Conditions: Advanced Hepatocellular Carcinoma
Keywords: MDV3100 advanced hepatocellular carcinoma enzalutamide Xtandi ASP9785
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 165
Healthy volunteers: no

Brief summary:
The purpose of the study was to evaluate the efficacy of enzalutamide in participants with advanced hepatocellular carcinoma (HCC) as measured by overall survival (OS).

This study also evaluated the safety of enzalutamide; pharmacokinetics of enzalutamide and the active metabolite N-desmethyl and Progression Free Survival (PFS) of enzalutamide as compared to placebo in participants with advanced HCC.

Detailed description:

Arms:
arm 1: Participants received enzalutamide 160 milligrams (mg) capsules, orally QD during double blind treatment period until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Eligible participants received enzalutamide 160 mg capsules, orally QD during open label period until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Median treatment duration was 64 days. arm 2: Participants received enzalutamide matching placebo orally, once daily (QD) during double blind treatment period until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Median treatment duration was 64 days.

Interventions: intervention 1: Enzalutamide intervention 2: Placebo
Intervention descriptions: intervention 1: Oral capsule intervention 2: Oral capsule

Protocol document:
Prot_000.pdf: 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study
to Assess the Efficacy and Safety of Enzalutamide in Subjects
with Advanced Hepatocellular Carcinoma
ISN/Protocol 9785-CL-3021
ClinicalTrials.gov Identifier: NCT02528643
Date of Protocol v5.0: 08 Mar 2018
Sponsor: Astellas Pharma Global Development, Inc. (APGD)
1 Astellas Way
Northbrook, IL 60062


Sponsor: APGD
ISN/Protocol 9785-CL-3021
EudraCT number 2014-004283-37
- CONFIDENTIAL -
08 Mar 2018
Astellas
Page 1 of 88
Version 5.0 Incorporating Substantial Amendment 4
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study 
to Assess the Efficacy and Safety of Enzalutamide in Subjects 
with Advanced Hepatocellular Carcinoma
Protocol for Phase 2 Study of Enzalutamide
ISN/Protocol 9785-CL-3021
Version 5.0
Incorporating Substantial Amendment 4 [See Section 13]
08 March 2018
IND 127,011
EudraCT 2014-004283-37
Sponsor:
Astellas Pharma Global Development, Inc. (APGD)
1 Astellas Way
Northbrook, IL 60062
Protocol History:
Version 1.0 [03 Jun 2015]
Version 2.0 Incorporating Substantial Amendment 1 [23 Sep 2015]
Version 2.1 [UK] Incorporating Country-Specific Non-Substantial Amendment 1 [14 Oct 2015]
Version 3.0 Incorporating Substantial Amendment 2 [29 Mar 2016]
Version 4.0 Incorporating Substantial Amendment 3 [10 Aug 2016]
Version 4.1 Incorporating Non-Substantial Amendment 2 [04 Apr 2017]
This confidential document is the property of the Sponsor.  No unpublished information 
contained in this document may be disclosed without prior written approval of the Sponsor.


Sponsor: APGD
ISN/Protocol 9785-CL-3021
EudraCT number 2014-004283-37
- CONFIDENTIAL -
08 Mar 2018
Astellas
Page 2 of 88
Version 5.0 Incorporating Substantial Amendment 4
Table of Contents
I.
SIGNATURES ······················································································ 7
II.
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL····························· 9
III.
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS ··················10
IV.
SYNOPSIS··························································································13
V.
FLOW CHART AND SCHEDULE OF ASSESSMENTS·································22
1
INTRODUCTION·················································································25
1.1
Background ····················································································25
1.2
Nonclinical and Clinical Data ·······························································26
1.2.1
Nonclinical Data·········································································26
1.2.1.1
Pharmacology ······································································26
1.2.1.2
Pharmacokinetics ··································································27
1.2.1.3
Toxicology··········································································27
1.2.2
Clinical Data ·············································································28
1.2.2.1
Pharmacokinetics ··································································29
1.3
Summary of Key Safety Information for Study Drugs ···································30
1.4
Benefit-Risk Assessment·····································································31
2
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS ··································31
2.1
Study Objectives ··············································································31
2.1.1
Primary Objective ·······································································31
2.1.2
Secondary Objectives ···································································32
2.1.3
Exploratory Objectives ·································································32
2.2
Study Design and Dose Rationale···························································32
2.2.1
Study Design·············································································32
2.2.2
Dose Rationale···········································································33
2.3
Endpoints·······················································································33
2.3.1
Primary Endpoints·······································································33
2.3.2
Secondary Endpoints····································································33
2.3.3
Exploratory Endpoints ··································································34
3
STUDY POPULATION··········································································34
3.1
Selection of Study Population ·······························································34
3.2
Inclusion Criteria··············································································34
3.3
Exclusion Criteria ·············································································36


Sponsor: APGD
ISN/Protocol 9785-CL-3021
EudraCT number 2014-004283-37
- CONFIDENTIAL -
08 Mar 2018
Astellas
Page 3 of 88
Version 5.0 Incorporating Substantial Amendment 4
4
TREATMENT(S)··················································································39
4.1
Identification of Investigational Product(s) ················································39
4.1.1
Enzalutamide·············································································39
4.1.2
Placebo····················································································39
4.2
Packaging and Labeling ······································································39
4.3
Study Drug Handling ·········································································39
4.4
Blinding ························································································40
4.4.1
Confirmation of the Indistinguishability of the Study Drugs ······················40
4.4.2
Retention of the Assignment Schedule and Procedures for Treatment Code 
Breaking ··················································································40
4.4.3
Breaking the Treatment Code for Emergency ·······································40
4.4.4
Breaking the Treatment Code by the Sponsor ·······································41
4.5
Assignment and Allocation ··································································41
5
TREATMENTS AND EVALUATION························································41
5.1
Dosing and Administration of Study Drug(s) and Other Medication(s)················41
5.1.1
Dose/Dose Regimen and Administration Period ····································41
5.1.2
Increase or Reduction in Dose of the Study Drug(s)································42
5.1.2.1
Dose Modification Plan for LFT Changes······································42
5.1.3
Previous and Concomitant Treatment (Medication and Nonmedication 
Therapy) ··················································································43
5.1.4
Treatment Compliance··································································44
5.2
Demographics and Baseline Characteristics ···············································44
5.2.1
Demographics············································································44
5.2.2
Medical History··········································································44
5.2.3
Diagnosis of the Target Disease, Severity and Duration of Disease ··············44
5.3
Efficacy and Pharmacodynamics Assessments············································45
5.3.1
Efficacy Assessment ····································································45
5.3.1.1
Survival Status and Subsequent Therapies ·····································45
5.3.1.2
Radiographic Assessment·························································45
5.3.2
·······················································45
5.3.2.1
·····································45
5.3.2.2
·········································46
5.3.2.3
·················································46
5.4
Safety Assessment ············································································46


Sponsor: APGD
ISN/Protocol 9785-CL-3021
EudraCT number 2014-004283-37
- CONFIDENTIAL -
08 Mar 2018
Astellas
Page 4 of 88
Version 5.0 Incorporating Substantial Amendment 4
5.4.1
Height and Weight ······································································46
5.4.2
Vital Signs················································································46
5.4.3
Adverse Events ··········································································46
5.4.4
Laboratory Assessments································································47
5.4.5
Physical Examination···································································47
5.4.6
Electrocardiogram (ECG) ······························································47
5.5
Adverse Events and Other Safety Aspects ·················································47
5.5.1
Definition of Adverse Events (AEs) ··················································47
5.5.2
Definition of Serious Adverse Events (SAEs) ·······································48
5.5.3
Criteria for Causal Relationship to the Study Drug ·································49
5.5.4
Criteria for Defining the Severity of an Adverse Event ····························49
5.5.5
Reporting of Serious Adverse Events (SAEs) ·······································50
5.5.6
Follow-up of Adverse Events··························································51
5.5.7
Monitoring of Common Serious Adverse Events ···································51
5.5.8
Procedure in Case of Pregnancy·······················································51
5.5.9
Emergency Procedures and Management of Overdose ·····························52
5.5.10
Supply of New Information Affecting the Conduct of the Clinical Study········52
5.6
Test Drug Concentration ·····································································53
5.6.1
Pharmacokinetic Assessments ·························································53
5.7
Other Measurements, Assessments or Methods ···········································53
5.7.1
Blood Sample for Future Pharmacogenomics (PGx) Analysis 
(Retrospective PGx Analysis)··························································53
5.8
Total Amount of Blood·······································································53
6
DISCONTINUATION············································································54
6.1
Discontinuation of Individual Subject(s)···················································54
6.2
Discontinuation of the Site···································································54
6.3
Discontinuation of the Study·································································54
7
STATISTICAL METHODOLOGY ···························································55
7.1
Sample Size····················································································55
7.2
Analysis Set····················································································55
7.2.1
Full Analysis Set (FAS) ································································56
7.2.2
Safety Analysis Set (SAF)······························································56
7.2.3
Pharmacokinetic Analysis Set (PKAS) ···············································56
7.2.4
Pharmacodynamic Analysis Set (PDAS) ·············································56


Sponsor: APGD
ISN/Protocol 9785-CL-3021
EudraCT number 2014-004283-37
- CONFIDENTIAL -
08 Mar 2018
Astellas
Page 5 of 88
Version 5.0 Incorporating Substantial Amendment 4
7.3
Demographics and Other Baseline Characteristics········································56
7.4
Analysis of Efficacy ··········································································56
7.4.1
Analysis of Primary Endpoint ·························································56
7.4.1.1
Primary Analysis···································································56
7.4.1.2
Secondary Analysis································································57
7.4.1.3
Subgroup Analysis·································································57
7.4.2
Analysis of Secondary Endpoints ·····················································57
7.4.3
Analysis of Exploratory Endpoints····················································57
7.5
Analysis of Safety·············································································57
7.5.1
Adverse Events ··········································································57
7.5.2
Laboratory Assessments································································58
7.5.3
Vital Signs················································································58
7.5.4
Physical Examination···································································58
7.5.5
ECGs······················································································58
7.6
Analysis of Pharmacokinetics ·······························································58
7.7
·····························································58
7.7.1
···························································58
7.7.2
···································59
7.8
Protocol Deviations and Other Analyses···················································59
7.9
Interim Analysis (and Early Discontinuation of the Clinical Study)····················59
7.10
Handling of Missing Data, Outliers, Visit Windows and Other Information ··········59
8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS ····················60
8.1
Procedure for Clinical Study Quality Control ·············································60
8.1.1
Data Collection ··········································································60
8.1.2
Specification of Source Documents···················································60
8.1.3
Clinical Study Monitoring······························································61
8.1.4
Direct Access to Source Data/Documents············································61
8.1.5
Data Management ·······································································61
8.1.6
Protocol Deviations ·····································································61
8.1.7
End of Trial in All Participating Countries···········································62
8.2
Ethics and Protection of Subject Confidentiality··········································62
8.2.1
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) / 
Competent Authorities (CA) ···························································62
8.2.2
Ethical Conduct of the Study···························································63


Sponsor: APGD
ISN/Protocol 9785-CL-3021
EudraCT number 2014-004283-37
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08 Mar 2018
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8.2.3
Informed Consent of Subjects ·························································63
8.2.3.1
Subject Information and Consent················································63
8.2.3.2
Supply of New and Important Information Influencing the Subject’s 
Consent and Revision of the Written Information ·····························63
8.2.4
Subject Confidentiality ·································································64
8.3
Administrative Matters ·······································································64
8.3.1
Arrangement for Use of Information and Publication of the Clinical Study ·····64
8.3.2
Documents and Records Related to the Clinical Study ·····························64
8.3.3
Protocol Amendment and/or Revision················································65
8.3.4
Insurance of Subjects and Others······················································65
8.3.5
Signatory Investigator for Clinical Study Report····································65
9
QUALITY ASSURANCE········································································66
10
STUDY ORGANIZATION······································································66
10.1
Data and Safety Monitoring Board (DSMB) ··············································66
10.2
Other Study Organization ····································································66
11
REFERENCES ····················································································67
12
APPENDICES ·····················································································69
12.1
List of Excluded Concomitant Medications················································69
12.2
Common Serious Adverse Events···························································70
12.3
Retrospective PGx Sub-Study ·······························································71
12.4
Barcelona Clinic Liver Cancer Staging System ···········································73
12.5
Child-Pugh Classification of Severity of Liver Disease··································74
12.6
ECOG Performance Status Scale····························································75
12.7
RECIST v1.1···················································································76
12.8
Safety Laboratory Assessments ·····························································78
12.9
Open-Label Period ············································································79
13
SUBSTANTIAL AMENDMENT 4 ····························································83
14
SPONSOR’S SIGNATURES····································································88
List of In-text Tables
Table 1
Schedule of Assessments·····································································23
Table 2
Dose Modification Table for Drug-Related Liver Toxicities ····························43


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ISN/Protocol 9785-CL-3021
EudraCT number 2014-004283-37
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I.
SIGNATURES
1.
SPONSOR’S SIGNATURE
Required signatures (e.g., Protocol authors, Sponsor’s reviewers and contributors, etc.) are 
located in Section 13, Sponsor’s Signatures; e-signatures (when applicable) are located at the 
end of this document.


Sponsor: APGD
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2.
INVESTIGATOR’S SIGNATURE
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Assess the 
Efficacy and Safety of Enzalutamide in Subjects with Advanced Hepatocellular 
Carcinoma
ISN/Protocol 9785-CL-3021
Version 5.0 / Incorporating Substantial Amendment 4
08 March 2018
I have read all pages of this clinical study protocol for which Astellas is the Sponsor. I agree 
to conduct the study as outlined in the protocol and to comply with all the terms and 
conditions set out therein. I confirm that I will conduct the study in accordance with 
International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines 
and applicable local regulations. I will also ensure that sub-Investigator(s) and other relevant 
members of my staff have access to copies of this protocol and the ICH GCP guidelines to 
enable them to work in accordance with the provisions of these documents.
Principal Investigator:
Signature:
Date (DD Mmm YYYY)
Printed Name:
Institution:
<Insert name and qualifications of the Investigator>
Address:




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III.
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS
Abbreviations used for laboratory or electrocardiogram assessments and commonly used 
abbreviations are not included in this list.
List of Abbreviations
Abbreviations
Description of abbreviations
AE
Adverse event
ALT
Alanine Aminotransferase (GPT)
APEBV
Astellas Pharma Europe B.V.
APGD
Astellas Pharma Global Development, Inc.
AR
Androgen Receptor
AST
Aspartate Aminotransferase (GOT)
AUST
Astellas United States Technologies
BCLC
Barcelona Clinic Liver Cancer
CCRK
Cell Cycle-related Kinase
CIOMS
Council for International Organizations of Medical Sciences
CLCR
Creatinine Clearance
CR
Complete Response
CRO
Contract Research Organization
CRPC
Castration-resistant Prostate Cancer
CT
Computed Tomography
CYP
Cytochrome P450
DCR
Disease Control Rate
DSMB
Data Safety Monitoring Board
EASL
European Association for the Study of the Liver
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EORTC
European Organisation for Research and Treatment of Cancer
FAS
Full Analysis Set
FSH
Follicle-stimulating Hormone
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HBV
Hepatitis B Virus
HCC
Hepatocellular Carcinoma
HCV
Hepatitis C Virus
HIPAA
Health Insurance Portability and Accountability Act
HR
Hazard Ratio
ICF
Informed Consent Form
ICH 
International Conference on Harmonisation
IEC
Independent Ethics Committee
IND
Investigational New Drug
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response System
ISN
International Study Number
IUD
Intrauterine Device
IUS
Intrauterine System


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Abbreviations
Description of abbreviations
LD
Longest Diameter
LFT
Liver Function Tests
mCRPC
Metastatic Castration-resistant Prostate Cancer
MRI
Magnetic Resonance Imaging
NASH
Nonalcoholic steatohepatitis
NCI CTCAE
National Cancer Institute Common Toxicity Criteria for Adverse Events
NDA
New Drug Application
NYHA
New York Heart Association
PD
Progressive Disease
PDAS
Pharmacodynamic Analysis Set
PFS
Progression Free Survival
P-gp
P-glycoprotein
PGx
Pharmacogenomics
PKAS
Pharmacokinetic Analysis Set
PR
Partial Response
OS
Overall Survival
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
Serious Adverse Event
SAF
Safety Analysis Set
SAP
Statistical Analysis Plan
SOC
Standard of Care
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reactions
TACE
Transarterial Chemoembolization
TBL
Total Bilirubin
TEAE
Treatment-emergent Adverse Event
VEGF
Vascular Endothelial Growth Factor
VEGFR
Vascular Endothelial Growth Factor Receptor


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Definition of Key Study Terms
Terms
Definition of terms
Baseline
Observed values/findings which are regarded observed starting point for 
comparison.
Intervention
The drug, therapy or process under investigation in a clinical study that is 
believed to have an effect on outcomes of interest in a clinical study 
(e.g., health-related quality of life, efficacy, safety, pharmacoeconomics).
Investigational 
period
Period of time where major interests of protocol objectives are observed, and 
where the test drug or comparative drug (sometimes without randomization) is 
usually given to a subject, and continues until the last assessment after 
completing administration of the test drug or comparative drug.
Screening period
Period of time before entering the investigational period, from the time of 
starting a subject signing consent until just before the test drug or comparative 
drug (sometimes without randomization) is given to a subject.
Randomization
The process of assigning trial subjects to treatment or control groups using an 
element of chance to determine assignments in order to reduce bias.
Screening
A process of active consideration of potential subjects for enrollment in a trial.
Screen failure
Potential subject who did not meet one or more criteria required for 
participation in a trial.
Study period
Period of time from the first site initiation date to the last site completing the 
study.
Variable
Any quantity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values.
Source data
All information in original records and certified copies of the original records 
of clinical findings, observations or other activities in a clinical study 
necessary for the reconstruction and evaluation of the clinical study.  Source 
data exist in source documents (original records or certified copies) or in an 
electronic data capture system.
Source documents
Original documents, data and records including source data.




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Study Population:
Male and female subjects with advanced (unresectable and/or metastatic) HCC with Barcelona Clinic 
Liver Cancer [BCLC] stage B or C of any etiology who have progressed on or were intolerant to 
sorafenib or other anti-vascular endothelial growth factor (VEGF) therapy in the advanced setting 
and are not amenable to local therapies or any curative treatments.  Subjects may have received 1 line 
of systemic therapy before or after sorafenib/anti-VEGF treatment.  
Number of Subjects to be Enrolled/Randomized:
Approximately 144 subjects were planned to be enrolled. 165 subjects were actually enrolled.
Study Design Overview:
This is a multicenter, randomized, double-blind, placebo-controlled phase 2 study evaluating the 
efficacy, safety, and tolerability of enzalutamide monotherapy in 165 subjects in Europe, Asia, and 
North America with HCC of any etiology who have progressed on or were intolerant to sorafenib or 
any other anti-VEGF therapy in the advanced setting. Each region will have no more than 70% of 
overall subjects enrolled.  Enrollment may be limited by the sponsor in any region or country in order 
to have representation of the patient population from all 3 regions as there may be a difference in 
responses to treatment or tolerability.
The study will consist of a Screening Period, Treatment Period and a Follow-up Period.  Eligible 
subjects will be stratified by geographic region (Asia versus others) and Eastern Cooperative 
Oncology Group (ECOG) performance status (0 versus 1) and randomized in a 2:1 ratio to receive 
enzalutamide 160 mg/day or placebo until disease progression, unacceptable toxicity, or any other 
discontinuation criterion is met.  Best supportive care will also be given to all subjects in addition to 
study drug.  Best supportive care may include medications and supportive measures deemed 
necessary per Investigator’s discretion to palliate disease-related symptoms and improve quality of 
life.  Study evaluations will occur as specified in the Schedule of Assessments.  
An end of treatment visit will be performed within 7 days of the last dose of study drug.  Upon 
discontinuation of treatment for any reason, subjects will enter the follow-up period. A follow-up visit 
will be performed approximately 30 days after the last dose of study drug.  All adverse events (AEs) 
that occur during the safety reporting period (from first dose through 30 days after the last dose or 
initiation of new treatment, whichever comes first) are to be followed up until resolved or judged to 
be no longer clinically significant, or until they become chronic to the extent that they can be fully
characterized.  This may be performed by telephone if applicable.  Long-term follow-up visits will be 
conducted every 30 days for up to 2 years to collect information on survival and subsequent therapies.  
During the study, study drug treatment may be interrupted for individual subjects who experience a 
National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) Grade ≥ 3 AE 
(except Liver Function Test AEs) that is attributed to the study drug and cannot be ameliorated with 
appropriate medical intervention.  Study drug may be resumed at the original dose (160 mg/day) or at 
a reduced dose (120 mg/day or 80 mg/day), after discussion with and approval by the Medical 
Monitor.  Treatment interruption for > 14 days must also be discussed with the Medical Monitor.  
For LFT changes, study drug dosing should be interrupted if a subject experiences clinically 
significant liver toxicity related to study drug (≥Baseline + 4 x ULN to < 20 x ULN for AST and 
ALT; grade 3 total bilirubin [TBL]).Testing should be repeated at Investigator’s discretion but at a 
minimum weekly to ensure that the subject’s LFT’s are returning to acceptable levels. If the subject’s 
toxicity resolves within 14 days to either ≤ grade 1 (if normal at baseline) or no more than 1 grade 
above baseline (but no higher than grade 2), study drug may be reintroduced at a dose of 120 mg/day
in consultation with the Medical Monitor. If the toxicity has not resolved within 14 days (as defined 
by either ≤ grade 1 or no more than 1 grade above screening but no higher than grade 2), then the 
Medical Monitor must be consulted to determine if further interruption is permitted.


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If any drug-related liver toxicity requiring dose interruption recurs or develops despite the initial dose 
reduction to 120 mg/day, the LFT monitoring instructions above should be followed and the study 
drug may be reintroduced at a dose of 80 mg/day. If any drug-related liver toxicity recurs at the 
reduced dose of 80 mg/day, the study drug should be discontinued.
Study drug must be discontinued for subjects with study drug related grade 4 LFTs (AST, ALT and 
TBL).
There will be an initial safety review of the first 21 subjects.  After the 21st randomized subject has 
been treated for 28 days or discontinued from the study (whichever occurs first), unblinded safety 
data will be evaluated by an independent Data Safety Monitoring Board (DSMB).  Emerging safety 
issues may lead to a decision to change the dose, implement additional safety steps or assessments or 
terminate the study.  Further safety review and details on the process and methods of the safety data 
review will be provided in the DSMB Charter.
Inclusion/Exclusion Criteria:
Waivers to the inclusion and exclusion criteria will NOT be allowed. 
Inclusion:
1.
Subject has consented and signed an Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) approved written Informed Consent and privacy language as per national 
regulations (e.g., Health Insurance Portability and Accountability Act [HIPAA] for U.S. sites) 
prior to any study-related procedures (including withdrawal of prohibited medication, if 
applicable).
2.
Subject is ≥ 18 years of age or is considered an adult according to local regulation at the time of 
signing informed consent.
3.
Subject has a documented diagnosis of advanced HCC of any etiology.  
4.
Subject has BCLC stage B or C.
5.
Subject’s lesions are not amenable to local therapies which may be beneficial, such as 
transarterial chemoembolization (TACE), radiofrequency ablation, radiotherapy, etc., and the 
subject is not a candidate for any curative treatments such as resection or liver transplant.
6.
Subject has hepatic function status of Child Pugh Class A at Screening. 
7.
Subject received prior systemic treatment for HCC with sorafenib or other anti-VEGF therapy and 
had confirmed disease progression or discontinued treatment due to a drug-related toxicity. 
Subject may have received 1 line of systemic therapy before or after sorafenib/anti-VEGF 
treatment.
8.
Subject has adequately recovered from toxicities due to prior HCC therapy to ≤ grade 1.
9.
Subject has an ECOG performance status ≤ 1 at Screening and on Day 1.
10. Subject has available formalin-fixed, paraffin-embedded tumor specimen with adequate viable 
tumor cells in a tissue block or unstained serial slides accompanied by an associated pathology 
report prior to enrollment. Archival or fresh biopsy tissue is required.
11. Subject has an estimated life expectancy of at least 3 months on Day 1, in the opinion of the 
Investigator.
12. Female subject is either:
Not of childbearing potential:
o
postmenopausal (defined as no spontaneous menses for at least 12 consecutive 
months prior to Screening with follicle-stimulating hormone [FSH] > 40 IU/L for 
women < 55 years of age at Screening), or
o
documented to be surgically sterile or status posthysterectomy (at least 1 month prior 


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to Screening).
Or, if of childbearing potential: 
o
must have a negative urine pregnancy test at Screening and on Day 1 before the first 
dose of study drug is administered, and
o
must use 2 acceptable methods of birth control* if sexually active from Screening 
through 3 months after the last dose of study drug.
13. Sexually active male subject and his female partner who is of childbearing potential must use 
2 acceptable methods of birth control* from Screening through 3 months after the last dose of 
study drug.
*Two acceptable methods of birth control are as follows:

Condom (barrier method of contraception); 
AND

One of the following is required:
○Placement of an intrauterine device (IUD) or intrauterine system (IUS) by the female 
subject or female partner of a male subject; 
○Additional barrier method: contraceptive sponge or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository by the female 
subject or female partner of a male subject.
○For male subject or male partner of female subject, vasectomy or other procedure 
resulting in infertility (e.g., bilateral orchiectomy) performed at least 6 months before 
Screening.
○Tubal ligation in the female partner of a male subject performed at least 6 months 
before Screening.
○Established and ongoing use of oral, injected, or implanted hormonal contraceptive 
by female partner of a male subject.
14. Female subject must not be breastfeeding at Screening or during the study period and for 
3 months after final study drug administration. 
15. Subject must agree not to donate sperm or ova from first dose of study drug through 3 months 
after the last dose of study drug.
16. Throughout the study, male subject must use a condom if having sex with a pregnant woman.
17. Subject must be able to swallow study drug and comply with study requirements. 
18. Subject agrees not to participate in another interventional study while on treatment.
Exclusion:  
1.
Subject has a severe concurrent disease, infection or comorbidity that, in the judgment of the 
Investigator, would make the subject inappropriate for enrollment.
2.
Subject has fibrolamellar variant of HCC.
3.
Subject has status of Child-Pugh Class B or C at Screening.
4.
Subject has a history of organ allograft including liver transplant.
5.
Subject has uncontrolled symptomatic ascites.
6.
Subject has known or suspected brain metastasis or active leptomeningeal disease. 
7.
Subject has a history of a non-HCC malignancy with the following exceptions: 
The subject with a previous history of a noninvasive carcinoma is eligible if in the opinion of 
the Investigator he/she has had successful curative treatment any time prior to Screening and 
requires no further therapy for the malignancy.


