Clinical trial NCT01650194
Conditions: Metastatic Castration-Resistant Prostate Cancer
Keywords: abiraterone acetate prednisone enzalutamide cancer prostate MDV3100
Sponsor: Astellas Pharma Global Development, Inc.
Start date: 2012-07-09; Completion date: 2018-01-04
Enrollment: 60 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study was to explore the safety and tolerability of enzalutamide in combination with abiraterone acetate plus prednisone. Subjects diagnosed with cancer of the prostate that was getting worse and spreading to the bone despite receiving hormone treatment were enrolled and received study treatment until disease progression.

Detailed description:
For the study duration, all subjects maintained androgen deprivation with a gonadotropin releasing hormone (GnRH) agonist or antagonist or orchiectomy. Study drug was administered until disease progression. Disease progression was defined as a composite endpoint consisting of either clinical deterioration, radiographic progression or prostate-specific antigen (PSA) progression according to the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria.

Arms: arm 1: Participants received enzalutamide combined with abiraterone acetate once daily plus prednisone twice daily.
Interventions: intervention 1: enzalutamide intervention 2: abiraterone acetate intervention 3: prednisone
Intervention descriptions: intervention 1: Participants received 160 mg of enzalutamide orally once daily (4 capsules, 40 mg each). intervention 2: Participants received 1000 mg of abiraterone acetate orally once daily (4 tablets, 250 mg each). intervention 3: Participants received 5 mg of prednisone orally twice daily (2 tablets, 5 mg each).

Protocol documents:
Prot_000.pdf: 
A Phase 2 Study Determining Safety and Tolerability of 
Enzalutamide (Formerly MDV3100) in Combination With 
Abiraterone Acetate in Bone Metastatic Castration-resistant 
Prostate Cancer Patients
ISN/Protocol 9785-CL-0011
ClinicalTrials.gov Identifier: NCT01650194
Date of Protocol Version 3.0: 18 Jun 2014
Sponsor: Astellas Pharma Global Development, Inc
1 Astellas Way
Northbrook, IL 60062


Sponsor: APGD
ISN/Protocol 9785-CL-0011
- CONFIDENTIAL -
18 Jun 2014
Astellas
Page 1 of 98
Version 3.0, Incorporating Substantial Amendment  2
A Phase 2 Study Determining Safety and Tolerability of 
Enzalutamide (formerly MDV3100) in Combination with 
Abiraterone Acetate in Bone Metastatic Castration-Resistant 
Prostate Cancer Patients
Protocol for Phase 2 Study of Enzalutamide
ISN/Protocol 9785-CL-0011
Version 3.0
Incorporating Substantial Amendment 2 [See Attachment 1]
18 June 2014
IND 74,563 
Sponsor:
Astellas Pharma Global Development, Inc. (APGD)
Research & Development 
1 Astellas Way
Northbrook, IL 60062
Protocol History:
Version 1.0 [27Mar2012]
Version 2.0 Incorporating Substantial Amendment 1 [16Jan2013]
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.


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Table of Contents 
I.
SIGNATURES ······················································································ 7
II.
CONTACT DETAILS OF KEY SPONSOR'S PERSONNEL····························· 9
III.
LIST OF ABBREVIATIONS AND KEY TERMS··········································10
List of Abbreviations·····················································································10
List of Key Study Terms·················································································12
IV.
SYNOPSIS··························································································13
V.
FLOW CHART AND SCHEDULE OF ASSESSMENTS·································22
Flow Chart·································································································22
Table 1: Schedule of Assessments······································································23
1
INTRODUCTION·················································································25
1.1
Background ····················································································25
1.1.1
Paracrine Androgen Signaling ·························································25
1.1.2
Androgen Biosynthesis ·································································25
1.2
Non-clinical and Clinical Data ······························································26
1.2.1
Non-clinical Data········································································26
1.2.2
Clinical Data ·············································································27
1.3
Summary of Key Safety Information for Study Drugs ···································28
1.3.1
Enzalutamide·············································································28
Table 2: Summary of Study Drug Exposure, Adverse Events, and Deaths (CRPC2)* ··········29
1.3.2
Abiraterone Acetate·····································································31
1.3.3
Prednisone················································································31
1.4
Risk-Benefit Assessment·····································································32
2
STUDY OBJECTIVE(S), DESIGN AND VARIABLE·····································34
2.1
Study Objectives ··············································································34
2.1.1
Primary Objective ·······································································34
2.1.2
Secondary Objectives ···································································34
2.1.3
Exploratory Objectives ·································································34
2.2
Study Design and Dose Rationale···························································34
2.2.1
Study Design·············································································34
2.2.2
Dose Rationale···········································································35
2.3
Variables ·······················································································36


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2.3.1
Primary Variable ········································································36
2.3.2
Secondary Variables ····································································36
2.3.3
Exploratory Variables···································································36
3
STUDY POPULATION··········································································36
3.1
Selection of Study Population ·······························································36
3.2
Inclusion Criteria··············································································37
3.3
Exclusion Criteria ·············································································38
3.4
Discontinuation Criteria for Individual Subjects ··········································39
4
STUDY DRUGS ···················································································41
4.1
Description of Study Drugs ··································································41
4.1.1
Enzalutamide·············································································41
4.1.2
Abiraterone Acetate·····································································41
4.1.3
Prednisone················································································41
4.2
Packaging and Labeling ······································································41
4.3
Study Drug Handling ·········································································42
4.4
Blinding ························································································43
4.5
Assignment and Allocation ··································································43
4.5.1
Registration ··············································································43
5
TREATMENTS AND EVALUATION························································43
5.1
Dosing and Administration of Study Drugs and Other Medications····················43
5.1.1
Dose/Dose Regimen and Administration Period ····································43
5.1.2
Reduction in Dose or Discontinuation of the Study Drugs·························44
5.1.3
Previous and Concomitant Medication (Drugs and Therapies)····················44
5.1.4
Treatment Compliance··································································47
5.1.5
Emergency Procedures and Management of Overdose ·····························47
5.1.6
Restrictions During the Study··························································47
5.2
Demographics and Baseline Characteristics ···············································47
5.2.1
Demographics············································································47
5.2.2
Medical History··········································································47
5.2.3
Diagnosis of the Target Disease, Severity, and Duration of Disease··············47
5.3
Efficacy Assessment··········································································47
5.3.1
CT/MRI and Bone Scan (Radiographic Assessments)······························47
5.3.2
PSA ·······················································································48


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5.4
Safety Assessment ············································································48
5.4.1
Adverse Events ··········································································48
5.4.1.1
Adverse Events of Possible Hepatic Origin ····································49
5.4.2
Vital Signs················································································49
5.4.3
Laboratory Assessments································································49
5.4.3.1
Abnormal Liver Function Tests··················································49
5.4.4
Physical Examination···································································49
5.4.5
Electrocardiogram (ECG) ······························································50
5.4.6
Imaging ···················································································50
5.4.7
Performance Status······································································50
Table 3:  ECOG Performance Status···································································50
5.5
Adverse Events and Other Safety Aspects ·················································51
5.5.1
Definition of Adverse Events (AEs) ··················································51
5.5.2
Definition of Serious Adverse Events (SAEs) ·······································52
5.5.3
Criteria for Causal Relationship to the Study Drug ·································53
5.5.4
Criteria for Defining the Severity of an Adverse Event ····························54
Table 4:  Criteria for Severity of Adverse Event Terms Not Specified Within NCI-
CTCAE·························································································54
5.5.5
Reporting of Serious Adverse Events (SAEs) ·······································54
5.5.6
Follow-up to Adverse Events ··························································55
5.5.7
Monitoring of Common Serious Adverse Events ···································56
5.5.8
Procedure in Case of Pregnancy·······················································56
5.5.9
Supply of New Information Affecting the Conduct of the Study··················57
5.6
Test Drug Concentration ·····································································57
5.6.1
Optional PK Sample Collection for Enzalutamide and Metabolites 
(MDPC0001 and MDPC0002)·························································57
5.6.2
Optional PK Sample Collection for Abiraterone ····································57
5.7
Other Measurements, Assessments, or Methods ··········································57
5.7.1
Bone Marrow Aspirate and Bone Marrow Biopsy ··································57
5.7.2
Urine N-telopeptide ·····································································58
5.7.3
Blood sample for androgen and androgen precursors levels and bone 
markers ···················································································58
5.7.4
Archival Prostate Tumor Sample······················································58
5.7.5
Whole Blood Sample for Optional Genotype Analysis·····························58
5.8
Total Amount of Blood·······································································58


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6
TERMINATION OF THE CLINICAL STUDY ············································58
7
STATISTICAL METHODOLOGY ···························································59
7.1
Sample Size····················································································59
7.2
Analysis Set····················································································59
7.2.1
Safety Analysis Set (SAF)······························································59
7.2.2
Biomarker Evaluable Set ·······························································59
7.2.3
Pharmacokinetic Analysis Set (PKAS) ···············································60
7.3
Demographics and Other Baseline Characteristics········································60
7.4
Analysis of Efficacy ··········································································60
7.5
Analysis of Safety·············································································61
7.6
Analysis of Pharmacokinetics ·······························································61
7.7
Protocol Deviations and Other Analyses···················································62
7.8
Interim Analysis (and Early Discontinuation of the Clinical Study)····················62
7.9
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········62
8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS ····················63
8.1
Procedure for Clinical Study Quality Control ·············································63
8.1.1
Data Collection ··········································································63
8.1.2
Specification of Source Documents···················································63
8.1.3
Clinical Study Monitoring······························································63
8.1.4
Direct Access to Source Data/Documents············································64
8.1.5
Data Management ·······································································64
8.1.6
Protocol Deviations ·····································································64
8.1.7
End of Trial in All Participating Countries···········································65
8.2
Ethics and Protection of Subject Confidentiality··········································65
8.2.1
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) / 
Competent Authorities (CA) ···························································65
8.2.2
Ethical Conduct of the Study···························································65
8.2.3
Informed Consent of Subjects ·························································65
8.2.3.1
Subject Information and Consent················································65
8.2.3.2
Supply of New and Important Information Influencing the Subject’s 
Consent and Revision of the Written Information ·····························66
8.2.4
Subject Confidentiality ·································································67
8.3
Administrative Matters ·······································································67
8.3.1
Arrangement for Use of Information and Publication of the Clinical Study ·····67


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8.3.2
Documents and Records Related to the Clinical Study ·····························68
8.3.3
Protocol Amendment and/or Revision················································69
8.3.4
Signatory Investigator for Clinical Study Report····································69
9
QUALITY ASSURANCE········································································70
10
STUDY ORGANIZATION······································································70
10.1
Data and Safety Monitoring Board (DSMB) ׀Data Monitoring Committee 
(DMC)··························································································70
10.2
Other Evaluation Committee(s) ·····························································70
10.3
Other Study Organization ····································································70
11
REFERENCES ····················································································71
12
APPENDICES ·····················································································72
12.1
Appendix 1:   List of  Excluded Concomitant Medication ·······························72
12.2
Appendix 2:   Laboratory Tests······························································73
12.3
Appendix 3:  Liver Safety Monitoring and Assessment··································74
12.4
Appendix 4:  Common Serious Adverse Events ··········································76
12.5
Appendix 5:  Soft Tissue Assessment (RECIST 1.1) ·····································77
12.6
Appendix 6:  Optional Pharmacogenomic Sub-study·····································78
13
ATTACHMENT 1:   SUBSTANTIAL AMENDMENT 2 ·································81
14
SPONSOR’S SIGNATURES····································································98


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I. SIGNATURES
1.  SPONSOR’S SIGNATURE
A Phase 2 Study Determining Safety and Tolerability of Enzalutamide (formerly
MDV3100) in Combination with Abiraterone Acetate in Bone Metastatic 
Castration-Resistant Prostate Cancer Patients
ISN/Protocol 9785-CL-0011 / Version 3.0, Incorporating Substantial Amendment 2
18 June 2014
Required signatures (e.g. protocol authors, sponsor’s reviewers and contributors) are located 
in Section 14; e-signatures (when applicable) are located at the end of this document.






