Percentage of subjects with permanent discontinuation by TEAEs
–
Percentage of subjects with dose modification (dose reduction or interruption) by TEAEs
–
Percentage of subjects with clinically significant abnormal laboratory values
–
Percentage of subjects with clinically significant abnormal vital sign measurements

OS
Additional Endpoints

ORR, per RECIST 1.1, by investigator

CBR, per RECIST 1.1, by investigator

PFS, per RECIST 1.1, by investigator

Duration of radiographic response

Plasma concentrations of cabozantinib

Changes in kidney cancer-related symptoms as assessed by the NCCN-FKSI-19

Changes in mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, and 
global health as assessed by the EQ-5D-5L
Exploratory Endpoints
Propert
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6.0
DETERMINATION OF SAMPLE SIZE
A study with 32 subjects will provide at least 80% power of binomial test to detect an ORR 
≥17% when testing a null hypothesis of ORR ≤3% at 1-sided significance level of 5%.
In Study XL184-308, the ORR by IRC was 17% (95% CI: [13, 22]%) and 3% (95% CI: [2, 6]%) 
in cabozantinib and everolimus group, respectively. In reference to the above results, an ORR of 
17% is assumed and the threshold is set at 3% in this study.
Assuming a 10% dropout rate, approximately 35 subjects will be enrolled.
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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

BMI (kg/m2): Weight (kg) / height (m)2

MSKCC Risk Factors: Risk factors are the following:
–
Karnofsky PS <80%
–
Hemoglobin <13 g/dL for males and <11.5 g/dL for females
–
Corrected calcium >10 mg/dL

Heng Criteria: Subjects will be categorized into three risk categories of favorable (no risk 
factors), intermediate (1 or 2 risk factors) or poor (3 to 6 risk factors) based on the following 
risk factors:
–
Karnofsky PS <80%
–
Time from initial diagnosis of RCC to initial VEGFR-TKI for RCC <1 year
–
Hemoglobin <LLN
–
Corrected calcium >10 mg/dL
–
Neutrophils/WBC >75%
–
Platelet count >ULN

Neutrophil-Lymphocyte Ratio: ANC (/μL) / lymphocytes (/μL)

Prior Nephrectomy  Prior nephrectomy is defined as surgeries/procedures performed prior to 
baseline and recorded on the eCRF as partial nephrectomy, simple nephrectomy, radical 
nephrectomy, or other surgeries/procedures which contain the term “nephrectomy.”

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.”

Prior Anticancer Therapy: Anticancer therapy (including medication, radiation and 
surgery/procedure) that started and stopped prior to baseline.

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
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
Concomitant and Subsequent VEGFR-TKI Agent: Medications whose preferred name coded 
by WHO Drug dictionary is AXITINIB, LENVATINIB, PAZOPANIB, SORAFENIB,
SUNITINIB or TIVOZANIB

Agent Targeting PD-1, PD-L1/L2: Medications whose preferred name coded by WHO Drug 
dictionary is ATEZOLIZUMAB, AVELUMAB, DURVALUMAB, NIVOLUMAB or 
PEMBROLIZUMAB

Concomitant and Subsequent Anticancer Chemotherapy: Medications whose preferred name 
coded by WHO Drug dictionary is CAPECITABINE, CARBOPLATIN, CISPLATIN, 
CYCLOPHOSPHAMIDE, FLUOROURACIL, GEMCITABINE, IXABEPILONE, 
MELPHALAN, VINBLASTINE or TEGAFUR;URACIL

Duration of Exposure to Study Drug (weeks): (Date of decision to discontinue study drug –
date of the first dose of study drug + 1) / 7 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) / 7

Average Daily Dose (mg): Total dose received (mg) / duration of exposure to study drug 
(days)

Dose Intensity (%): 100 * average daily dose (mg) / 60 mg

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

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

Treatment for Anemia: The definition of treatment for anemia is given in Appendix
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 (i.e., 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.
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7.1.4
Significance Level and Confidence Coefficient

Confidence coefficient:
–
Analyses for ORR: 90% (two-sided)
–
Analyses for other endpoints: 95% (two-sided)
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 RCC
–
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 (including date of prior surgery/procedure)
–
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 (assuming the start date of the prior anticancer therapy <date of 
informed consent)

Incomplete start date of concomitant and subsequent non-radiation 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
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7.2
Analysis Sets