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For all other malignancies, the subject is eligible if he/she has undergone potentially curative 
therapy and has been considered disease free for at least 3 years prior to Screening.
8.
Subject has inadequate marrow, hepatic, and/or renal function at the Screening Visit defined as:
Absolute neutrophil count < 1.5 x109/L (< 1500 cells/mm3)
Platelet count < 50 x109/L (< 50,000 cells/mm3)
Hemoglobin < 8.5 g/dL (< 5.3 mmol/L)
International normalized ratio > 1.7
Albumin < 2.8 g/dL (< 28 g/L)
TBL > 2 x ULN
AST or ALT > 5 x ULN
Creatinine > 1.5 x ULN
Note: Transfusions/infusions to meet eligibility criteria are not allowed but if in the opinion of the 
Principal Investigator, it is beneficial, the patient may be rescreened after receiving one of these 
procedures.
9.
Subject has a history of seizure or any condition that may predispose to seizure (e.g., prior cortical 
stroke, significant brain trauma, encephalopathy within 3 months of Day 1).
10. Subject has a history of bleeding esophageal varices within 3 months before the Day 1 visit.
11. Subject has a history of loss of consciousness or transient ischemic attack within 12 months 
before the Day 1 visit.
12. Subject has clinically significant cardiovascular disease including:
Myocardial infarction within 6 months before the Day 1 visit. 
Uncontrolled angina within 6 months before the Day 1 visit.
Congestive heart failure New York Heart Association (NYHA) Class III or IV or history of 
congestive heart failure NYHA Class III or IV in the past, UNLESS a Screening 
echocardiogram or multi-gated acquisition scan performed within 3 months before the Day 1 
visit reveals a left ventricular ejection fraction that is ≥ 45%.
History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, 
ventricular fibrillation, Torsade de Pointes).
History of Mobitz II second degree or third degree heart block without a permanent 
pacemaker in place.
Hypotension as indicated by systolic blood pressure < 86 mmHg on 2 consecutive 
measurements at the Screening visit.
Bradycardia (in the presence of known cardiovascular disease) as indicated by a heart rate of 
< 50 beats per minute on the Screening electrocardiogram (ECG) recording.
Uncontrolled hypertension as indicated by systolic blood pressure > 170 mmHg or diastolic 
blood pressure > 105 mmHg on 2 consecutive measurements at the Screening visit.
13. Subject has a gastrointestinal disorder affecting absorption.
14. Subject had previous local therapy (e.g., surgery, radiation therapy, hepatic arterial therapy, 
chemoembolization, radiofrequency ablation, percutaneous ethanol injection or cryoablation) 
within 14 days prior to Day 1, has not recovered from toxicities from prior local therapy or may 
require major surgical procedure during the course of the study.
15. Subject has received chemotherapy, immunotherapy or any other systemic anticancer therapy 
(including sorafenib) or any other investigational drug within 14 days prior to the Day 1 visit. 
16. Subject has received an agent that either blocks androgen synthesis or targets the AR (e.g., 
abiraterone acetate, bicalutamide, enzalutamide, ARN-509 or other investigational AR signaling 


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inhibitors). The exception of spironolactone is allowed after Medical Monitor consultation. 
17. Subject has used any of the following within 28 days before the Day 1visit:
5-α reductase inhibitors
Systemic androgens and estrogens (vaginal estrogen creams are allowed)
Herbal therapies with an antitumor effect.
18. Subject has a known history of positive test for Human Immunodeficiency Virus.
19. Subject has shown a hypersensitivity reaction to the active pharmaceutical ingredient or any of 
the enzalutamide capsule components, including caprylocaproyl polyoxylglycerides (Labrasol), 
butylated hydroxyanisole and butylated hydroxytoluene.
20. Subject has addictive/substance abuse problems.
21. Subject has any other condition or reason that, in the opinion of the Investigator, interferes with 
the ability of the subject to participate in the trial, places the subject at undue risk or complicates 
the interpretation of safety data.
Investigational Product(s):
Enzalutamide 40 mg gelatin capsules
Dose(s):
Enzalutamide 160 mg once daily (4 capsules once daily)
Mode of Administration:
Enzalutamide is an oral capsule.
Comparative Drug(s):
Placebo.
Dose(s):  
4 placebo capsules to match enzalutamide.
Mode of Administration:
Oral.
Concomitant Medication Restrictions or Requirements:
Medications taken within 14 days before the Screening visit and up to the 30-Day Follow-up visit will 
be documented on the appropriate case report form.  Prior and concomitant medications include all 
vitamins, herbal remedies, over the counter, and prescription medications.  Subject with viral etiology 
(hepatitis B virus [HBV], hepatitis C virus [HCV]) should be on stable doses of antiviral therapy at 
the time of study entry, if the Investigator feels these are of benefit to the subject. The Investigator
should consult with Medical Monitor if initiation of antiviral therapy is deemed necessary during the 
study.
Concomitant use of enzalutamide with drugs with a narrow therapeutic index that are metabolized by
cytochrome P450 (CYP) 3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, 
pimozide, quinidine, sirolimus, tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 
(e.g., S-mephenytoin) should be avoided if possible as enzalutamide may decrease their exposure. If 
coadministration with warfarin cannot be avoided, additional international normalization ratio (INR)
monitoring should be conducted.
Coadministration of enzalutamide with strong CYP2C8 inhibitors should be avoided. If 
coadministration of enzalutamide with strong CYP2C8 inhibitors cannot be avoided, the enzalutamide 
dose should be reduced to 80 mg/day. If coadministration of the strong inhibitor is discontinued, the 
enzalutamide dose should be returned to the dose used before initiation of the strong CYP2C8 
inhibitor




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Statistical Methods:
Sample Size Considerations: 
This sample size was primarily determined to provide sufficient clinical experience to support the 
design of later-stage clinical development, such as phase 3 studies.
Sample size calculations were performed using EAST 5 software based on the following assumptions: 

2:1 randomization for enzalutamide vs placebo.

Median OS for placebo and enzalutamide are 7.0 months and 10.77 months (HR=0.65), 
respectively.

A study enrollment period of 18 months and a total study duration of 27 months.
With 109 death events, the study can achieve 80% power to detect a statistically significant difference 
using 1-sided log-rank test with 10% level of significance.  Assuming no loss to follow-up, 
approximately 144 subjects were originally planned to reach this number of events.
Efficacy:
Efficacy analyses will be conducted using the Full Analysis Set (FAS).  The FAS will consist of all
randomized subjects.  The primary endpoint, OS, will be defined as the time from the date of 
randomization until the documented date of death from any cause.  Subjects who are still alive at the 
time of the data cutoff date will be censored on the last date known to be alive.  The null hypothesis is 
that OS distributions of the two treatments are equivalent.  The alternative hypothesis is that OS is 
prolonged in the enzalutamide arm.  The null hypothesis will be tested using a stratified one-sided 
log-rank test at the 0.10 level (stratified by geographic region and ECOG performance status).  The 
hazard ratio of the treatment effect and the two-sided 95% CI will also be calculated using a Cox 
proportional hazard model.  Additional sensitivity analysis will be done using the unstratified test. 
Similar analyses will be conducted for the secondary efficacy endpoint PFS. The subgroup of AR+ 
(defined as ≥10% of tumor cells with nuclear expression) patients will be used to repeat the analyses 
described above.
Safety:  
Safety analyses will be conducted using the Safety Analysis Set (SAF). The SAF is defined as all 
subjects who have taken at least 1 dose of study drug. The treatment-emergent period will be defined 
as the period of time from the first dose date of study drug to 30 days after the last dose date of study 
drug or initiation of a new antineoplastic or new investigational agent (whichever is first).  Safety will 
be assessed through descriptive statistics for the frequency of TEAEs by system organ class, preferred 
term, and the NCI CTCAE grade, the frequency of treatment discontinuations due to AEs, vital signs, 
ECG and laboratory evaluations.  
The severity of all AEs is to be evaluated by the Investigator based on the NCI CTCAE, version 4.03.  
All AEs will be coded to preferred term and system organ class using MedDRA.  The number and 
percentage of subjects with AEs will be presented by MedDRA system organ class and preferred 
term, relationship to study treatment, and NCI CTCAE grade. A subject reporting the same AE more 
than once is counted once at the maximum severity or strongest relationship to study drug treatment, 
when calculating incidence.  
Laboratory data consist of hematology, chemistry, coagulation, viral load (if applicable), pregnancy 
and urinalysis test results. Where applicable, NCI CTCAE version 4.03 will be used to categorize 
toxicity grades for the laboratory parameters. Laboratory shift tables compared to baseline results for 
each subsequent visit will be produced. For each laboratory parameter, the baseline laboratory value 
is defined as the last laboratory value collected on or prior to the first dose date of study drug.
Changes in body weight and vital signs will be described with similar methods.


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Pharmacokinetics:
Pharmacokinetic analysis will be conducted using the pharmacokinetic analysis set (PKAS). The 
PKAS is defined as the subset of the SAF population for which at least one quantifiable enzalutamide 
and N-desmethyl enzalutamide concentration value based on a predose sample is available. The 
enzalutamide and N-desmethyl enzalutamide concentration-time data will be summarized by 
descriptive statistics at each visit. Additional model-based analyses may be performed but will be 
reported separately.
Interim Analysis: 
There is no planned interim analysis; however, there will be periodic safety reviews throughout the 
study. After the 21st randomized subject has been treated for 28 days or has discontinued from the 
study (whichever occurs first), unblinded safety data will be evaluated by an independent DSMB.  
Further safety review and details on the process and methods of the safety data review will be 
provided in the DSMB Charter.


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V.
FLOW CHART AND SCHEDULE OF ASSESSMENTS
Flow Chart
Informed 
Consent
→
Screening
Period
(Days -21 to -1)
→
Day 1 Predose
Confirmation of 
eligibility criteria 
and enrollment
Treatment Period
(Day 1 - until a discontinuation criterion is met)
Visits at Weeks 3, 5, then every 4 weeks
Tumor Assessment will be done every 8 weeks 
(+/- 7 days) and measurement of 
HBV viral load (for subjects with HBV) 
to be done per Institution SOC
End of Treatment
Visit (within 7 days 
after last dose)
Follow-up Period
(Approx. 30 days 
after last dose of 
study drug, then
q30 days to 
collect information 
on survival and subsequent 
therapies)
Abbreviations: HBV= hepatitis B virus, q = every, SOC = standard of care


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Table 1
Schedule of Assessments
Assessments
Screen
Treatment Period
Unscheduled
Visit
Follow-up Period
Study Week/Visit
-3 to -1
1
3
5
9
13
17 + Q4 
Weeks
EOT
30D FU1
Long-term 
FU1
Study Day
-21 to -1
1
15
29
57
85
113+
N/A
≤ 7D after 
last dose
30D after 
last dose
Q30 days
Window (days)
N/A
0
+/-3
+/-3
+/-3
+/-3
+/-3
N/A
N/A
+10
+10 
Informed consent
X
Inclusion/exclusion criteria
X
X
Return and/or dispense study drug
X
X
X
X
X
X
X [OPT]
X
Concomitant medications2
X
X
X
X
X
X
X
X
X
X
Demographics, medical and disease history 
X
BCLC staging
X
Child-Pugh classification
X
HBV/HCV status3
X
Tumor assessment4
X
To be performed Q8Weeks (+/- 7 D) from Day 1
X [OPT]
Height
X
Weight
X
X
X
X
X
X
X [OPT]
X
Vital signs
X
X
X
X
X
X
X
X [OPT]
X
Adverse events5
X
X
X
X
X
X
X
X
X
X
Clinical laboratory tests6
X7
X8
X
X
X
X
X
X [OPT]
X
Urine pregnancy test9
X
X
X
X
X
X
X [OPT]
X
Physical examination
X
X
X
X
X
X
X
X [OPT]
X
12-lead ECG
X
X
X [OPT]
X
ECOG PS
X
X
X
X
X
X
X
X [OPT]
X
Alpha-fetoprotein
X
X8
X
X
X
X
X
X [OPT]
X
HBV viral load (if applicable)
X
To be done per SOC or as clinically indicated
Pharmacokinetic sample10
X
X
X
X [OPT]
 
X
X
Tumor tissue collection12
X
Blood samples for PGx biobanking (optional)
X
Survival and subsequent treatment
X
X
 
X
X
X
X
X
Footnotes appear on next page




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1
INTRODUCTION
1.1
Background
Hepatocellular carcinoma (HCC) represents more than 90% of primary liver cancers and 
remains a major global health problem. Globally, HCC is the 6th most common cancer and 
the 3rd leading cause of cancer-related mortality, with approximately 750,000 new cases 
world-wide annually. HCC has a strong male prevalence with a male to female ratio estimated 
to be 2.4. Worldwide, the mean age at diagnosis is between 50 and 60 years, and the incidence 
and mortality is increasing.
High incidence areas include East Asia, sub-Saharan Africa and Melanesia. In most European 
countries and the United States, the incidence is lower with the exception of Southern Europe, 
where the occurrence of HCC in men is significantly higher than in other developed regions. 
Approximately 90% of HCCs are associated with a known underlying risk factor, including 
chronic viral hepatitis (types B and C), alcohol intake, aflatoxin exposure and nonalcoholic 
steatohepatitis (NASH).  In Africa and East Asia, the most common etiology is hepatitis B 
(60%) whereas in the developed Western world, chronic hepatitis C appears to be the major 
risk factor [European Association for the Study of the Liver (EASL)- European Organisation 
for Research and Treatment of Cancer (EORTC) Clinical Practice Guidelines, 2012]. 
HCC characteristically occurs in the background of a cirrhotic liver, and usually secondary to 
hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection. Up to 80% of patients with 
HCC have cirrhosis which restricts therapeutic options. In addition, HCC is most often 
diagnosed at an advanced stage, when potentially curative therapies (e.g., resection, 
transplantation, percutaneous radiofrequency ablation) are of limited utility. Only about 30% 
to 40% of the patients are diagnosed at an early stage with only approximately 20% of 
patients being candidates for surgery. About 20% of patients are diagnosed at an intermediate 
stage and can benefit from transarterial chemoembolization (TACE). Other locoregional 
therapies being used includes liver transplantation, cryoablation, chemoembolization, 
radioembolization, bland embolization, percutaneous ethanol injection and hepatic arterial 
infusion chemotherapy with doxorubicin. However, after an initial therapeutic benefit, up to 
70% of patients who undergo these procedures will have recurrent disease within 5 years and 
reach a more advanced tumor stage [Bruix et al., 2012]. Many patients are nonsymptomatic in 
the early stages of liver cancer. When symptoms appear, HCC typically presents with 
jaundice, anorexia, weight loss, abdominal swelling and upper abdominal pain. Computed 
tomography (CT), magnetic resonance imaging (MRI), and ultrasonography are commonly 
used to then identify whether a tumor is present [NCCN Guidelines 2013]. The level of alpha-
fetoprotein is elevated in 60% to 70% of HCC patients [Arrieta et al., 2007].
Sorafenib is a multi-targeted tyrosine kinase inhibitor that blocks the activity of Raf serine/
threonine kinase isoforms, as well as the receptor tyrosine kinases vascular endothelial 
growth factor receptor (VEGFR)-2 and -3, platelet-derived growth factor receptor β, c-KIT, 
FLT-3, and RET, to inhibit tumor angiogenesis and tumor cell proliferation. The SHARP trial 
demonstrated that sorafenib significantly improved overall survival (OS) in patients with 


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advanced HCC and well-preserved liver function (>95% Child–Pugh A), and that 
drug-related adverse events (AEs) were manageable. Median OS in the sorafenib and placebo 
groups was 10.7 and 7.9 months, respectively (hazard ratio [HR] 0.69, 95% CI 0.55–0.87, 
p <0.001); median time to radiologic progression was 5.5 and 2.8 months, respectively 
(HR 0.58, 95% CI 0.45–0.74; p <0.001); and disease control rate (DCR) was 43% and 32%, 
respectively (p = 0.002) [Llovet et al., 2008]. This positive impact of sorafenib in improving 
survival and delaying tumor progression was confirmed in the phase 3 sorafenib Asia-Pacific 
trial, performed in China, South Korea and Taiwan [Cheng et al., 2009]. 
Despite these data supporting the effectiveness of sorafenib leading to its approval as first-line 
systemic therapy for patients with advanced HCC, the outcome for patients with advanced 
HCC remains dismal and new treatment approaches are urgently needed. Literature review 
suggests androgen and androgen receptor (AR) signaling may play an important role in HCC. 
In patients with HBV-related HCC, the incidence is higher in males and postmenopausal 
females compared to other females. The high levels of serum testosterone in males with an 
HBV infection have been reported to be associated with their development of HCC and their 
active AR gene alleles [Liu and Liu, 2014; Yu et al., 2001; Wang et al., 2009]. AR regulates 
the production of HBV X viral protein in a transgenic mouse model, which is implicated in 
HBV-mediated HCC [Chui et al., 2007]. In addition to high androgen levels, overexpression 
of the AR has been demonstrated in 60-80% of human HCCs [Nagasue et al., 1989]. AR 
overexpression is correlated with cell cycle-related kinase (CCRK), an AR signaling mediator 
that drives hepatocarcinogenesis via a signaling pathway dependent on β-catenin and T cell 
factor [Feng et al., 2011]. 
Recent genetic studies have further established the pivotal role of AR in hepatocarcinogenesis. 
Liver-specific knockout of AR significantly reduced tumorigenicity in carcinogen- and 
HBV-induced HCC mouse models [Ma et al., 2008; Wu et al., 2010]. Jiang et al. [2014] 
reported that apoptosis in HepG2 cells, human HCC cell line, was induced via inhibition of 
AR signaling.  These findings suggested that the activation of the AR signaling pathway 
might be involved in HCC. Although the molecular mechanisms of AR-induced 
hepatocarcinogenesis have not been clarified, these data warrant further clinical investigation 
into AR as a potential therapeutic target for the treatment of HCC. As enzalutamide is an 
inhibitor of the AR signaling pathway, the present study seeks to assess the efficacy and 
safety of enzalutamide in subjects with advanced HCC.
1.2
Nonclinical and Clinical Data
1.2.1
Nonclinical Data
1.2.1.1 Pharmacology
The primary pharmacodynamic effect of enzalutamide is inhibition of the AR signaling 
pathway. Primary pharmacodynamics have been defined in experiments that demonstrated 
inhibition of AR binding, inhibition of AR nuclear translocation, inhibition of AR chromatin 
association, inhibition of AR-dependent transcription and cancer cell proliferation, induction 
of cell death and tumor regression. On the whole, nonclinical data on the primary 


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pharmacodynamics of enzalutamide show that it is an AR inhibitor, and further that it is 
distinct from other antiandrogens in affecting multiple steps in the AR signaling pathway in 
the setting of AR overexpression. A major human metabolite of enzalutamide, N-desmethyl 
enzalutamide, demonstrated key primary pharmacodynamics with similar potency to the 
parent molecule. [Refer to the current Investigator’s Brochure].
In vitro and in vivo efficacy studies of enzalutamide have been conducted using a limited 
number of AR-positive HCC cell lines and the importance of AR signaling inhibition in HCC 
has not been demonstrated yet.
While enzalutamide did not have acute neurobehavioral effects (as assessed by functional 
observational battery endpoints) in the rat, convulsions were observed with this compound 
after a single dose in mice.  
Because enzalutamide was demonstrated to bind to and inhibit the gamma aminobutyric 
acid-gated chloride channel, an in vivo study in mice to investigate convulsion potential was 
conducted.  Convulsions occurred in mice given 400 mg/kg enzalutamide as a single dose or 
200 mg/kg per day enzalutamide for 7 days.  Based on the totality of the data, enzalutamide 
is associated with dose-dependent convulsions in mice.  
Enzalutamide had no effect on any other clinical observations or respiratory function 
assessments at doses up to and including 200 mg/kg.
The nonclinical and clinical data suggest that enzalutamide is not associated with an 
increased risk of QT prolongation, ischemic heart disease, heart failure or arrhythmias [Refer 
to the current Investigator’s Brochure].
1.2.1.2 Pharmacokinetics
Following oral administration in animals, enzalutamide is eliminated slowly from plasma 
with a long t1/2 across species.  In vitro studies show that enzalutamide is metabolized by 
human recombinant cytochrome P450 (CYP) isoenzymes CYP2C8 and CYP3A4/5.
Enzalutamide and/or its major human metabolites caused direct in vitro inhibition of multiple 
CYP enzymes including CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4/5.  
In vitro, enzalutamide caused time-dependent inhibition of CYP1A2.  Based on in vitro data, 
enzalutamide is an inducer of CYP3A4 but is not expected to induce CYP1A2 at 
therapeutically relevant concentrations.
In vitro data show that enzalutamide and its active metabolite N-desmethyl enzalutamide are 
potential inhibitors, but not substrates, of the efflux transporter P-glycoprotein (P-gp) [Refer 
to the current Investigator’s Brochure].
1.2.1.3 Toxicology
Overall, enzalutamide was generally well tolerated in nonclinical species with the most 
prominent effects occurring in reproductive and hormone-sensitive tissues. In studies in rats 
(4 and 26 weeks) and dogs (4, 13 and 39 weeks), changes in the reproductive organs 
associated with enzalutamide were decreases in organ weight with atrophy of the prostate and 


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epididymis. Additional changes to reproductive and hormone-sensitive tissues included 
hypertrophy/hyperplasia of the pituitary gland and atrophy in seminal vesicles in rats and 
testicular hypospermia, seminiferous tubule degeneration and hypertrophy/hyperplasia of the 
Leydig cells in dogs.  Gender differences were noted in rat mammary glands (i.e., male 
atrophy and female lobular hyperplasia). Changes in the reproductive organs in both species 
were consistent with the pharmacological activity of enzalutamide and reversed or partially 
resolved after an 8-week recovery period. There were no other important changes in clinical 
pathology or histopathology in any other organ system including the liver, in either species.
Hepatocellular toxicity is commonly associated with other antiandrogen compounds, such as 
flutamide and nilutamide, and both compounds are associated with liver injury in humans 
(Brahm et al., 2011; Gomez et al., 1992). In contrast to other antiandrogens, enzalutamide 
showed no evidence of hepatotoxicity in animals or in the clinical program.
Electrocardiogram (ECG) and cardiovascular assessments in a toxicity study in dogs showed 
no treatment-related effects. In vivo and in vitro safety pharmacology studies also 
demonstrated the absence of cardiovascular enzalutamide-related effects. 
Enzalutamide was non mutagenic in bacteria, nonclastogenic in mammalian cells and non 
genotoxic in vivo in mice. The 2 major human metabolites (N-desmethyl enzalutamide and 
an inactive carboxylic acid derivative) were negative for mutagenicity in the bacterial reverse 
mutation assay (Ames) [Refer to the current Investigator’s Brochure].
1.2.2
Clinical Data
As of the data cutoff date of 28 February 2016, over 5500 patients with prostate cancer, over 
400 women with breast cancer, and over 300 subjects with no known cancer including 
healthy male subjects and subjects with hepatic impairment have received at least 1 dose of 
enzalutamide in completed and ongoing clinical studies (not including the expanded access 
program or 2 compassionate use programs). 
The safety profile of enzalutamide in patients with castration-resistant prostate cancer 
(CRPC) is derived primarily from two phase 3 studies. Study CRPC2 (AFFIRM) was a 
randomized, double-blind, placebo-controlled, efficacy and safety clinical study of 
enzalutamide (160 mg daily) in 1199 patients with progressive metastatic CRPC (mCRPC) 
previously treated with docetaxel-based chemotherapy.  MDV3100-03 (PREVAIL) was a 
multinational, randomized, double-blind, placebo-controlled, efficacy and safety study of 
enzalutamide in 1717 chemotherapy-naïve patients with mCRPC who have failed androgen 
deprivation therapy.
Findings from the two phase 3 CRPC studies, study showed that AEs  occurring in at least 
5% of the patients treated with 160 mg/day enzalutamide (n = 1671) and at an incidence of at 
least 2% greater than in placebo patients were: asthenia, fatigue, back pain, diarrhea, 
constipation, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, 
muscular weakness, dizziness, insomnia, spinal cord compression, dysgeusia, hematuria, 
anxiety, hypertension, fall, decreased appetite, and weight decreased. The proportion of 


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patients with AEs associated with discontinuation of study drug in the combined controlled 
population was 17.7% in the enzalutamide group and 23.5% in the placebo group. 
Seizures occurred in 7 (0.9%) of the enzalutamide treated patients and none (0%) of the 
placebo-treated patients in the blinded CRPC2 study. A lower seizure rate was observed in 
MDV3100-03 study (1 enzalutamide-treated patient [0.1%]).
There have been rare reports of posterior reversible encephalopathy syndrome (PRES) in 
patients receiving enzalutamide. PRES is a rare, reversible, neurological disorder which can 
present with rapidly evolving symptoms including seizure, headache, confusion, blindness, 
and other visual and neurological disturbances, with or without associated hypertension
[refer to the current Investigator’s Brochure].
1.2.2.1 Pharmacokinetics
The pharmacokinetics and metabolism of enzalutamide have been evaluated in more than 
2500 patients with prostate cancer and in more than 200 healthy male subjects and subjects 
with mild, moderate, or severe hepatic impairment. Individual daily doses have ranged from 
30 to 600 mg. 
The pharmacokinetics of a single oral 160 mg dose of enzalutamide were examined in 
subjects with baseline mild, moderate, or severe hepatic impairment (Child-Pugh Class A, B, 
and C, respectively) and in matched control subjects with normal hepatic function 
(Study 9785-CL-0009 and Study 9785-CL-0404). Mild, moderate or severe hepatic 
impairment did not have a clinically relevant effect on the composite AUC of enzalutamide 
plus N-desmethyl enzalutamide. Therefore, the results indicate that no starting dose 
adjustment is necessary for patients with baseline mild, moderate or severe hepatic 
impairment.
After oral administration to patients with CRPC, the median time to reach maximum 
enzalutamide plasma concentrations was 1 hour, and the mean terminal half-life was 5.8 days.  
Enzalutamide steady state was achieved by day 28, and the accumulation ratio was 8.3-fold.  
At steady state, enzalutamide showed approximately dose proportional pharmacokinetics 
over the range of 30 to 360 mg/day. Steady state plasma levels of the active metabolite are 
similar to those of enzalutamide.
A mass balance and biotransformation study in healthy male volunteers showed that 
enzalutamide is primarily eliminated by hepatic metabolism.
A food-effect study showed that food does not have a clinically relevant effect on the AUC of 
enzalutamide or N-desmethyl enzalutamide; therefore, enzalutamide can be taken with or 
without food.
Based on population pharmacokinetics modeling, age, weight and renal function (creatinine 
clearance [CLCR ≥30 mL/min] do not have clinically meaningful effects on enzalutamide 
exposures, therefore, no dose adjustments are indicated for these covariates. Based on 
pharmacokinetic data from a study in Japanese patients with prostate cancer, there were no 
clinically relevant differences in exposure between Japanese and Caucasian patients. Clinical 


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data are insufficient to assess the potential effect of severe renal impairment 
(CLCR < 30 mL/min) and end-stage renal disease on enzalutamide pharmacokinetics.
A clinical drug-drug interaction study in prostate cancer patients showed that enzalutamide 
can affect exposures to certain comedications. At steady state, enzalutamide reduced the 
AUC of oral midazolam (CYP3A4 substrate), S-warfarin (CYP2C9 substrate) and 
omeprazole (CYP2C19 substrate) by 86%, 56% and 70%, respectively. Therefore, 
enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer.  
Substrates of CYP3A4, CYP2C9 and CYP2C19 with a narrow therapeutic index are to be 
avoided, as enzalutamide may decrease plasma exposure of these drugs. If enzalutamide is 
coadministered with warfarin (CYP2C9 substrate), additional international normalized ratio 
(INR) monitoring needs to be conducted. Enzalutamide (160 mg/day) did not have a 
clinically relevant effect on exposure to intravenous docetaxel (CYP3A4 substrate) or to oral 
caffeine (CYP1A2 substrate), dextromethorphan (CYP2D6 substrate), or pioglitazone 
(CYP2C8 substrate). 
Another clinical drug-drug interaction study in healthy subjects showed that concomitant 
medications can affect exposure to enzalutamide.  Coadministration of gemfibrozil (a strong 
CYP2C8 inhibitor) increased the composite AUC of enzalutamide plus N-desmethyl 
enzalutamide by 2.2-fold; therefore, strong CYP2C8 inhibitors are to be avoided.  If 
coadministration with a strong CYP2C8 inhibitor is necessary, the dose of enzalutamide 
needs to be reduced to 80 mg once daily. Coadministration of itraconazole (strong CYP3A4 
inhibitor) increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 
1.3-fold; as this small change is not clinically meaningful, no starting dose adjustment is 
needed when coadministering enzalutamide with CYP3A4 inhibitors.  Co-administration of 
rifampin (strong CYP3A4 and moderate CYP2C8 inducer) decreased the composite AUC of 
enzalutamide plus N-desmethyl enzalutamide by 37%, while Cmax remained unchanged 
(study 9785-CL-0405); as these changes are not considered clinically relevant, no starting 
dose adjustment is needed when coadministering enzalutamide with moderate CYP2C8 
inducers or CYP3A4 inducers.
The pharmacokinetics of oral enzalutamide is being investigated in women with advanced 
breast cancer (MDV3100-08). Preliminary data demonstrate similar pharmacokinetics of 
enzalutamide and N-desmethyl enzalutamide in women relative to men with CRPC.
Refer to the current Investigator’s Brochure for more information.
1.3
Summary of Key Safety Information for Study Drugs
For more information on the investigational product enzalutamide and on the clinical study 
experience, refer to the current Investigator’s Brochure of enzalutamide.