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III.
LIST OF ABBREVIATIONS AND KEY TERMS
List of Abbreviations
Abbreviation
Definition of abbreviation
AE
Adverse event
ALT
Alanine Aminotransferase
APED/APEL
Astellas Pharma Europe Ltd
APGD
Astellas Pharma Global Development
AST
Aspartate Aminotransferase
AT
Aminotransferase
AR
Androgen Receptor
AUC
Area under the plasma concentration versus time curve
BID
Twice a Day
CAT (CT scan)
Computed Axial Tomography
CFR
Code of Federal Regulations
Cmax
Maximum concentration
Cmin
Minimum concentration
CR
Complete Response
CRPC
Castration-Resistant Prostate Cancer
CRO
Contract Research Organization
Ctrough
The point of minimum concentration of a drug
CTCAE
Common Terminology Criteria for Adverse Events
CTD
Common Technical Document
CTEP
Cancer Therapy and Evaluation Program
CYP
Cytochrome P450
CXR
Chest x-ray
DES
Diethylstilbestrol
DHEA
Dehydroepiandrosterone
DHT
Dihydrotestosterone
DILI
Drug-Induced Liver Injury
DNA
Deoxyribonucleic Acid
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG PS
Eastern Cooperative Oncology Group Performance Status
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EDTA
Ethylenediaminetetraacetic Acid
ESR
Expedited Safety Report
ET
End of Treatment
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GnRH
gonadotropin releasing hormone
HIPAA
Health Insurance Portability and Accountability Act
IC50
Half maximal inhibitory concentration
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee


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Abbreviation
Definition of abbreviation
IHC
Immunohistochemistry
IND
Investigational New Drug (Application)
INR
International Normalized Ratio
IRB
Institutional Review Board
ISN
International Study Number
LDH
Lactate dehydrogenase
LFT
Liver Function Test
LHRH
Luteinizing hormone-releasing hormone
LVEF
Left Ventricle Ejection Fraction 
MDACC
MD Anderson Cancer Center
MedDRA
Medical Dictionary for Regulatory
mg
Milligram
mmHg
Millimeters of Mercury
MRI
Magnetic Resonance Imaging
MUGA
Multi-Gated Acquisition
NCI
National Cancer Institute
NDA
New Drug Application
NYHA
New York Heart Association
PB
Privacy Board
PCWG2
Prostate Cancer Clinical Trials Working Group 2
PD
Progressive Disease
PFS
Progression Free Survival
PHI
Personal Health Information
PK
Pharmacokinetics
PKAS
Pharmacokinetic Analysis Set
PO
By Mouth
PR
Partial Response
PSA
Prostate-Specific Antigen
PT
Prothrombin Time
PTT
Partial thromboplastin time
QD
Once Daily
QRS
QRS Interval
QTcF
QTC Fridericia Calculator
RECIST
Response Evaluation Criteria In Solid Tumors
SAE
Serious Adverse Event
SAF
Safety Analysis Set
SAP
Statistical Analysis Plan
SD
Stable Disease
SFL
Screening Failure
SUSAR
Suspected Unexpected Serious Adverse Reaction
TBL
Total bilirubin Level
tmax
time to maximum concentration
t½
Apparent Terminal Elimination Half-life
ULN
Upper Limit of Normal
WBC
White Blood Count


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List of Key Study Terms
Terms
Definition of terms
Adverse Event
An adverse event is as any untoward medical occurrence in a subject 
administered a study drug and which does not necessarily have a causal 
relationship with this treatment.
AFFIRM
A Multinational Phase 3, Randomized, Double-Blind, Placebo-Controlled 
Efficacy and Safety Study of Oral MDV3100 in Patients with Progressive 
Castration-Resistant Prostate Cancer Previously Treated with Docetaxel-
Based Chemotherapy
Baseline
A period that begins at the Screening visit where all initial subject
assessments and findings will be obtained prior to study drug administration
on Day 1.
Discontinuation
A discontinuation is a subject who is enrolled in the study and for whom 
study drug is terminated for any reason.  
Enroll
To register or enter into the study following the signing of informed consent. 
Screening period
Period of time between Day -28 and Day -1.
Screening failure
Screened subject, but did not fulfill protocol inclusion and/or exclusion 
criteria and failed to receive open label study treatment, or decided not to 
participate anymore (withdrew consent) prior to completing pre-
investigational period.
Study Drug
Agents given as part of a clinical trial. In this study, enzalutamide, abiraterone 
acetate and prednisone are the study drugs.
Subject
An individual who participates in this clinical trial, and will be a recipient of 
the study drug.
Variable
Any quantity that varies; any attribute, phenomenon or event that can have 
different qualitative or quantitative values.


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IV.
SYNOPSIS
Title of Study
A Phase 2 Study Determining Safety and Tolerability of Enzalutamide
(formerly MDV3100) in Combination with Abiraterone Acetate in Bone 
Metastatic Castration-Resistant Prostate Cancer Patients
Planned Study 
Period
From 10 July 2012 to 17 June 2014
Study Objective(s)
Primary

To explore the safety and tolerability of enzalutamide in combination with 
abiraterone acetate plus prednisone.
Secondary

To explore the effect of enzalutamide in combination with abiraterone 
acetate plus prednisone on androgen receptor signaling and androgen 
levels.

To explore the antitumor activity of enzalutamide in combination with 
abiraterone acetate plus prednisone as assessed by serum prostate-specific 
antigen (PSA), imaging of soft tissue and bone metastases and markers of 
bone metabolism.
Exploratory

To measure pre-dose concentrations of abiraterone on Day 4 and Day 29 
(optional).
Planned Total 
Number of Study 
Centers and 
Location
One center in the United States
Design and 
Methodology
This is an open label study to determine the safety and tolerability of 
enzalutamide in combination with abiraterone acetate plus prednisone in 
castration-resistant prostate cancer patients with bone metastases by clinical 
evaluations at protocol specified intervals.
The study will also determine the modulation of androgen receptor (AR) 
signaling and androgen levels as measured by testosterone concentration in 
bone marrow aspirate and blood by Liquid Chromatography Mass spectrometry, 
expression of AR and its subcellular localization by immunohistochemistry 
(IHC), presence of known and assessable splice variants and CYP17 expression 
in epithelial and host compartment of the cancer by IHC. Tumor tissue will be 
collected to determine AR signaling and candidate pathways that may be part 
of a signaling network implicated in therapy resistance. The baseline 
determination and subsequent assessment of AR signaling will be correlated 
with progression-free survival (radiographic progression, PSA progression, 
clinical deterioration). 
Approximately 60 subjects will receive enzalutamide 160 mg daily, abiraterone 
acetate 1000 mg daily, prednisone 5 mg twice daily to be taken orally. Subjects 
will be unable to continue in the study if one of the above study drugs is
discontinued. 


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Design and 
Methodology
continued
There will be a 28 day screening period to determine subject eligibility. For the 
study duration, all subjects will maintain androgen deprivation with a GnRH
agonist or antagonist or orchiectomy. 
Study drug will be administered until disease progression. Disease progression
is defined as a composite endpoint consisting of clinical deterioration, 
radiographic progression or PSA progression according to the PCWG2 criteria.
Optional PK blood samples for the determination of plasma concentrations of 
abiraterone will be collected pre-dose on Day 4 and Day 29. In addition,
optional PK blood sample for the determination of plasma concentrations of
enzalutamide and its metabolites MDPC0001 and MDPC0002 will be collected 
on Day 29.
The following assessments of prostate cancer status will be collected during the 
course of the trial: soft tissue disease on computed tomography (CT) scan or on 
magnetic resonance imaging (MRI), bone disease on radionuclide bone scans, 
and PSA. Study films (abdominopelvic CT/MRI [lung when applicable] and 
bone scan) should be read on site. Throughout the study, safety and tolerability 
will be assessed by the recording of adverse events, monitoring of vital signs 
and physical examination, safety laboratory evaluations, and 12-lead 
electrocardiograms (ECGs).  
All subjects discontinuing study drug for any reason will have a safety follow-
up visit 30 days after their last dose of study drug or prior to initiation of 
subsequent anti-neoplastic therapy for prostate cancer, whichever occurs first.
Number of Subjects 
Planned
Approximately 60 subjects 
Selection Criteria
Inclusion Criteria:
Subject is eligible for the study if all of the following apply:
1.
Institutional Review Board (IRB)-/Independent Ethics Committee (IEC)-
approved written Informed Consent and privacy language as per national 
regulations (e.g., HIPAA Authorization for U.S. sites) must be obtained 
from the subject or legally authorized representative prior to any study-
related procedures (including withdrawal of prohibited medication, if 
applicable).
2.
Histologically or cytologically confirmed adenocarcinoma of the prostate 
without neuroendocrine differentiation or small cell features.
3.
Presence of metastatic disease to the bone at the Screening visit. 
4.
Ongoing androgen deprivation therapy with a gonadotropin releasing 
hormone (GnRH) analogue or orchiectomy (i.e., surgical or medical 
castration). 
5.
Serum testosterone level ≤50 ng/dL at the Screening visit. 
6.
Subject receiving bisphosphonate or denosumab therapy must have been on 
stable doses for at least 4 weeks prior to Day 1.


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Selection Criteria
Continued
Inclusion Criteria continued:
7.
Progressive disease defined as one or more of the following three criteria
(Note: subjects who received an antiandrogen must demonstrate disease 
progression following discontinuation of antiandrogren):
PSA progression defined by a minimum of two rising PSA levels with an 
interval of ≥ 1 week between each determination. The PSA value at the 
Screening visit should be ≥ 2 ng/mL.
Soft tissue disease progression as defined by the Response Evaluation 
Criteria in Solid Tumors (RECIST 1.1).
Bone disease progression defined by PCWG2 criteria (two or more new 
lesions on bone scan compared with prior scan).
8.
Subject previously treated with chemotherapy must have no more than two 
prior chemotherapy regimens for the treatment of metastatic prostate cancer.
9.
Eastern Cooperative Oncology Group (ECOG) performance status of 0–2.
10. Estimated life expectancy of ≥ 6 months. 
11. Able to swallow the study drug and comply with study requirements. 
12. Agree to use a double-barrier method of contraception which involves the 
use of a condom in combination with one of the following: contraceptive 
sponge, diaphragm, or cervical ring with spermicidal gel or foam, if having 
sex with a woman of child-bearing potential during the length of the study 
and for one week after abiraterone is discontinued and for at least three 
months after enzalutamide is discontinued.
13. Subject agrees not to participate in another interventional study while on 
treatment.
Exclusion Criteria:
Subject will be excluded from participation if any of the following apply:
1.
Known allergy to the study drugs or any of its components.
2.
Severe, concurrent disease, infection, or co-morbidity that, in the judgment 
of the investigator, would make the subjects inappropriate for enrollment.
3.
Medical condition that would make prednisone/prednisolone 
(corticosteroid) use contraindicated.
4.
Known or suspected metastases in the brain.
5.
Absolute neutrophil count < 1,000/μL, platelet count < 75,000/μL, and 
hemoglobin < 9 g/dL at the Screening visit; (NOTE: subject may not have 
received any growth factors or blood transfusions within seven days of the 
hematologic laboratory values obtained at the Screening visit).
6.
Total bilirubin (TBL), alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) > 2.5 times the upper limit of normal at the 
Screening visit.
7.
Creatinine (Cr) > 2 mg/dL at the Screening visit.
8.
History of another malignancy within the previous 2 years other than 
curatively treated non-melanomatous skin cancer.
9.
Treatment with androgen receptor antagonists (bicalutamide, flutamide, 
nilutamide), 5-α reductase inhibitors (finasteride, dutasteride), estrogens, 
chemotherapy, or biologic therapy within 4 weeks of Day 1 visit.