FAS:
All subjects who received at least one dose of study drug

Response-evaluable analysis set:
All FAS subjects with measurable disease at baseline, and at least one postbaseline tumor 
assessment

Safety analysis set:
All subjects who received at least one dose of study drug
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.
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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]
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.
7.3.5
Disposition of Subjects
Analysis Set:
All Subjects Enrolled into the Treatment Period
Analysis Variables:
Study Drug Administration Status
[Not Treated]
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Reason for Not Being Treated
[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]
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]
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. When calculating percentages for the 
reasons for not being treated, the total number of subjects not treated by the study 
drug will be used as the denominator. 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]
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Analytical Methods:
(1) Protocol Deviations
Frequency distributions will be provided 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]
Response-Evaluable Analysis Set
[Included]
Safety Analysis Set
[Included]
Analytical Methods:
(1) Analysis Sets
Frequency distributions will be provided.
7.4
Demographic and Other Baseline Characteristics
Analysis Set:
Full Analysis Set
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]
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Time from Initial Diagnosis of RCC to Enrollment (years)
[Min<= - <1, 1<= - <=Max]
Time from Radiographic Progression after Most-Recent VEGFR-TKI to Enrollment 
(months)
[Min<= - <3, 3<= - <=Max]
Current Disease Stage
[Stage IV, Stage III, Unknown]
Extent of Baseline Disease per IRC
Bone (CT or MRI)
[Yes]
Lung
[Yes]
Liver
[Yes]
Lung or Liver
[Yes]
Lung or Liver, and Bone (CT or MRI)
[Yes]
Brain
[Yes]
Lymph Node
[Yes]
Kidney
[Yes]
Other
[Yes]
Number of Involved Organs per IRC at Baseline
[1, 2, 3<= <=Max]
Sum of Diameters of Target Lesions (mm) per IRC at Baseline
MSKCC Risk Factors at Baseline
[0, 1, 2 or 3]
Heng Criteria at Baseline
[Favorable, Intermediate, Poor]
Karnofsky PS (%)
[Min<= - <70, 70, 80, 90, 100]
[Min<= - <80, 80<= - <=Max]
ECOG PS at Baseline
[0, 1, 2, 3, 4]
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Time from Initial Diagnosis of RCC to Initial VEGFR-TKI for RCC (years)
[Min<= - <1, 1<= - <=Max]
Hemoglobin (g/dL) at Baseline
[Min<= - <13 for Males or 11.5 for Females, 13 for Males or
11.5 for Females <= - <=Max]
[Min<= - <LLN, LLN<= - <=Max]
Corrected Calcium (mg/dL) at Baseline
[Min<= - <=10, 10<- <=Max]
Neutrophils/WBC (%) at Baseline
[Min<= - <=75, 75<- <=Max]
Platelet Count (104/μL) at Baseline
[Min<= - <=ULN, ULN<- <=Max]
LDH (U/L) at Baseline
[Min<= - <=ULN, ULN<- <=Max]
Neutrophil-Lymphocyte Ratio at Baseline
Prior Nephrectomy
[Yes, No]
Analytical Methods:
(1) Summary of Demographics and Baseline Characteristics
Frequency distributions for categorical variables and descriptive statistics for 
continuous variables will be provided.
7.5
Medical History and Concurrent Medical Conditions
Analysis Set:
Safety Analysis Set
Analysis Variables:
Medical History
Concurrent Medical Conditions
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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. 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.
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. 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.
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7.7
Prior Surgery and Procedure
Analysis Set:
Safety Analysis Set
Analysis Variables:
Prior Surgery/Procedure
[Yes, No]
Prior Surgery Type
Partial Nephrectomy
[Yes]
Simple Nephrectomy
[Yes]
Partial or Simple Nephrectomy
[Yes]
Radical Nephrectomy
[Yes]
Other
[Yes]
History of Surgical/Procedural Wound Healing Complications
[Yes, No]
Analytical Methods:
(1) Prior Surgery and Procedure
Frequency distributions will be provided.
7.8
Prior Non-Surgical Anticancer Therapy
Analysis Set:
Safety Analysis Set
Analysis Variables:
Number of Prior Systemic Non-Radiation Anticancer Agent
Number of Prior VEGFR-TKI Agent
[1, 2<= - <=Max]
[1, 2, 3<= - <=Max]
Type of Prior VEGFR-TKI Agent
Sunitinib
[Yes]
Sunitinib Only
[Yes]
Sorafenib
[Yes]
Sorafenib Only
[Yes]
Pazopanib
[Yes]
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Pazopanib Only
[Yes]
Axitinib
[Yes]
Axitinib Only
[Yes]
Other VEGFR-TKI Agent [Yes]
First VEGFR-TKI Treatment Duration (months)
[Min<= - <=6, 6<- <=Max]
Prior Treatment with Agent Targeting PD-1, PD-L1/L2
[Yes, No]
Prior Radiation Therapy
[Yes, No]
Number of Prior Radiation Therapy Types