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1.4
Benefit-Risk Assessment
The approval of sorafenib (Nexavar®) in 2007 changed the understanding of HCC and brought 
in a new era in the management of liver cancer. Sorafenib, a multi-target kinase inhibitor, was 
found to improve survival of patients with advanced-stage HCC (median OS 10.7 months vs 
7.9 months for placebo, HR 0.69, P < 0.0006) [Llovet et al., 2008] in Western patients. A 
phase 3 trial [Cheng et al., 2009] demonstrated a similar magnitude of benefit in Asian-Pacific 
patients (HR 0.68 P = 0.014), although overall survival values were lower (6.5 months for 
sorafenib vs 4.2 months for placebo). Sorafenib, where approved, is now considered the 
standard systemic therapy for HCC patients with advanced disease [Llovet et al., 2008].
However, despite this advancement in treatment of HCC, the outcome for patients remains 
poor and there is an unmet need for patients who have progressed after or were unable to 
tolerate first-line sorafenib treatment. Additional efforts in understanding the molecular 
regulation and the identification of new molecular targets are needed.
Hepatocellular carcinoma ranks among the top 5 oncology conditions in terms of unmet need 
after pancreatic and lung cancer (Zitter Managed Care Oncology Index 2013) primarily due 
to a lack of targeted treatment options and high mortality rates. Major unmet needs include 
new therapies for second-line advanced HCC patients who progress on sorafenib and tailored 
therapy (stratification according to biomarkers).
The high AR expression in HCC combined with data in the literature suggesting a potential 
role of AR signaling in HCC progression as well as growth and the lack of therapeutic 
options, support the development of enzalutamide in this indication.
Enzalutamide given at 160 mg/day is the FDA and EMA approved dose for use in men with 
mCRPC.  This dose has been evaluated and found to be well tolerated in subjects with 
impaired hepatic function and is also being evaluated in women with breast cancer. Placebo 
was selected as the comparative drug because there are no approved treatments for advanced 
HCC in patients who have progressed on or were intolerant of sorafenib or other antivascular 
endothelial growth factor (VEGF) inhibitors.
The above provides significant rationale for proceeding with this trial in the advanced HCC 
patient population.
2
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS
2.1
Study Objectives
2.1.1
Primary Objective
The primary objective of this study is:
●
To evaluate the efficacy of enzalutamide in subjects with advanced HCC, as measured 
by OS


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2.1.2
Secondary Objectives
The secondary objectives of this study are:
●
To evaluate the safety of enzalutamide in subjects with advanced HCC
●
To evaluate the pharmacokinetics of enzalutamide and the active metabolite N-desmethyl 
enzalutamide in subjects with advanced HCC
●
To evaluate Progression Free Survival (PFS) of enzalutamide as compared to placebo in 
subjects with advanced HCC
2.1.3
Exploratory Objectives
The exploratory objectives of this study are:
●
 
 
 
2.2
Study Design and Dose Rationale
2.2.1
Study Design
This is a multicenter, randomized, double-blind, placebo-controlled phase 2 study evaluating 
the efficacy, safety, and tolerability of enzalutamide monotherapy in 165 subjects in Europe, 
Asia and North America with HCC of any etiology who have progressed on or were 
intolerant to sorafenib or other anti-VEGF therapy in the advanced setting. Each region will 
have no more than 70% of overall subjects enrolled.  Enrollment may be limited by the 
sponsor in any region or country in order to have representation of the patient populations
from all 3 regions as there may be a difference in responses to treatment or tolerability.
The study will consist of a Screening Period, Treatment Period and a Follow-up Period.  
Eligible subjects will be stratified by geographic region (Asia versus others) and Eastern 
Cooperative Oncology Group (ECOG) performance status (0 versus 1) and randomized in a 
2:1 ratio to receive enzalutamide 160 mg/day or placebo until disease progression, 
unacceptable toxicity, or any other discontinuation criterion is met. Study evaluations will 
occur as specified in the Schedule of Assessments. 
An end of treatment visit will be performed within 7 days of the last dose of study drug.  
Upon discontinuation of treatment for any reason, subjects will enter the follow-up period. A 
follow-up visit will be performed approximately 30 days after the last dose of study drug.  
All AEs that occur during the safety reporting period (from the first dose of study drug 
through 30 days after the last dose of study drug or initiation of a new antineoplastic or new 
investigational agent, whichever occurs first) are to be followed up until resolved or judged 
to be no longer clinically significant, or until they become chronic to the extent that they can 


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be fully characterized. This may be performed by telephone if applicable. Long-term 
follow-up visits will be conducted every 30 days for up to 2 years to collect information on 
survival and subsequent therapies. 
During the study, study drug treatment may be interrupted for individual subjects who 
experience a National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE) Grade ≥ 3 AE that is attributed to the study drug and cannot be ameliorated 
with appropriate medical intervention. Study drug may be resumed at the original dose 
(160 mg/day) or at a reduced dose (120 mg/day or 80 mg/day), after discussion with and 
approval by the Medical Monitor. Treatment interruption for > 2 weeks must also be discussed 
with the Medical Monitor.  
There will be an initial safety review of the first 21 subjects. After the 21st randomized subject 
has been treated for 28 days or discontinued from the study (whichever occurs first), unblinded 
safety data will be evaluated by an independent Data Safety Monitoring Board (DSMB). 
Emerging safety issues may lead to a decision to change the dose, implement additional safety 
steps or assessments or terminate the study. Further safety review and details on the process 
and methods of the safety data review will be provided in the DSMB Charter.
2.2.2
Dose Rationale
Enzalutamide given at 160 mg/day has been approved by the FDA and EMA for use in men 
with mCRPC. Pharmacokinetics and tolerability of enzalutamide in men and women are 
similar and there is no clinically meaningful difference in pharmacokinetics between subjects 
with mild, moderate or severe hepatic impairment (Child-Pugh Class A, B and C, respectively) 
versus healthy volunteers after a single 160 mg dose of enzalutamide. Safety will be monitored 
on an ongoing basis. The first review of unblinded data will occur after 21 randomized subjects 
have been treated for 28 days or discontinued from the study (whichever occurs first). If 
warranted, a dose adjustment can be made based on the safety data review.  
2.3
Endpoints
2.3.1
Primary Endpoints
The primary efficacy variable is OS.  OS is defined as the time from the date of randomization 
until date of death from any cause.
2.3.2
Secondary Endpoints
Safety Endpoints:
The safety of enzalutamide will be assessed on an ongoing basis by evaluation of AEs/serious 
AEs (SAEs), clinical safety laboratory tests, vital signs and other safety measures.
Pharmacokinetic Endpoints:
Predose plasma concentrations of enzalutamide and N-desmethyl enzalutamide will be 
analyzed.  


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Efficacy Endpoints:
●
PFS, defined as the time from the date of randomization until the date of documented 
radiographic disease progression according to Response Evaluation Criteria in Solid 
Tumors (RECIST) 1.1 or death from any cause on study, whichever occurs first as 
assessed by the Investigator.
2.3.3
Exploratory Endpoints
 
 
 
 
 
 
3
STUDY POPULATION
3.1
Selection of Study Population
The study population will include male and female subjects with advanced (unresectable 
and/or metastatic) HCC with Barcelona Clinic Liver Cancer [BCLC] stage B or C of any 
etiology who have progressed on or were intolerant to sorafenib or other anti-VEGF therapy 
in the advanced setting and are not amenable to local therapies or any curative treatments.  
Subjects may have received 1 line of systemic therapy before or after sorafenib/anti-VEGF 
treatment.
3.2
Inclusion Criteria
Subject is eligible for the study if all of the following apply:
1.
Subject has consented and signed an Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC) approved written Informed Consent and privacy language as per 
national regulations (e.g., Health Insurance Portability and Accountability Act [HIPAA] 
for U.S. sites) prior to any study-related procedures (including withdrawal of prohibited 
medication, if applicable).


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2.
Subject is ≥ 18 years of age or is considered an adult according to local regulation at the 
time of signing informed consent.
3.
Subject has a documented diagnosis of advanced HCC of any etiology.  
4.
Subject has BCLC stage B or C.
5.
Subject’s lesions are not amenable to local therapies which may be beneficial, such as 
TACE, radiofrequency ablation, radiotherapy, etc., and the subject is not a candidate for 
any curative treatments such as resection or liver transplant.
6.
Subject has hepatic function status of Child-Pugh Class A at Screening.
7.
Subject has received prior systemic treatment for HCC with sorafenib or other anti-
VEGF therapy and had confirmed disease progression or had discontinued treatment due 
to a drug-related toxicity.  Subjects may have received 1 line of systemic therapy before 
or after sorafenib/anti-VEGF treatment
8.
Subject has adequately recovered from toxicities due to prior HCC therapy to ≤grade 1.
9.
Subject has an ECOG performance status ≤ 1 at Screening and on Day 1.
10. Subject has available formalin-fixed, paraffin-embedded tumor specimen with adequate 
viable tumor cells in a tissue block or unstained serial slides accompanied by an 
associated pathology report prior to enrollment. Archival or fresh biopsy tissue is 
required.
11. Subject has an estimated life expectancy of at least 3 months on Day 1, in the opinion of 
the Investigator.
12. Female subject is either:
●Not of childbearing potential:
postmenopausal (defined as no spontaneous menses for at least 12 consecutive 
months prior to Screening with FSH > 40 IU/L for women < 55 years of age at 
Screening), or
documented surgically sterile or status posthysterectomy (at least 1 month prior 
to Screening).
●Or, if of childbearing potential: 
must have a negative urine pregnancy test at Screening and on Day 1 before the 
first dose of study drug is administered, and
must use 2 acceptable methods of birth control* if sexually active from 
Screening through 3 months after the last dose of study drug.
13. Sexually active male subject and his female partner who is of childbearing potential must 
use 2 acceptable methods of birth control* from Screening through 3 months after the last 
dose of study drug. 


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*Two acceptable methods of birth control are as follows:
●Condom (barrier method of contraception); 
AND
●One of the following is required:
o
Placement of an intrauterine device (IUD) or intrauterine system (IUS) by the 
female subject or female partner of a male subject; 
o
Additional barrier method: contraceptive sponge or occlusive cap (diaphragm 
or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository by 
the female subject or female partner of a male subject.
o
For male subject or male partner of female subject, vasectomy or other 
procedure resulting in infertility (e.g., bilateral orchiectomy) performed at 
least 6 months before Screening.
o
Tubal ligation in the female partner of a male subject performed at least 
6 months before Screening.
o
Established and ongoing use of oral, injected, or implanted hormonal 
contraceptive by female partner of a male subject.
14. Female subject must not be breastfeeding at Screening or during the study period and for 
3 months after final study drug administration. 
15. Subject must agree not to donate sperm or ova from first dose of study drug through 
3 months after the last dose of study drug.
16. Throughout the study, male subject must use a condom if having sex with a pregnant 
woman.
17. Subject must be able to swallow study drug and comply with study requirements. 
18. Subject agrees not to participate in another interventional study while on treatment.
Waivers to the inclusion criteria will NOT be allowed.
3.3
Exclusion Criteria
Subject will be excluded from participation if any of the following apply:
1.
Subject has a severe concurrent disease, infection or comorbidity that, in the judgment of 
the Investigator, would make the subject inappropriate for enrollment.
2.
Subject has fibrolamellar variant of HCC.
3.
Subject has status of Child-Pugh Class B or C at Screening.
4.
Subject has a history of organ allograft including liver transplant.
5.
Subject has uncontrolled symptomatic ascites.
6.
Subject has known or suspected brain metastasis or active leptomeningeal disease. 


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7.
Subject has a history of a non-HCC malignancy with the following exceptions: 
●
The subject with a previous history of a noninvasive carcinoma is eligible if in the 
opinion of the Investigator he/she has had successful curative treatment any time 
prior to Screening and requires no further therapy for the malignancy.
●
For all other malignancies, the subject is eligible if he/she has undergone potentially 
curative therapy and has been considered disease free for at least 3 years prior to 
Screening.  
8.
Subject has inadequate marrow, hepatic, and/or renal function at the Screening Visit 
defined as:
●
Absolute neutrophil count < 1.5 x109/L (< 1500 cells/mm3)
●
Platelet count < 50 x109/L (< 50,000 cells/mm3)
●
Hemoglobin < 8.5 g/dL (< 5.3 mmol/L)
●
INR > 1.7
●
Albumin < 2.8 g/dL (< 28 g/L)
●
Total Bilirubin (TBL) > 2 x ULN
●
AST or ALT > 5 x ULN
●
Creatinine > 1.5 x ULN 
Note: Transfusions/infusions to meet eligibility criteria are not allowed but if in the 
opinion of the Principal Investigator, it is beneficial, the patient may be rescreened after 
receiving one of these procedures.
9.
Subject has a history of seizure or any condition that may predispose to seizure (e.g., prior 
cortical stroke, significant brain trauma, encephalopathy within 3 months of Day 1).
10. Subject has a history of bleeding esophageal varices within 3 months before the Day 1 
visit.
11. Subject has a history of loss of consciousness or transient ischemic attack within 
12 months before the Day 1 visit.
12. Subject has clinically significant cardiovascular disease including:
●
Myocardial infarction within 6 months before the Day 1 visit. 
●
Uncontrolled angina within 6 months before the Day 1 visit.
●
Congestive heart failure New York Heart Association (NYHA) Class III or IV or 
history of congestive heart failure NYHA Class III or IV in the past, UNLESS a 
Screening echocardiogram or multi-gated acquisition scan performed within 
3 months before the Day 1 visit reveals a left ventricular ejection fraction that is 
≥45%.
●
History of clinically significant ventricular arrhythmias (e.g., ventricular 
tachycardia, ventricular fibrillation, Torsade de Pointes).
●
History of Mobitz II second degree or third degree heart block without a permanent 
pacemaker in place.
●
Hypotension as indicated by systolic blood pressure < 86 mmHg on 2 consecutive 
measurements at the Screening visit.


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●
Bradycardia (in the presence of known cardiovascular disease) as indicated by a 
heart rate of < 50 beats per minute on the Screening ECG recording.
●
Uncontrolled hypertension as indicated by systolic blood pressure > 170 mmHg or
diastolic blood pressure > 105 mmHg on 2 consecutive measurements at the 
Screening visit.
13. Subject has a gastrointestinal disorder affecting absorption.
14. Subject had previous local therapy (e.g., surgery, radiation therapy, hepatic arterial 
therapy, chemoembolization, radiofrequency ablation, percutaneous ethanol injection or 
cryoablation) within 14 days prior to Day 1, has not recovered from toxicities from prior 
local therapy or may require major surgical procedure during the course of the study.
15. Subject has received chemotherapy, immunotherapy or any other systemic anticancer 
therapy (including sorafenib) or any investigational drug within 14 days prior to the 
Day 1 visit. 
16. Subject has received an agent that either blocks androgen synthesis or targets the AR 
(e.g., abiraterone acetate, bicalutamide, enzalutamide, ARN-509 or other investigational 
AR signaling modulator). The exception of spironolactone is allowed after Medical 
Monitor consultation.
17. Subject has used any of the following within 28 days before the Day 1 visit:
●
5-α reductase inhibitors
●
Systemic androgens and estrogens (vaginal estrogen creams are allowed)
●
Herbal therapies, with an antitumor effect
18. Subject has a known history of positive test for Human Immunodeficiency Virus.
19. Subject has shown a hypersensitivity reaction to the active pharmaceutical ingredient or 
any of the enzalutamide capsule components, including caprylocaproyl 
polyoxylglycerides (Labrasol), butylated hydroxyanisole and butylated hydroxytoluene.
20. Subject has addictive/substance abuse problems.
21. Subject has any other condition or reason that, in the opinion of the Investigator
interferes with the ability of the subject to participate in the trial, places the subject at 
undue risk or complicates the interpretation of safety data.
Waivers to the exclusion criteria will NOT be allowed.


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4
TREATMENT(S)
4.1
Identification of Investigational Product(s)
4.1.1
Enzalutamide
Enzalutamide is an opaque white to off-white oblong liquid-filled soft gelatin capsule for oral 
administration. Each capsule contains 40 mg enzalutamide.  
4.1.2
Placebo
The corresponding placebo is an opaque white to off-white oblong liquid-filled soft gelatin 
capsule for oral administration.
4.2
Packaging and Labeling
Both enzalutamide and the corresponding placebo are supplied by APGD.  Enzalutamide and 
placebo will be packaged in high-density polyethylene bottles with child-resistant induction 
seal closure. There are 124 capsules per bottle. All medication used in this study will be 
prepared, packaged, and labeled under the responsibility of qualified staff at APGD- Astellas 
United States Technologies (AUST) or Sponsor’s designee in accordance with APGD-AUST 
or Sponsor’s designee Standard Operating Procedures (SOPs), Good Manufacturing Practice 
(GMP) guidelines, ICH Good Clinical Practice (GCP) guidelines, and applicable local 
laws/regulations.
Each bottle will bear a label conforming to regulatory guidelines, GMP and local laws and 
regulations which identifies the contents as investigational drug.
A qualified person of Astellas Pharma Europe B.V. (APEBV) or Sponsor’s designee will 
perform the final release of the medication according to Directive 2003/94/EC annex 13.
4.3
Study Drug Handling
Enzalutamide and the corresponding placebo will be stored in a secure location with limited 
access at 20°C to 25°C (68°F to 77°F) with excursions permitted to 15°C to 30°C (59°F to 
86°F).  Subjects will be instructed to store study drug at room temperature and out of the 
reach of children. 
Current ICH GCP Guidelines require the Investigator to ensure that study drug deliveries 
from the Sponsor are received by the Investigator/or designee (e.g., pharmacist), and:
●
That such deliveries are recorded,
●
That study drug is handled and stored according to labeled storage conditions,
●
That study drug with appropriate expiry/retest and is only dispensed to study subjects in 
accordance with the protocol, and
●
That any unused study drug is returned to the Sponsor.
Drug inventory and accountability records for the study drugs will be kept by the 
Investigator/ or designee. Study drug accountability throughout the study must be 
documented and reconciled. The following guidelines are therefore pertinent:


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●
The Investigator agrees not to supply study drugs to any persons except the eligible 
subjects in this study in accordance with the protocol.
●
The Investigator or designee will keep the study drugs in a pharmacy or other locked and 
secure storage facility under controlled storage conditions, accessible only to those 
authorized by the Investigator to dispense these test drugs.
●
A study drug inventory will be maintained by the Investigator or designee. The inventory 
will include details of material received and a clear record of when they were dispensed 
and to which subject.
●
At the conclusion or termination of this study, the Investigator or designee agrees to 
conduct a final drug supply inventory and to record the results of this inventory on the 
Drug Accountability Record. It must be possible to reconcile delivery records with those 
of used and/or returned medication. Any discrepancies must be accounted for and 
documented. Appropriate forms of deliveries and returns must be signed by the site staff 
delegated this responsibility.
●
The site must return study drug to the Sponsor or designee at the end of the study or 
upon expiration.
4.4
Blinding
This is a double-blind study.  Subjects will be randomized to receive enzalutamide or placebo 
in a double-blind fashion such that the Investigator, Sponsor’s study management team, 
clinical staff nor the subject will know which agent is being administered. The randomization 
number will be assigned based on information obtained from the Interactive Response 
Technology (IRT). 
4.4.1
Confirmation of the Indistinguishability of the Study Drugs
The control for this blinded study will be the placebo capsules that appear identical to the 
enzalutamide capsules. Study drug will be dispensed in the same manner regardless of 
assigned treatment arm. Subjects will ingest the same number of capsules throughout the 
study. 
4.4.2
Retention of the Assignment Schedule and Procedures for Treatment Code 
Breaking
The randomization list and study medication blind will be maintained by the IRT system.
The DSMB will be provided access to the treatment assignment for periodic review of the 
unblinded data as documented in the DSMB Charter.  
4.4.3
Breaking the Treatment Code for Emergency
The treatment code for each randomized subject will be provided by the IRT in the event of a 
medical emergency requiring knowledge of the treatment assigned to the subject. The time, 
date, subject number and reason for obtaining any of these codes, and therefore breaking the 
blind, must be documented in the study file. They must only be requested by the Investigator
or other persons designated as sub-Investigators. No subjects or other study personnel will be 


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made aware of the treatment given to any subject unless a medical emergency necessitates 
such disclosure.
Unblinding of the study medication should only be considered for subject safety or when 
critical therapeutic decisions are contingent upon knowing the blinded study drug assignment.  
Any unblinding by the investigational staff must be reported immediately to the Sponsor and 
must include an explanation of why the study medication was unblinded. If possible, the 
Sponsor should be contacted prior to unblinding of the study medication.
4.4.4
Breaking the Treatment Code by the Sponsor
The Sponsor may break the treatment code for subjects who experience a Suspected 
Unexpected Serious Adverse Reaction (SUSAR), in order to determine if the individual case 
or a group of cases requires expedited regulatory reporting. Individual Emergency Codes will 
be provided to the limited staff who are responsible to break the codes for all SUSAR cases 
for reporting purposes.
4.5
Assignment and Allocation
Subjects will be entered into the IRT system at Screening and assigned a number. Subjects 
who meet inclusion/exclusion criteria will be stratified by geographic region (Asia versus 
other) and ECOG performance status (0 versus 1) and randomized in a 2:1 ratio to receive 
enzalutamide 160 mg/day or placebo on Day 1. Randomization will be performed via IRT.  
Prior to the initiation of the study treatment, the site staff will contact the IRT in order to 
determine the randomly assigned treatment. Specific procedures for randomization through 
the IRT are contained in the IRT procedures manual. 
5
TREATMENTS AND EVALUATION
5.1
Dosing and Administration of Study Drug(s) and Other Medication(s)
5.1.1
Dose/Dose Regimen and Administration Period
Eligible subjects will receive enzalutamide 160 mg/day (4 x 40 mg capsules) or placebo until 
disease progression, unacceptable toxicity, or any other discontinuation criteria are met. Best 
supportive care will be given to all subjects in addition to study drug. Best supportive care 
may include medications and supportive measures deemed necessary per Investigator’s 
discretion to palliate disease-related symptoms and improve quality of life. Subjects on 
strong CYP2C8 (e.g., gemfibrozil) inhibitor should start study drug at 80mg/day after 
consultation with the Medical Monitor, if coadministration cannot be avoided.
Study drug will be self-administered at home by the subject, except for visit days where 
pharmacokinetic samples are collected. On visit days with pharmacokinetic sampling, study 
drug will be administered in clinic after the pharmacokinetic sample is collected. Subjects 
will keep a diary to record the date and time of study drug dose on the 2 days before 
pharmacokinetic visit days. 