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Selection Criteria
continued
10. Radiation therapy within 3 weeks (if single fraction of radiotherapy within 2 
weeks) of Day 1 visit or radionuclide therapy within 8 weeks of Day 1.
11. Planned palliative procedures for alleviation of bone pain such as radiation 
therapy or surgery.
12. Structurally unstable bone lesions suggesting impending fracture.
13. History of seizure or any condition that may predispose to seizure 
including, but not limited to underlying brain injury, stroke, primary brain 
tumors,  brain metastases, or alcoholism. Also, history of loss of 
consciousness or transient ischemic attack within 12 months of enrollment 
(Day 1 visit).
14. Clinically significant cardiovascular disease including: 
Myocardial infarction within 6 months of Screening visit. 
Uncontrolled angina within 3 months of Screening visit. 
Congestive heart failure New York Heart Association (NYHA) class 3 or 
4, or subjects with history of congestive heart failure NYHA class 3 or 4 
in the past, or history of anthracycline or anthracenedione (mitoxantrone) 
treatment, unless a screening echocardiogram or multi-gated acquisition 
scan (MUGA) performed within three months of the Screening visit
results in a left ventricular ejection fraction that is ≥ 45%.
History of clinically significant ventricular arrhythmias (e.g., ventricular 
tachycardia, ventricular fibrillation, torsade de pointes).
Prolonged corrected QT interval by the Fridericia correction formula 
(QTcF) on the screening electrocardiogram (ECG) > 470 msec.
History of Mobitz II second degree or third degree heart block without a 
permanent pacemaker in place.
Hypotension (systolic blood pressure <86 mmHg or bradycardia with a 
heart rate of <50 beats per minute on the Screening ECG, unless 
pharmaceutically induced and thus reversible (i.e. beta blockers).
Uncontrolled hypertension as indicated by a resting systolic blood 
pressure >170 mmHg or diastolic blood pressure >105 mmHg at the 
Screening visit.
15. Prior use of ketoconazole, abiraterone or enzalutamide, or participation in a 
previous clinical trial of ketoconazole, abiraterone acetate or enzalutamide.
16. Use of an investigational agent within 4 weeks of Day 1.
17. Gastrointestinal disorder that may affect absorption (e.g., gastrectomy) of 
study drug.
18. Major surgery within 4 weeks prior to Day 1.
19. History of significant bleeding disorder unrelated to cancer, including:
Diagnosed congenital bleeding disorders (e.g., von Willebrand’s
disease).
Diagnosed acquired bleeding disorder within one year (e.g., acquired 
anti-factor VIII antibodies) of Screening visit.
History of GI bleeding within 6 months of Screening visit. 
20. Active or symptomatic viral hepatitis or chronic liver disease.
21. Known history of pituitary or adrenal dysfunction.


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Discontinuation 
Criteria 
Subject will be discontinued from treatment if any of the following occur: 

Subject develops disease progression defined as a composite endpoint, 
consisting of either clinical deterioration, radiographic progression or PSA 
progression according to the PCWG2 criteria. Subjects with PSA 
progression alone will not be withdrawn from the study.

Subject develops an adverse event or toxicity, where continued 
administration of study drug is deemed not in the subject’s best interest by 
the investigator.

Abnormal lab values defined as:  creatinine > 305  µmol/L (4.0 mg/dL), 
absolute neutrophil count of ≤ 750 /µL and platelet count of < 50,000/µL.

LFTs that meet one of the following:
a. An ALT or AST value of > 8x ULN
b. An ALT or AST value of > 5x ULN for more than 2 weeks
c. An ALT or AST value of > 3x ULN and TBL > 2x ULN or INR > 1.5
d. If close monitoring for a subject with moderate (defined in Appendix 
3 as ALT or AST > 3x ULN or total bilirubin > 2x ULN) hepatic 
laboratory tests is not possible, study drug should be discontinued.
e. ALT or AST > 3x ULN with the appearance of fatique, nausea, 
vomitting, right upper quadrant pain or tenderness, fever, rash and/or 
eosinophilia (> 5%).

Any seizure.

Investigator or study Medical Monitor decision that study drug 
continuation is not in the best interest of the subject.

Subject who is, in the opinion of the investigator or the Medical Monitor, 
grossly non-compliant with the protocol’s requirements. 

Subject is unable to continue in the study, if one of the study drugs is 
discontinued. 

Subject withdraws consent.
Test Drug Dose
Mode of 
Administration
Duration of 
Treatment
Enzalutamide 160 mg QD and abiraterone acetate 1000 mg QD, prednisone 5 
mg twice daily 
Oral
Subject will receive study drug treatment until disease progression or 
unacceptable toxicity.  
Reference Therapy 
Dose
None
Concomitant 
Medication 
The following medications are prohibited while the subject is continuing on 
study treatment:

Chemotherapeutic, biologic, or other agents with anti-tumor activity 
against prostate cancer other than the investigational agents in this study

Anti-androgens

5-α reductase inhibitors


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Concomitant 
Medication
continued

Estrogens, progestational agents

Androgens

Ketoconazole

Herbal products that may decrease PSA levels (e.g., saw palmetto)
Please refer to Appendix 1 (List of Excluded Concomitant Medication).
Subjects who had been receiving stable dose of bisphosphonates, denosumab
or GnRH agonist or antagonist for 4 weeks prior to Day 1 may continue on 
therapy at the same dose.
Caution is advised when considering the concomitant use of the following 
medications:

Medications known to lower the seizure threshold. These  include but are 
not limited to: 
o
Aminophylline/theophylline 
o
Atypical antipsychotics (e.g., clozapine, olanzapine, risperidone, 
ziprasidone)
o
Bupropion
o
Lithium
o
Pethidine
o
Phenothiazine antipsychotics (e.g., chlorpromazine, mesoridazine, 
thioridazine)
o
Tricyclic and tetracyclic antidepressants (e.g., amitriptyline, 
desipramine, doxepin, imipramine, maprotiline, mirtazapine)

Sensitive P-gp substrates (e.g., digoxin, fexofenadine)

Medications that inhibit platelet function or anticoagulants should be used 
with caution while receiving study treatment. Standard of care monitoring 
of anticoagulation should be implemented.  

Abiraterone is an inhibitor of CYP2D6 ( based on drug-drug interaction 
trial) and a substrate of CYP3A4 (based on the vitro data). Avoid co-
administration of abiraterone acetate with substrate of CYP2D6 with a 
narrow therapeutic index. If an alternative treatment cannot be used,
exercise caution and consider a dose reduction of the concomitant 
CYP2D6 substrate drug. Avoid or use with caution, strong inhibitors and 
inducers of CYP3A4 during abiraterone treatment.

Based on in vitro data, enzalutamide is an inhibitor of CYP2B6, CYP2C8, 
CYP2C9, and CYP2C19 and may be an inducer of CYP3A4. Substrates of 
CYP2B6, CYP2C8, CYP2C9, and CYP2C19 that have a narrow 
therapeutic index (e.g., paclitaxel, phenytoin, warfarin) should be used 
with caution.

Additionally, co-administration of enzalutamide with CYP3A4/5 substrates 
may affect oral bioavailability and/or elimination of the CYP3A4/5 
substrate. Substrates of CYP3A4/5 that have a narrow therapeutic index 
should be used with caution. In vitro studies showed that enzalutamide is 
metabolized by CYP2C8 and CYP3A4/5. Use caution when co-


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administering a strong CYP2C8 inhibitor (e.g., gemfibrozil) or strong 
CYP3A4/5 inhibitors (e.g., clarithromycin, itraconazole, ketoconazole, 
grapefruit juice) during enzalutamide treatment.
Primary Variables

Nature, frequency and severity of adverse events 

Safety laboratory tests: chemistry and hematology

Vital signs (blood pressure, pulse rate and temperature)

12 Lead ECG parameters

Physical examination results
Secondary 
Variables

Androgen receptor signaling
o
Expression and localization of AR 
o
CYP17 expression
o
Splice variants

Pathways linked with non-classical AR signaling & Bone 
development
Androgens 
o
Testosterone concentration in bone marrow aspirate and 
blood
o
DHT concentration in bone marrow aspirate and blood

Androgen pre-cursors and other associated metabolites.  For 
example:
o
Cortisol
o
Androstenedione
o
Pregnenolone
o
Progesterone

PSA levels

Progression-free Survival (PFS)

Objective response according to RECIST 1.1

Bone scan results

Markers of bone metabolism (bone specific alkaline phosphatase and 
urine N-telopeptides)
Exploratory
Variables
Pre-dose concentrations of abiraterone on Day 4 and Day 29 (optional).
Statistical Methods
Unless otherwise specified, categorical variables will be summarized as counts 
and percentages, and continuous variables will be summarized using descriptive 
statistics (number of subjects, mean, standard deviation [SD], median, 
minimum and maximum).


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Statistical Methods
continued
Sample size calculation
A total of 60 subjects will provide sufficient data to assess the safety of the drug 
combination. 
The sample size and power calculation are based on the change of testosterone 
concentration or gene expressions (i.e. AR and CYP17) before and after 
therapy, which can be characterized based on effect size (i.e. mean difference of 
testosterone concentration or gene expression divided by standard deviation).
Considering subjects with baseline and Week 9 laboratory results derived from 
bone marrow samples, a sample of 30 subjects provides 82% power to detect a 
change of testosterone concentration or gene expression with an effect size of at 
least 0.55, using a two sided paired t-test at a 0.05 significance level. A total of 
60 subjects will be accrued to obtain at least 30 evaluable patients based on the 
prediction that the yield of evaluable bone marrow samples with prostate cancer 
cells is approximately 50%.
Safety Analyses
Safety will be assessed through summaries of adverse events, laboratory 
evaluations, vital signs, physical examinations, and ECGs. Safety analyses will 
be based on all enrolled subjects who receive any amount of study drug.  
Severity of all adverse events is to be evaluated by the investigator based on the 
National Cancer Institute’s Common Terminology Criteria for Adverse Events 
(CTCAE), version 4.03 and will be coded to preferred term, higher level term, 
and system organ class using the Medical Dictionary for Regulatory Activities 
(MedDRA). The number and percentage of subjects with adverse events will be 
presented by MedDRA system organ class and preferred term, relationship to 
study treatment and severity. Descriptive statistics will be used rather than 
inferential statistics.  
Laboratory values will be classified by toxicity grade based on the National 
Cancer Institute’s Common Terminology Criteria for Adverse Events 
(CTCAE), version 4.03. Laboratory shift tables of the baseline results to each 
of the subsequent visits will be produced.  
Efficacy Analyses

Anti-tumor Activity
Efficacy analysis will be conducted on all enrolled subjects who received any 
amount of study drug. Progression-free survival (PFS) is defined as the time 
interval from the date of starting treatment until the date of documented 
progression or death in absence of progression. PFS will be reported using 
Kaplan-Meier methods, including the median and its 95% CI. PSA and PSA 
change from baseline over time will be descriptively summarized.
Proportion of patients showing RECIST 1.1 objective response (partial or 
complete response) will be descriptively summarized. Bone specific alkaline 
phosphatase and urine N-telopeptides will be descriptively summarized.

Androgens, Androgen Receptor Signaling Androgen pre-cursors and other 
associated metabolites
Considering subjects with baseline and Week 9 laboratory results derived from 
bone marrow samples, androgens, androgen receptor signaling, androgen pre-


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Statistical Methods
continued
cursors and other associated metabolites will be summarized by descriptive 
statistics and, if appropriate, a paired t-test at a 0.05 level of significance will be 
performed on the change from baseline at Week 9. 
Analysis of Pharmacokinetics
Summary statistics will be presented for each predose plasma concentration of 
abiraterone, enzalutamide and its metabolites MDPC0001 and MDPC0002, by 
scheduled visit. Summary statistics for the concentration data will include 
number of subjects, mean, SD, coefficient of variation (CV), geometric mean, 
median, minimum and maximum. 
Pre-dose concentrations of abiraterone obtained on Day 4 and on Day 29 will 
be compared to assess the potential effect of enzalutamide on the PK of 
abiraterone. 
Drug Exposure
Drug exposure, including data on dose reduction will be summarized by 
descriptive statistics based on study drug accountability.