Type of Prior Radiation Therapy
EBRT
[Yes]
SRS
[Yes]
2DXRT
[Yes]
3DCRT
[Yes]
IGRT
[Yes]
IMRT
[Yes]
Proton-Therapy
[Yes]
Other
[Yes]
Brachytherapy
[Yes]
Radioisotope Therapy
[Yes]
Analytical Methods:
(1) Prior Non-Surgical Anticancer Therapy
Frequency distributions for categorical variables and descriptive statistics for 
continuous variables will be provided.
7.9
Concomitant and Subsequent Anticancer Therapy
Analysis Set:
Safety Analysis Set
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Analysis Variables:
Concomitant and Subsequent Non-Surgical Anticancer Therapy
[Yes, No]
Concomitant and Subsequent Non-Surgical Non-Radiation Anticancer Therapy
[Yes, No]
Systemic
[Yes]
Palliative
[Yes]
Salvage
[Yes]
Unknown
[Yes]
Local
[Yes]
Palliative
[Yes]
Salvage
[Yes]
Unknown
[Yes]
VEGFR-TKI Agent
[Yes]
Agent Targeting PD-1, PD-L1/L2
[Yes]
Chemotherapy
[Yes]
Concomitant and Subsequent Radiation Therapy
[Yes, No]
Indication
Disease under Study
[Yes]
Other
[Yes]
Therapy Type
EBRT
[Yes]
SRS
[Yes]
2DXRT
[Yes]
3DCRT
[Yes]
IGRT
[Yes]
IMRT
[Yes]
Proton-Therapy
[Yes]
Other
[Yes]
Brachytherapy
[Yes]
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Radioisotope Therapy
[Yes]
Site
Bone
[Yes]
Soft Tissue
[Yes]
Systemic
[Yes]
Unknown
[Yes]
Surgery that Impacted Tumor Lesions
[Yes]
Analytical Methods:
(1) Concomitant and Subsequent Anticancer Therapy After Enrollment
For concomitant and subsequent anticancer therapies taken/performed during the 
treatment period, frequency distributions will be provided.
7.10
Study Drug Exposure and Compliance
Analysis Set:
Safety Analysis Set
Analysis Variables:
Duration of Exposure to Study Drug (weeks)
Average Daily Dose (mg)
Dose Intensity (%)
Analytical Methods:
(1) Study Drug Exposure and Compliance
Descriptive statistics for continuous variables will be provided.
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]
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20 mg Due to AE
[Yes]
Lowest Dose Level Received Due to AE (Excluding Dose Interruption) (mg)
[20, 40, 60]
Last Dose Level Received (Excluding Dose Interruption) (mg)
[20, 40, 60]
Last Dose Level Received (Including Dose Interruption) (mg)
[0, 20, 40, 60]
Total Duration of Treatment (days) at:
More than 0 mg
60 mg
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
Total Duration of Dose Interruption Due to AE (days)
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)
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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)
Analytical Methods:
(1) Dose Modification
Frequency distributions for categorical variables and descriptive statistics for 
continuous variables will be provided.
7.12
Efficacy Analysis
7.12.1 Primary Endpoint
Analysis Set:
FAS
Response-Evaluable Analysis Set
Analysis Variables:
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 7.12.2 Secondary 
Endpoints, 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, 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.
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Analytical Methods:
(1) Primary Analysis
The following analyses will be conducted using the FAS.
Best overall response, per RECIST 1.1, by IRC will be summarized using the 
categories of Confirmed CR, Confirmed PR, SD, 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 90% exact CI will 
be provided.
A waterfall plot of best percent change in target lesion size by IRC will be presented.
Time to tumor response (months), which is defined as time from the first day of 
study drug administration to the first confirmed CR or confirmed PR per RECIST 1.1 
by IRC, will be summarized using the descriptive statistics for the subjects with 
confirmed CR or confirmed PR in the FAS.
(2) Secondary Analysis
The same analyses as those in the primary analysis for best overall response, per 
RECIST 1.1, by IRC and ORR, per RECIST 1.1, by IRC will be conducted using the 
response-evaluable analysis set.
7.12.2 Secondary Endpoints
Analysis Set:
FAS
Response-Evaluable Analysis Set
Analysis Variables:
CBR, per RECIST 1.1 by IRC
CBR 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 assessment of SD have to be made at least 8 weeks
(≥51 days) after the first day of study drug administration. CBR will be determined 
using the same data as those used in the determination of ORR.
PFS, 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 per RECIST 1.1 or death due to any cause. PFS will be expressed 
in months, i.e. PFS = (earliest date of progression or death – date of the first day of 
study drug administration + 1) / 30.4375.
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Only adequate tumor assessments (overall response of CR, PR, SD 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 anticancer therapy (including radiation 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 