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Subjects should not make up missed or vomited doses; dosing should resume on the next 
calendar day unless otherwise instructed. For the purposes of this study, a “missed dose” is 
considered a dose not administered within 4 hours of the regular dosing time. 
Subjects may take study drug with or without food. Subjects must swallow capsules whole. 
Study drug may not be chewed, dissolved or capsules opened.
5.1.2
Increase or Reduction in Dose of the Study Drug(s)
During the study, study drug treatment may be interrupted for individual subjects who 
experience a NCI CTCAE Grade ≥ 3 AE (except LFT AEs) that is attributed to the study 
drug and cannot be ameliorated with appropriate medical intervention. Study drug may be 
resumed at the original dose (160 mg/day) or at a reduced dose (120 mg/day or 80 mg/day), 
after discussion with and approval by the Medical Monitor. Treatment interruption for 
> 2 weeks must also be discussed with the Medical Monitor. The Sponsor may make a 
decision to change the dose based on recommendation from the DSMB’s safety review.  
5.1.2.1 Dose Modification Plan for LFT Changes
Study drug dosing should be interrupted if a subject experiences clinically significant liver 
toxicity related to study drug (≥Baseline + 4 x ULN to < 20 x ULN for AST and ALT; 
grade 3 TBL). Testing should be repeated at Investigator’s discretion but at a minimum
weekly to ensure that the subject’s LFT’s are returning to acceptable levels. If the subject’s 
toxicity resolves within 14 days to either ≤ grade 1 (if normal at baseline) or no more than 
1 grade above baseline (but no higher than grade 2), study drug may be reintroduced at a dose 
of 120 mg/day in consultation with the Medical Monitor. If the toxicity has not resolved 
within 14 days (as defined by either ≤ grade 1 or no more than 1 grade above screening but 
no higher than grade 2), then the Medical Monitor must be consulted to determine if further 
interruption is permitted.
If any drug-related liver toxicity requiring dose interruption recurs or develops despite the 
initial dose reduction to 120 mg/day, the LFT monitoring instructions above should be 
followed and the study drug may be reintroduced at a dose of 80 mg/day. If any drug-related 
liver toxicity recurs at the reduced dose of 80 mg/day, the study drug should be discontinued.
Study drug must be discontinued for subjects with study drug related grade 4 LFTs (AST, 
ALT and TBL).


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Table 2
Dose Modification Table for Drug-Related Liver Toxicities
NCI CTCAE V4.03
Dose Interruption
Dose Reduction
Grade 1 (AST, ALT, TBL)
No Change
No Change
Grade 2 to  < Baseline + 4 
x ULN (AST and ALT)
No Change
No Change
Grade 2 (TBL)
No Change
No Change
≥ Baseline + 4 x ULN and 
below 20 x ULN (AST and 
ALT)
Hold until grade 1 or, if event was 
grade 1 or 2 at screening, until 
returns to grade 2 or lower.
If it takes over 14 days to reduce 
toxicity to acceptable levels then the 
MM should be consulted
1st episode – reduce to 120 mg/ day 
2nd episode – reduce to 80 mg/day
3rd episode – Discontinue treatment
Grade 3 (TBL)
Hold until grade 1 or, if event was 
grade 2 at screening, until returns to 
grade 2 or lower.
If it takes over 14 days to reduce 
toxicity to acceptable levels then the 
MM should be consulted
1st episode – reduce to 120 mg/day 
2nd episode – reduce to 80 mg/day
3rd episode – Discontinue treatment
Grade 4 (AST, ALT, TBL)
Discontinue Treatment
Discontinue Treatment
Abbreviations: ALT: alanine aminotransferase; AST: aspartate aminotransferase; NCI CTCAE: National Cancer 
Institute Common Toxicity Criteria for Adverse Events; TBL: total bilirubin; ULN: upper limit or normal
Note: For any Grade 3 or 4 hepatic toxicity that does not resolve within 14 days to CTCAE 
Grade ≤ 1 (or CTCAE Grade ≤ 2 if liver infiltration with tumor present), an abdominal CT 
scan should be performed to assess if the event is related to disease progression. Subjects 
with a history of viral hepatitis and an ALT or AST ≥ Baseline + 4 x ULN while on treatment 
should have a hepatitis B and C viral loads performed per institutional guidelines to check for 
possible reactivation. 
For Grade 4 LFTs (AST, ALT, TBL), increases related to the underlying disease or other 
nonstudy drug related causes, the Investigator in consultation with the Medical Monitor may 
consider holding study drug until values return to baseline or lower.
5.1.3
Previous and Concomitant Treatment (Medication and Nonmedication Therapy)
Medications taken within 14 days before the Screening visit and up to the 30-Day Follow-up 
visit will be documented on the appropriate case report form.
Prior and concomitant medications include all vitamins, herbal remedies, over the counter, 
and prescription medications. 
Subject with viral etiology (HCV, HBV) should be on stable doses of antiviral therapy at the 
time of study entry, if the Investigator feels these are of benefit to the subject. The 
Investigator should consult with Medical Monitor if initiation of antiviral therapy is deemed 
necessary during the study.
Concomitant use of enzalutamide with drugs with a narrow therapeutic index that are 
metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, 
fentanyl, pimozide, quinidine, sirolimus, tacrolimus), CYP2C9 (e.g., phenytoin, warfarin)
and CYP2C19 (e.g., S-mephenytoin) should be avoided if possible as enzalutamide may 


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decrease their exposure. If coadministration with warfarin cannot be avoided, additional INR 
monitoring should be conducted.
Coadministration of enzalutamide with strong CYP2C8 inhibitors should be avoided. If 
coadministration of enzalutamide with strong CYP2C8 inhibitors cannot be avoided, the 
enzalutamide dose should be reduced to 80 mg/day. If coadministration of the strong 
inhibitor is discontinued, the enzalutamide dose should be returned to the dose used before 
initiation of the strong CYP2C8 inhibitor.
Subject should avoid use of any herbal medications or dietary supplements including 
products containing Hypericum perforatum (e.g., St. John’s wort).
The following medications or therapies are prohibited during the receipt of study drug:
●
Medications, including herbal therapies, with an antitumor effect
●
Any investigational agent
●
AR antagonists (e.g., bicalutamide, flutamide, nilutamide), however, spironolactone 
initiation during the study is allowed after Medical Monitor consultation
●
5-α reductase inhibitors (e.g., finasteride, dutasteride)
●
Systemic androgens and estrogens (vaginal estrogen creams are allowed)
5.1.4
Treatment Compliance
Study subjects should be counseled on the need to meet 100% compliance with study drug.  
The Investigator or designee should ensure that study subjects meet this goal throughout the 
study period.  
Treatment compliance should be monitored closely as sites will perform accountability of 
study drug doses dispensed and returned and deviation in overall compliance < 80% should 
be reported to the Sponsor.  
5.2
Demographics and Baseline Characteristics
5.2.1
Demographics
Demographic information will be collected at Screening for all subjects and will include age 
or date of birth, sex, race, ethnicity (as local regulations allow) and history of smoking and 
alcohol use.  
5.2.2
Medical History
Medical history includes all significant medical conditions that have occurred or are currently 
ongoing at the time of consent. The condition, onset date, and recovery date will be collected.  
NCI CTCAE grade will be collected for conditions that are ongoing at the time of consent.
5.2.3
Diagnosis of the Target Disease, Severity and Duration of Disease
Diagnosis of advanced HCC will be captured including dates of diagnosis, etiology and the 
presence/absence of cirrhosis. Prior systemic treatment for advance HCC with sorafenib or 
other anti-VEGF therapy and confirmed disease progression or discontinuation of sorafenib 


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due to intolerance will also be collected. BCLC stage (Appendix 12.4) and the Child-Pugh 
class status (Appendix 12.5) will be documented during Screening.
5.3
Efficacy and Pharmacodynamics Assessments
5.3.1
Efficacy Assessment
5.3.1.1 Survival Status and Subsequent Therapies
Subjects who are alive after the completion of the 30-day Follow-up Visit will continue to be 
contacted by site personnel for long-term survival follow-up every 30 days. This assessment 
may be conducted by telephone if the subject is unable to travel. Information on survival 
status and subsequent therapies will be obtained. Follow-up will continue for up to 2 years 
after the 30-day Follow-up Visit or until the final analysis.
5.3.1.2 Radiographic Assessment
Disease response and progression will be evaluated in this study using the RECIST criteria 
(version 1.1, 2009) and assessed by the Investigator. Radiographic imaging technique will be 
performed using either diagnostic CT scan or MRI with contrast.  
Imaging may be performed at any time to confirm suspected progression of disease.  
Assessment will include tumor measurements for target lesions, nontarget lesions and 
assessment for any new lesions. An overall assessment will be characterized for each time 
point evaluation. At the end of study for that subject, the overall best response to the study 
regimen will be characterized. Refer to Appendix 12.7 RECIST v1.1 for additional details.
Baseline imaging performed prior to informed consent may be used so long as it is performed 
within 28 days prior to Day 1. Subsequent scans including chest/abdominal/pelvic imaging 
will be done every 8 weeks (± 7 days) from Day 1 until disease progression or other 
discontinuation criterion is met. Scans should be done every 8 weeks regardless of treatment 
interruption or delays.  To ensure comparability, the radiology/scans throughout the study 
should be performed using identical techniques (e.g., scans performed immediately following 
bolus contrast administration should be made with a standard volume of contrast, the 
identical contrast agent and preferably the same scanner). The same method should be 
employed and assessed by the same individual on each occasion, when possible.
 
 
 
 


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5.3.2.3
 
 
5.4
Safety Assessment
5.4.1
Height and Weight
Height and weight will be measured using standard institution practice and equipment.  
5.4.2
Vital Signs
Vital signs will include systolic and diastolic blood pressure (mmHg), radial pulse 
(beats/min) and temperature. All vital signs will be measured with the subject in the sitting or 
supine position.  
5.4.3
Adverse Events
All observed or spontaneously reported AEs will be documented within the source. The 
Investigator will avoid asking leading questions to influence the reporting of AEs.
AE collection will begin at the time the informed consent form (ICF) is signed and continue 
through to 30 days after the last dose date of study drug or initiation of a new antineoplastic 
or new investigational agent, whichever comes first.
See Section 5.5 Adverse Events and Other Safety Aspects for information regarding AE
collection and data handling.


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5.4.4
Laboratory Assessments
Routine laboratory samples for hematology, chemistry, coagulation, viral load (if applicable), 
pregnancy and urinalysis will be collected and analyzed at the Institution’s local laboratory.  
The local laboratory must be accredited to perform the protocol required tests and a 
certificate of accreditation and laboratory normal ranges must be provided to the Sponsor.  
Please refer to Appendix 12.8 Laboratory Assessments for a listing of analytes to be assessed.
5.4.5
Physical Examination
Standard, full physical examinations will be performed at Screening and Day 1 to assess 
general appearance, skin, eyes, ears, nose, throat neck, cardiovascular, chest and lungs, 
abdomen, musculoskeletal, neurologic status, mental status, and lymphatic systems.  
Genitourinary and rectal system examinations are to be performed only if clinically indicated.  
After Day 1, a brief symptom directed physical examination may be performed. 
New or worsening clinically significant findings on physical exam will be recorded as AEs if 
they meet the criteria in Section 5.5.1 Definition of Adverse Events.
5.4.6
Electrocardiogram (ECG)
A 12-lead ECG will be performed on all subjects at the Institution and interpreted by the 
Institution’s medically trained staff.  Parameters that include heart rate, PR interval, RR 
interval, QRS interval, QT interval will be collected. Abnormalities and clinical significance 
as judged by the Investigator will be reported as well. It is recommended that ECG reports 
are printed in duplicate and photocopied to prevent fading.
ECG should be obtained after the subject has rested quietly and is awake in a fully supine 
position or semi-recumbent, if supine not tolerated) for 10 minutes.
All on-treatment ECGs will be obtained prior to drug administration. Whenever a study 
procedure coincides with the scheduled time point for an ECG, the study activities are ideally 
undertaken in a fixed sequence: ECG first, vital signs.
5.5
Adverse Events and Other Safety Aspects
5.5.1
Definition of Adverse Events (AEs)
AEs will be collected from the time of consent until 30 days after the last dose of study drug 
or initiation of a new antineoplastic or new investigational agent, whichever comes first. An 
AE is defined as any untoward medical occurrence in a subject administered a study drug or 
has undergone study procedures and which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a study drug, 
whether or not related to the study drug.
Some countries may have additional local requirements for events that are required to be 
reported as AEs or in an expedited manner similar to an SAE. In these cases, it is the 


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Investigator’s responsibility to ensure that these AEs or other reporting requirements are 
followed and the information is appropriately recorded in the source data accordingly.
Adverse events are events that begin or worsen from the time of informed consent through 
the 30-day Follow-up Period or initiation of a new antineoplastic or new investigational
agent, whichever comes first. Treatment-emergent AEs (TEAEs) are events that begin or 
worsen from the date of first study drug administration through the 30-day Follow-up Period 
or initiation of new treatment, whichever comes first.
An abnormality identified during a medical test (e.g., laboratory parameter, vital sign, ECG 
data, physical exam) should be defined as an AE only if the abnormality meets one of the 
following criteria:
●
Induces clinical signs or symptoms
●
Requires active intervention
●
Requires interruption or discontinuation of study medication
●
The abnormality or investigational value is clinically significant in the opinion of the 
Investigator.
5.5.2
Definition of Serious Adverse Events (SAEs)
An AE is considered “serious” if, in the view of either the Investigator or Sponsor, it results 
in any of the following outcomes:
●
Results in death
●
Is life threatening (an AE is considered “life-threatening” if, in the view of either the 
Investigator or Sponsor, its occurrence places the subject at immediate risk of death.  It 
does not include an AE that, had it occurred in a more severe form, might have caused 
death)
●
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions 
●
Results in congenital anomaly, or birth defect
●
Requires inpatient hospitalization or leads to prolongation of hospitalization 
(hospitalization for treatment/observation/examination caused by AE is to be considered 
as serious) 
●
Other medically important events
Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. These events, including those that may result in disability/incapacity, 
should also usually be considered serious. Examples of such events are intensive treatment in 
an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
that do not result in hospitalization; or development of drug dependency or drug abuse.


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Safety events of interest on the medicinal products administered to the subject as part of the 
study (e.g., study drug, comparator, background therapy) that may require expedited 
reporting and/or safety evaluation include, but are not limited to:
●
Overdose of the study drug(s)
●
Suspected abuse/misuse of the study drug(s)
●
Inadvertent or accidental exposure to the study drug(s)
●
Medication error involving the study drug(s) (with or without subject/patient exposure to 
the Sponsor medicinal product, e.g., name confusion)
All of the events of interest noted above should be documented within the source. Any 
situation involving these events of interest that also meets the criteria for an SAE should be 
handled as described in Section 5.5.5 Reporting of Serious Adverse Events. 
The Sponsor has a list of events that they classify as “always serious” events. If an AE is 
reported that is considered to be an event per this classification as “always serious”, 
additional information on the event may be requested.
5.5.3
Criteria for Causal Relationship to the Study Drug
Adverse events that fall under either "Possible" or "Probable" should be defined as "AEs 
whose relationship to the study drugs could not be ruled out".
Causal relationship to 
the study drug
Criteria for causal relationship
Not related
A clinical event, including laboratory test abnormality, with a temporal 
relationship to drug administration which makes a causal relationship 
improbable, and/or in which other drugs, chemicals or underlying disease 
provide plausible explanations.
Possible
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the drug, but which could also be 
explained by concurrent disease or other drugs or chemicals. Information 
on drug withdrawal may be lacking or unclear.
Probable
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the drug, unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and which follows a 
clinically reasonable response on readministration (rechallenge) or 
withdrawal (dechallenge).
5.5.4
Criteria for Defining the Severity of an Adverse Event
AEs, including abnormal clinical laboratory values, will be graded using the NCI CTCAE 
guidelines (Version 4.03). The items that are not stipulated in the NCI CTCAE Version 4.03 
will be assessed according to the criteria below and will be documented within the source:


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Grade
Assessment Standard
1-Mild
Asymptomatic, or mild symptoms, clinical or diagnostic observations noted; 
intervention not indicated.
2-Moderate
Local or noninvasive intervention indicated.
3-Severe
Medically significant but not immediately life-threatening, hospitalization 
or prolonged hospitalization.
4-Life-threatening
Life-threatening consequences, urgent intervention indicated
5-Death
Death related to AE
5.5.5
Reporting of Serious Adverse Events (SAEs)
In the case of a SAE, which will be collected from signing of the ICF until 30 days after last 
study drug administration, the Investigator must contact the Sponsor by telephone, fax or 
email immediately (within 24 hours of awareness).
The Investigator should complete and submit an SAE Worksheet containing all information 
that is required by the regulatory authorities to the Sponsor by fax or email immediately 
(within 24 hours of awareness). If the faxing or emailing of an SAE Worksheet is not 
possible or is not possible within 24 hours, the local drug safety contact shown in Section II 
Contact Details of Key Sponsor’s Personnel should be informed by telephone.
For contact details, see Section II Contact Details of Key Sponsor's Personnel. Please fax or 
email the SAE Worksheet to:
Astellas Pharma Global Development – United States
Pharmacovigilance
Fax number: +1 847 317 1241 
Email: safety-us@astellas.com
If there are any questions, or if clarification is needed regarding the SAE, please contact the 
Sponsor's Medical Monitor/Expert or his/her designee (see Section II Contact Details of Key 
Sponsor’s Personnel). 
Follow-up information for the event should be sent promptly (within 7 days of the initial 
notification.
Full details of the SAE should be recorded on the medical records and on the electronic case 
report form (eCRF).
The following minimum information is required:
●
International Study Number (ISN)/Clinical Study Number, 
●
Subject number, sex and age,
●
The date of report,
●
A description of the SAE (event, seriousness of the event), and
●
Causal relationship to the study drug.
The Sponsor or Sponsor's designee will submit expedited safety reports (i.e., Investigational 
New Drug [IND] Safety Reports) to the regulatory agencies (i.e., FDA) as necessary, and will


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inform the Investigators of such regulatory reports. Investigators must submit safety reports 
as required by their IRB/IEC within timelines set by regional regulations (i.e., EU, eCTD, 
FDA).  Documentation of the submission to and receipt by the IRB/IEC of expedited safety 
reports should be retained by the site.
The Sponsor will notify all Investigators responsible for ongoing clinical studies with the 
study drug of all SAEs which require submission per local requirements (IRB/IEC / head of 
the study site).
The Investigators should provide written documentation of IRB/IEC notification for each 
report to the Sponsor.
The Investigator may contact the Sponsor's Medical Monitor/Expert for any other problem 
related to the safety, welfare or rights of the subject.
For SUSAR from a blinded trial, unblinded Council for International Organizations of 
Medical Sciences (CIOMS)-I report will be submitted to the authorities and IEC where 
required.
5.5.6
Follow-up of Adverse Events
All AEs occurring during or after the subject has discontinued the study are to be followed up 
until resolved or judged to be no longer clinically significant, or until they become chronic to 
the extent that they can be fully characterized. 
If during AE follow-up, the AE progresses to an "SAE", or if a subject experiences a new 
SAE, the Investigator must immediately report the information to the Sponsor. 
5.5.7
Monitoring of Common Serious Adverse Events
Common SAEs are SAEs commonly anticipated to occur in the study population independent 
of drug exposure.  SAEs classified as “common” are provided in Appendix 12.2 Common 
Serious Adverse Events. The list does NOT change the Investigator’s reporting obligations or 
prevent the need to report an AE meeting the definition of an SAE as detailed above. The 
purpose of this list is to alert the Investigator that some events reported as SAEs may not 
require expedited reporting to the regulatory authorities based on the classification of 
“common SAEs” as specified in Appendix 12.2 Common Serious Adverse Events. The 
Sponsor will monitor these events throughout the course of the study for any change in 
frequency. Any changes to this list will be communicated to the participating investigational 
sites. Investigators must report individual occurrences of these events as stated in 
Section 5.5.5 Reporting of Serious Adverse Events.
5.5.8
Procedure in Case of Pregnancy
If a female subject or partner of a male subject becomes pregnant during treatment, this 
should be reported as if it was an SAE (refer to Section 5.5.8 Procedure in Case of 
Pregnancy). Administration of study drug must be discontinued in case evidence of 
pregnancy is obtained during the treatment period. The expected date of delivery or expected 
date of the end of the pregnancy, last menstruation, estimated conception date, pregnancy 


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result and neonatal data etc., should be included in this information. Should the partner of the 
male subject become pregnant, a separate ICF will be submitted for IRB/IEC review and 
approval that, upon signing by the pregnant female, will allow medical supervision during the 
pregnancy and allow follow-up after the birth of the infant.
The Investigator will follow the medical status of the mother, as well as the fetus, as if the 
pregnancy is an SAE and will report the outcome to the Sponsor.
When the outcome of the pregnancy falls under the criteria for SAEs [spontaneous abortion, 
induced abortion, stillbirth, death of newborn, congenital anomaly (including anomaly in a 
miscarried fetus)], the Investigator should respond in accordance with the report procedure 
for SAEs.  Additional information regarding the outcome of a pregnancy (which is 
categorized as an SAE) is mentioned below.  
●
"Spontaneous abortion" includes miscarriage, abortion and missed abortion
●
Death of an infant within 1 month after birth should be reported as an SAE regardless of 
its relationship with the study drug
●
If an infant dies more than 1 month after the birth, it should be reported if a relationship 
between the death and intrauterine exposure to the study drug is judged as "possible" by 
the Investigator
●
In the case of a delivery of a living newborn, the "normality" of the infant is evaluated at 
the birth
●
Unless a congenital anomaly are identified prior to spontaneous abortion or miscarriage, 
the embryo or fetus should be assessed for congenital defects by visual examination
5.5.9
Emergency Procedures and Management of Overdose
If an overdose of enzalutamide occurs, the Medical Monitor must be contacted. An overdose 
is defined as any dose greater than the protocol-specified dose of enzalutamide 160 mg once 
daily. In the event of an overdose, stop treatment with study drug and initiate general 
supportive measures taking into consideration the enzalutamide t1/2 of 5.8 days. 
Neither the effects of overdose of enzalutamide nor an antidote to overdose are known.  
Subjects may be at increased risk of seizures following an overdose of enzalutamide.
All overdose events are to be reported within 24 hours of awareness by the study site per 
Section 5.5.2, whether or not the event meets AE criteria.
5.5.10
Supply of New Information Affecting the Conduct of the Clinical Study
When new information becomes available necessary for conducting the clinical study 
properly, the Sponsor will inform all Investigators involved in the clinical study as well as the 
regulatory authorities. Investigators should inform the IRB/IEC of such information when 
needed.
The Investigator will also inform the subjects, who will be required to sign an updated ICF in 
order to continue in the clinical study.


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5.6
Test Drug Concentration
5.6.1
Pharmacokinetic Assessments
Plasma samples will be analyzed to determine enzalutamide and N-desmethyl enzalutamide 
concentrations in all subjects treated in the study.  In addition, inactive metabolite (M1) of 
enzalutamide may be analyzed. Pharmacokinetic samples will be obtained before study drug 
dosing. Blood samples will be collected from a vein or port that is not used for drug 
infusions. Blood sampling, processing, storage and shipment instructions are provided in a 
lab manual. Samples will be shipped to and analyzed by a Sponsor designated analytical 
laboratory.
5.7
Other Measurements, Assessments or Methods
5.7.1
Blood Sample for Future Pharmacogenomics (PGx) Analysis (Retrospective 
PGx Analysis)
A PGx research may be conducted in the future to analyze or determine genes of relevance to 
clinical response, pharmacokinetics and toxicity/safety issues. After randomization (see 
schedule of assessments), approximately 5 mL sample of whole blood for possible 
retrospective PGx analysis will be collected using a vacutainer tube containing 
ethylenediaminetetraacetic acid. After collection, gently invert the blood sample 8 to 
10 times. The blood collection tube may either be stored upright at 4°C for up to 5 days prior 
to shipment or stored frozen at -20°C or below at the site for extended storage. Samples will 
be shipped to a Sponsor designated banking contract research organization (CRO).
Labels should uniquely identify each sample and contain at least:
●
Protocol number (9785-CL-3021),
●
Subject number, and
●
Purpose and biological matrix (i.e., “biobanking”, “whole blood”).
Details on sample collection, labeling, storage and shipment procedures will be provided in a 
separate laboratory manual.
See Appendix 12.3, Retrospective PGx Sub-study for further details on the banking
procedures.
5.8
Total Amount of Blood
The total amount of blood for each subject will vary depending on the course of their disease, 
duration on treatment, and local laboratory requirements. At any time during the study, if any 
laboratory abnormalities are found for a subject, additional blood may be drawn for 
monitoring.
The maximum amount of blood estimated over any approximate 3 month period is from 
Day 1 through Week 13 where approximately 89.5 mL may be drawn.