ISN/Protocol 9785-CL-0011
T AND SCHEDULE OF ASSESSMENTS
First Dose of  
Enzalutamide, 
Abiraterone 
Acetate and 
Prednisone
Monthly safety 
assessments and 
disease 
progression 
evaluation 
Day 1
Week 5 to 
Week 21
Safety 
assessments 
and disease 
progression 
evaluation
Week  25 and 
every 
subsequent 
12 weeks
Documented  
disease  
progression or 
other 
discontinuation 
criteria
End of Treatment 
30 days after 
last dose
Safety 
Follow Up


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Table 1: Schedule of Assessments
Study Day
Screening 
Visit
1
4
29
57
85
113
141
169
ET
Safety F/U
Week
−4 to −1 
(28 days)
1
1
5
9
13
17
21
25 and every 
subsequent 
12 weeks
End of 
Treatment
30 Days 
after last dose e
Window (days)
± 3
± 3
± 3
± 3
± 3
± 3
+ 3
± 7
Informed Consent
X
Medical History
X
Inclusion/Exclusion Criteria
X
X
Vital Signsa
X
X
X
X
X
X
X
X
X
X
Physical Examination, Weight, 
Height J
X
Xd
Xn
Xn
Xn
Xn
Xn
Xn
Xn
Xn
12-Lead ECG
X
Xd
Xr
Xr
Xr
Xr
Xr
Xr
Xr
Xr
PT/PTT/ INR b
X
Xd
X
X
X
X
X
X
X
X
Clinical Labs b
Including liver function test c
X
Xd
X
X
X
X
X
X
X
X
PK of Abiraterone l
X
X
PK of enzalutamide m
X
PSA
X
Xd
X
X
X
X
X
X
X
X
Urine N-telopeptide
X
X
Xg
Blood testosterone and DHT levels
q
X
X
Xg
CT/MRI and Bone Scan
Xi
X
X
X
CXR or Chest CT
Xk
Xk
Xk
MUGA or ECHO f
X
ECOG Performance Status
X
X
X
X
X
X
X
X
X
X
Bone Marrow Aspirate and Biopsy  
Xh
X
Xg
Archival Tumor Tissue o
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
Previous & Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
Study Drug Dispensing
X
X
X
X
X
X
X
Study Drug Treatment
X
X
X
X
X
X
X
Blood Sample for Genotypingp
X


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Table 1 Footnotes:
a.
Vital signs will be obtained prior to study drug administration and 1-2 hours after study drug administration.
b.
Clinical labs(hematology and chemistry) and, PT/PTT & INR, will be obtained prior to study drug administration. Day 1 chemistry and 
hematology do not need to be completed if the screening assessments were completed within 3 days prior to Day 1.
c.
Subjects will have liver function tests (including alkaline phosphatase, AST, ALT, direct and total bilirubin, and LDH) every 2 weeks for the 
first 12 weeks of treatment. 
d.
If Day 1 visit occurs within 72 hours after screening, these assessments do not need to be repeated.
e.
All subjects discontinuing study drug for any reason will have a safety follow-up visit 30 days after their last dose of study drug or prior to 
initiation of subsequent anti-neoplastic therapy for prostate cancer, whichever occurs first.
f.
A MUGA scan or echocardiogram showing LVEF ≥ 45% is required for subjects with a history of anthracycline or anthracenedione 
(mitoxantrone) treatment, or if the subjects has congestive heart failure New York Heart Association (NYHA) class 3 or 4, or subjects with 
history of congestive heart failure NYHA class 3 or 4 in the past.
g.
Bone marrow biopsy and aspirate, blood sample for testosterone and DHT and urine sample for N-telopeptide will be collected at Screening, 
Week 9, and at the End of Treatment (ET) visits. If the End of Treatment visit falls between Week 9 and Week 13, and these samples were 
collected at Week 9 then an ET collection will not be required.  
h.
Bone marrow aspirate and biopsy will be taken between screening and prior to first dose of study drug.
i.
Subjects must be assessed with CT/MRI and bone scan within 6 weeks prior to study drug administration (Day 1). 
j.
Height will be recorded at the screening visit only. 
k.
At screening, a chest X-ray or a chest CT will be performed. If the chest X-ray is performed and demonstrates metastatic chest 
disease, a chest CT is required. In the case of metastatic chest disease, additional chest CT’s should be performed as follow-up at 
Week 13 (Day 85) and end of treatment (ET) visit.
l.
Optional PK blood sample for determination of plasma concentrations of abiraterone will be obtained predose on Day 4 and Day 29.
m. Optional PK blood sampling for determination of plasma concentrations of enzalutamide and its metabolites MDPC0001 and MDPC0002 will
be obtained predose on week 5 (Day 29).
n.
A physical exam will be performed including weight.
o.
Archival tumor tissue will be obtained any time prior to Day 1.
p.
Sample for optional genotyping sub-study will be collected prior to Day 1 dosing.
q.
Blood sample testosterone and DHT should be collected within 2 hours of bone marrow biopsy and aspirate.
r.
ECG must be performed prior to dosing.


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1
INTRODUCTION
1.1
Background
Cancer is a major health care problem in the US and worldwide. Prostate cancer is the most 
common cancer in males. It is anticipated that the incidence of prostate cancer, an age 
dependent neoplasm, will only increase with progressive aging of the population worldwide. 
Unlike other advanced cancer types, only modest advances have been made in therapy. The 
mainstay of therapy for patients with advanced cancer remains as androgen ablation. In further 
progression of disease, chemotherapy only achieves modest responses and is mostly palliative 
in nature. These observations stress the need to develop new therapeutic strategies based on 
the improved understanding of the biology driving prostate cancer progression.
Recently, a representative of a new drug class, androgen biosynthesis inhibitor, abiraterone 
acetate, has demonstrated  improved survival in a post-chemotherapy CRPC patient population. 
Also, a novel androgen signaling inhibitor enzalutamide (formerly MDV3100) has demonstrated 
significant antitumor activity in a Phase 3 trial in this same patient population. However, this
gain in survival might eventually be overcome by disease progression and death from the 
malignant disease. Thus, there is a need to explore the effect of novel combination of 
enzalutamide and abiraterone acetate.
1.1.1
Paracrine Androgen Signaling
There is increasing evidence that “intracrine” (autocrine/paracrine) androgen signaling is 
implicated in the castration resistant progression of prostate cancer. Enzalutamide is a novel 
small molecule designed to have increased affinity for the androgen receptor and more 
effective suppression of the downstream androgen signaling pathway. In pre-clinical models, 
enzalutamide has been shown to target the androgen signaling pathway at three distinct points:
it blocks testosterone binding to the AR, impairs movement of the AR to the nucleus of 
prostate cancer cells (nuclear translocation), and inhibits binding to DNA. Enzalutamide has 
been shown to suppress cancer cell growth and induce cancer cells’ death (apoptosis). 
1.1.2
Androgen Biosynthesis
CYP17 is an important enzyme in the synthetic pathway for the production of androgens in the 
testes and adrenal glands. It catalyzes the conversion of pregnenolone or progesterone into 
dehydroepiandrosterone (DHEA) or androstenedione, respectively, both are precursors of 
testosterone. 
Abiraterone acetate is an FDA approved CYP17 inhibitor indicated for use in combination 
with prednisone for the treatment of patients with metastatic castration-resistant prostate 
cancer who have received prior chemotherapy containing docetaxel [Centocor Ortho Biotech 
Inc., April 2011].  
It inhibits the production of testosterone in adrenal glands and testes. Testosterone, a C19 
androgen, is further converted to the more potent androgen, dihydrotestosterone (DHT), by 


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testosterone 5α-reductase in the prostate; both testosterone and DHT are principal promoters 
of prostate cancer growth [Haidar, 2003; Ideyama, 1998; Duc, 2003].
The suppression of androgen signaling is effective in CRPC. Abiraterone acetate, a novel 
androgen biosynthesis inhibitor and enzalutamide, novel androgen signaling inhibitor, have 
shown efficacy in patient with CRPC with acceptable toxicity profiles [de Bono, 2011; Scher, 
2010; Efstathiou, 2011]. Ligand-independent AR signaling has been implicated in abiraterone
acetate resistance and increased testosterone in patients treated with enzalutamide [Efstathiou, 
2010]. These observations are consistent with the hypothesis that persistent AR signaling is 
implicated in CRPC progression and provides rationale for the combination of enzalutamide
with abiraterone acetate and prednisone.
1.2
Non-clinical and Clinical Data
1.2.1
Non-clinical Data
Prostate cancer is known to be androgen sensitive and responds to inhibition of androgen 
receptor (AR) signaling. Despite low or even undetectable levels of androgen, AR signaling 
continues to promote disease progression. Stimulation of tumor cell growth via the androgen 
receptor requires nuclear localization and DNA binding. Enzalutamide is a potent AR 
signaling inhibitor that blocks several steps in the androgen receptor signaling pathway. 
Enzalutamide competitively inhibits binding of androgens to androgen receptors in the 
cytosol, inhibits nuclear translocation of activated receptors and inhibits the association of the 
activated androgen receptor with DNA even in the setting of androgen receptor over 
expression and in prostate cancer cells resistant to anti-androgens. Enzalutamide decreases the 
growth of prostate cancer cells and can induce cancer cell death and tumor regression. 
Enzalutamide lacks androgen receptor agonist activity. In addition to the human androgen 
receptor, the targets for which significant interaction with enzalutamide was detected were 
only the human progesterone receptor (IC50 = 16.1 μM) and the rat gamma amino butyric acid 
(GABA)-gated chloride channel (IC50 = 2.6 μM). A major human metabolite, M2, also 
demonstrated significant binding to the progesterone receptor (IC50 = 6.2 μM) and the 
GABA-gated chloride channel (IC50 = 7.1 μM). A cell-based activity assay for the GABA-
gated chloride channel (α1β3 GABA-A receptor subtype) demonstrated that both parent and 
metabolite M2 were functional inhibitors of this channel.
Available non-clinical and clinical data from abiraterone acetate and enzalutamide show that 
targeting androgen biosynthesis in the tumor micro-environment as well as androgen signaling 
is effective in CRPC. While non-clinical studies of the combination of enzalutamide and 
abiraterone acetate have not been conducted, available data suggests there is potential for 
additive effects if the two targeting approaches are used concomitantly. 
Abiraterone is an inhibitor of CYP2D6 and a substrate of CYP3A4. Based on in vitro data, 
enzalutamide is an inhibitor of CYP2B6, CYP2C8, CYP2C9, and CYP2C19 and may be an 
inducer of CYP3A4. Additionally, in vitro studies showed that enzalutamide is metabolized by 
CYP2C8 and CYP3A4/5. 


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1.2.2
Clinical Data
The tolerability, pharmacokinetics (PK), and antitumor activity of enzalutamide were studied 
in a multi-center, open-label, dose-escalation study of enzalutamide in 140 subjects with 
advanced prostate cancer. Subjects were treated with enzalutamide at doses of 30–600 mg/day 
until disease progression or intolerable side effects developed [Scher, 2010]. 
At the highest dose of 600 mg/day, two of three subjects had dose-limiting toxicities (seizure 
and rash, respectively). One witnessed seizure at 360 mg/day and a possible seizure at 
480 mg/day were also reported. No deaths and no other drug-related serious adverse events 
were reported. Fatigue was the most frequently reported adverse event, with dose-dependent 
increases of Grade 3 fatigue (0% at 150, 9% at 240, 15% at 360, and 20% at 480 mg/day 
groups). Only one subject discontinued treatment due to fatigue. The dose of 240 mg/day was 
defined as the maximum tolerated dose.  
Enzalutamide was absorbed rapidly after oral administration, with the median time to 
maximum plasma concentrations after a single dose occurring at 1 hour post dose (range 0.42 
to 4 hours). No major deviations from dose proportionality were observed over the dose range 
30 to 600 mg. Due to the long t½ (~ 5.8 days), it took approximately 1 month to reach steady 
state. With daily oral administration, enzalutamide accumulated approximately 8.3-fold 
relative to a single dose. The peak-to-trough ratio was approximately 1.25, indicating that the 
average difference between the peak (Cmax) and trough (Cmin) concentrations was ≤25%. As a 
result of the low daily fluctuations, plasma profiles at steady-state resembled a constant 
infusion. The Cmin values in individual subjects remained constant beyond Day 28 of chronic 
therapy, suggesting time-linear pharmacokinetics once steady state was achieved.
A total of 1199 subjects were enrolled in a Phase 3 randomized, double-blind, placebo-
controlled study in patients with progressive castration resistant prostate cancer previously 
treatment with docetaxel-based chemotherapy (CRPC2/AFFIRM). The primary endpoint of this 
trial was overall survival. 800 study subjects were treated with enzalutamide at doses of 160 mg
and 399 were treated with placebo.
An Independent Data Monitoring Committee (IDMC) has recommended unblinding of the 
AFFIRM study because the results met the requirements of a pre-specified interim analysis, 
and a positive median overall survival benefit to subjects treated with enzalutamide has been 
demonstrated compared to placebo. Results of the interim analysis demonstrated a statistically 
significant improvement (p<0.0001) in overall survival with a median improvement over 
placebo of 4.8 months [hazard ratio (HR) = 0.631]. The estimated median survival for men 
treated with enzalutamide was 18.4 months compared with 13.6 months for men treated with 
placebo. Enzalutamide provided a 37 percent reduction in risk of death compared to placebo 
(Hazard Ratio=0.631). Data with a data cut-off of 25 September 2011 show that 71.1% on the 
enzalutamide treatment arm and 95.2% on the placebo arm discontinued treatment. The median 
exposure in weeks was 36.3 weeks for enzalutamide and 13.0 weeks for placebo. In total 
98.1% (enzalutamide) and 97.7% (placebo) presented with ≥ 1 treatment-emergent adverse 
event. There were 45.3% (enzalutamide) and 53.1% seen with ≥ 1 treatment-emergent adverse 
event. (Grade 3 or higher). The percentage of patients with treatment-emergent adverse event