throughout the first 12 months and >26 weeks thereafter) 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.
OS
Overall survival is defined as time from the first day of study drug administration to 
death due to any cause. OS will be expressed in months, i.e. 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:
(1) CBR, per RECIST 1.1, by IRC
For CBR, per RECIST 1.1, by IRC, point estimate and the 2-sided 95% exact CI will 
be provided using the FAS.
Similar analysis using the response-evaluable analysis set will also be conducted.
(2) PFS, per RECIST 1.1, by IRC
The following analyses will be conducted using the FAS.
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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 6, 12, 18 and 24 months will also be provided.
The Kaplan-Meier plot of PFS will be presented.
(3) OS
For OS, the same analyses as those for PFS will be conducted using the FAS
7.12.3 Additional Endpoints
7.12.3.1 ORR, CBR and PFS by Investigator
Analysis Set:
FAS
Analysis Variables:
ORR, per RECIST 1.1, by Investigator
CBR, per RECIST 1.1 by Investigator
PFS, per RECIST 1.1, by Investigator
Analytical Methods:
(1) ORR, per RECIST 1.1, by Investigator
The same analyses as those for ORR, per RECIST 1.1, by IRC in 7.12.1 (1) Primary 
Analysis will be conducted.
(2) CBR, per RECIST 1.1 by Investigator
The same analyses as those for CBR, per RECIST 1.1, by IRC in 7.12.2 (1) CBR, per 
RECIST 1.1, by IRC will be conducted using the FAS.
(3) PFS, per RECIST 1.1, by Investigator
The same analyses as those for PFS, per RECIST 1.1, by IRC in 7.12.2 (2) PFS, per 
RECIST 1.1, by IRC will be conducted.
7.12.3.2 Duration of Radiographic Response
Analysis Set:
FAS
Analysis Variables:
Duration of Radiographic Response, per RECIST 1.1, by IRC
Duration of Radiographic Response, per RECIST 1.1, by Investigator
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Duration of radiographic response is defined as time from the first confirmed CR or 
confirmed PR to the earlier of progressive disease per RECIST 1.1 or death due to any 
cause. Duration of radiographic response will be expressed in months, i.e. duration of 
radiographic response = (earliest date of progression or death – date of the first 
confirmed CR or confirmed PR + 1) / 30.4375.
Only adequate tumor assessments will be considered in the determination of 
progression and censoring date. The same censoring rules as those in the PFS analysis 
will be applied.
Analytical Methods:
(1) Duration of Radiographic Response, per RECIST 1.1, by IRC
(2) Duration of Radiographic Response, per RECIST 1.1, by Investigator
The same analyses as those in 7.12.2 (2) PFS, per RECIST 1.1, by IRC will be 
conducted for the subjects with confirmed CR or confirmed PR in the FAS.
7.12.3.3 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]
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]
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Analytical Methods:
(1) Concordance between IRC and Investigator Tumor Assessment Results
For disease progression status and response status, frequency distributions will be 
provided using the FAS, 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 the subjects in the FAS whose disease progression/response status by 
both IRC and investigator is Yes.
7.12.3.4 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 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.
7.12.3.5 Health-Related Quality of Life Assessment
Analysis Set:
FAS
Analysis Variables:
NCCN-FKSI-19
Total Score
Disease Related Symptoms – Physical Score
Disease Related Symptoms – Emotional Score
Treatment Side Effects Score
Function/Well-Being Score
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Total score and subscale scores will be calculated in accordance with NCCN/FKSI-
19 Scoring Guidelines (Version 4) if and only if more than 50% of the items for the 
score are non-missing
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:
(1) Summary of Total and Subscale Scores of NCCN-FKSI-19 by Visit
Descriptive statistics and the two-sided 95% CI of the mean will be provided for 
each visit.
(2) Summary of Change from Baseline in Total and Subscale Scores of NCCN-FKSI-19 
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.
(3) Frequency Distributions for EQ-5D-5L Descriptive System
Frequency distributions will be provided for each of the 5-dimention descriptive 
system for each visit.
(4) 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.
(5) 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.
7.12.3.6 Neutrophil-Lymphocyte Ratio
Analysis Set:
FAS
Analysis Variables:
Neutrophil-Lymphocyte Ratio
ORR, per RECIST 1.1, by IRC
Subgroups:
For Baseline Neutrophil-Lymphocyte Ratio
MSKCC Risk Factors at Baseline
[0, 1, 2 or 3]
Heng Criteria at Baseline