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6
DISCONTINUATION
6.1
Discontinuation of Individual Subject(s)
A discontinuation is a subject who enrolled in the study and for whom study treatment is 
permanently discontinued for any reason.  
The subject is free to withdraw from the study treatment and/or study for any reason and at 
any time without giving reason for doing so and without penalty or prejudice. The 
Investigator is also free to terminate a subject's involvement in the study at any time if the 
subject's clinical condition warrants it or for reasons of gross noncompliance.
If a subject is discontinued from the study with an ongoing AE or an unresolved laboratory 
result that is significantly outside of the reference range, the Investigator will attempt to 
provide follow-up until the condition stabilizes or no longer is clinically significant.
Discontinuation Criteria from Treatment for Individual Subjects:
●
Evidence of symptomatic and radiographic disease progression per Investigator’s 
assessment.
●
Subject develops an unacceptable drug-related AE, based on the opinion of the 
Investigator and in consultation with the Medical Monitor
●
Seizure of any grade.
●
Subject’s disease becomes amenable to local or curative treatments. 
●
Subject is lost to follow up despite reasonable efforts by the Investigator to locate the 
subject
●
There is a significant protocol violation or non-compliance that occurs with a subject that 
compromises study objectives or subject safety. 
●
Female subject becomes pregnant
●
Subject’s death
●
Increased liver function tests per discontinuation criteria in Section 5.1.2.1 Dose 
Modification Plan for LFT Changes 
Discontinuation Criteria from Post-Treatment Follow Up for Individual Subjects:
●
Subject withdraws consent for further study participation
●
Subject is lost to follow up despite reasonable efforts by the Investigator to locate the 
subject
●
Subject’s death
6.2
Discontinuation of the Site
If an Investigator intends to discontinue participation in the study, the Investigator must 
immediately inform the Sponsor.
6.3
Discontinuation of the Study
The Sponsor may terminate this study prematurely, either in its entirety or at any study site, 
for reasonable cause provided that written notice is submitted in advance of the intended 


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termination. Advance notice is not required if the study is stopped due to safety concerns. If 
the Sponsor terminates the study for safety reasons, the Sponsor will immediately notify the 
Investigator and subsequently provide written instructions for study termination.
A DSMB will be used to monitor safety during the study. Emerging safety issues may lead to 
a decision to terminate the study.
7
STATISTICAL METHODOLOGY
The statistical analysis will be coordinated by the responsible biostatistician of APGD-US.  A 
Statistical Analysis Plan (SAP) will be written to provide details of the analysis, along with 
specifications for tables, listings and figures to be produced. The SAP will be drafted before 
first subject enrolled and finalized before the database soft lock. Any changes from the 
analyses planned in SAP will be justified in the clinical study report.
Prior to database lock, a meeting for final review of data and tables, listings and figures will 
be held to allow a review of the clinical trial data and to verify the data that will be used for 
analysis set classification. If required, consequences for the statistical analysis will be 
discussed and documented. A meeting to determine analysis set classifications may also be 
held prior to database lock.
In general, all data will be summarized with descriptive statistics (number of subjects, mean, 
standard deviation, minimum, median and maximum) for continuous endpoints, and 
frequency and percentage for categorical endpoints.  
7.1
Sample Size
This sample size was primarily determined to provide sufficient clinical experience to 
support the design of later-stage clinical development, such as phase 3 studies.
Sample size calculations were performed using EAST 5 software based on the following 
assumptions: 
●
2:1 randomization for enzalutamide vs placebo.
●
Median OS for placebo and enzalutamide are 7.0 months and 10.77 months (HR=0.65), 
respectively.
●
A study enrollment period of 18 months and a total study duration of 27 months.
With 109 death events, the study can achieve 80% power to detect a statistically significant 
difference using 1-sided log-rank test with 10% level of significance. Assuming no loss to 
follow-up, approximately 144 subjects were originally planned to reach this number of 
events.  
7.2
Analysis Set
Detailed criteria for analysis sets will be laid out in Classification Specifications and the 
allocation of subjects to analysis sets will be determined prior to database hard-lock.


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7.2.1
Full Analysis Set (FAS)
The full analysis set will consist of all randomized subjects. This will be the primary analysis 
set for efficacy analyses using randomized treatments.
7.2.2
Safety Analysis Set (SAF)
For the statistical summary of the safety data, the SAF will be used. The SAF consists of all 
subjects who took at least one capsule of study medication, and will be used for safety 
analyses using the actual treatment received.  
7.2.3
Pharmacokinetic Analysis Set (PKAS)
The PKAS is defined as the subset of the SAF population for which at least one quantifiable 
enzalutamide and N-desmethyl enzalutamide concentration value from the same predose 
sample is available.
7.2.4
Pharmacodynamic Analysis Set (PDAS)
The pharmacodynamic analysis set (PDAS) will include the subjects from the SAF 
population for whom sufficient pharmacodynamic measurements (a baseline and at least one 
post baseline value) were collected. The PDAS will be used for all analyses of 
pharmacodynamic data.
Any formal definitions for exclusion of subjects from the PDAS will be documented in the 
Classification Specifications.
7.3
Demographics and Other Baseline Characteristics
Demographics and other baseline characteristics will be summarized by treatment group for 
the FAS and if different for the SAF. Descriptive statistics will include number of subjects, 
mean, standard deviation, minimum, median and maximum for continuous endpoints, and 
frequency and percentage for categorical endpoints.
7.4
Analysis of Efficacy
Efficacy analysis will be conducted on the FAS.  
7.4.1
Analysis of Primary Endpoint
7.4.1.1 Primary Analysis
The primary endpoint, OS will be defined as the time from the date of randomization until 
the documented date of death from any cause. Subjects who are still alive at the time of the 
data cutoff date will be censored on the last date known to be alive or at the data cutoff date, 
whichever occurs first. The null hypothesis is that OS distributions of the 2 arms are 
equivalent. The alternative hypothesis is that OS is prolonged in enzalutamide arm. The null 
hypothesis will be tested using a stratified one-sided log-rank test at the 0.10 level (stratified 
by geographic region and ECOG performance status). The hazard ratio of the treatment effect 
along with two-sided 95% CI will also be calculated using a Cox proportional hazard model.  


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7.4.1.2 Secondary Analysis
A sensitivity analysis of the primary endpoint will be performed using the unstratified test. 
7.4.1.3 Subgroup Analysis
The same analysis of the primary endpoint as described in Section 7.4.1.1 will be conducted 
using the subgroup of AR+ (defined as ≥10% of tumor cells with nuclear expression) patients 
and other subgroups such as age, gender, geographic region, ECOG status and etiology.  
Results will be presented as forest plots.  
7.4.2
Analysis of Secondary Endpoints
Similar analysis of the primary endpoint as described in Section 7.4.1.1 will also be 
conducted on the secondary endpoint PFS. Patients who have not progressed or died before 
the data cutoff date for analysis will be censored at the date of last disease assessment which 
is the date of last scan. Detailed rules for censoring will be provided in the SAP.
7.4.3
Analysis of Exploratory Endpoints
 
 
7.5
Analysis of Safety
7.5.1
Adverse Events
Safety will be assessed through descriptive statistics for the frequency of TEAEs by system 
organ class, preferred term, and the NCI CTCAE grade, the frequency of treatment 
discontinuations due to AEs, vital signs, ECG and laboratory evaluations. 
The severity of all AEs is to be evaluated by the Investigator based on the NCI CTCAE, 
version 4.03. All AEs will be coded to preferred term and system organ class using 
MedDRA. The number and percentage of subjects with TEAEs will be presented by 
MedDRA system organ class and preferred term, relationship to study treatment, and NCI 
CTCAE grade.  TEAE is defined as an AE observed during the treatment-emergent period, 
which is from the first dose date of study drug to 30 days after the last dose date of study 
drug or the start of subsequent treatment, whichever is first. A subject reporting the same AE 
more than once is counted once and at the maximum severity or strongest relationship to 
study drug treatment, when calculating incidence. 
The number and percentage of TEAEs, serious TEAEs, AEs leading to discontinuation and 
TEAEs related to study drug will be summarized by system organ class, preferred term and 
treatment group.  The number and percentage of TEAEs by severity will also be summarized.  
All AEs will be listed.  


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7.5.2
Laboratory Assessments
Laboratory data consist of hematology, chemistry, coagulation, viral load (if applicable), 
pregnancy and urinalysis test results. Where applicable, NCI CTCAE version 4.03 will be 
used to categorize toxicity grades for the laboratory parameters. Laboratory shift tables 
compared to baseline results for each subsequent visit will be produced. For each laboratory 
parameter, the baseline laboratory value is defined as the last laboratory value collected on or 
prior to the first dose date of study drug.
For quantitative laboratory measurements descriptive statistics will be used to summarize 
results and change from baseline by treatment group and time point. Shifts relative to normal 
ranges from baseline to each time point during treatment period in lab tests will also be 
tabulated.  Laboratory data will be displayed in listings.
7.5.3
Vital Signs
Descriptive statistics will be used to summarize vital sign and body weight results, including 
change from baseline, by treatment group and time. Categorical analysis will be done by 
means of frequency tables of relevant decrease or increase in the vital sign values. Vital signs 
and body weight data will be displayed in listings.  
7.5.4
Physical Examination
Physical examination will be listed by treatment group.
7.5.5
ECGs
The 12-lead ECG results will be summarized by treatment group and time point. 
Abnormalities and clinical significance as judged by the Investigator will be reported as well.
7.6
Analysis of Pharmacokinetics
Pharmacokinetic analysis will be conducted using the pharmacokinetic analysis set (PKAS).  
The PKAS is defined as the subset of the SAF population for which at least one quantifiable 
enzalutamide and N-desmethyl enzalutamide concentration value from the same predose 
sample is available. The enzalutamide and N-desmethyl enzalutamide concentration-time 
data will be summarized by descriptive statistics at each visit. Additional model-based 
analyses may be performed but will be reported separately.  
 
 
 


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7.7.2
 
 
 
 
 
. 
7.8
Protocol Deviations and Other Analyses
Protocol deviations as defined in Section 8.1.6 Protocol Deviations will be summarized for 
all randomized subjects by treatment group and total as well as by site. A data listing will be 
provided by site and subject.
The protocol deviation criteria will be uniquely identified in the summary table and listing.  
The unique identifiers will be as follows:
PD1 - Entered into the study even though they did not satisfy entry criteria, 
PD2 - Developed withdrawal criteria during the study and was not withdrawn,
PD3 - Received wrong treatment or incorrect dose,
PD4 - Received excluded concomitant treatment.
7.9
Interim Analysis (and Early Discontinuation of the Clinical Study)
There is no planned interim analysis; however, there will be periodic safety reviews 
throughout the study. After the 21st randomized subject has been treated for 28 days or has 
discontinued from the study (whichever occurs first), unblinded safety data will be evaluated 
by an independent DSMB. Further safety reviews and details on the process and methods of 
the safety data review will be provided in the DSMB Charter. 
7.10
Handling of Missing Data, Outliers, Visit Windows and Other 
Information
As a general principle, no imputation of missing data will be done.  Exceptions are the start 
and stop dates of AEs and concomitant medication. The imputed dates will be used to 
allocate the concomitant medication and AEs to a treatment group, in addition to determining 
whether an AE is/is not treatment emergent. Listings of the AEs and concomitant 
medications will present the actual partial dates; imputed dates will not be shown.
Further details including the definitions for windows to be used for analyses by visit, will be 
described in the SAP.  


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8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS
8.1
Procedure for Clinical Study Quality Control
8.1.1
Data Collection
The Investigator or site designee will enter data collected using an Electronic Data Capture 
(EDC) system.  The Investigator or site designee is responsible to ensure that all data in the 
eCRFs and queries are accurate and complete and that all entries are verifiable with source 
documents. These documents should be appropriately maintained by the site.
The monitor should verify the data in the eCRFs with source documents and confirm that 
there are no inconsistencies between them.
Analytical laboratory tests for pharmacokinetic and pharmacodynamic measures will be 
collected and managed by Sponsor designated vendors during the study.  Laboratory data will 
be transferred electronically to the Sponsor or designee at predefined intervals during the 
study. The laboratory will provide the Sponsor or designee with a complete and clean copy of 
the data. 
For Screen failures the demographic data, reason for failing, informed consent, inclusion and 
exclusion criteria and AEs will be collected in the eCRF.  
8.1.2
Specification of Source Documents
Source data must be available at the site to document the existence of the study subjects and 
to substantiate the integrity of study data collected. Source data must include the original 
documents relating to the study, as well as the medical treatment and medical history of the 
subject.
The following information should be included within the source records:
●
Demographic data (age, sex, race, ethnicity, height and body weight, history of smoking 
and alcohol use)
●
Inclusion and exclusion criteria details
●
Participation in study and original signed and dated ICFs 
●
Visit dates
●
Medical history and physical examination details
●
Key efficacy and safety data, if applicable (as specified in the protocol)
●
Adverse events and concomitant medications 
●
Results of relevant examinations (e.g., ECG charts, X-ray films etc.)
●
Laboratory printouts (if applicable)
●
Dispensing and return of study drug details
●
Reason for premature discontinuation (if applicable)
●
Randomization number (if applicable)


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8.1.3
Clinical Study Monitoring
The Sponsor or delegated CRO is responsible for monitoring the clinical study to ensure that 
subject's human rights, safety, and well-being are protected, that the study is properly 
conducted in adherence to the current protocol and GCP, and study data reported by the 
Investigator/sub-Investigator are accurate and complete and that they are verifiable with 
study-related records such as source documents. The Sponsor is responsible for assigning 
study monitor(s) to this study for proper monitoring. They will monitor the study in 
accordance with planned monitoring procedures.  
8.1.4
Direct Access to Source Data/Documents
The Investigator and the study site must accept monitoring and auditing by the Sponsor or 
delegated CRO as well as inspections from the IRB/IEC and relevant regulatory authorities.  
In these instances, they must provide all study-related records, such as source documents 
(refer to Section 8.1.2 Specification of Source Documents) when they are requested by the 
Sponsor monitors and auditors, the IRB/IEC, or regulatory authorities. The confidentiality of 
the subject's identities shall be well protected consistent with local and national regulations
when the source documents are subject to direct access.
8.1.5
Data Management
Data Management will be coordinated by the Data Science department of the Sponsor in 
accordance with the SOPs for data management. All study specific processes and definitions 
will be documented by Data Management. eCRF completion will be described in the eCRF 
instructions. Coding of medical terms and medications will be performed using MedDRA 
and World Health Organization Drug Dictionary respectively. 
8.1.6
Protocol Deviations
A protocol deviation is generally an unplanned excursion from the protocol that is not 
implemented or intended as a systematic change. The Investigator is responsible for ensuring 
the study is conducted in accordance with the procedures and evaluations described in this 
protocol and must protect the rights, safety and welfare of subjects. The Investigator should 
not implement any deviation from, or changes of, the protocol, unless it is necessary to 
eliminate an immediate hazard to trial subjects.  
A protocol waiver is a documented prospective approval of a request from an Investigator to 
deviate from the protocol. Protocol waivers are strictly prohibited.
For the purposes of this protocol, deviations requiring notification to the Sponsor are defined 
as any subject who:
●
Entered into the study even though they did not satisfy entry criteria. 
●
Developed withdrawal criteria during the study and not withdrawn
●
Received wrong treatment or incorrect dose. 
●
Received excluded concomitant treatment.


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When a deviation from the protocol is identified for an individual subject, the Investigator or 
designee must ensure the Sponsor is notified. The Sponsor will follow-up with the 
Investigator, as applicable, to assess the deviation and the possible impact to the safety and /
or efficacy of the subject to determine subject continuation in the study. 
If a deviation impacts the safety of a subject, the Investigator must contact the Sponsor 
immediately.
The Investigator will also assure that deviations meeting IRB/IEC and applicable regulatory 
authorities’ criteria are documented and communicated appropriately. All documentation and 
communications to the IRB/IEC and applicable regulatory authorities will be provided to the 
Sponsor and maintained within the Trial Master File.  
NOTE:  Other deviations outside of the categories defined above that are required to be 
reported by the IRB/IEC in accordance with local requirements will be reported, as 
applicable.
8.1.7
End of Trial in All Participating Countries
The end of trial in all participating countries is defined as the Last Subject’s Last Visit.  
8.2
Ethics and Protection of Subject Confidentiality
8.2.1
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) / 
Competent Authorities (CA)
GCP requires that the clinical protocol, any protocol amendments, the Investigator’s 
Brochure, the informed consent and all other forms of subject information related to the study 
(e.g., advertisements used to recruit subjects) and any other necessary documents be 
reviewed by an IEC/IRB.  The IEC/IRB will review the ethical, scientific and medical 
appropriateness of the study before it is conducted.  IEC/IRB approval of the protocol, 
informed consent and subject information and/or advertising, as relevant, will be obtained 
prior to the authorization of drug shipment to a study site.
Any substantial amendments to the protocol will require IEC/IRB approval prior to 
implementation of the changes made to the study design at the site. The Investigator will be 
required to submit, maintain and archive study essential documents according to ICH GCP.
Any SAEs that meet reporting criteria, as dictated by local regulations, will be reported to 
both responsible Ethics Committees and Regulatory Agencies, as required. During the 
conduct of the study, the Investigator should promptly provide written reports (e.g., ICH 
Expedited Reports, and any additional reports required by local regulations) to the IEC/IRB 
of any changes that affect the conduct of the study and/or increase the risk to subjects.  
Written documentation of the submission to the IEC/IRB should also be provided to the 
Sponsor.
If required by local regulations, the Investigator shall make accurate and adequate written 
progress reports to the IEC/IRB at appropriate intervals, not exceeding one year. The 


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Investigator shall make an accurate and adequate final report to the IRB/IEC within 90 days
after the close-out visit for APGD-sponsored studies.
8.2.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing clinical study conduct and the ethical principles that 
have their origin in the Declaration of Helsinki.
8.2.3
Informed Consent of Subjects
8.2.3.1 Subject Information and Consent
The Investigator or his/her representative will explain the nature of the study to the subject or 
his/her guardian or legal representative, and answer all questions regarding this study.  Prior 
to any study-related Screening procedures being performed on the subject, the informed 
consent statement will be reviewed and signed and dated by the subject or his/her guardian or 
legal representative, the person who administered the informed consent and any other 
signatories according to local requirements. A copy of the signed ICF will be given to the 
subject and the original will be placed in the subject’s medical record. An entry must also be 
made in the subject’s dated source documents to confirm that informed consent was obtained 
prior to any study-related procedures and that the subject received a signed copy.
The signed consent forms will be retained by the Investigator and made available (for review 
only) to the study monitor and auditor regulatory authorities and other applicable individuals 
upon request.
8.2.3.2 Supply of New and Important Information Influencing the Subject’s Consent 
and Revision of the Written Information
1.
The Investigator or his/her representative will immediately inform the subject orally 
whenever new information becomes available that may be relevant to the subject’s 
consent or may influence the subject’s willingness to continue to participate in the study 
(e.g., report of serious drug adverse drug reaction). The communication must be 
documented in the subject’s medical records and must document whether the subject is 
willing to remain in the study or not.
2.
The Investigator must update their ICF and submit it for approval to the IRB/IEC.  The 
Investigator or his/her representative must obtain written informed consent from the 
subject on all updated ICFs throughout their participation in the study. The Investigator
or his/her designee must re-consent subjects with the updated ICF even if relevant 
information was provided orally. The Investigator or his/her representative who obtained 
the written informed consent and the subject should sign and date the ICF.  A copy of the 
signed ICF will be given to the subject and the original will be placed in the subject’s 
medical record. An entry must be made in the subject’s records documenting the 
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8.2.4
Subject Confidentiality
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited. Such medical information may be 
given only after approval of the subject to the subject's physician or to other appropriate 
medical personnel responsible for the subject's well-being.
The Sponsor shall not disclose any confidential information on subjects obtained during the 
performance of their duties in the clinical study without justifiable reasons.
The Sponsor affirms the subject's right to protection against invasion of privacy. Only a 
subject identification number and/or initials will identify subject data retrieved by the 
Sponsor. However, the Sponsor requires the Investigator to permit the Sponsor, Sponsor's 
representative(s), the IRB/IEC and when necessary, representatives of the regulatory health 
authorities to review and/or to copy any medical records relevant to the study.
The Sponsor will ensure that the use and disclosure of protected health information obtained 
during a research study complies with the federal and/or regional legislation related to the 
privacy and protection of personal information (i.e., Health Insurance Portability and 
Accountability Act).
8.3
Administrative Matters
8.3.1
Arrangement for Use of Information and Publication of the Clinical Study
Information concerning the study drug, patent applications, processes, unpublished scientific 
data, the Investigator's Brochure and other pertinent information is confidential and remains 
the property of the Sponsor. Details should be disclosed only to the persons involved in the 
approval or conduct of the study. The Investigator may use this information for the purpose 
of the study only. It is understood by the Investigator that the Sponsor will use the 
information obtained during the clinical study in connection with the development of the 
drug and therefore may disclose it as required to other clinical Investigators or to regulatory 
agencies. In order to allow for the use of the information derived from this clinical study, the 
Investigator understands that he/she has an obligation to provide the Sponsor with all data 
obtained during the study.
Publication of the study results is discussed in the Clinical Study Agreement.
8.3.2
Documents and Records Related to the Clinical Study
The Investigator will archive all study data (e.g., Subject Identification Code List, source 
data, eCRFs and Investigator's File) and relevant correspondence. These documents are to be 
kept on file for the appropriate term determined by local regulation [for US sites, two years 
after approval of the New Drug Application (NDA) or discontinuation of the IND
application. The Sponsor will notify the site/Investigator if the NDA/Marketing 
Authorisation Application/Japanese NDA is approved or if the IND/Investigational Medical 
Product Dossier/Clinical Trial Notification (CHIKEN TODOKE) is discontinued. The 
Investigator agrees to obtain the Sponsor's agreement prior to disposal, moving, or 


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transferring of any study-related records. The Sponsor will archive and retain all documents 
pertaining to the study according to local regulations. 
Data generated by the methods described in the protocol will be recorded in the subjects' 
medical records and/or study progress notes. All data will be entered on the eCRFs supplied 
for each subject. 
The Investigator and sponsor will mutually agree upon the storage format for the retention of 
electronic data.
8.3.3
Protocol Amendment and/or Revision
Any changes to the study that arise after approval of the protocol must be documented as 
protocol amendments (substantial and/or nonsubstantial). Depending on the nature of the 
amendment, either IRB/IEC, Competent Authority approval or notification may be required.  
The changes will become effective only after the approval of the Sponsor, the Investigator, 
the regulatory authority and the IRB/IEC (if applicable). Amendments to this protocol must 
be signed by the Sponsor and the Investigator. Written verification of IRB/IEC approval will 
be obtained before any amendment is implemented which affects subject safety or the 
evaluation of safety, and/or efficacy. Modifications to the protocol that are administrative in 
nature do not require IRB/IEC approval, but will be submitted to the IRB/IEC for their 
information, if required by local regulations.
If there are changes to the Informed Consent, written verification of IRB/IEC approval must 
be forwarded to the Sponsor. An approved copy of the new Informed Consent must also be 
forwarded to the Sponsor.
8.3.4
Insurance of Subjects and Others
The Sponsor has covered this study by means of an insurance of the study according to 
national requirements. The name and address of the relevant insurance company, the 
certificate of insurance, the policy number and the sum insured are provided in the 
Investigator's File.  
8.3.5
Signatory Investigator for Clinical Study Report
ICH E3 guidelines recommend and EU Directive 2001/83/EC requires that a final study 
report which forms part of a marketing authorization application be signed by the
representative for the Coordinating Investigator(s) or the Principal Investigator(s). The 
representative for the Coordinating Investigator (s) or the Principal Investigator(s) will have 
the responsibility to review the final study results to confirm to the best of his/her knowledge 
it accurately describes the conduct and results of the study. The representative for
Coordinating Investigator(s) or the Principal Investigator(s) will be selected from the 
participating Investigators by the Sponsor prior to database lock.


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9
QUALITY ASSURANCE
The Sponsor is implementing and maintaining quality assurance and quality control systems 
with written SOPs to ensure that trials are conducted and data are generated, documented, 
recorded and reported in compliance with the protocol, GCP and applicable regulatory 
requirement(s). Where applicable, the quality assurance and quality control systems and 
written SOPs of the CRO will be applied.
The Sponsor or Sponsor's designee may arrange to audit the clinical study at any or all 
investigational sites and facilities. The audit may include on-site review of regulatory 
documents, case report forms, and source documents. Direct access to these documents will 
be required by the auditors.  
10
STUDY ORGANIZATION
10.1
Data and Safety Monitoring Board (DSMB)
A DSMB will evaluate the unblinded safety data of the first 21 patients enrolled and then on 
periodic basis during the study. After the 21st randomized subject has been treated for 28 days 
or discontinued from the study (whichever occurs first). DSMB members will be clinicians 
(who are not Investigators for this trial and not an APGD employee) with expertise in HCC 
oncology trials. A separate DSMB charter will outline safety review details, processes and 
methods to be followed.
10.2
Other Study Organization
Not applicable.


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11
REFERENCES
Arreita O, Cacho B, Morales-Espinosa D, Ruelas-Villavicencio A, Flores-Estrada D, Hernández-
Pedro N. The progressive elevation of alpha fetoprotein for the diagnosis of hepatocellular 
carcinoma in patients with liver cirrhosis. BMC Cancer. 2007;7:28.
Brahm J, Brahm M, Segovia R, Latorre R, Zapata R, Poniachik J, et al. Acute and fulminant hepatitis 
induced by flutamide: case series report and review of the literature. Ann Hepatol. 
2011;10:93-8.
Bruix J, Raoul JL, Sherman M, Mazzaferro V, Bolondi L, Craxi A, et al. Efficacy and safety of 
sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial. J 
Hepatol. 2012;57:821–9.
Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of sorafenib in 
patients in the Asia Pacific region with advanced hepatocellular carcinoma: a phase III 
randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10:25-34.
Chui CM, Yeh SH, Chen PJ, Kuo TJ, Chang CJ, Chen PJ, et al. Hepatitis B virus X protein enhances
androgen receptor-responsive gene expression depending on androgen level. Proc Natl Acad 
Sci USA. 2007;104:2571-8.
EASL-EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol. 
2012;56:908-43.
Feng H, Cheng ASL, Tsang DP, Li MS, Go MY, Cheung YS, et al. Cell cycle-related kinase is a 
direct androgen receptor-regulated gene that drives β-catenin/T call factor-dependent 
hepatocarcinogenesis. J Clin Invest. 2011;121:3159-75.
Gomez JL, Dupont A, Cusan L, Tremblay M, Suburu R, Lemay M, et al. Incidence of liver toxicity 
associated with the use of flutamide in prostate cancer patients. Am J Med. 1992;92:465-70.
Investigator’s Brochure. Enzalutamide (MDV3100) for the treatment of cancer. 
Jiang X, Kanda T, Nakamoto S, Miyamura T, Wu S, Yokosuka O. Involvement of androgen receptor 
and glucose-regulated protein 78 kDa in human hepatocarcinogenesis. Exp Cell Res.
2014;323:326-36.
Liu WC, Liu QY. Molecular mechanisms of gender disparity in hepatitis B virus-associated 
hepatocellular carcinoma. World J Gastroenterol. 2014;20:6252-61.
Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced 
hepatocellular carcinoma. N Engl J Med. 2008;359:378-90.
Ma WL, Hsu CL, Wu MH, Wu CT, Wu CC, Lai JJ, et al. Androgen receptor is a new potential 
therapeutic target for the treatment of hepatocellular carcinoma. Gastroenterology. 
2008;135:947–55.
Nagasue N, Chang YC, Hayashi T, Galizia G, Kohno H, Nakamura T, et al. Androgen receptor in 
hepatocellular carcinoma as a prognostic factor after hepatic resection. Ann Surg. 
1989;209:424–27.