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(Grade 3 or higher) was 33.5% for enzalutamide and 38.6% for placebo. Enzalutamide was 
generally well-tolerated. Overall, the incidence of serious adverse events and deaths was higher 
among those treated with placebo compared to enzalutamide in the CRPC2 (AFFIRM) study. 
Five seizures, four witnessed and one unwitnessed, were reported in the study as of the data 
cut-off date, all occurred in patients randomized to enzalutamide representing an incidence of 
0.6%.
Additionally, two separate trials have been performed to study the effect of enzalutamide or
abiraterone on androgen signaling and bone marrow parameters. 
Study CRPC-MDA-1 was a Phase 2 study designed to explore the effect of treatment with 
enzalutamide on androgen signaling and expression of survival/escape pathways in the bone 
marrow of patients with castration-resistant metastatic prostate cancer. Out of the 60 patients 
treated with 160 mg daily of enzalutamide, 75% had a decrease in PSA levels on therapy, 
48.3% had a ≥ 50% decrease in PSA levels, and 25% had a ≥ 90% decrease in PSA levels. 
Results show elevated levels of testosterone in bone marrow prior to enzalutamide therapy, as 
well as tumor expression of androgen receptor and CYP17 which support the hypothesis that 
there is persistent androgen receptor signaling in castration-resistant prostate cancer. Further, it 
suggests that therapy with enzalutamide is associated with increases in blood and bone marrow 
testosterone indicative of a biologic response to effective androgen blockade.
There were no deaths due to adverse events in this study. There were two adverse events as the 
primary cause of study drug discontinuation, however neither event was assessed as related to 
enzalutamide therapy. The most commonly reported adverse events in this study were fatigue 
(reported in 71.7% of patients), anorexia (28.3%), constipation (28.3%), arthralgia (26.7%) and 
back pain (23.3%).
In another open label, observational study 57 patients with bone-metastatic CRPC received 
abiraterone acetate and prednisone. The results showed a strong correlation between pre-
treatment circulating and microenvironment bone marrow aspirate testosterone levels and 
abiraterone acetate achieved sustained suppression of testosterone in both blood and bone 
marrow aspirate. In a limited number of patients an increase of AR copy numbers was 
observed.
Enzalutamide and abiraterone acetate plus prednisone have individually demonstrated 
suppression of androgen signaling and efficacy in subjects with CRPC. However, no formal
trials has been conducted to further explore additive or synergistic activity. 
1.3
Summary of Key Safety Information for Study Drugs
1.3.1
Enzalutamide
The safety and tolerability of enzalutamide have been evaluated in 13 studies, including 2
completed studies (Phase 1), 7 active studies (Phase 1 through 3), and 4 enrolling studies
(Phase 2 through 3). It is estimated that a total of 124 healthy volunteers, 16 subjects with
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to enzalutamide in completed, open-label, and ongoing blinded studies. In the completed
interim analysis of the randomized, double-blind, placebo-controlled Phase 3 efficacy and
safety study in patients with progressive castration-resistant prostate cancer previously treated 
with docetaxel-based chemotherapy (CRPC2), 800 patients received enzalutamide (160 mg 
daily). The duration of enzalutamide exposure in this study ranged from 1 day to 23.3 months 
(median 8.3 months). No study has been terminated early for safety reasons.
Safety data are presented from the formal interim analysis of data from the CRPC2 study, with 
a data cut-off date of 25 September 2011. Table 2 provides an overview of exposure to study 
drug, adverse events, and deaths.
Table 2: Summary of Study Drug Exposure, Adverse Events, and Deaths (CRPC2)*
Treated (Safety Population)
enzalutamide
(n = 800)
Placebo 
(n = 399)
Discontinued Treatment
569 (71.1%)
380 (95.2%)
Treatment Duration (median months)
8.3
3.0
Patients with ≥ 1 Treatment Emergent Adverse Event 
785 (98.1%)
390 (97.7%)
Patients with ≥ 1 Treatment Emergent Adverse Event  (Grade 3 or Higher)
362 (45.3%) 
212 (53.1%)
Patients with ≥1 Serious Treatment Emergent Adverse Event
268 (33.5%)
154 (38.6%)
Patients with an Adverse Event Leading to Death
23 (2.9%)
14 (3.5%)
Patients with Adverse Events Leading to Study Drug Discontinuation
61 (7.6%)
39 (9.8%)
SUSARs (all in unique patients)
10
6
Deaths
308 (38.5%)
212 (53.1%)
*For up to date study information refer to the current edition of the Investigator’s Brochure
Enzalutamide (160 mg daily) was generally well-tolerated in the placebo-controlled CRPC2
study of 1199 patients with progressive castration-resistant prostate cancer previously treated
with docetaxel-based chemotherapy. Adverse events reported by those treated with
enzalutamide (160 mg daily) with an incidence of at least 5% and by at least 2% greater than 
by those who received placebo included fatigue (33.6% v 29.1%), diarrhea (21.4% v 17.5%),
hot flush (20.3% v 10.3%), musculoskeletal pain (13.6% v 10.0%), headache (11.6% v 5.5%), 
insomnia (8.6% v 6.0%), anxiety (6.4% vs. 4.0%), hypertension (6.1% v 2.8%), and
nasopharyngitis (5.1% v 3.0%). 
Other adverse events reported less commonly than 5% but that may be associated with
enzalutamide treatment after careful assessment of the adverse events include: falls (4.0% vs.
1.3%), dry skin (3.6% vs. 1.3%), and pruritus (3.5% vs. 1.3%). A greater proportion of patients 
in the enzalutamide-treated group (4.1% vs. 1.8%) reporting the following adverse event terms: 
memory impairment, cognitive disorder, amnesia, disturbance of attention, and dementia. In 


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addition, event terms related to hallucination (visual hallucination, tactile hallucination, 
hallucination) were reported more frequently in the enzalutamide-treated group (1.6% vs. 0.3%).
Serious adverse events that occurred at a ≥ 0.5% absolute difference in event frequency and
more frequently in the enzalutamide arm than the placebo arm included: spinal cord
compression (6.0% vs. 3.8%), bone pain (1.5% vs. 1.0%), metastatic pain (1.5% vs. 0.8%),
pathological fracture (1.5% vs. 0.5%), urinary tract infection (0.9% vs. 0.3%), and cauda
equina syndrome (0.8% vs. 0.0%).
Seizure is a known potential toxicity of enzalutamide. In vitro studies have shown that
enzalutamide and its metabolite M2 bind to the GABA-gated chloride channel with IC50 
values of 1.2 μg/mL and 3.3 μg/mL, respectively and in a cell-based assay inhibit the channel’s
activity with IC50 values of 1.4 μg/mL and 1.07 μg/mL, respectively. Some compounds that
inhibit the GABA-gated chloride channel are associated with seizures[Foster, 2011].
In the first clinical study of enzalutamide (S-3100-1-01), a dose-escalation study in men with
castration-resistant prostate cancer with and without prior exposure to chemotherapy, the 
following doses were evaluated: 30, 60, 150, 240, 360, 480 (as 240 mg twice per day [BID]), 
and 600 (as 300 mg BID) mg/day. Three patients were reported to have dose-limiting toxicities 
of seizure, one each at doses of 360, 480, and 600 mg/day (Section 6.2.2.1). The results of this 
study led to the selection of the clinical dose of enzalutamide of 160 mg/day.
As of the database cut-off date for the respective unblinded or open-label studies reported in the
Investigator’s Brochure, 7 patients out of a total of 1100 patients (0.6%) exposed to
enzalutamide at a dose of 160 mg/day have reported a seizure during the enzalutamide treatment 
emergent adverse event reporting period. These include one patient each in studies 9785-CL-
0007 and 9785-CL-0321, and 5 patients in the CRPC2 study. Two additional patients have been 
identified by the Sponsor to have experienced adverse events that may have been seizures, 
including one case reported by the Investigator as syncope (CRPC2) and the other reported as a 
transient ischemic attack with an abnormal electroencephalogram (CRPC-MDA-1). As of the 
data cut-off date, treatment with enzalutamide at a daily dose of 160 mg is associated with a 
0.6-0.8% risk of seizure in men with late-stage castration-resistant prostate cancer. 
Taking into account information from ongoing blinded studies and events occurring after the 
database cut-off date, the range for seizure risk is unchanged. No seizures have been reported in 
the blinded placebo-controlled Phase 3 study enzalutamide-03 (PREVAIL) with over 1300 
patients enrolled (randomized 1:1 to enzalutamide 160 mg/day or placebo). One additional 
patient in the CRPC2 study has been reported to have had a seizure after the safety  data cut-off 
date, and one additional patient in an ongoing blinded study (9785-CL-0222) has also reported a 
seizure.
Please see the most current version of the Investigator Brochure for additional details.


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1.3.2
Abiraterone Acetate
The most common adverse reactions (≥ 5%) are joint swelling or discomfort, hypokalemia, 
edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, 
arrhythmia, urinary frequency, nocturia, dyspepsia, and upper respiratory tract infection. 
In addition abiraterone acetate is known to cause the following conditions:
Mineralocorticoid excess: abiraterone acetate should be used with caution in subjects with 
a history of cardiovascular disease. The safety of abiraterone acetate in subjects with LVEF 
< 50% or NYHA Class III or IV heart failure is not established. Hyper-tension should be 
controlled and hypokalemia should be corrected before treatment. Blood pressure, serum 
potassium and symptoms of fluid retention should be monitored at least monthly.
Adrenocortical insufficiency: symptoms and signs of adrenocortical insufficiency should 
be monitored. Increased dosage of corticosteroids may be indicated before, during and after 
stressful situations.
Hepatotoxicity: Increases in liver enzymes have led to drug interruption, dose modification 
and/or discontinuation. Liver function should be monitored and modify, interrupt, or 
discontinue abiraterone acetate dosing as recommended. Study subjects will have liver 
function tests (including alkaline phosphatase, AST, ALT, direct and total bilirubin, and 
LDH) every 2 weeks for the first 12 weeks of treatment. 
Abiraterone acetate must be taken on an empty stomach. Exposure of abiraterone increases up 
to 10 fold when abiraterone acetate is taken with meals. 
Abiraterone acetate may harm a developing fetus; thus, women who are pregnant or women 
who may be pregnant should not handle abiraterone acetate without protection (e.g., gloves). 
Subjects will also be informed that it is not known whether abiraterone acetate or its metabolites 
are present in semen and they should use a condom if having sex with a pregnant woman. The 
subjects should use a condom and another effective method of birth control if he is having sex 
with a woman of child-bearing potential. These measures are required during and for one week 
after treatment with abiraterone acetate.
Details and data in the package insert are to be referenced for more details [Centocor Ortho 
Biotech Inc., April 2011].  
1.3.3
Prednisone
Fluid and electrolyte disturbances: sodium retention, fluid retention, congestive heart failure in 
susceptible patients, potassium loss, hypokalemic alkalosis, hypertension. 
Musculoskeletal: muscle weakness, steroid myopathy, loss of muscle mass, osteoporosis, 
tendon rupture, particularly of the Achilles tendon, vertebral compression fractures, aseptic 
necrosis of femoral and humeral heads, pathological fracture of long bones.
Gastrointestinal: peptic ulcer with possible perforation and hemorrhage, pancreatitis, 
abdominal distention, ulcerative esophagitis, increases in alanine transaminase (ALT, SGPT), 
aspartate transaminase (AST, SGOT) and alkaline phosphatase have been observed following 