[Favorable, Intermediate, Poor]
For ORR, per RECIST 1.1, by IRC
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Percent Change from Baseline in Neutrophil-Lymphocyte Ratio (%) at Week 7 Day 1
[Min<= - <=-25.0, -25.0<- <25.0, 25.0<= - Max]
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:
(1) Summary of Neutrophil-Lymphocyte Ratio and Percent Change from Baseline by 
Visit
Descriptive statistics for observed values for each visit and percent changes from 
baseline will be provided.
(2) Relationship of Baseline Neutrophil-Lymphocyte Ratio with Other Prognostic 
Factors
Descriptive statistics of Baseline Neutrophil-Lymphocyte Ratio will be provided for 
the above each subgroup.
(3) Relationship of ORR, per RECIST 1.1, by IRC with Percent Change from Baseline 
in Neutrophil-Lymphocyte Ratio
Point estimate of ORR, per RECIST 1.1, by IRC and the 2-sided 90% exact CI will 
be provided for the above each subgroup. Subjects who progressed or died <38 days 
after the first day of study drug administration or who have missing percent change 
from baseline in neutrophil-lymphocyte ratio at Week 7 Day 1 will be excluded from 
this analysis.
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.
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7.12.4.4 Multiple Comparison/Multiplicity
Not applicable.
7.12.4.5 Use of an “Efficacy Subset” of Subjects
In addition to the analyses on the primary endpoint using the FAS, a secondary analysis will also
be performed using the response-evaluable analysis set.
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
Analysis Variables:
ORR, per RECIST 1.1, by IRC
Subgroups:
Age (years)
[Min<= - <65, 65<= - <=Max]
Gender
[Male, Female]
Time from Initial Diagnosis of RCC to Enrollment (years)
[Min<= - <1, 1<= - <=Max]
Time from Radiographic Progression after Most-Recent VEGFR-TKI to Enrollment 
(months)
[Min<= - <3, 3<= - <=Max]
Bone Metastases (CT or MRI) per IRC at Baseline
[Yes, No]
Lung Metastases per IRC at Baseline
[Yes, No]
Liver Metastases per IRC at Baseline
[Yes, No]
Lung or Liver Metastases per IRC at Baseline
[Yes, No]
Lung or Liver, and Bone Metastases (CT or MRI) per IRC at Baseline
[Yes, No]
Brain Metastases per IRC at Baseline
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[Yes, No]
Number of Involved Organs per IRC at Baseline
[1, 2, 3<= - <=Max]
Sum of Diameters of Target Lesions (mm) per IRC at Baseline
[Min<= - <Median, Median<= - <=Max]
MSKCC Risk Factors at Baseline
[0, 1, 2 or 3]
Heng Criteria at Baseline
[Favorable, Intermediate, Poor]
ECOG PS at Baseline
[0, 1, 2<= - <=Max]
Neutrophil-Lymphocyte Ratio at Baseline
[Min<= - <Median, Median<= - <=Max]
Prior Nephrectomy
[Yes, No]
Number of Prior VEGFR-TKI Agent [1, 2<= - <=Max]
Only Prior VEGFR-TKI Sunitinib
[Yes, No]
Only Prior VEGFR-TKI Pazopanib
[Yes, No]
First VEGFR-TKI Treatment Duration (months)
[Min<= - <=6, 6<- <=Max]
Prior Treatment with Agent Targeting PD-1, PD-L1/L2
[Yes, No]
Analytical Methods:
(1) Subgroup Analysis for ORR, per RECIST 1.1, by IRC
Point estimate of ORR, per RECIST 1.1, by IRC and the 2-sided 90% exact CI will 
be provided for the above each subgroup.
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
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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.
(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)
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 (i.e., 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.
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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.
TEAEs 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 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 (Grade ≥3), 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
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(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)
(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)
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(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)Grade 3 or Higher Treatment-Emergent Adverse Events of Hemorrhage by System 
Organ Class and Preferred Term
(28)Treatment-Emergent Arterial Thrombotic Adverse Events by System Organ Class 
and Preferred Term (Any Grade and Grade ≥3)
(29)Treatment-Emergent Venous and Mixed/Unspecified Thrombotic Adverse Events by 
System Organ Class and Preferred Term (Any Grade and Grade ≥3)
(30)Treatment-Emergent Adverse Events of Wound Complication by System Organ 
Class and Preferred Term (Any Grade and Grade ≥3)
(31)Treatment-Emergent Adverse Events of Hypertension by System Organ Class and 
Preferred Term (Any Grade and Grade ≥3)
(32)Treatment-Emergent Adverse Events of Osteonecrosis by System Organ Class and 
Preferred Term (Any Grade and Grade ≥3)