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National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN 
guidelines®) hepatobiliary cancers: version 1. 2013. 94 pp.  
Wang SH, Yeh SH, Lin WH, Wang HY, Chen DS, Chen PJ. Identification of androgen response 
elements in the enhancer I of hepatitis B virus: a mechanism for sex disparity in chronic 
hepatitis B. Hepatology. 2009;50:1392-402.
Wu MH, Ma WL, Hsu CL, Chen YL, Ou JH, Ryan CK, et al. Androgen receptor promotes hepatitis B 
virus–induced hepatocarcinogenesis through modulation of hepatitis B virus RNA 
transcription. Sci Transl Med. 2010;2:32ra35.
Yu MW, Yang YC, Yang SY, Cheng SW, Liaw YF, Lin SM, et al. Hormonal markers and hepatitis B 
virus-related hepatocellular carcinoma risk: a nested case-control study among men. J Natl 
Cancer Inst. 2001;93:1644-51.
Zitter Health Insights. The managed care oncology index: Winter 2013. 147 pp. 


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12
APPENDICES
12.1
List of Excluded Concomitant Medications
The following medications or therapies are prohibited during the receipt of study drug:
●
Medications, including herbal therapies, with an antitumor effect (Use of luteinizing 
hormone-releasing hormone agonist used to induce menopause in women of 
childbearing potential is permitted).
●
Any investigational agent
●
AR antagonists (e.g., bicalutamide, flutamide, nilutamide) however, spironolactone 
initiation during the study is allowed after Medical Monitor consultation
●
5-α reductase inhibitors (e.g., finasteride, dutasteride) 
●
Systemic androgens and estrogens (vaginal estrogen creams are allowed)
●
Megestrol acetate for appetite stimulation may be used at Investigator discretion.
Subject should avoid use of any herbal medications or dietary supplements including 
products containing Hypericum perforatum (e.g., St. John’s wort).
Concomitant use of enzalutamide with drugs with a narrow therapeutic index that are 
metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, 
fentanyl, pimozide, quinidine, sirolimus, tacrolimus), CYP2C9 (e.g., phenytoin, warfarin)
and CYP2C19 (e.g., S-mephenytoin) should be avoided if possible as enzalutamide may 
decrease their exposure. If coadministration with warfarin cannot be avoided, additional INR 
monitoring should be conducted.
Coadministration of enzalutamide with strong CYP2C8 inhibitors should be avoided. If 
coadministration of enzalutamide with strong CYP2C8 inhibitors cannot be avoided, the 
enzalutamide dose should be reduced to 80 mg/day. If coadministration of the strong 
inhibitor is discontinued, the enzalutamide dose should be returned to the dose used before 
initiation of the strong CYP2C8 inhibitor.
Refer to the following website for a complete list:
http://medicine.iupui.edu/clinpharm/ddis/main-table


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12.2
Common Serious Adverse Events
The following is a list of SAEs that the Sponsor considers to be associated with the disease 
state being studied. The list does NOT change the Investigator’s reporting obligations or 
prevent the need to report an AE meeting the definition of an SAE as detailed in
Section 5.5.2 Definition of Serious Adverse Event (SAE). The purpose of this list is to alert 
the Investigator that some events reported as SAEs may not require expedited reporting to the 
regulatory authorities based on the classification of “common SAEs”. The Investigator is 
required to follow the requirements detailed in Section 5.5.5 Reporting of Serious Adverse 
Events (SAE).
For IND safety reporting, single occurrences of the following events may be excluded from 
expedited reporting to the FDA. If aggregate analysis of these events indicates they occur 
more frequently with study drug, an expedited IND safety report may be submitted to the 
FDA.
●
Weight loss
●
Decreased appetite/Anorexia
●
Asthenia / Fatigue/general weakness
●
Nausea
●
Vomiting
●
Jaundice
●
Abdominal pain
●
Ascites
●
Cancer pain
●
Hepatomegaly
●
Metastatic liver cancer
●
Metastases to lung
●
Metastases to peritoneum
●
Metastases to abdominal lymph nodes
●
Metastases to bone 
●
Bone pain


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12.3
Retrospective PGx Sub-Study
INTRODUCTION
PGx research aims to provide information regarding how naturally occurring changes in a 
subject’s gene and/or expression based on genetic variation may impact what treatment 
options are best suited for the subject. Through investigation of PGx by technologies such as 
genotyping, gene sequencing, statistical genetics and Genome-Wide Association Studies, the 
relationship between gene profiles and a drug’s kinetics, efficacy or toxicity may be better 
understood. As many diseases may be influenced by one or more genetic variations, PGx 
research may identify which genes are involved in determining the way a subject may or may 
not respond to a drug.
OBJECTIVES
The PGx research that may be conducted in the future with acquired blood samples is 
exploratory. The objective of this research will be to analyze or determine genes of relevance 
to clinical response, pharmacokinetics and toxicity/safety issues.
By analyzing genetic variations, it may be possible to predict an individual subject’s response 
to treatment in terms of efficacy and/or toxicity.
SUBJECT PARTICIPATION
Subjects who have consented to participate in this study may participate in this PGx
sub-study.  As part of this sub-study, subjects must provide separate written consent prior to 
providing any blood samples that may be used at a later time for genetic analysis.
SAMPLE COLLECTION AND STORAGE
Subjects who consent to participate in this sub-study will provide one approximately 5 mL 
tube of whole blood per Astellas’ instructions. Each sample will be identified by the unique 
subject number (first code). Samples will be shipped frozen to a designated banking CRO 
either directly from site or via a central laboratory as directed by Astellas.
PGx ANALYSIS
Details on the potential PGx analysis cannot be established yet. Astellas may initiate the PGx 
analysis in case evidence suggests that genetic variants may be influencing the drug’s 
kinetics, efficacy and/or safety.
DISPOSAL OF PGx SAMPLES / DATA
All PGx samples collected will be stored for a period of up to 15 years following study 
database hard lock. If there is no requirement for analysis, the whole blood sample will be 
destroyed after the planned storage period. The subject has the right to withdraw consent at 
any time. When a subject’s withdraw notification is received, the PGx sample will be 
destroyed. The results of any PGx analysis conducted on a sample prior to its withdrawal will 
be retained at Astellas indefinitely.


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INFORMATION DISCLOSURE TO THE SUBJECTS
Exploratory PGx analysis may be conducted following the conclusion of the clinical study, if 
applicable. The results of the genetic analysis will not be provided to any Investigators or 
subjects, nor can the results be requested at a later date. Any information that is obtained 
from the PGx analysis will be the property of Astellas.  


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12.4
Barcelona Clinic Liver Cancer Staging System
Reference
Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet. 2003;362:1907-17.


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12.5
Child-Pugh Classification of Severity of Liver Disease
A total score of 5-6 is considered Class A (well-compensated disease), 7-9 is Class B 
(significant functional compromise) and 10-15 is Class C (decompensated disease). 
The score employs five clinical measures of liver disease.  Each measure is scored 1-3, with 
3 indicating most severe derangement.
Measure
1 point
2 points
3 points
Total bilirubin, μmol/L (mg/dL)
< 34 (< 2)
34-50 (2-3)
> 50 (> 3)
Serum albumin, g/L
> 35
28-35
< 28
Prothrombin time/International 
normalized ratio
< 1.7
1.71-2.30
> 2.30
Ascites
None
Mild
Moderate to Severe
Hepatic encephalopathy
None
Grade I-II (or suppressed with 
medication)
Grade III-IV (or 
refractory)


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12.6
ECOG Performance Status Scale
GRADE
0
Fully active, able to carry on all predisease performance without restriction.
1
Restricted in physically strenuous activity, but ambulatory and able to carry out 
work of a light or sedentary nature, (e.g., light housework, office work).
2
Ambulatory and capable of all self-care, but unable to carry out any work 
activities. Up and about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair.


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12.7
RECIST v1.1
Objective Response Criteria (RECIST)
All patients will have their BEST RESPONSE on study classified as outlined below:
Complete Response (CR):  Disappearance of all target and nontarget lesions including 
normalization of elevated tumor marker level. Any pathological lymph nodes (whether target 
or nontarget) must have reduction in short axis to < 10 mm. All nontarget lymph nodes must 
be nonpathological in size (< 10 mm short axis). 
Partial Response (PR):  At least a 30% decrease in the sum of the longest diameter (LD) of 
target lesions taking as reference the baseline sum LD.
Stable Disease (SD):  Steady state of disease; neither sufficient shrinkage to qualify for PR 
nor sufficient increase to qualify for progressive disease (PD), taking as reference the 
smallest sum diameters of target lesions while on study. There may be no appearance of new 
lesions for this category.
Progressive Disease (PD):  At least a 20% increase (and an absolute increase of at least 
5 mm) in the sum of LD of measured lesions taking as references the smallest sum LD 
recorded since the treatment started. Appearance of new lesions will also constitute PD.  In 
exceptional circumstances, unequivocal progression of nontarget lesions may be accepted as 
evidence of disease progression. 
NonCR/NonPD:  Persistence of 1 or more nontarget lesions and/or maintenance of tumor 
marker level above the normal limits. 
Summary of RECIST v1.1 Response Criteria
Target 
Lesions
Nontarget Lesions
New Lesions
Overall 
Response
Best Response for this Category 
also Requires
CR
CR
No
CR
CR
NonCR/NonPD
No
PR
CR
Not evaluated
No
PR
PR
NonPD or not all 
evaluated
No
PR
SD
NonPD or not all 
evaluated
No
SD
Documented at least once ≥4 weeks 
from baseline
Not All 
Evaluated
NonPD
No
NE
NE
PD
Any
Yes or No
PD
No prior SD, PR or CR
Any
PDa
Yes or No
PD
Any
Any
Yes
PD
Abbreviations: CR = complete response, NE = not evaluable, PD = progressive disease, PR = partial response, 
SD = stable disease
a
In exceptional circumstances, unequivocal progression in nontarget lesions may be accepted as disease 
progression.


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Time Point Response:  Patients with Nontarget Disease Only
Nontarget Lesions
New Lesions
Overall Response
CR
No
CR
NonCR/NonPD
No
NonCR/NonPDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
Abbreviations: CR = complete response, NE = not evaluable, PD = progressive disease
a
‘NonCR/nonPD’ is preferred over ‘stable disease’ for nontarget disease since SD is increasingly used as 
endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be measured is 
not advised.
Reference
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 
2009;45:228-47.


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12.8
Safety Laboratory Assessments
Test
Parameters to be analyzed
Hematology
Red blood cell count
Hemoglobin
Hematocrit
White blood cell count
Platelet count
White blood cell count differentials/absolute neutrophil count will be 
recorded
Biochemistry
Albumin
Alkaline phosphatase
Alanine aminotransferase
Aspartate aminotransferase
Bicarbonate
Blood urea nitrogen/Blood urea
Serum creatinine
Calcium
Chloride
Glucose
Lactate dehydrogenase
Magnesium
Phosphorus
Potassium
Sodium
Total bilirubin (including direct and indirect if available)
Total protein
Follicle-stimulating hormone (required for postmenopausal women 
< 55 years of age at Screening)
Urinalysis (standard 
urine dipstick)
Color
Appearance
Specific gravity
pH
Bilirubin
Blood
Glucose
Ketones
Leukocyte esterase
Nitrite
Protein
Urobilinogen
Coagulation
International normalized ratio (with prothrombin time/prothrombin time
percent if reported, or partial thromboplastin time ratio if reported)
Activated partial thromboplastin time or partial thromboplastin time
Pregnancy Test -Urine
Human chorionic gonadotropin (hCG)
Hepatitis Virus
Hepatitis C virus Antibody
Hepatitis B virus Surface Antigen
Hepatitis B viral load
Biomarker
Alpha-fetoprotein


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12.9
Open-Label Period
NOTE: This appendix contains cross-references to the main protocol text where study 
procedures are to be conducted in the same manner.
Following the results of the primary analysis, which demonstrated no statistically significant 
advantage of enzalutamide compared to placebo as assessed by the primary endpoint, all 
ongoing enzalutamide treated subjects will be offered open-label enzalutamide at the 
discretion of the subject and study investigators after approval of the amendment at the local 
institution. Subjects continuing to the Open-Label Period must not have met any 
discontinuation criteria as outlined in Section 6 of the main protocol and must meet the 
eligibility requirements of the Open-Label Period. Subjects who do not participate in the 
Open-Label Period or withdraw consent for further treatment will have a 30-day safety 
follow-up visit as per protocol. Following the 30-day safety follow-up visit their participation 
in the study will end.
The sponsor has the right to terminate the study at any time. However, the sponsor will 
ensure that enzalutamide will be available to subjects who participate in the Open-Label 
Period and have not met discontinuation criteria for as long as they are deriving clinical 
benefit as assessed by the investigator.
Schedule and Assessments for the Open-Label Period:
Subjects who meet eligibility requirements for the Open-Label Period will sign the informed 
consent on Open-Label day 1 (or their next regularly scheduled visit following the approval 
of the protocol at the study site). Subjects participating in the Open-Label period will have 
clinic visits every 8 weeks.
Study assessments will include the collection and review of adverse events and concomitant 
medications. Assessment of laboratory tests, physical examination, weight, and vital signs 
will also be conducted. 
Vital signs include blood pressure and pulse rate.
Routine laboratory assessment for hematology and chemistry will be collected and analyzed 
at the local laboratory. Laboratory assessments will be assessed at every clinic visit.  
Hematology assessments required for the Open-Label Period include red blood cell count 
(RBC), hemoglobin (Hgb), hematocrit (HCT), white blood cell count (WBC), platelets, and 
WBC differential/absolute neutrophil count.
Chemistry analytes required for the Open-Label Period include sodium, potassium, calcium, 
chloride, magnesium, phosphorus, glucose, creatinine, alkaline phosphatase, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, total protein, 
albumin, bicarbonate (CO2), blood urea nitrogen (BUN), lactate dehydrogenase.
Subjects will have a safety follow-up visit 30 days after the date of last dose of Open-Label 
enzalutamide or prior to initiation of a new antineoplastic or new investigational agent


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(whichever is first). If a new cytotoxic or investigational anticancer treatment is initiated 
before 30 days after the last dose, then safety follow-up should occur immediately before 
starting the new treatment.
Refer to Section 5.5, Adverse Events and Other Safety Aspects during the Open-Label Period 
of the study.
Flow Chart
Eligible for 
Open-Label 
Period 
Participation
→
Day 1 -
Obtain 
Informed 
Consent
Administer 
Open-Label 
Enzalutamide
→
Treatment Period 
Every 8 weeks until 
discontinuation 
criteria are met
End of 
Treatment
Visit (within 
7 days after 
last dose)
Follow-up Period
(Approx. 30 days 
after last dose of 
study drug)
Open-Label Period Inclusion Criteria:
Subjects must continue to meet inclusion criteria 1, 12, 13, 14, 15, 16, 18 and meet the new 
criterion 19.
19. Received double-blind enzalutamide study treatment during the main study.
Open-Label Period Exclusion Criteria:
22. Received double-blind placebo during the main study.
23. Subject has met discontinuation criteria during the main study.
24. Subject has any other condition or reason that, in the opinion of the Investigator,
interferes with the ability of the subject to participate in the trial or places the subject 
at undue risk.


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Schedule of Assessments
Assessments
Open Label 
Day 1
Treatment 
Period
Unscheduled
Visit
Follow-up Period
Study Week/Visit
11
Q8 Weeks
N/A
EOT
30D FU2
Window (days)
N/A
+/-3
N/A
+7
+10
Informed consent
X
Inclusion/exclusion criteria
X
Return and/or dispense study drug
X
X [OPT]
X
Concomitant medications3
X
X
X
X
X
Tumor assessment4
X
X [OPT]
Vital signs
X
X
X [OPT]
X
Adverse events5
X
X
X
X
X
Clinical laboratory tests6
X
X
X [OPT]
X
Urine pregnancy test7
X
X
X [OPT]
X
12-lead ECG
X
X [OPT]
X
ECOG PS
X
X
X [OPT]
X
Abbreviations: D: day(s), ECG: electrocardiogram, ECOG PS: Eastern Cooperative Oncology Group 
Performance Status, EOT: end of treatment, FSH: follicle-stimulating hormone, FU: follow-up, N/A: not 
applicable, OPT: optional, Q: every, SOC: standard of care
1.
The D1 visit of the open label period will continue from the visit numbering of the main study 
schedule.
2.
Phone call may be conducted if subject is unable to travel. Visit to be conducted 30 days after last 
dose or prior to initiating a new antineoplastic treatment, whichever comes first.
3.
Medications taken up to the 30-day Follow-up Visit will be collected.
4.
Computed tomography (CT)/magnetic resonance imaging (MRI) of the chest/abdomen/pelvis will 
be done every 8 weeks (+/- 7 days) from D1 until treatment discontinuation criterion is met. To 
ensure comparability, the Screening and subsequent assessment should be performed using 
identical techniques.
5.
Adverse events will be collected through the 30-day Follow-up Visit or through the day prior to the 
initiation of new antineoplastic treatment or investigational agent, whichever comes first.
6.
Clinical laboratory assessments include hematology: red blood cell count (RBC), hemoglobin 
(Hgb), hematocrit (HCT), white blood cell count (WBC), platelets, and WBC differential/absolute 
neutrophil count, Chemistry: sodium, potassium, calcium, chloride, magnesium, phosphorus, 
glucose, creatinine, alkaline phosphatase, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), total bilirubin, total protein, albumin, bicarbonate (CO2), blood urea 
nitrogen (BUN), lactate dehydrogenase, and pregnancy.
7.
Urine pregnancy test will be performed in women of childbearing potential. Testing at treatment 
visits must occur prior to study drug administration.
Enzalutamide Administration, Storage, Packaging and Accountability:
Refer to Section 5.1 Dosing and Administration of Study Drug(s) and Other Medication(s)
for dose modification guidance.
After signing Open-Label Period informed consent, subjects will be assigned Open-Label 
enzalutamide through the Interactive Response System (IRT).
Enzalutamide will be supplied in bottles and labeled in compliance with local regulations. 
Enzalutamide will be stored in a secure location with limited access at 20°C to 25°C (68°F to 


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ISN/Protocol 9785-CL-3021
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08 Mar 2018
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Version 5.0 Incorporating Substantial Amendment 4
77°F) with excursions permitted to 15°C to 30°C (59°F to 86°F).  Subjects will be instructed 
to store study drug at room temperature and out of the reach of children. 
All subjects will self-administer 4, 40 mg soft gelatin enzalutamide capsules (160 mg/day) by 
mouth once daily with or without food, unless they were receiving a reduced dose during 
double-blind treatment (treatment will continue at the reduced dose). Subjects should return 
all study drug bottles to the site at each visit. Study site personnel must make reasonable 
efforts to obtain all bottles and unused study drug from subjects.
Concomitant and Prohibited Medications:
Refer to Section 5.1.3 and Appendix 12.1 for Concomitant and Prohibited Medications. 
Medications taken up to the 30-day Follow-up visit will be documented on the appropriate 
case report form.
Duration of Treatment and Criteria for Discontinuation:
Refer to Section 6 for Criteria for Discontinuation. 
Statistical Methods:
Data from the open-label period will be listed by patient. Listings will focus on adverse 
events, safety laboratory parameters, and tumor assessment data.


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13
SUBSTANTIAL AMENDMENT 4
I.  The purpose of this amendment is:
Substantial Changes
1.
Add an Open-Label Period
DESCRIPTION OF CHANGE:
Add open-label period to allow subjects to continue on enzalutamide after the double-blind 
period.
RATIONALE:
An open label extension period is added to ensure continuing treatment of enzalutamide 
treated subjects receiving clinical benefit from study participation after unblinding as a result 
of the primary analysis. 
Non-Substantial Changes
1.
Update Contact Details of Key Sponsor’s Personnel
DESCRIPTION OF CHANGE: 
Update Clinical Research Contact details.
RATIONALE:
Sponsor personnel details are updated based on changes to study team members.
II.  Amendment Summary of Changes:
A. Substantial Changes
IV Synopsis
ADDED:
Double-Blind Period:
The double-blind period is the study period when investigators and subjects are 
blinded to the study drug they receive. The double-blind period will conclude 
following the results of the primary analysis.
Open-Label Period:
The open-label period will begin following the results of the primary analysis. At the 
time of unblinding, open-label enzalutamide will be provided for subjects who meet 
eligibility criteria. The complete details for the conduct of the open-label period are 
provided in Appendix 12.9 Open-Label Period.


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Version 5.0 Incorporating Substantial Amendment 4
12.9 Open-Label Period
ADDED:
NOTE: This appendix contains cross-references to the main protocol text where study 
procedures are to be conducted in the same manner.
Following the results of the primary analysis, which demonstrated no statistically 
significant advantage of enzalutamide compared to placebo as assessed by the primary 
endpoint, all ongoing enzalutamide treated subjects will be offered open-label 
enzalutamide at the discretion of the subject and study investigators after approval of 
the amendment at the local institution. Subjects continuing to the Open-Label Period 
must not have met any discontinuation criteria as outlined in Section 6 of the main 
protocol and must meet the eligibility requirements of the Open-Label Period. Subjects 
who do not participate in the Open-Label Period or withdraw consent for further 
treatment will have a 30-day safety follow-up visit as per the main protocol. Following 
the 30-day safety follow-up visit their participation in the study will end.
The sponsor has the right to terminate the study at any time. However, the sponsor will 
ensure that enzalutamide will continue to be available to subjects who participate in the 
Open-Label Period and have not met discontinuation criteria for as long as they are 
deriving clinical benefit as assessed by the investigator.
Schedule and Assessments for the Open-Label Period:
Subjects who meet eligibility requirements for the Open-Label Period will sign the 
informed consent on Open-Label day 1 (or their next regularly scheduled visit following 
the approval of the protocol at the study site). Subjects participating in the Open-Label 
period will have clinic visits every 8 weeks.
Study assessments will include the collection and review of adverse events and 
concomitant medications. Assessment of laboratory tests, physical examination, weight, 
and vital signs will also be conducted. 
Vital signs include blood pressure and pulse rate.
Routine laboratory assessment for hematology and chemistry will be collected and 
analyzed at the local laboratory. Laboratory assessments will be assessed at every clinic 
visit.  
Hematology assessments required for the Open-Label Period include red blood cell 
count (RBC), hemoglobin (Hgb), hematocrit (HCT), white blood cell count (WBC), 
platelets, and WBC differential/absolute neutrophil count.
Chemistry analytes required for the Open-Label Period include sodium, potassium, 
calcium, chloride, magnesium, phosphorus, glucose, creatinine, alkaline phosphatase, 
alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, 
total protein, albumin, bicarbonate (CO2), blood urea nitrogen (BUN), lactate 
dehydrogenase.
Subjects will have a safety follow-up visit 30 days after the date of last dose of Open-
Label enzalutamide or prior to initiation of a new antineoplastic or new investigational 
agent (whichever is first). If a new cytotoxic or investigational anticancer treatment is 
initiated before 30 days after the last dose, then safety follow-up should occur 


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ISN/Protocol 9785-CL-3021
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Version 5.0 Incorporating Substantial Amendment 4
immediately before starting the new treatment.
Refer to Section 5.5, Adverse Events and Other Safety Aspects during the Open-Label 
Period of the study.
Flow Chart
Eligible for 
Open-Label 
Period 
Participation
→
Day 1 -
Obtain 
Informed 
Consent
Administer 
Open-Label 
Enzalutamide
→
Treatment Period 
Every 8 weeks 
until 
discontinuation 
criteria are met
End of 
Treatment
Visit (within 
7 days after 
last dose)
Follow-up 
Period
(Approx. 
30 days 
after last dose 
of study drug)
Open-Label Period Inclusion Criteria:
Subjects must continue to meet inclusion criteria 1, 12, 13, 14, 15, 16, 18 and meet the 
new criterion 19.
19. Received double-blind enzalutamide study treatment during the main study.
Open-Label Period Exclusion Criteria:
22. Received double-blind placebo during the main study.
23. Subject has met discontinuation criteria during the main study.
24. Subject has any other condition or reason that, in the opinion of the investigator,
interferes with the ability of the subject to participate in the trial or places the 
subject at undue risk.
Schedule of Assessments
Assessments
Open Label 
Day 1
Treatment 
Period
Unscheduled
Visit
Follow-up Period
Study Week/Visit
11
Q8 Weeks
N/A
EOT
30D FU2
Window (days)
N/A
±3
N/A
+7
+10
Informed consent
X
Inclusion/exclusion criteria
X
Return and/or dispense study drug
X
X [OPT]
X
Concomitant medications3
X
X
X
X
X
Tumor assessment4
X
X [OPT]
Vital signs
X
X
X [OPT]
X
Adverse events5
X
X
X
X
X
Clinical laboratory tests6
X7
X
X [OPT]
X
Urine pregnancy test7
X
X
X [OPT]
X
12-lead ECG
X
X [OPT]
X
ECOG PS
X
X
X [OPT]
X
Abbreviations: D: day(s), ECG: electrocardiogram, ECOG PS: Eastern Cooperative Oncology Group 
Performance Status, EOT: end of treatment, FSH: follicle-stimulating hormone, FU: follow-up, N/A: not 
applicable, OPT: optional, Q: every, SOC: standard of care
1.
The D1 visit of the open label period will continue from the visit numbering of the main 
study schedule.
2.
Phone call may be conducted if subject is unable to travel. Visit to be conducted 30 days 
after last dose or prior to initiating a new antineoplastic treatment, whichever comes 
first.