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corticosteroid treatment. These changes are usually small, not associated with any clinical 
syndrome are reversible upon discontinuation.
Dermatologic: impaired wound healing, thin fragile skin, petechiae and ecchymoses, facial 
erythema, increased sweating, may suppress reactions to skin tests. 
Neurological: convulsions, increased intracranial pressure with papilledema (pseudo-tumor 
cerebri) usually after treatment, vertigo, headache.
Endocrine: menstrual irregularities; development of Cushingoid state; suppression of growth in 
children; secondary adrenocortical and pituitary unresponsiveness, particularly in times of 
stress, as in trauma, surgery or illness; decreased carbohydrate tolerance; manifestations of 
latent diabetes mellitus; increased requirements for insulin or oral hypoglycemic agents in 
diabetics.
Ophthalmic: posterior subcapsular cataracts, increased intraocular pressure, glaucoma, 
exophthalmos.
Metabolic: negative nitrogen balance due to protein catabolism.
Additional reactions: Urticaria, and other allergic, anaphylactic or hypersensitivity reactions.
For more details refer to package insert from [Actavis UK Ltd., July 2011].
1.4
Risk-Benefit Assessment 
Enzalutamide (160 mg daily) was generally well-tolerated in the placebo-controlled CRPC2 
study of 1199 patients with progressive CRPC previously treated with docetaxel-based 
chemotherapy. Adverse events reported by those treated with enzalutamide (160 mg daily) with 
an incidence of at least 5% and by at least 2% greater than by those who received placebo 
included:

fatigue  

diarrhea  

hot flush   

musculoskeletal pain  

headache  

insomnia  

anxiety 

hypertension 

nasopharyngitis 
Other adverse events reported less commonly than 5% but that may be associated with
enzalutamide treatment after careful assessment of the adverse events include: 

falls

dry skin

pruritus 


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Additionally, a greater proportion of patients in the enzalutamide-treated group reporting the 
following combined adverse event terms: memory impairment, cognitive disorder, amnesia, 
disturbance of attention, and dementia. In addition, combined event terms related to 
hallucination (visual hallucination, tactile hallucination, hallucination) were reported more 
frequently in the enzalutamide-treated group.  
Furthermore, enzalutamide has been demonstrated in nonclinical studies to induce seizures in a
dose-dependent fashion. Inhibition of the GABA-gated chloride channel is a hypothesized-
mechanism of action for this effect. Seizures have occurred in enzalutamide-treated patients
and there appears to be a greater risk of seizure at higher doses. Confounding factors likely
contributed to the occurrence of seizures in several of these cases; however, a role of
enzalutamide in lowering the seizure threshold cannot be excluded. Caution should be used in 
administering enzalutamide to patients with a history of seizures or other predisposing factors 
including, but not limited to, underlying brain injury, stroke, primary brain tumors or brain 
metastases, or alcoholism. In addition, the risk of seizure may be increased in patients 
receiving concomitant medications that may lower the seizure threshold. Enzalutamide should 
be permanently discontinued in patients who have a seizure while on treatment.
The totality of the efficacy and safety data suggests a positive benefit/risk assessment of the 
use of enzalutamide in men with castration-resistant prostate cancer. The 4.8 month 
improvement in median survival observed in enzalutamide treated patients compared with 
placebo represents a major advantage for patients with castration-resistant prostate cancer that 
has progressed following chemotherapy. Moreover, enzalutamide was generally well-tolerated 
as described above, with seizures reported in less than 1% of patients. Taken together, the 
overall risk/benefit assessment is very favorable for enzalutamide.
Abiraterone acetate is an FDA approved CYP17 inhibitor indicated for use in combination 
with prednisone and the safety profile is described in the current package insert.
Enzalutamide and abiraterone acetate have not yet been given together, however, based on the 
safety and tolerability profile of both drugs, no severe toxicity with the proposed combinations
is expected. Patient safety will be monitored through clinical vigilance. Subject safety is 
assured through clinical monitoring during the study. Any unusual clinical observations will be 
discussed immediately with the Principal Investigator, sponsor, or a sub-investigator if the PI is 
absent or not available. All subjects will be treated at M.D. Anderson Cancer Center and will 
be provided with their treating physicians and research nurse contact information. 
In vitro studies showed that abiraterone acetate is a substrate of CYP3A4 and that 
enzalutamide may be an inducer of CYP3A4. Co-administration of enzalutamide with 
CYP3A4/5 substrates may affect oral bioavailability and/or elimination of the CYP3A4/5 
substrate. There is a potential for drug interaction when administering both drugs at the same 
time in which enzalutamide may lower the circulating levels of abiraterone. An optional 
evaluation in this study will be performed to explore the effect of enzalutamide on the PK of 
abiraterone.  


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Abiraterone acetate may cause fetal harm when administered to a pregnant woman and is 
contraindicated in women who are or may become pregnant. Instructions will be given that 
women should not handle abiraterone acetate without protection (e.g., gloves).
The use of abiraterone is mandating the additional co-administration of prednisone for the 
treatment of its related adrenalcortical insufficiency. Though the long term use of prednisone 
carry a risk of potential side effects (see list above) the safety profile of prednisone is 
acceptable.
2
STUDY OBJECTIVE(S), DESIGN AND VARIABLE
2.1
Study Objectives
2.1.1
Primary Objective
To explore the safety, and tolerability of enzalutamide in combination with abiraterone acetate 
plus prednisone.
2.1.2
Secondary Objectives

To explore the effect of enzalutamide in combination with abiraterone acetate plus 
prednisone on androgen receptor signaling and androgen levels.

To explore the antitumor activity of enzalutamide in combination with abiraterone acetate 
plus prednisone as assessed by serum prostate-specific antigen (PSA), imaging of soft 
tissue and bone metastases, and markers of bone metabolism.
2.1.3
Exploratory Objectives
To measure pre-dose concentrations of abiraterone on Day 4 and Day 29 (optional).
2.2
Study Design and Dose Rationale
2.2.1
Study Design
This is an open label study to determine the safety and tolerability of enzalutamide in 
combination with abiraterone acetate plus prednisone in CRPC subjects with bone metastases 
by clinical evaluations at protocol specified intervals. The study will also determine the 
modulation of androgen receptor (AR) signaling in bone marrow biopsy and androgen levels as 
measured by testosterone concentration in bone marrow aspirate and blood by Liquid 
Chromatography Mass spectrometry, expression of AR and its subcellular localization by 
immunohistochemistry (IHC), presence of known and assessable splice variants and CYP17 
expression in epithelial and host compartment of the cancer by IHC. Tumor tissue will be 
collected to determine AR signaling and candidate pathways that may be part of a signaling 
network implicated in therapy resistance. The baseline determination and subsequent 


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assessment of AR signaling will be correlated with progression-free survival (radiographic 
progression, PSA progression, and/or clinical deterioration).
Approximately 60 subjects will receive enzalutamide 160 mg daily, abiraterone acetate 
1,000 mg daily, and prednisone 5 mg twice daily to be taken orally. 
Throughout the study, safety and tolerability will be assessed by the recording of adverse 
events, monitoring of vital signs and physical examinations, safety laboratory evaluations, and 
12-lead electrocardiograms (ECGs).
The occurrence of an adverse event or toxicity, where continued administration of study drug is 
deemed to be not in the subject’s best interest by the investigator and/or the sponsor, will result 
in the removal of the subject from therapy.  
For the study duration, all subjects will maintain androgen deprivation with a GnRH agonist or 
antagonist or orchiectomy. 
Study drug will be administered until disease progression. Disease progression is defined as a 
composite endpoint, consisting of clinical deterioration, radiographic progression or PSA 
progression according to the PCWG2 criteria. 
The following assessments of prostate cancer status will be collected during the course of the 
trial: soft tissue disease on computed tomography (CT) scan or on magnetic resonance imaging 
(MRI), bone disease on radionuclide bone scans, and PSA. 
Study films (abdominopelvic CT/MRI [lung when applicable] and bone scan) should be read 
on site.
Optional PK blood samples for determination of plasma concentrations of abiraterone will be 
collected pre-dose on Day 4 and Day 29. In addition optional PK blood sampling for 
determination of plasma concentrations of enzalutamide and its metabolites MDPC0001 and 
MDPC0002 will be collected on Day 29.
Archival tumor tissue samples will be collected to allow for tumor profiling. Samples will be 
obtained and stored until qualified assays become available.
All subjects discontinuing study drug for any reason will have a safety follow-up visit 30 days 
after their last dose of study drug or prior to initiation of subsequent anti-neoplastic therapy for 
prostate cancer, whichever occurs first.
2.2.2
Dose Rationale
This study will utilize an enzalutamide dose of 160 mg/day, which has proven safety and 
efficacy in the Phase 3 AFFIRM trial.
An abiraterone acetate dose of 1000 mg/day together with prednisone 5 mg twice daily will be
taken. It is the FDA approved daily dose.


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2.3
Variables
2.3.1
Primary Variable

Nature, frequency and severity of adverse events

Safety laboratory tests: chemistry and hematology

Vital signs (blood pressure, pulse rate and temperature)

12 Lead ECG parameters

Physical examination results
2.3.2
Secondary Variables

Androgen receptor signaling
o
Expression and localization of AR 
o
CYP17 expression
o
Splice variants

Pathways linked with non-classical AR signaling & Bone development

Androgens 
o
Testosterone concentration in bone marrow aspirate and blood
o
DHT concentration in bone marrow aspirate and blood

Androgen pre-cursors and other associated metabolites.  For example:
o
Cortisol
o
Androstenedione
o
Pregnenolone
o
Progesterone

PSA levels

Progression-free Survival (PFS)

Objective response according to RECIST 1.1

Bone scan results

Markers of bone metabolism (bone specific alkaline phosphatase and urine N-
telopeptides)
2.3.3
Exploratory Variables
Pre-dose concentrations of abiraterone on Day 4 and Day 29 (optional). Other variables may 
be explored.
3
STUDY POPULATION
3.1
Selection of Study Population
The study population will include approximately 60 men with castration-resistant prostate 
cancer and bone metastasis. 


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3.2
Inclusion Criteria
Subject is eligible for the study if all the following apply:
1. Institutional Review Board (IRB)-/Independent Ethics Committee (IEC)-approved written 
Informed Consent and privacy language as per national regulations (e.g., HIPAA 
Authorization for U.S. sites) must be obtained from the subject or legally authorized 
representative prior to any study-related procedures (including withdrawal of prohibited 
medication, if applicable).
2. Histologically or cytologically confirmed adenocarcinoma of the prostate without
neuroendocrine differentiation or small cell features.
3. Presence of metastatic disease to the bone at the Screening visit.
4. Ongoing androgen deprivation therapy with a gonadotropin releasing hormone (GnRH) 
analogue or orchiectomy (i.e., surgical or medical castration).
5. Serum testosterone level ≤50 ng/dL at the Screening visit.
6. Subject receiving bisphosphonate or denosumab therapy must have been on stable doses 
for at least 4 weeks prior to Day 1.
7. Progressive disease defined as one or more of the following three criteria (Note: subjects 
who received an antiandrogen must demonstrate disease progression following 
discontinuation of antiandrogren): 

PSA progression defined by a minimum of two rising PSA levels with an interval of 
≥ 1 week between each determination. The PSA value at the Screening visit should be 
≥ 2 ng/mL.

Soft tissue disease progression as defined by the Response Evaluation Criteria in 
Solid Tumors (RECIST 1.1).

Bone disease progression defined by PCWG2 criteria (two or more new lesions on 
bone scan compared with prior scan).
8. Subject previously treated with chemotherapy must have no more than two prior chemo-
therapy regimens for the treatment of metastatic prostate cancer.
9. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
10. Estimated life expectancy of ≥ 6 months.
11. Able to swallow the study drug and comply with study requirements.
12. Agree to use a double-barrier method of contraception which involves the use of a 
condom in combination with one of the following: contraceptive sponge, diaphragm, or 
cervical ring with spermicidal gel or foam, if having sex with a woman of child-bearing 
potential during the length of the study and for one week after abiraterone is discontinued 
and for at least three months after enzalutamide is discontinued.
13. Subject agrees not to participate in another interventional study while on treatment.


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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. Known allergy to the study drugs or any of its components.
2. Severe, concurrent disease, infection, or co-morbidity that, in the judgment of the 
investigator, would make the subject inappropriate for enrollment.
3. Medical condition that would make prednisone/prednisolone (corticosteroid) use 
contraindicated.
4. Known or suspected metastases in the brain.
5. Absolute neutrophil count < 1,000/μL, platelet count < 75,000/μL, and hemoglobin 
< 9 g/dL at the Screening visit; (NOTE: subject may not have received any growth factors 
or blood transfusions within seven days of the hematologic laboratory values obtained at 
the Screening visit).
6. Total bilirubin (TBL), alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
> 2.5 times the upper limit of normal at the Screening visit.
7. Creatinine (Cr) > 2 mg/dL at the Screening visit.
8. History of another malignancy within the previous 2 years other than curatively treated 
non-melanomatous skin cancer.
9. Treatment with androgen receptor antagonists (bicalutamide, flutamide, nilutamide), 5-α 
reductase inhibitors (finasteride, dutasteride), estrogens, chemotherapy, or biologic therapy 
within 4 weeks of Day 1 visit.
10. Radiation therapy within 3 weeks (if single fraction of radiotherapy within 2 weeks) of 
Day 1 visit, or radionuclide therapy within 8 weeks of Day 1.
11. Planned palliative procedures for alleviation of bone pain such as radiation therapy or surgery.
12. Structurally unstable bone lesions suggesting impending fracture.
13. History of seizure or any condition that may predispose to seizure including, but not 
limited to underlying brain injury, stroke, primary brain tumors,  brain metastases, or 
alcoholism. Also, history of loss of consciousness or transient ischemic attack within 12 
months of enrollment (Day 1 visit)
14. Clinically significant cardiovascular disease including: 

Myocardial infarction within 6 months of Screening visit; 

Uncontrolled angina within 3 months of Screening visit; 

Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or 
subjects with history of congestive heart failure NYHA class 3 or 4 in the past, or 
history of anthracycline or anthracenedione (mitoxantrone) treatment, unless a 


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screening echocardiogram or multi-gated acquisition scan (MUGA) performed within 
three months of the Screening visit results in a left ventricular ejection fraction that is 
≥ 45%.