(33)Treatment-Emergent Adverse Events of PPES by System Organ Class and Preferred 
Term (Any Grade and Grade ≥3)
(34)Treatment-Emergent Adverse Events of Proteinuria by System Organ Class and 
Preferred Term (Any Grade and Grade ≥3)
(35)Treatment-Emergent Adverse Events of RPLS by System Organ Class and Preferred 
Term (Any Grade and Grade ≥3)
(36)Treatment-Emergent Adverse Events of Diarrhea by System Organ Class and 
Preferred Term (Any Grade and Grade ≥3)
(37)Treatment-Emergent Adverse Events of QT Prolongation by System Organ Class 
and Preferred Term (Any Grade and Grade ≥3)
(38)Treatment-Emergent Adverse Events of Renal Failure by System Organ Class and 
Preferred Term (Any Grade and Grade ≥3)
(39)Treatment-Emergent Adverse Events of Hypothyroidism by System Organ Class and 
Preferred Term (Any Grade and Grade ≥3)
(40)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.
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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
GI Perforation, Fistula, Abscess, Intra-Abdominal and Pelvic Abscess, 
Hemorrhage (Grade ≥3), 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 will be provided 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]
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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.
7.13.1.5 Displays of Pretreatment Events
Analysis Set:
All Subjects Who Signed the Informed Consent Form
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
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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, Bicarbonate, 
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
Categories:
Toxicity Grade
[Grade 0, Grade 1, Grade 2, Grade 3, Grade 4]
[Grade 0, Grade 1 – Grade 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
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Analytical Methods:
For each variable, summaries (1) to (2) will be provided.
For applicable variables, summaries (3) to (8) will be provided.
(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.
(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 ALT or AST >3xULN
Descriptive statistics of the time from the first day of study drug administration to 
first occurrence of ALT or AST >3xULN through 30 days after the date of the last 
dose will be provided for subjects experienced ALT or AST >3xULN 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: 
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
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
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 applicable variables, summaries (3) and (4) will be provided.
(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
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Descriptive statistics of the time from the first day of study drug administration to 
first occurrence of decrease in weight ≥10% 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]
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) to (3) will be provided.
For 12-lead ECG interpretation, summary (4) will be provided.
(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.
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7.13.5 Other Observations Related to Safety
7.13.5.1 ECOG Performance Status
Analysis Set:
Safety Analysis Set
Analysis Variables:
ECOG Performance Status
Analytical Methods:
(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.
(2) Number and Percentage of Subjects with Increase in ECOG PS
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:
Treatment for Anemia
Any Treatment for Anemia after Enrollment
[Yes, No]
No Prior Treatment for Anemia ≤28 Days before Enrollment
[Yes]
Any Treatment for Anemia after Enrollment
[Yes, No]
Any Prior Treatment for Anemia ≤28 Days before Enrollment
[Yes]
Any Treatment for Anemia after Enrollment
[Yes, No]
Number of Treatment for Anemia after Enrollment
Platelet Transfusion
Any Platelet Transfusion after Enrollment
[Yes, No]
No Prior Platelet Transfusion ≤28 Days before Enrollment
[Yes]
Any Platelet Transfusion after Enrollment
[Yes, No]
Any Prior Platelet Transfusion ≤28 Days before Enrollment
[Yes]
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Any Platelet Transfusion after Enrollment
[Yes, No]
Number of Platelet Transfusion after Enrollment
Analytical Methods:
(1) Transfusion
Frequency distributions for categorical variables will be provided. For number of 
treatment/transfusion after enrollment, descriptive statistics will be provided for all 
subjects and for subjects with any treatment/transfusion in the safety analysis set.
7.14
Interim Analysis
Not applicable.
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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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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
ERYTHROPOIETIN