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3.
Medications taken up to the 30-day Follow-up Visit will be collected.
4.
Computed tomography (CT)/magnetic resonance imaging (MRI) of the 
chest/abdomen/pelvis will be done every 8 weeks (± 7 days) from D1 until treatment 
discontinuation criterion is met. To ensure comparability, the Screening and subsequent 
assessment should be performed using identical techniques.
5.
Adverse events will be collected through the 30-day Follow-up Visit or through the day 
prior to the initiation of new antineoplastic treatment or investigational agent, whichever 
comes first. 
6.
Clinical laboratory assessments include hematology: red blood cell count (RBC), 
hemoglobin (Hgb), hematocrit (HCT), white blood cell count (WBC), platelets, and WBC 
differential/absolute neutrophil count, chemistry: sodium, potassium, calcium, chloride, 
magnesium, phosphorus, glucose, creatinine, alkaline phosphatase, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, total protein, 
albumin, bicarbonate (CO2), blood urea nitrogen (BUN), lactate dehydrogenase,, and 
pregnancy. .
7.
Urine pregnancy test will be performed in women of childbearing potential. Testing at 
treatment visits must occur prior to study drug administration.
Enzalutamide Administration, Storage, Packaging and Accountability:
Refer to Section 5.1 Dosing and Administration of Study Drug(s) and Other 
Medication(s) for dose modification guidance.
After signing Open-Label Period informed consent, subjects will be assigned Open-
Label enzalutamide through the Interactive Response System (IRT).
Enzalutamide will be supplied in bottles and labeled in compliance with local 
regulations. Enzalutamide will be stored in a secure location with limited access at 20°C 
to 25°C (68°F to 77°F) with excursions permitted to 15°C to 30°C (59°F to 86°F).  
Subjects will be instructed to store study drug at room temperature and out of the 
reach of children. 
All subjects will self-administer 4, 40 mg soft gelatin enzalutamide capsules 
(160 mg/day) by mouth once daily with or without food, unless they were receiving a 
reduced dose during double-blind treatment (treatment will continue at the reduced 
dose). Subjects should return all study drug bottles to the site at each visit. Study site 
personnel must make reasonable efforts to obtain all bottles and unused study drug 
from subjects.
Concomitant and Prohibited Medications:
Refer to Section 5.1.3 and Appendix 12.1 for Concomitant and Prohibited Medications. 
Medications taken up to the 30-day Follow-up visit will be documented on the 
appropriate case report form.
Duration of Treatment and Criteria for Discontinuation:
Refer to Section 6 for Criteria for Discontinuation. 
Statistical Methods:
Data from the open-label period will be listed by patient. Listings will focus on adverse 
events, safety laboratory parameters, and tumor assessment data.




Sponsor: APGD
ISN/Protocol 9785-CL-3021
EudraCT number 2014-004283-37
- CONFIDENTIAL -
08 Mar 2018
Astellas
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Version 5.0 Incorporating Substantial Amendment 4
14
SPONSOR’S SIGNATURES

SAP_001.pdf: 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study
to Assess the Efficacy and Safety of Enzalutamide in Subjects
with Advanced Hepatocellular Carcinoma
ISN/Protocol 9785-CL-3021
ClinicalTrials.gov Identifier: NCT02528643
Date of Statistical Analysis Plan, Final Version 2.0:
07 Sep 2018
Sponsor: Astellas Pharma Global Development, Inc. (APGD)
1 Astellas Way
Northbrook, IL 60062


Sponsor: Astellas Pharma Inc.
SAP Final Version 2.0   07-September-2017
ISN/Protocol 9785-CL-3021
Astellas
Page 1 of 35
STATISTICAL ANALYSIS PLAN
Final Version 2.0, dated 07-September-2017
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study 
to Assess the Efficacy and Safety of Enzalutamide in Subjects 
with Advanced Hepatocellular Carcinoma
ISN/Protocol: 9785-CL-3021
EudraCT number: 2014-004283-37
IND number: 127011
Astellas Pharma Global Development, Inc. (APGD)
1 Astellas Way,
Northbrook, IL 60062
This confidential document is the property of the sponsor.  No unpublished information 
contained in this document may be disclosed without prior written approval of the sponsor.


Sponsor: Astellas Pharma Inc.
SAP Final Version 2.0   07-September-2017
ISN/Protocol 9785-CL-3021
Astellas
Page 2 of 35
Table of Contents
1
INTRODUCTION·················································································· 8
2
FLOW CHART AND VISIT SCHEDULE···················································· 9
3
STUDY OBJECTIVE(S) AND DESIGN······················································12
3.1
Study Objective(s) ············································································12
3.1.1
Primary Objective ·······································································12
3.1.2
Secondary Objectives ···································································12
3.1.3
Exploratory Objectives ·································································12
3.2
Study Design···················································································12
3.3
Randomization·················································································13
4
SAMPLE SIZE·····················································································13
5
ANALYSIS SETS ·················································································14
5.1
Full Analysis Set (FAS) ······································································14
5.2
Safety Analysis Set (SAF) ···································································14
5.3
Pharmacokinetics Analysis Set (PKAS)····················································14
5.4
Pharmacodynamic Analysis Set (PDAS)···················································14
6
ANALYSIS VARIABLES ·······································································15
6.1
Efficacy Endpoints············································································15
6.1.1
Primary Efficacy Endpoint(s)··························································15
6.1.2
Secondary Efficacy Endpoints·························································15
6.1.3
Other Efficacy Variables ·······························································15
6.2
Safety Variables ···············································································16
6.2.1
Adverse Events ··········································································16
6.2.2
Laboratory Assessments································································16
6.2.3
Vital Signs················································································16
6.2.4
Electrocardiogram (ECG) ······························································17
6.2.5
Other Safety-Related Observations ···················································17
6.3
Pharmacokinetic Variables···································································17
6.4
·································································17
6.4.1
························································17
6.5
Other Variables················································································17
6.5.1
Previous and Concomitant Treatment·················································17
6.5.2
·············································································17


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7
STATISTICAL METHODOLOGY ···························································17
7.1
General Considerations·······································································17
7.2
Study Population ··············································································18
7.2.1
Disposition of Subjects ·································································18
7.2.2
Protocol Deviations ·····································································18
7.2.3
Demographic and Other Baseline Characteristics ···································19
7.2.4
Previous and Concomitant Medications ··············································19
7.3
Study Drugs····················································································19
7.3.1
Exposure··················································································19
7.3.2
Treatment Compliance··································································20
7.4
Analysis of Efficacy ··········································································20
7.4.1
Analysis of Primary Endpoint(s) ······················································20
7.4.2
Analysis of Secondary Endpoints ·····················································21
7.4.3
····················································21
7.5
Analysis of Safety·············································································23
7.5.1
Adverse Events ··········································································23
7.5.2
Clinical Laboratory Evaluation ························································24
7.5.3
Vital Signs················································································25
7.5.4
Electrocardiograms (ECGs)····························································26
7.5.5
Other Safety-Related Observations ···················································26
7.6
Analysis of Pharmacokinetics ·······························································26
7.7
·····························································27
7.7.1
···························································27
7.7.2
···································27
7.8
Subgroups of Interest ·········································································27
7.9
Interim Analysis (and Early Discontinuation of the Clinical Study)····················28
7.10
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········28
7.10.1
Missing Data ·············································································28
7.10.2
Missing Dates············································································28
7.10.3
Outliers ···················································································29
7.10.4
Visit Windows ···········································································29
8
DOCUMENT REVISION HISTORY ·························································30
9
REFERENCES ····················································································32
10
APPENDICES ·····················································································33


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10.1
Appendix 1: Definition of Efficacy Endpoints ············································33
10.1.1
Overall Survival ·········································································33
10.1.2
Progression-Free Survival······························································33
10.1.3
·····································································33
10.2
Appendix 2: Signatures·······································································35


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I.
LIST OF ABBREVIATIONS AND KEY TERMS
List of Abbreviations
Abbreviations
Description of abbreviations
AE
Adverse Event
ALT
Alanine Aminotransferase (GPT)
APGD
Astellas Pharma Global Development, Inc.
AR
Androgen Receptor
AST
Aspartate Aminotransferase (GOT)
BCLC
Barcelona Clinic Liver Cancer
BLOQ
Below the Lower Limit of Quantification
CR
Complete Response
CRF
Case Report Form
CS
Classification Specifications
CSR
Clinical Study Report
CT
Computer Tomography
DSMB
Data Safety Monitoring Board
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
ELISA
Enzyme-Linked Immunosorbent Assay
EMA
European Medicines Agency
FAS
Full Analysis Set
FSH
Follicle Stimulating Hormone
FU
Follow-Up
GCP
Good Clinical Practice
GMP
Good Manufacturing Practices
HBV
Hepatitis B Virus
HCC
Hepatocellular Carcinoma
HCV
Hepatitis C Virus
ICH 
International Conference on Harmonization 
IRT
Interactive Response System
ISN
International Study Number
LFT
Liver Function Tests
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic Resonance Imaging
NCI CTCAE
National Cancer Institute Common Toxicity Criteria for Adverse Events
OPT
Optional
OS
Overall Survival
PD
Progressive Disease
PD
Protocol Deviation
PDAS
Pharmacodynamic Analysis Set
PFS
Progression Free Survival
PGx
Pharmacogenomics
PK
Pharmacokinetics
PKAS
Pharmacokinetic Analysis Set
PPS
Per Protocol Set


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Abbreviations
Description of abbreviations
PR
Partial Response
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
Serious Adverse Event
SAF
Safety Analysis Set
SD
Stable Disease
SD
Standard Deviation
SOC
Standard of Care
SOC
System Organ Class
TBL
Total Bilirubin
TEAE
Treatment-emergent Adverse Event
TLF
Table, Listings, and Figures
ULN
Upper Limit of Normal
VEGF
Vascular Endothelial Growth Factor


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List of Key Terms
Terms
Definition of terms
Baseline
Observed values/findings which are regarded observed starting point for 
comparison. 
Intervention
The drug, therapy or process under investigation in a clinical study that is 
believed to have an effect on outcomes of interest in a study. (e.g., health-
related quality of life, efficacy, safety, pharmacoeconomics). 
Screening period
Period of time before entering the investigational period, usually from the time 
of starting a subject signing consent until just before the test drug or 
comparative drug (sometimes without randomization) is given to a subject.
Randomization
The process of assigning trial subjects to treatment or control groups using an 
element of chance to determine assignments in order to reduce bias.
Screening
A process of active consideration of potential subjects for enrollment in a trial.
Screen failure
Potential subject who did not meet one or more criteria required for 
participation in a trial.
Study period
Period of time from the first site initiation date to the last site completing the 
study.
Variable
Any quantity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values.


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1
INTRODUCTION
This Statistical Analysis Plan (SAP) contains a more technical and detailed elaboration of the 
principal features of the analysis described in the protocol, and includes detailed procedures 
for executing the statistical analysis of the primary and secondary endpoints and other data.
The SAP will be drafted before first subject enrolled and finalized before the database soft 
lock. If needed, revisions to the approved SAP may be made prior to database hard lock. 
Revisions will be version controlled.
This statistical analysis plan is coordinated by the responsible biostatistician of APGD-US.
Any changes from the analyses planned in the SAP will be justified in the Clinical Study 
Report (CSR).
Prior to database hard lock, a final review of data and Table, Listings, and Figures (TLFs)
meeting will be held to allow a review of the clinical trial data and to verify the data that will 
be used for analysis set classification. If required, consequences for the statistical analysis 
will be discussed and documented. A meeting to determine analysis set classifications may 
also be held prior to database hard lock.


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2
FLOW CHART AND VISIT SCHEDULE
Informed 
Consent
→
Screening
Period
(Days –21 to –1)
→
Day 1 Pre-dose
Confirmation of 
eligibility criteria 
and enrollment
Treatment Period
(Day 1 - until a discontinuation criterion is met)
Visits at Weeks 3, 5, then every 4 weeks
Tumor Assessment will be done every 8 weeks (+/-
7 days) and measurement of 
HBV viral levels (for subjects with HBV) 
to be done per Institution SOC
End of Treatment
Visit (within 7 days after 
last dose)
Follow-up Period
(Approx.30-days after last 
dose of study drug, 
then q30 days to 
collect information 
on survival and subsequent 
therapies)
Abbreviations: HBV= hepatitis B virus, q = every, SOC = standard of care


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Assessments
Screen
Treatment Period
Unscheduled
Visit
Follow-up Period
Study Week/Visit
-3 
to -1
1
3
5
9
13
17 + Q4 Weeks
EOT
30D FU1
Long Term 
FU1
Study Day
-21 
to -1
1
15
29
57
85
113+
N/A
≤ 7D after 
last dose
30D after last 
dose
Q30 days
Window (days)
N/A
0
+/-3
+/-3
+/-3
+/-3
+/-3
N/A
N/A
+10
+10
Informed Consent
X
Inclusion/Exclusion Criteria
X
X
Return and/or Dispense of study drug
X
X
X
X
X
X
X [OPT]
X
Concomitant Medications2
X
X
X
X
X
X
X
X
X
X
Demographics, Medical and Disease 
History 
X
BCLC Staging
X
Child-Pugh Classification
X
HBV/HCV Status3
X
Tumor Assessment4
X
To be performed Q8Weeks (+/- 7 D) From Day 1
X [OPT]
Height
X
Weight
X
X
X
X
X
X
X [OPT]
X
Vital Signs
X
X
X
X
X
X
X
X [OPT]
X
Adverse Events5
X
X
X
X
X
X
X
X
X
X
Clinical Laboratory Tests6
X6
X7
X
X
X
X
X
X [OPT]
X
Urine Pregnancy Test9
X
X
X
X
X
X
X [OPT]
X
Physical Examination
X
X
X
X
X
X
X
X [OPT]
X
12-Lead ECG
X
X
X [OPT]
X
ECOG PS
X
X
X
X
X
X
X
X [OPT]
X
Alpha-fetoprotein
X
X6
   X
   X
   X
   X
   X
     X [OPT]
X
HBV Viral Levels (if applicable)
X
To be done per SOC or as clinically indicated
Pharmacokinetic Sample10
X
X
X
X [OPT]
 
X
X
Tumor Tissue Collection12
X
Blood Samples for PGx Biobanking 
(optional)
X
Survival and Subsequent Treatment
X
X
X
X
X
X
X
Footnotes appear on next page
Abbreviations: BCLC = Barcelona Clinic Liver Cancer, D = day(s), ECG = electrocardiogram, ECOG PS = Eastern Cooperative Oncology Group Performance


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Status, EOT = end of treatment, FSH = follicle-stimulating hormone, FU = follow-up, HBV = hepatitis B virus, HCV = hepatitis C virus, N/A = not applicable,
OPT = optional, PGx = pharmacogenomics, Q = every, SOC = standard of care
1. Phone call may be conducted if subject is unable to travel. Long-term follow-up will occur for up to 2 years, until death or subject withdraws consent or final
analysis.
2. Medications taken within 14 days before the Screening visit and up to the 30-day Follow-up Visit will be collected.
3. HBV/HCV status will be assessed at Screening. HBV should be assessed using an assay for hepatitis B surface antigen. HCV testing should be performed
using an antiHCV antibody assay (enzyme immunoassay [EIA] or enhanced chemiluminescence immunoassay [CIA]).
4. Computed tomography (CT)/magnetic resonance imaging (MRI) of the chest/abdomen/pelvis as well as any other anatomical region appropriate for the
subject’s disease must be performed within 28 days prior to day 1. Results from CT/MRI assessments performed prior to consent and within 28 days of day 1
may be used for Screening if available. Subsequent scans will be done every 8 weeks (+/- 7days) from Day 1 until treatment discontinuation criterion is met. To ensure
comparability, the Screening and subsequent assessment should be performed using identical techniques.
5. Adverse events will be collected from the time of informed consent through the 30-day Follow-up Visit or through the day prior to the initiation of new
antineoplastic treatment or investigational agent, or whichever comes first.
6. Clinical laboratory assessments include hematology, chemistry, coagulation, viral load (if applicable), pregnancy and urinalysis (urine dipstick). Lab
parameters to be analyzed are listed under Appendix 12.8 Laboratory Assessments.
7. FSH testing is also required for postmenopausal women who are < 55 years of age at Screening.
8. Day 1 clinical laboratory tests do not need to be repeated if Screening labs were performed within 7 days prior to Day 1.
9. Urine pregnancy test will be performed in women of childbearing potential. Testing at treatment visits must occur prior to study drug administration.
10. Pharmacokinetic samples will be collected prior to dosing. Subjects will be instructed to record on a diary the date and time that study drug was taken on the
2 days before the visit and not to take study drug until after the pharmacokinetic sample is collected. The date and time that the subject took the previous
2 doses of study drug should be recorded, even if the most recent dose was inadvertently taken earlier the same day.
11. 
12. Subject has available formalin-fixed, paraffin-embedded tumor specimen with adequate viable tumor cells in a tissue
block  or unstained serial slides accompanied by an associated pathology report prior to enrollment. Archival or
fresh biopsy tissue is  required. Ensure that subject meets all other study entry criteria prior to performing a biopsy (as applicable).
13


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3
STUDY OBJECTIVE(S) AND DESIGN
3.1
Study Objective(s)
3.1.1
Primary Objective
To evaluate the efficacy of enzalutamide as compared to placebo in subjects with advanced 
hepatocellular carcinoma (HCC), as measured by overall survival (OS).
3.1.2
Secondary Objectives
●
To evaluate Progression Free Survival (PFS) of enzalutamide as compared to placebo in 
subjects with advanced HCC.
●
To evaluate the safety of enzalutamide in subjects with advanced HCC.
●
To evaluate the pharmacokinetics (PK) of enzalutamide and the active metabolite N-
desmethyl enzalutamide in subjects with advanced HCC.
3.1.3
Exploratory Objectives
●
 
 
 
 
3.2
Study Design
This is a multicenter, randomized, double-blind, placebo-controlled phase 2 study evaluating 
the efficacy, safety, and tolerability of enzalutamide monotherapy in approximately 
144 subjects in Europe, Asia and North America with HCC of any etiology who have 
progressed on or were intolerant to sorafenib or other anti-VEGF therapy in the advanced 
setting. Each region will have no more than 70% of overall subjects enrolled. Enrollment may 
be limited by the sponsor in any region or country in order to have representation of the patient 
populations from all 3 regions as there may be a difference in responses to treatment or 
tolerability.
The study will consist of a Screening Period, Treatment Period and a Follow-up Period.  
Eligible subjects will be stratified by geographic region (Asia versus other) and Eastern 
Cooperative Oncology Group (ECOG) performance status (0 versus 1) and randomized in a 
2:1 ratio to receive enzalutamide 160 mg/day or placebo until disease progression, 
unacceptable toxicity, or any other discontinuation criterion is met. Study evaluations will 
occur as specified in the Schedule of Assessments. 
An end of treatment visit will be performed within 7 days of the last dose of study drug.  
Upon discontinuation of treatment for any reason, subjects will enter the follow-up period. A 


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follow-up visit will be performed approximately 30 days after the last dose of study drug.  
All Adverse Events (AEs) that occur during the safety reporting period (from the first dose of 
study drug through 30 days after the last dose of study drug or initiation of a new 
antineoplastic or new investigational agent, whichever occurs first) are to be followed up 
until resolved or judged to be no longer clinically significant, or until they become chronic to 
the extent that they can be fully characterized. This may be performed by telephone if 
applicable. Long-term follow-up visits will be conducted every 30 days for up to 2 years to 
collect information on survival and subsequent therapies. 
During the study, study drug treatment may be interrupted for individual subjects who 
experience a National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE) Grade ≥ 3 AE that is attributed to the study drug and cannot be ameliorated 
with appropriate medical intervention. Study drug may be resumed at the original dose 
(160 mg/day) or at a reduced dose (120 mg/day or 80 mg/day), after discussion with and 
approval by the Medical Monitor. Treatment interruption for > 2 weeks must also be 
discussed with the Medical Monitor.  
There will be an initial safety review of the first 21 subjects. After the 21st randomized 
subject has been treated for 28 days or discontinued from the study (whichever occurs first), 
unblinded safety data will be evaluated by an independent Data Safety Monitoring Board 
(DSMB). Emerging safety issues may lead to a decision to change the dose, implement 
additional safety steps or assessments or terminate the study. Further safety review and 
details on the process and methods of the safety data review will be provided in the DSMB 
Charter.
3.3
Randomization
Subjects who meet the inclusion/exclusion criteria will be randomly assigned to receive 
enzalutamide or placebo using a 2:1 randomization schedule, with two-third of the subjects 
being randomized to the enzalutamide treatment group and the other one-third of the subjects 
being randomized to the placebo group. Subjects randomization will be stratified by two 
primary regions (Asia versus Other), and ECOG performace status (0 versus 1).
Randomization will be performed via an Interactive Response Technology (IRT).
4
SAMPLE SIZE
This sample size was primarily determined to provide sufficient clinical experience to 
support the design of later-stage clinical development, such as phase 3 studies.
Sample size calculations were performed using EAST 5 software based on the following 
assumptions: 
●
2:1 randomization for enzalutamide vs placebo.
●
Median OS for placebo and enzalutamide are 7.0 months and 10.77 months (Hazard 
Ratio=0.65), respectively.
●
A study enrollment period of 18 months and a total study duration of 27 months.


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With 109 death events, the study can achieve 80% power to detect a statistically significant 
difference using 1-sided log-rank test with 10% level of significance. Assuming no loss to 
follow-up, approximately 144 subjects are needed to reach this number of events. 
5
ANALYSIS SETS
In accordance with International Conference on Harmonization (ICH) recommendations in 
guidelines E3 and E9, the following analysis sets will be used for the analyses.
Detailed criteria for analysis sets will be laid out in Classification Specifications (CS) and the 
allocation of subjects to analysis sets will be determined prior to database hard lock.
5.1
Full Analysis Set (FAS)
The full analysis set will consist of all randomized subjects, regardless of whether or not 
subjects received study drug. This will be the primary analysis set for efficacy analyses.
5.2
Safety Analysis Set (SAF)
The Safety Analysis Set (SAF) consists of all subjects who have received at least 1 or partial 
capsule of study drug.
The SAF will be used for the statistical summary of the safety data.
5.3
Pharmacokinetics Analysis Set (PKAS)
The pharmacokinetic analysis set (PKAS) consists of the subset of the SAF population for 
which at least one quantifiable enzalutamide or N-desmethyl enzalutamide concentration 
value is available. Any formal definitions for exclusion of subjects or time-points from the 
PKAS will be documented in the Classification Specifications. Additional subjects may be 
excluded from the PKAS at the discretion of the pharmacokineticist. Details will be reported 
in the CSR.
The PKAS is used for all tables and graphical summaries of the PK data.
5.4
Pharmacodynamic Analysis Set (PDAS)
The pharmacodynamic analysis set (PDAS) will include the subjects from the SAF 
population for whom sufficient pharmacodynamic measurements (a baseline and at least one 
post-baseline sample) were collected.
Any formal definitions for exclusion of subjects from the PDAS will be documented in the 
Classification Specifications.
The PDAS will be used for all analyses of pharmacodynamic data.


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6
ANALYSIS VARIABLES
6.1
Efficacy Endpoints
6.1.1
Primary Efficacy Endpoint(s)
6.1.1.1 Primary Analysis
The primary endpoint, overall survival (OS) will be defined as the time from the date of 
randomization until the documented date of death from any cause. For detailed information 
for definition, please refer to Appendix 10.1  
The null hypothesis is that OS distributions of the 2 arms are equivalent. The alternative 
hypothesis is that OS is prolonged in enzalutamide arm. The null hypothesis will be tested 
using a stratified one-sided log-rank test at the 0.10 level (stratified by geographic regions 
[Asia versus Other] and ECOG performance status [0 versus 1]). The hazard ratio of the 
treatment effect along with two-sided 95% confidence interval will also be calculated using a 
Cox proportional hazard model, stratified by geographic regions and ECOG performance 
status. In addition, an 80% two-sided confidence interval will also be provided to correspond 
to the 0.1 one-sided alpha level for the primary analysis.
Time to death for a given subject will be defined as the number of days from the date that the 
subject was randomized to the date of the subject’s death. The primary analysis is triggered 
by the occurrence of the 109th event. All events of death will be included, regardless of 
whether the event occurred while the subject was still taking study drug, or after the subject 
discontinued study drug. If a subject has not died, then the data will be censored at the date 
when the subject was last known to be alive or at the data cutoff date, whichever occurs first.
6.1.1.2 Secondary Analysis
Sensitivity analysis on OS will be done using the unstratified analysis.  
6.1.1.3 Subgroup Analysis
The same analysis of the primary endpoint as described in 6.1.1.1 will be conducted using the
subgroups of AR (defined as Ventana Total AR Nuclear) patients and other subgroups such 
as age, gender, geographic region, ECOG status, hepatitis medical history, HepB surface 
antigen and HCV antibody. Please refer to section 7.8 for details of subgroups of interest.
6.1.2
Secondary Efficacy Endpoints
The Secondary efficacy analyses comparing the effects of Enzalutamide versus placebo will 
also be performed on progression-free survival (PFS). PFS is defined as the time from the 
date of randomization until the date of disease progression per RECIST 1.1 or death from any 
cause on study, whichever occurs first. For detailed information for censoring rules, please 
refer to Appendix 10.1
6.1.3
Other Efficacy Variables
 


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●
 
 
 
  
 
 
6.2
Safety Variables
Safety will be assessed by evaluation of the following variables:
●
Treatment-emergent adverse events (TEAEs); frequency of TEAEs by system organ 
class, preferred term, NCI CTCAE grade, frequency of treatment discontinuations due to 
AEs, severity, and relationship to study drug.
●
Clinical laboratory variables (hematology, biochemistry including liver function tests, 
coagulation parameters and urinalysis, viral load, and pregnancy test).
●
Vital signs (systolic and diastolic blood pressure and pulse rate) and body weight.
●
12-lead electrocardiogram (ECG).
6.2.1
Adverse Events
TEAE is defined as an adverse event observed during the treatment emergent period, which is 
from the first dose date of enzalutamide to 30 days after the last dose date of enzalutamide or 
the start of subsequent treatment, whichever is first. If the adverse event occurs on Day 1 and 
the onset check box is marked “Onset after first dose of study drug” or the onset check box is 
left blank, then the adverse event will be considered treatment emergent. If the adverse event 
occurs on Day 1 and the onset check box is marked “Onset before first dose of study drug”, 
then the adverse event will not be considered treatment emergent.
A drug-related TEAE is defined as any TEAE with at least possible relationship to study 
treatment as assessed by the investigator or with missing assessment of the causal 
relationship.
6.2.2
Laboratory Assessments
Routine laboratory samples for hematology, biochemistry, coagulation, viral load (if 
applicable), pregnancy and urinalysis will be collected and analyzed at the Institution’s local 
laboratory. The local laboratory must be accredited to perform the protocol required tests and 
a certificate of accreditation and laboratory normal ranges must be provided to the Sponsor.
6.2.3
Vital Signs
Vital signs will include systolic and diastolic blood pressure (mmHg), radial pulse (beats/min) 
and temperature.