History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, 
ventricular fibrillation, torsade de pointes).

Prolonged corrected QT interval by the Fridericia correction formula (QTcF) on the
screening Electrocardiogram (ECG) > 470 msec.

History of Mobitz II second degree or third degree heart block without a permanent 
pacemaker in place.

Hypotension (systolic blood pressure < 86 mmHg or bradycardia with a heart rate of 
<50 beats per minute on the Screening ECG., unless pharmaceutically induced and
thus reversible (i.e. beta blockers).

Uncontrolled hypertension as indicated by a resting systolic blood pressure >170 
mmHg or diastolic blood pressure >105 mmHg at the Screening visit.
15. Prior use of ketoconazole, abiraterone acetate or enzalutamide, or participation in a 
previous clinical trial of ketoconazole, abiraterone acetate or enzalutamide.
16. Use of an investigational agent within 4 weeks of Day 1.
17. Gastrointestinal disorder that may affect absorption (e.g., gastrectomy) of study drug.
18. Major surgery within 4 weeks prior to Day 1.
19. History of significant bleeding disorder unrelated to cancer, including:

Diagnosed congenital bleeding disorders (e.g., von Willebrand’s disease).

Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII 
antibodies) of Screening visit.

History of GI bleeding within 6 months of Screening visit. 
20. Active or symptomatic viral hepatitis or chronic liver disease.
21. Known history of pituitary or adrenal dysfunction.
Waivers to the exclusion criteria will not be allowed.
3.4
Discontinuation Criteria for Individual Subjects
A discontinuation is a subject who enrolled in the study and for whom study treatment is 
terminated prematurely 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. Discontinued 
subjects will not be replaced. The investigator is also free to terminate a subject's involvement 
in the study at any time if in the opinion of the investigator the subject's clinical condition 
warrants it.


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Discontinuation criteria for individual subjects:

Subject develops disease progression defined as a composite endpoint, consisting of 
clinical deterioration, radiographic progression or PSA progression according to the 
PCWG2 criteria. Subject with PSA progression alone will not be withdrawn from the 
study.

Subject develops an adverse event or toxicity, where continued administration of study 
drug is deemed not in the subject’s best interest by the Investigator.

Abnormal lab values defined as:  creatinine > 305 µmol/L (4.0 mg/dL), an absolute 
neutrophil count of ≤ 750 /µL and  platelet count of< 50,000/µL.

LFTs that meet one of the following:
a. An ALT or AST value of > 8x ULN
b. An ALT or AST value of > 5x ULN for more than 2 weeks
c. An ALT or AST value of > 3x ULN and TBL > 2x ULN or INR > 1.5
d. If close monitoring for a subject with moderate (defined in Appendix 3 as ALT or 
AST > 3x ULN or total bilirubin > 2x ULN) hepatic laboratory tests is not possible, 
study drug should be discontinued.
e. ALT or AST > 3x ULN with the appearance of fatique, nausea, vomitting, right 
upper quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%).

Any seizure.

Investigator or study Medical Monitor decision that study drug continuation is not in the 
best interest of the subject.

Subjects who is, in the opinion of the Investigator or the Medical Monitor, grossly non-
compliant with the protocol’s requirements. 

Subject is unable to continue in the study, if one of the study drugs is discontinued. 

Subject withdraws consent.
All subjects discontinuing study drug for any reason will have a safety follow-up visit 30 days 
after their last dose of study drug or prior to initiation of subsequent anti-neoplastic therapy for 
prostate cancer, whichever occurs first.


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4
STUDY DRUGS
4.1
Description of Study Drugs
4.1.1
Enzalutamide
Enzalutamide has the chemical name 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-
4-oxo-2-thioxoimidazolidin-1-yl}-2-fluoro-N-methylbenzamide. It is a white to off-white solid 
that is insoluble in water and no salt forms are available at ~pH 2 to 10.
Enzalutamide capsules are white to off-white oblong capsules, printed with either “MDV” or 
“ENZ” in black ink. The soft gelatin capsules are filled with a clear, yellowish solution which 
contains the two antioxidants, butylated hydroxyanisole, and butylated hydroxytoluene , and 
enzalutamide active ingredient (40 mg), all dissolved in the non-ionic surfactant, Labrasol® 
(Caprylocaproyl Polyoxylglycerides). Enzalutamide capsules are provided in white, opaque, 
high-density polyethylene (HDPE) bottles with child-resistant induction seal closure.
4.1.2
Abiraterone Acetate
Abiraterone acetate is designated chemically as (3β)- 17-(3-pyridinyl)androsta-5,16-dien-3-yl 
acetate. It is a white to off-white, non-hygroscopic, crystalline powder, its molecular formula is 
C26H33NO2 and it has a molecular weight of 391.55. Abiraterone acetate is a lipophilic 
compound with an octanol-water partition coefficient of 5.12 (Log P) and is practically 
insoluble in water.
Abiraterone acetate 250 mg tablets are white to off-white, oval-shaped tablets debossed with 
AA250 on one side and provided in bottles with child-resistant induction seal closure.
4.1.3
Prednisone
Prednisone is a glucocorticoid. Glucocorticoids are adrenocortical steroids, both naturally 
occurring and synthetic, which are readily absorbed from the gastrointestinal tract. The 
molecular formula for prednisone is C21H26O5. Chemically, it is 17,21-dihydroxypregna-1, 4-
diene-3,11, 20-trione. Prednisone is a white to practically white, odorless, crystalline powder 
and has a molecular weight of 358.44. It melts at about 230°C with some decomposition. 
Prednisone is very slightly soluble in water, slightly soluble in alcohol, chloroform, dioxane,
and methanol.
Prednisone inactive ingredients are: anhydrous lactose, colloidal silicon dioxide, magnesium 
stearate, microcrystalline cellulose, sodium starch glycolate, and talc.
Prednisone 5 mg tablets are white round-shaped tablets and provided in bottles with child-
resistant induction seal closure.
4.2
Packaging and Labeling
Enzalutamide used in this study will be prepared, packaged, and labeled under the 
responsibility of a qualified person at Astellas US Technologies, Inc. (AUST) in accordance 


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with AUST Standard Operating Procedures (SOPs), Good Manufacturing Practice (GMP) 
guidelines, ICH GCP guidelines, and applicable local laws/regulations.
Abiraterone acetate and prednisone will be labeled and supplied to the study subjects through 
the site designated pharmacy.
Enzalutamide capsules are packaged either in a white, opaque, high-density polyethylene 
(HDPE) bottles. 
Abiraterone acetate and prednisone tablets will be supplied in bottles. Information presented on 
the labels for investigational product will comply with applicable local regulations.
Site pharmacist or medically qualified staff will dispense the study treatment to each subjects
in accordance with this protocol.
4.3
Study Drug Handling
Current ICH GCP Guidelines require the investigator to ensure that study drug deliveries from 
the sponsor are received by a responsible person (e.g. pharmacist), and

that such deliveries are recorded

that study drug is handled and stored safely and properly

that study drug is only dispensed to study subjects in accordance with the protocol

that any unused study drug is returned to the sponsor or standard procedures for the 
alternative disposition of unused study drug are followed.
Drug inventory and accountability records for the study drugs will be kept by the investigator/
pharmacist. Study drug accountability throughout the study must be documented. The 
following guidelines are therefore pertinent:

The investigator agrees not to supply study drugs to any persons except the subjects in 
this study.

The investigator/pharmacist 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/pharmacist. 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/pharmacist 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 returned medication. Any discrepancies must be accounted for. Appropriate 
forms of deliveries and returns must be signed by the person responsible.

Used or unused study drug may be destroyed at the study center according to standard 
institutional procedures after drug accountability has been conducted only if agreed upon 
by the Sponsor. A copy of the standard institutional procedure for destroying 
investigational drugs will be provided to the Sponsor or designee upon request. Unused 


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study drug not destroyed at the site must be returned to the Sponsor or designee at the 
end of the study or upon expiration.
Enzalutamide should be stored in a secure location with limited access at 77°F (25°C), with 
excursions permitted to 59°F to 86°F (15°C to 30°C). Bottles will be labeled with the study 
protocol number, medication or bottle number, contents, directions for use, storage directions, 
clinical trial statement, and Medivation as sponsor. Subjects will be instructed to store study 
drug at room temperature out of the reach of children.
Abiraterone acetate and prednisone will be provided by the local pharmacy and will be stored 
and handled according to the manufactures specifications and the pharmacy standards of 
operation.
4.4
Blinding
Not applicable.
4.5
Assignment and Allocation
4.5.1
Registration
This is an open-label study, subjects who meet all inclusion criteria and no exclusion criteria
will be assigned to begin study treatment. Registration must occur following informed consent 
process and prior to initiation of investigational therapy. A unique subjects/treatment number 
will be assigned to each subjects enrolled in the study. Discontinued subjects will not be 
replaced. 
5
TREATMENTS AND EVALUATION
5.1
Dosing and Administration of Study Drugs and Other Medications
5.1.1
Dose/Dose Regimen and Administration Period
Enzalutamide: Subjects will be instructed to take 4 capsules (40 mg each) per day orally. 
Enzalutamide may be taken with or without food. Enzalutamide should be taken as close to the 
same time each day as possible.
Abiraterone acetate: Subjects will be instructed to take 4 tablets (250 mg each) orally (PO) at 
least 2 hour before a meal or 1 hour after a meal. Treatment with abiraterone acetate will 
continue throughout the duration of participation.
Prednisone: Subjects will be instructed to take 5-mg oral prednisone, twice daily. Treatment 
with prednisone will continue throughout the duration of participation.


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All subjects who meet the inclusion/exclusion criteria are therefore assigned to begin treatment 
as follows:
Drug
Dose
Frequency
Route of Administration
enzalutamide
160mg
QD
oral
abiraterone acetate
1000mg 
QD 
oral
prednisone  
5mg
BID
oral
All subjects will be treated until disease progression or meets one of the discontinuation 
criteria (see section 3.4).
5.1.2
Reduction in Dose or Discontinuation of the Study Drugs
In subjects who experience toxicity which cannot be ameliorated by the use of adequate 
medical intervention, dose reductions can be performed. In these cases dose reductions of 
abiraterone acetate should be performed first, followed by reduction in enzalutamide doses (if 
needed).
For abiraterone acetate, 2 dose reductions are allowed. At each dose reduction, one tablet of 
abiraterone acetate will be removed, e.g., 4→3 tablets, and 3→2 tablets. Any return to protocol 
dose level after dose reduction or after treatment interruption must follow documentation of 
adverse event resolution and a discussion between the Principal Investigator and the sponsor.
Subjects who experience a Grade 3 or greater toxicity considered to be related to enzalutamide
that cannot be ameliorated by the use of adequate medical intervention should have their 
treatment interrupted until the toxicity improves to a Grade 2 or lower severity. Subjects may 
subsequently be re-started on study drug at a reduced dose follow a discussion between the 
Principal Investigator and the sponsor. Subjects will remain on abiraterone acetate and 
prednisone during enzalutamide dose interruption.
No dose reductions for prednisone are allowed. Subjects experiencing toxicity considered to be 
related to the use of prednisone for which a dose reduction is needed cannot participate in the 
study any longer.
Subjects should be able to take all three study drugs (enzalutamide, abiraterone acetate and 
prednisone) to participate in the study. An interruption of one of these drugs is allowed as per 
instruction above. Permanent discontinuation of one of the drugs, while continuing the two 
other drugs, is not allowed.
5.1.3
Previous and Concomitant Medication (Drugs and Therapies)
Medication taken within four weeks prior to Screening visit must be captured on the case 
report form (CRF).
At each visit, all concomitant treatments, including blood and blood products, must be reported 
on the source documentation and on the concomitant medications page of the CRF. 
Concomitant medications must also be documented at the time of discontinuation and at the 
30 day follow-up visit. Please refer to Appendix 1 (list of excluded concomitant medication).