ERYTHROPOIETIN HUMAN

FLAVINE ADENINE DINUCLEOTIDE DISODIUM;LIVER EXTRACT

FLAVINE ADENINE DINUCLEOTIDE;LIVER EXTRACT

INOSINE;LIVER EXTRACT

LEXAPTEPID PEGOL

LIVER EXTRACT;LIVER HYDROLYSATE

LIVER EXTRACT;SPLEEN EXTRACT, PROTEINFREE

LIVER FRACTION 1

LIVER INJECTION

LUSPATERCEPT

METHOXY POLYETHYLENE GLYCOL-EPOETIN BETA

MOLIDUSTAT

PEGINESATIDE

PEGINESATIDE ACETATE

RECOMBINANT HUMAN THROMBOPOIETIN

ROXADUSTAT
9.4
Definition of Treatment-Emergent Adverse Events to Monitor

GI Perforation
Abdominal hernia perforation; Appendicitis perforated; Diverticular perforation; Duodenal 
perforation; Duodenal ulcer perforation; Duodenal ulcer perforation, obstructive; Duodenal 
ulcer repair; Gastric perforation; Gastric ulcer perforation; Gastric ulcer perforation, 
obstructive; Gastrointestinal perforation; Gastrointestinal 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 rupture; 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 tracheo-oesophageal fistula; Anal fistula; Anal fistula excision; Anal fistula 
infection; Anastomotic fistula; Anovulvar fistula; Aortoenteric fistula; Aorto-oesophageal 
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fistula; Arterioenteric fistula; Arteriovenous fistula; Arteriovenous fistula aneurysm; 
Arteriovenous fistula occlusion; Arteriovenous fistula operation; Arteriovenous fistula site 
complication; Arteriovenous fistula site infection; Arteriovenous fistula thrombosis; Biliary 
fistula; Biliary 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; Diverticular fistula; Dural arteriovenous fistula; Enterocolonic fistula; 
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; 
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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; 
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 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 
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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 
haemorrhage; Eyelid bleeding; Foetal-maternal haemorrhage; Gastric haemorrhage; Gastric 
ulcer haemorrhage; Gastric ulcer haemorrhage, obstructive; Gastric varices haemorrhage; 
Gastritis haemorrhagic; Gastroduodenal haemorrhage; Gastroduodenitis haemorrhagic; 
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 anaemia; 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 
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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; 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 
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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; 
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 
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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 
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; 
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; 
Metabolic syndrome; 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
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
Osteonecrosis
Alveolar osteitis; Bone debridement; Bone infarction; Dental necrosis; Exposed bone in jaw; 
Osteonecrosis; Osteonecrosis of jaw; Osteoradionecrosis; Periodontal destruction; Primary 
sequestrum; Secondary sequestrum; Tertiary sequestrum

PPES
Palmar-plantar erythrodysaesthesia syndrome

Proteinuria
Albumin urine; Albuminuria; Nephrotic syndrome; Protein urine; Proteinuria

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

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 
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disease; Hepatocellular foamy cell syndrome; Hepatocellular injury; Hepatopulmonary 
syndrome; Hepatorenal failure; Hepatorenal syndrome; Hepatotoxicity; Intestinal varices; 
Intestinal varices haemorrhage; Liver and small intestine transplant; Liver dialysis; Liver 
disorder; Liver injury; Liver operation; Liver transplant; Lupoid hepatic cirrhosis; Minimal 
hepatic encephalopathy; Mixed liver injury; Nodular regenerative hyperplasia; Non-
alcoholic fatty liver; 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 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 fulminant; Hepatitis toxic; Immune-mediated 
hepatitis; Ischaemic hepatitis; Lupus hepatitis; Non-alcoholic steatohepatitis; Radiation 
hepatitis; Steatohepatitis; 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
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