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Change from baseline, defined as the post-baseline value minus the baseline value will be 
calculated for each assessment. 
6.2.4
Electrocardiogram (ECG)
A 12-lead ECG will be performed  and parameters that include heart rate, PR interval, RR 
interval, QRS interval, QT interval will be collected. 
Abnormalities and clinical significance as judged by the Investigator will be reported as well. 
6.2.5
Other Safety-Related Observations
6.2.5.1 ECOG
ECOG performance status data are collected according to Schedule of Assessment.
6.3
Pharmacokinetic Variables
Pharmacokinetic variables include pre-dose plasma concentrations of enzalutamide, its active 
metabolite N-desmethyl enzalutamide, and sum of enzalutamide plus N-desmethyl 
enzalutamide.
6.4
 
 
6.5
Other Variables
6.5.1
Previous and Concomitant Treatment
Previous medication is defined as a medication with at least one dose taken before the date of 
first dose of study drug. Concomitant medication is defined as a medication with at least one 
dose taken after the date of first dose (inclusive). According to the protocol, concomitant 
medications were to be recorded up to the 30-Day Follow-up visit.
6.5.2
7
STATISTICAL METHODOLOGY
7.1
General Considerations
In general, all data will be summarized with descriptive statistics (number of subjects, mean, 
median, standard deviation (SD), minimum, and maximum) for continuous endpoints, and 
frequency and percentage for categorical endpoints.


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For continuous variables, descriptive statistics will include the number of subjects (n), mean, 
standard deviation, median, minimum and maximum. When needed, the use of other 
percentiles (e.g.10%, 25%, 75% and 90%) will be mentioned in the relevant section. 
Frequencies and percentages will be displayed for categorical data. Percentages by categories 
will be based on the number of subjects with no missing data, i.e. will add up to 100%.
For time to events variables (OS, PFS and 
), descriptive statistics will include the number 
of subjects (n), the number of events, the number of censored subjects, median time and 95% 
CI. Kaplan-Meier plots will also be generated.
Summaries based on FAS (e.g. baseline and efficacy data) will be presented, unless 
specifically stated otherwise. Safety analysis and other summaries based on SAF will be 
presented.
All data processing, summarization, and analyses will be performed using SAS® Version 9.3
or higher on Unix. Specifications for table, figures, and data listing formats can be found in 
the TLF specifications for this study.
7.2
Study Population
7.2.1
Disposition of Subjects
Number and percentage of subjects with informed consent, enrolled, discontinued before 
enrollment will be presented for all subjects.
The following subject data will be presented for the All Randomized Subjects:
●
Number and percentage of subjects in each analysis set;
●
Number and percentage of subjects discontinued treatment, by primary reason for 
treatment discontinuation;
●
Number and percentage of subjects discontinued study, by primary reason for study
discontinuation;
●
Number and percentage of subjects completed the study. 
7.2.2
Protocol Deviations
Protocol deviations as defined in the study protocol (Section 7.8 Protocol Deviations and 
Other Analyses) will be assessed for the FAS. The number and percentage of subjects 
meeting any criteria will be summarized for each criterion and overall as well as by study site. 
Subjects deviating from a criterion more than once will be counted once for the 
corresponding criterion. Any subjects who have more than one protocol deviation will be 
counted once in the overall summary. A data listing will be provided by site and subject.
The protocol deviation (PD) criteria will be uniquely identified in the summary table and 
listing. The unique identifiers will be as follows:
PD1 - Entered into the study even though they did not satisfy entry criteria,
PD2 - Developed withdrawal criteria during the study and was not withdrawn,
PD3 - Received wrong treatment or incorrect dose,


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PD4 - Received excluded concomitant treatment. 
7.2.3
Demographic and Other Baseline Characteristics
Number and percentage of subjects enrolled in each country and site will be presented  for 
the FAS.
For demographics table, descriptive statistics for age, sex, race, ethinicity, weight, body mass 
index (BMI), height, and history of smoking and alcohol use at study entry will be presented
by treatment group. Frequency tabulations for ethnicity, age group and race will be presented
by treatment group. This will be done for the SAF and FAS populations. Descriptive statistics 
will include number of subjects, mean, standard deviation, minimum, median and maximum 
for continuous endpoints, and frequency and percentage for categorical endpoints.
For disease history table, descriptive statistics for time from initial diagnostic will be 
presented by treatment group. Frequency tabulations for histopathology at diagnosis, 
histologic grade, anatomic staging/prognostic category at initial diagnosis, primary tumor 
stage, regional lymph node stage, distant metastasis, Barcelona Clinic Liver Cancer (BCLC) 
stage at screening will be presented by treatment group. Disease history will be summarized 
by descriptive statistics for the FAS.
HCC etiology factors, presence/absence of cirrhosis, prior systemic treatment for HCC with 
sorahenib or other anti-VEGF therapy, confirmed disease progression or discontinuation of 
sorafenib due to intolerance, child-pugh scoring, and HBV/HCV status will be summarized 
by treatment group for the FAS.
Medical history is coded in MedDRA, and will be summarized by System Organ Class 
(SOC) and Preferred Term (PT) as well as by PT alone, for the SAF.
7.2.4
Previous and Concomitant Medications
Previous medications are coded with WHO-DD, and will be summarized by therapeutic 
subgroup (ATC 2nd level) and chemical subgroup (ATC 4th level) and preferred WHO name 
for the SAF. Prior HCC treatment will also be summarized for the FAS.
As with previous medication, concomitant medication are coded with WHO-DD, and will be 
summarized by therapeutic subgroup (ATC 2nd level) and chemical subgroup (ATC 4th 
level) and preferred WHO name for the SAF. Subjects taking the same medication multiple 
times will be counted once per medication and investigational period. A medication which 
can be classified into several chemical and/or therapeutic subgroups is presented in all 
chemical and therapeutic subgroups.
7.3
Study Drugs
7.3.1
Exposure
The following information on drug exposure will be presented for the SAF:
●
Descriptive statistics for cumulative amount of the drug a subject was exposed to and 
average daily dose; and
●
Number and percent of subjects with dose increase, decreases or interruptions.


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Duration of exposure (defined in days as the date of last dosing - the date of first dosing + 1) 
will be summarized in two ways.
●
Descriptive statistics will be presented.
●
Exposure time will be categorized according to the following categories by study drug:

less than 3 months

at least 3 months and less than 6 months

at least 6 months
Counts and percentages of subjects in each of these categories will be summarized for the 
SAF.
7.3.2
Treatment Compliance
Overall compliance with the dosing schedule will be examined for subjects in the SAF whose 
total study drug count and first and last days of treatment are known.
Percent overall compliance (defined as the percentage of the total study drug taken over total 
planned study drug doses) for Enzalutamide and placebo will be summarized in two ways for 
the SAF:
●
Descriptive statistics will be presented by study drug.
●
Percent compliance will be categorized according to the following categories by study 
drug:

less than 80%

at least 80%, less or equal to 90%

at least 90%, less or equal to 100%

greater than 100%
7.4
Analysis of Efficacy 
All efficacy analysis will be performed using the FAS unless otherwise stated.
7.4.1
Analysis of Primary Endpoint(s)
The primary endpoint, OS will be defined as the time from the date of randomization until the 
documented date of death from any cause. Subjects who are still alive at the time of the data 
cutoff date will be censored on the last date known to be alive or at the data cutoff date, 
whichever occurs first.  
The null hypothesis is that OS distributions of the 2 arms are equivalent. The alternative 
hypothesis is that OS is prolonged in enzalutamide arm. 
The null hypothesis will be tested using a stratified one-sided log-rank test at the 0.10 level 
(stratified by geographic region and ECOG performance status). The hazard ratio of the 
treatment effect along with two-sided 95% CI will also be calculated using a Cox 
proportional hazard model, stratified by geographic region and ECOG performance status. In 
addition, an 80% two-sided confidence interval will also be provided to correspond to the 0.1 
one-sided alpha level for the primary analysis. Unstratified analysis will be performed too as 
sensitivity analysis. 


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A sensitivity analysis same as primary analysis but for subjects randomized and treated will 
be performed if needed, depending on number of patients randomized and not treated, this
analysis will be decided at the Final Data Review meeting if needed. 
7.4.2
Analysis of Secondary Endpoints
Similar analysis of the primary endpoint as described in Section 7.4.1 will also be conducted 
on the secondary endpoint PFS.
PFS is defined as the time from the date of randomization until the date of disease 
progression (radiographic progression) per RECIST 1.1, or death from any cause on study, 
whichever occurs first. 
The following subjects will be censored at the date of the last radiological assessment
showing no progression: 
1) subjects who initiated another anti-tumor therapy before documented PD or death, 
2) subjects who progressed or died after missing two or more consecutive radiological 
assessments. 
Subjects are considered to have missed two or more consecutive radiological assessments if 
duration between two consecutive imaging scans are more than 20 weeks while on treatment.  
Subjects who have no valid post-baseline tumor assessment will be censored at day 1.
The distribution of PFS will be estimated for each treatment group using Kaplan-Meier 
methodology and compared between the Enzalutamide and placebo treatment groups using 
the stratified log-rank test. Stratification will be done by the regions (Asia versus Other) and 
ECOG performance status (0 versus 1). Additionally, unstratified analysis will be performed 
as well. 
A sensitivity analysis for subjects randomized and treated will be performed if needed, 
depending on number of patients randomized and not treated, this will be decided at the Final 
Data Review if this analysis is needed or not. 
A sensitivity analysis will be done if needed with similar PFS definition, and the initiation of 
another anti-tumor therapy will be considered as an event, and evidence of progression could 
come from two sources: radiographical or clinical. This sensitivity analysis will be performed 
only if further investigation is needed.
7.4.3
Analysis of Exploratory Endpoints
 
 
 
 


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.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
●
 
 
 


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7.5
Analysis of Safety
Safety will be assessed on an ongoing basis by physical examination, measurement of vital 
signs, laboratory assessments, 12-lead ECGs, and evaluation of TEAEs/serious TEAEs.
Safety analyses will be conducted using the SAF. The SAF is defined as all subjects who 
have initiated at least 1 or partial capsule of study drug. The treatment emergent period will 
be defined as the period of time from the first dose date of study drug to 30 days after the last 
dose date of study drug or the start of subsequent treatment (whichever is first). Only data 
within this period will be summarized in safety analysis. Safety will be assessed through 
descriptive statistics for the frequency of adverse events by system organ class (SOC), 
preferred term (PT), and NCI CTCAE grade, the frequency of treatment discontinuations due 
to adverse events, vital signs, ECG, and laboratory evaluations.
All safety summaries will be provided using the SAF population.
7.5.1
Adverse Events
The severity of all adverse events is to be evaluated by the Investigator based on the NCI
CTCAE, version 4.03. All adverse events will be coded to preferred term and system organ 
class using Medical Dictionary for Regulatory Activities (MedDRA). The number and 
percentage of subjects with treatment emergent adverse events will be presented by MedDRA 
system organ class and preferred term, relationship to study treatment, and NCI CTCAE 
grade. A subject reporting the same adverse event more than once is counted once and at the 
maximum severity or strongest relationship to study drug treatment, when calculating 
incidence.
The coding dictionary for this study will be MedDRA. It will be used to summarize AEs by 
SOC and PT.
An overview table will include the following details:
●
Number of TEAEs,
●
Number and percentage of subjects with TEAEs,
●
Number of drug related TEAEs,
●
Number and percentage of subjects with drug related TEAEs,
●
Number of serious TEAEs,
●
Number and percentage of subjects with serious TEAEs,
●
Number of serious drug related TEAEs,
●
Number and percentage of subjects with serious drug related TEAEs,
●
Number of TEAEs leading to withdrawl of treatment,
●
Number and percentage of subjects with TEAEs leading to withdrawl of treatment, 
●
Number of drug related TEAEs leading to withdrawl of treatment,


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●
Number and percentage of subjects with drug related TEAEs leading to withdrawl of 
treatment, 
●
Number of TEAEs leading to death,
●
Number and percentage of subjects with TEAEs leading to death, 
●
Number of drug related TEAEs leading to death,
●
Number and percentage of subjects with drug related TEAEs leading to death, and
●
Number and percentage of subjects with death.
The number and percentage of subjects with TEAEs, as classified by SOC and PT will be 
summarized. Summaries will be provided for:
●
TEAEs
●
drug related TEAEs,
●
serious TEAEs, 
●
grade 3 or higher TEAEs.
●
drug related serious TEAEs,
●
TEAEs leading to withdrawl of treatment,
●
drug related TEAEs leading to withdrawal of treatment,
TEAEs and the number and percentage of subjects with TEAEs, as classified by SOC and PT 
will also be summarized by grade and by relationship to study drug. If an adverse event 
changes in grade or relationship, then the subject will be counted only once with the 
maximum grade and highest degree of relationship. The adverse event however will be 
presented in each category they were classified to. If a subject has an event more than once 
with missing grade/relationship and with non-missing grade/relationship, then the subject 
will be counted as missing grade/relationship. Drug related TEAEs will be presented in a 
similar way by grade only.
The Always Serious Terms List is a list of AEs that a Sponsor determines regardless of 
Investigator assessment are to be captured as serious. Serious TEAEs table will include both 
investigator reported and Astellas upgraded ones according to Always Serious Terms List. In 
the listing they will be presented with different flag.
7.5.2
Clinical Laboratory Evaluation
For each quantitative laboratory parameter, summary statistics of change from baseline value 
by visit will be presented. The baseline laboratory value is defined as the last laboratory 
value collected on or prior to the first dose date of study drug.
Using the definitions provided in the NCI CTCAE, lab values will be classified as Grade 0 
through 4, where possible. For each lab parameter at each scheduled collection time point, 
the number and percentage of subjects who have lab values within the categories defined by 
each of the grades will be displayed. If a subject has multiple lab values that fall into more 
than one NCI CTCAE grade, the highest NCI CTCAE grade will be displayed for that 
subject. In the event the NCI CTCAE grade is listed as > ULN or < LLN, standard laboratory 
normal values will be used for the purposes of comparison. These values are maintained by 


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the Data Management group using the New England Journal of Medicine SI Unit Conversion 
Guide as a reference.
It is acknowledged that data summaries based upon the standard normal laboratories may 
result in observations falling into different NCI CTCAE/normal/abnormal categories than 
those that the treating physician reports.
Shift tables will be created for each of the lab parameters after classifying by NCI CTCAE 
criteria. Shift from baseline to the highest NCI CTCAE grade will be presented. 
Lab abnormalities will also be summarized by CTCAE Grade with number and percent, by 
visit and overall during the study.
Shift table for highest CTCAE grade urinalysis and urinalysis by CTCAE will not be 
provided.
Summary shifts of reference range changes from baseline to each treatment visit will be 
presented.
7.5.2.1 Liver Function Tests 
The number and percentage of subjects with potentially clinically significant values in liver 
function tests will be presented.
For LFT changes, study drug dosing should be interrupted if a subject experiences clinically 
significant liver toxicity related to study drug (≥ Baseline + 4 x ULN to < 20 x ULN for AST 
and ALT; grade 3 total bilirubin [TBL]). Clinically significant values in liver function tests 
leading to interrup dosing will be summarized.
7.5.3
Vital Signs
Vital signs (systolic blood pressure, diastolic blood pressure, body temperature, weight and 
pulse rate) will be summarized using n, mean, standard deviation, minimum, maximum and 
median by visit. Additionally, a within-subject change will be calculated as the post-baseline 
measurement minus the baseline measurement and summarized by visit.
The number and proportion fo patiensts experiencing potentially clinically significant 
abnormalities during the treatment-emergent period will be summarized. The definition of 
potentially clinically significant abnormalities are provided in the Table below.


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Parameter
Criteria for Potentially Clinically Significant Abnormalities
Systolic blood pressure
Absolute result > 180 mm Hg and increase from baseline > 40 mm Hg
Absolute result < 90 mm Hg and decrease from baseline > 30 mm Hg
Final visit or 2 consecutive visits results ≥20 mm Hg change from baseline
Most extreme postbaseline result ≥140 mm Hg
Most extreme postbaseline result ≥180 mm Hg
Most extreme result ≥180 mm Hg and ≥20 mm Hg change from baseline
Most extreme result ≥140 mm Hg and ≥20 mm Hg change from baseline
Diastolic blood pressure
Absolute result > 105 mm Hg and increase from baseline >30 mm Hg
Absolute result < 50 mm Hg and decrease from baseline >20 mm Hg
Final visit or 2 consecutive visits results ≥15 mm Hg change from baseline
Most extreme post-baseline result ≥90 mm Hg
Most extreme post-baseline result ≥105 mm Hg
Most extreme result ≥105 mm Hg and ≥15 mm Hg change from baseline
Most extreme result ≥90 mm Hg and ≥15 mm Hg change from baseline
Heart Rate
Absolute result >120 bpm and increase from baseline >30 bpm
Absolute result < 50 bpm and decrease from baseline >20 bpm
bpm, beats per minute; mm Hg, millimeters of mercury.
7.5.4
Electrocardiograms (ECGs)
Number and percent of subjects with normal, not clinically significant abnormal, and 
clinically significant abnormal results for the 12-lead ECG will be summarized by treatment 
group and time point.
Continuous ECG parameters, such as heart rate, PR, QRS, QT and RR, will be summarized 
by treatment group and time point.
7.5.5
Other Safety-Related Observations
7.5.5.1 ECOG
Summary statistics and the shift table for ECOG from baseline to post-baseline visits will be 
provided by treatment group.
7.6
Analysis of Pharmacokinetics
Pharmacokinetic analyses will be conducted using the PKAS.
Individual and summary tables of plasma concentration of enzalutamide and N-desmethyl 
enzalutamide and a listing of blood collection times and concentrations will be provided. 
Summary statistics will be provided including n, mean, standard deviation (SD), geometric 
mean, minimum, median, maximum, and %CV. Values below the lower limit of 
quantification (BLOQ) will be set to not be calculated if all values are BLOQ. In cases where 


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more than half of the individual data in a group are BLOQ, SD and %CV will not be 
calculated. If one or more values are BLOQ, the geometric mean will not be calculated.
Additional model-based analyses may be performed and will be described in a separate 
population PK analysis plan.
For analysis of PK data, only samples for which the time of sampling relative to the dose and 
the exact dose is known will be included.
7.7
 
 
 
 
 
 
 
 
 
 
 
7.8
Subgroups of Interest
The same analysis of the primary endpoint as described in Section 7.4.1 will be conducted 
separately, using the following subgroups:
●
Region (Asia vs Other)
●
Baseline ECOG status (0 vs 1)
●
AR, defined as Ventana Total AR Nuclear %, (<10% ; AR>=10% ;  AR>=30% ; 
AR>=50%;  AR>=80%)
●
Age (<65 vs >=65)
●
Gender (Male vs Female)
●
Number of prior lines (1; >=2)
●
Alpha fetoprotein (<= 400 ug/L ; >400 ug/L) at baseline
●
Medical history (HBV, HCV, or non-viral)


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●
HepB surface antigen (positive, negative)
●
HCV antibody (positive, negative)
●
Patients with medical history of HBV (HBV positive) , examine AR <10% and 
>=10%
●
Patients with medical history of HCV (HCV positive) , examine AR <10% and 
>=10%
Results will be presented as forest plots.  
7.9
Interim Analysis (and Early Discontinuation of the Clinical Study)
There is no planned interim analysis; however, unblinded safety data will be evaluated by an
independent DSMB. Further safety reviews and details on the process and methods of the 
safety data review will be provided in the DSMB Charter.
7.10
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information
As a general principle, no imputation of missing data will be done. Exceptions are the start and 
stop dates of AEs and concomitant medication. The imputed dates will be used to allocate the 
concomitant medication and AEs to a treatment period, in addition to determining whether an 
AE is/is not treatment emergent. Listings of the AEs and concomitant medications will present 
the actual partial dates; imputed dates will not be shown.
7.10.1
Missing Data
Subjects who do not satisfy the criteria to be counted as responders or have insufficient data 
to determine or confirm a response per the RECIST 1.1 Criteria will be considered as 
non-responders in the primary final analysis of response rates. No imputation of data will be 
done to determine individual subject response.
For continuous variables (e.g., clinical laboratory measurement, vital signs), subjects with 
missing baseline variable will be excluded from the analysis of change from baseline.
Visit-by-visit analyses of data will exclude subjects who did not provide data at the visit in 
question. For visit by visit summary of ECOG, no imputation will be made.
Adverse events with missing grade will be displayed as “Missing”, no imputation will be 
made.
For all analyses other than PK analysis, all values will be included in the analyses. 
7.10.2
Missing Dates
As a general rule, the worst case scenario imputation rule is used. Completely missing dates 
will not be imputed.
To calculate Time from initial diagnosis, 1st day of the Month will be used when Month and 
Year are available; and 1st of January will be used if only Year is available, as defined below.


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Reported Date (from the eCRF)
Analysis Date (Derived)
--/MM/YYYY
01/MM/YYYY
--/--/YYYY 
01/01/YYYY
DD/--/----, or
--/MM/----, or
--/--/----
No imputation 
7.10.3
Outliers
All values will be included in the analyses.
7.10.4
Visit Windows
Labs, vital signs, weight, PE, urine preganancy test and ECG will be analyzed based on the 
following visit window.
Visit (study day)
Lab, Vital signs, PE
Weight, Urine Pregnancy Test
ECG
Baseline (1)
<= 1
<= 1
<= 1
Week 3 (15)
>=2 – <22
NA
NA
Week 5 (29)
>=22 – < 43
>=22 – < 43
NA
Week 9 (57)
>=43 – <71
>=43 – <71
NA
Week 13 (85)
>=71 – <99
>=71 – <99
CRF visit
Week 17 (113)
>=99 – <127
>=99 – <127
NA
Week 21 (141)
>=127 – <155
>=127 – <155
NA
Week 25 (169)
>=155 – <183
>=155 – <183
NA
Week 29 (197)
>=183 – <211
>=183 – <211
NA
Week 33 (225)
>=211 – <239
>=211 – <239
NA
Week x (7*x -6) (x is 
every 4 weeks after 
week 5)
>=7*x-20 – <7*x+8
>=7*x-20 – <7*x+8
NA
Final
Last Value within 7 
days of last dose of 
study drug
Last Value within 7 days of last 
dose of study drug
Last Value 
within 7 days 
of last dose of 
study drug


Sponsor: Astellas Pharma Inc.
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Page 30 of 35
8
DOCUMENT REVISION HISTORY
Version
Change
1
Finalized before protocol amendment but never 
signed.
Document was finalized after protocol 
amendment and fully approved on the 
22OCT2015 as verion 2.0 when it should be 
version 1.0.
Additional note to document this has been 
archived in the study TMF.
2
Updated section 7.10.3 visit window.
Footnote of Schedule of Assessment table was 
updated based on protocol v3.0.
Section 7.5.4 was removed.
Added more analysis details to sections 7.6, 7.7 
and 7.8.
Updated section 7.10.1.
 
Added viral /non-viral medical history to 
subgroup analysis section 7.8
Updated the list of Abbreviations.
Added sections 6.2.1, 6.2.2, 6.2.3 and 6.2.4 to 
describe AE, labs, vital signs, and ECG 
respectively.
Added section 6.2.5 for ECOG, and section 6.5 
for previous and concomitant medications.
Used the population “All Randomized Subjects” 
instead of “FAS” to summarize subject 
disposition (section 7.2.1).
Added sensistivity analyses for efficacy 
endpoints when needed (section 7.4).


Sponsor: Astellas Pharma Inc.
SAP Final Version 2.0    07-September-2017
ISN/Protocol 9785-CL-3021
Astellas
Page 31 of 35
Version
Change
 
 
 
Specified the populations for efficacy and safety 
analyses.
Changed to use standard term “withdrawl of 
treatment” instead of “permanent discontinuation 
of study drug” for AE analysis (section 7.5.1).
Added summary shifts to replace shift tables for 
abnormalities by reference range, and updated 
analysis: Shift table for highest CTCAE grade 
urinalysis and urinalysis by CTCAE will not be 
provided (section 7.5.2).
Added the details for LFT changes, study drug 
dosing should be interrupted (section 7.5.2.1).
Added the descriptions for continuous ECG 
parameters (section 7.5.4).
 
 
More subgroups were added for subgroup 
analysis and updated the subgroups categories 
(section 7.8).
Updated the definition for AR+ (section 7.8).
Updated the description for interim analysis 
(section 7.9).
Added section 7.10.2 for the imputation rule to 
calculate the time from initial diagnosis.


Sponsor: Astellas Pharma Inc.
SAP Final Version 2.0    07-September-2017
ISN/Protocol 9785-CL-3021
Astellas
Page 32 of 35
9
REFERENCES
ICH Harmonized Tripartite Guideline E 3. Structure and Content of Clinical Study Reports, 
November 1995. (www.ich.org; Guidelines; "Efficacy" Topics)
ICH Harmonized Tripartite Guideline E 9. Statistical Principles for Clinical Trials, February 1998. 
(www.ich.org; Guidelines; "Efficacy" Topics)
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al.: New Response 
Evaluation Criteria in Solid Tumours: Revised RECIST guideline (Version 1.1). Eur J Cancer. 
2009; 45(2):228-247.


Sponsor: Astellas Pharma Inc.
SAP Final Version 2.0    07-September-2017
ISN/Protocol 9785-CL-3021
Astellas
Page 33 of 35
10
APPENDICES
10.1
Appendix 1: Definition of Efficacy Endpoints
10.1.1
Overall Survival
Overall survival is defined as the time from the date of randomization until the documented 
date of death from any cause.  
Subjects who are still alive at the time of the data cutoff date will be censored on the last date 
known to be alive or at the data cutoff date, whichever occurs first.
10.1.2
Progression-Free Survival
Progression-free survival (PFS) is defined as the time interval from the date of randomization
to the date of disease progression as determined by the investigator using RECIST 1.1 or the 
date of on-study death due to any cause, whichever occurs first. Please refer to section 7.4.2.
Patients who die after receiving the first dose of enzalutamide without postbaseline tumor 
assessments evaluable using RECIST 1.1, will be considered to have a PFS event on the date 
of death.
The censoring rules for the primary and sensitivity analyses of PFS are summarized in the 
following table. The earliest of the following censoring times will be used:
Analysis
Censoring Rules
Date of Censoring
Primary analysis of PFS
No evaluable post-baseline 
imaging assessments, nor 
death
Date of randomization
No radiographical 
progression nor death before 
analysis cutoff date
Date of last radiological 
assessment before analysis 
cutoff date
No radiographical 
progression nor death before 
new HCC treatment
Date of last radiological 
assessment before start of 
new HCC treatment
10.1.3