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The dosage and regimen of the following medications and any chronic permitted concomitant 
medications should be stabilized for 4 weeks prior to Day 1 and held constant throughout the 
study:

Bisphosphonates

Denosumab

GnRH agonist/antagonist
No other new systemic therapy or new radiotherapy for treatment of prostate cancer is 
permitted while subject is on study. Subjects with pre-existing non-target lesions (e.g. bone 
metastases) receiving palliative radiotherapy for pain treatment before participation in the
study are allowed to continue receiving radiotherapy during the study.  
The following medications are prohibited while the subject is on study drug:

Chemotherapeutic, biologic, or other agents with anti-tumor activity against prostate 
cancer other than assigned study drug.

Anti-androgens(steroidal or non-steroidal) such as cyproterone acetate, flutamide, 
nilutamide, bicalutamide, etc. other than assigned study drug.

5-α reductase inhibitors such as finasteride, dutasteride, anabolic steroids, etc.

Estrogens, progestational agents such as megestrol, medroxyprogesterone, DES, 
cyproterone, spironolactone > 50 mg/kg.

Androgens such as testosterone, dehydroepiandrosterone [DHEA].

Ketoconazole.

Herbal products that may decrease PSA levels (e.g., saw palmetto).
Caution is advised when considering the concomitant use of the following medications:

Medications known to lower the seizure threshold. These  include but are not limited to:
o
Aminophylline/theophylline.
o
Atypical antipsychotics (e.g., clozapine, olanzapine, risperidone, ziprasidone).
o
Bupropion.
o
Lithium.
o
Pethidine.
o
Phenothiazine antipsychotics (e.g., chlorpromazine, mesoridazine, thioridazine).
o
Tricyclic and tetracyclic antidepressants (e.g., amitriptyline, desipramine, 
doxepin, imipramine, maprotiline, mirtazapine).

Sensitive P-gp substrates (e.g., digoxin, fexofenadine).Medications that inhibit platelet 
function and anticoagulants should be used with caution while the subject is on study drug:
Src-family kinase inhibitors potentially reduce platelet aggregation. Caution should thus be 
exercised if subjects are required to take one of the following medications that inhibit platelet 
function or anticoagulants.

aspirin or aspirin-containing combinations.


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
clopidogrel, dipyridamole, tirofiban, dipyridamole, epoprostenol, eptifibatide, cilostazol.

abciximab, ticlopidine, cilostazol warfarin.

heparin/low molecular weight heparin [eg, danaparoid, dalteparin, tinzaparin, enoxaparin].
Low-dose warfarin for prophylaxis to prevent catheter thrombosis and heparin for flushes of 
intravenous lines are allowed.

Cytochrome P 450 inhibitors, inducers, and substrates. 
It is currently unknown which CYP enzyme pathways are responsible for clearing enzalutamide.
To limit the risk of unpredictable increases or decreases in circulating concentrations of 
enzalutamide, potent inhibitors or inducers should be taken with caution, and alternative products 
used when available. In vitro data suggest that enzalutamide may have the potential to induce 
CYP3A4 and inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and 
CYP3A4/5; therefore, concomitant medications that are substrates of any of these enzymes 
should be used with caution, and relevant monitoring should be considered, especially for 
substrates known to cause seizure, because the possibility of drug-drug interactions cannot be 
fully excluded. To determine if a particular drug is a potent CYP inhibitor or inducer, the 
investigator should consult the product label.
Drugs metabolized through the CYP2D6 and CYP1A2 pathways should be used with caution 
while participating in this study. 
In vitro studies showed that enzalutamide is an inhibitor of CYP2C8 and CYP2C19 with lesser 
inhibitory effects on CYP2B6 and CYP2C9. Substrates of CYP2B6, CYP2C8, CYP2C9, and 
CYP2C19 that have a narrow therapeutic index (e.g., phenytoin, warfarin) should be used with 
caution. 
In vitro studies showed that enzalutamide may be an inducer of CYP3A4. Co-administration of 
enzalutamide with CYP3A4/5 substrates may affect oral bioavailability and/or elimination of 
the CYP3A4/5 substrate. Substrates of CYP3A4/5 that have a narrow therapeutic index should 
be used with caution. Co-administration of enzalutamide and abiraterone may lower circulating 
levels of abiraterone acetate. An optional evaluation in this study will be performed to explore 
the effect of enzalutamide on the PK of abiraterone.  
In vitro studies showed that enzalutamide is metabolized by CYP2C8 and CYP3A4/5. Use 
caution when co-administering a strong CYP2C8 inhibitor (e.g., gemfibrozil) or strong 
CYP3A4/5 inhibitors (e.g., clarithromycin, itraconazole, ketoconazole, grapefruit juice) during 
enzalutamide treatment.
Use caution when co-administering a CYP2C8 inducer (e.g., rifampin) or strong CYP3A4/5 
inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s wort) during enzalutamide
administration. 
Please refer to the following link for an up to date list of CYP inhibitors and inducers.
http://medicine.iupui.edu/clinpharm/ddis/


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5.1.4
Treatment Compliance
Study drug accountability will be performed to document compliance with the dosing regimen. 
Subjects will be asked to bring back all remaining study drug at each study visit for drug 
accountability. 
5.1.5
Emergency Procedures and Management of Overdose
There is no antidote for enzalutamide. In the event of an overdose, stop treatment with 
enzalutamide and initiate general supportive measures based on the clinical presentation of the 
patient. Subjects may be at increased risk of seizures following an overdose.  
In case of abiraterone acetate overdose, there is no specific antidote; treatment of an overdose 
should be symptomatic. 
5.1.6
Restrictions During the Study
Abiraterone acetate must be taken on an empty stomach. No food should be consumed for at 
least two hours before the dose of abiraterone acetate is taken and for at least one hour after the 
dose of abiraterone acetate is taken.
5.2
Demographics and Baseline Characteristics
5.2.1
Demographics
Demographic information is to be obtained at screening and will include date of birth, ethnicity, 
race as described by the subject, height and weight.
5.2.2
Medical History
Medical history will include any significant conditions or diseases other than prostate cancer 
that occurred prior to informed consent. 
5.2.3
Diagnosis of the Target Disease, Severity, and Duration of Disease 
A complete medical history of the target disease will be recorded at screening. This includes 
documenting the subject’s initial diagnosis of prostate cancer, Gleason score at time of 
diagnosis dates and type of primary therapy and other disease specific information as 
designated in the eCRF.
5.3
Efficacy Assessment
5.3.1
CT/MRI and Bone Scan (Radiographic Assessments)
Imaging will be performed as per the schedule of assessment. Imaging performed prior to 
informed consent may be used as baseline assessment if  it was performed within 6 weeks prior 
to study drug administration (Day 1).  


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Scans should be scheduled in such a way that the scan results are available at the regularly 
scheduled visit.
Additional imaging may be performed at any time to confirm suspected progression of disease. 
Radiographic evaluation of metastatic disease is determined separately for soft -tissue and bone 
disease. Radiographic disease assessment for soft tissue is based on CT or MRI scan and is 
defined by RECIST 1.1. Radiographic disease progression for bone lesions is based on bone 
scan and is defined when a minimum of two new lesions are observed [Scher, 2008]. The total 
number of lesions will be collected on the eCRF.
Soft tissue assessment will include tumor measurements for target lesions, non-target lesions, 
and assessment for any new lesions. An overall assessment will be characterized for that time 
point evaluation. At the end of study for that subject, the overall best radiographic response to 
the study regimen will be characterized (Please refer to Appendix 5).
At screening, a chest X-ray or a chest CT will be performed. If the chest X-ray is performed and 
demonstrates metastatic chest disease, a chest CT is required. In the case of metastatic chest 
disease, additional chest CT’s should be performed as follow-up at Week 13 (Day 85) and end 
of treatment (ET) visit.
Study films (abdominopelvic CT/MRI[lung when applicable]and bone scan) should be read on 
site. The principal investigator or a sub-investigator will evaluate the images for all subjects for 
the duration of the study.
The same imaging method used for an individual subjects at baseline should be used throughout 
the entire study for that subjects, unless for medical reasons that the method must be changed 
(e.g. inability to receive contrast agent).
If a subject is unable to return for restaging scans due to symptoms of progressive disease, the 
subject may have scans done by a local facility. These scans should be sent to the investigator
for review. Total number of bone lesions will be recorded on the eCRF.
PET scans should not be used to determine disease progression.
5.3.2
PSA
Samples for PSA will be collected and analyzed at the local laboratory. PSA testing will be 
performed as per the schedule of assessment. The PSA test performed at the screening visit 
does not need to be repeated on Day 1 if the Day 1 visit occurs within 72 hours of screening.
5.4
Safety Assessment
5.4.1
Adverse Events
Adverse events will be assessed regularly as per schedule of assessments.
Adverse event collection will begin at the time the informed consent form is signed and 
continue up to 30 days following last dose of study drug.


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Baseline conditions that worsen during the study will be recorded as adverse events.
Adverse events ongoing at the final visit will be followed up for as long as necessary to 
adequately evaluate the subject’s safety or until the event stabilizes. 
5.4.1.1 Adverse Events of Possible Hepatic Origin
Subjects with AE’s of hepatic origin accompanied by Liver Function Test (LFT) abnormalities 
should be carefully monitored. See Appendix 12.3 Liver Safety Monitoring and Assessment for 
detailed information on liver abnormalities, monitoring and assessment.
5.4.2
Vital Signs
Vital signs including blood pressure, pulse rate, and temperature will be assessed at Screening, 
at every clinic visit while on study drug, and at the safety follow-up visit.
Per schedule of assessment vital signs will be obtained prior to and 1 to 2 hours after study 
drug administration. Subjects should withhold dosing of study medication on clinic visit days. 
Study drug will be administered in clinic.
Vital signs should be assessed after 3 minutes rest, preferably supine position or in semi-
recumbent, if supine is not tolerated.
5.4.3
Laboratory Assessments
Routine laboratory assessments for hematology, chemistry and PT/PTT and INR will be 
collected and analyzed at the local laboratory and will be obtained as per schedule of 
assessment. The laboratory assessments performed at the screening visit do not need to be 
repeated on Day 1 if the Day 1 visit occurs within 3 days of screening.
Laboratory assessments must be obtained prior to study drug administration.
Please refer to Appendix 2 for the specification of the laboratory tests.
Please refer to Appendix 3 (Liver Safety Monitoring and Assessment) for additional DILI 
laboratory testing requirements and timing.
5.4.3.1 Abnormal Liver Function Tests
If laboratory testing for a subject enrolled in a study and receiving study drug reveals an 
increase of serum aminotransferases (AT) > 3× ULN, or bilirubin > 2.5× ULN, at least all four 
of the usual serum measures (ALT, AST, ALP, and TBL) should be repeated within 48 – 72 
hours of notification of the test results. See Appendix 3 (Liver Safety Monitoring and 
Assessment) for additional information on monitoring and assessment of abnormal liver 
function tests.
5.4.4
Physical Examination 
Standard, full physical examinations will be performed to assess weight, general appearance, 
head, eyes, ears, nose, throat, neck, cardiovascular, chest and lungs, abdomen, musculoskeletal, 


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neurologic status, mental status, lymphatic, and genitourinary system. Any clinically 
significant abnormalities will be collected as medical history or adverse events. Weight will be 
recorded at each visit. Height will be recorded at the screening visit only. The physical 
examination performed at the screening visit does not need to be repeated on Day 1 if the Day 
1 visit occurs within 72 hours of Screening visit.
5.4.5
Electrocardiogram (ECG) 
A standard 12-lead ECG will be performed on all subjects. Parameters that include heart rate, 
PR interval, RR interval, QRS interval, QT interval will be collected on the (e)CRF. 
Abnormalities and clinical significance as judged by the Investigator will be reported as well. 
An ECG will be performed as per schedule of assessment. All ECGs will be performed prior to 
study drug administration. The subject should have rested in supine position (or semi-
recumbent, if supine is not tolerated) for 5-10 minutes.
5.4.6
Imaging 
A MUGA scan or echocardiogram showing LVEF ≥ 45% is required at Screening only for 
subjects with a history of anthracycline or anthracenedione (mitoxantrone) treatment, or if the 
subject has congestive heart failure New York Heart Association (NYHA) class 3 or 4, or the 
subject has a history of congestive heart failure NYHA class 3 or 4.
5.4.7
Performance Status
The ECOG scale [Oken et al, 1982] will be used to assess performance status.
Table 3:  ECOG Performance Status
Grade
Description
0
Fully active, able to carry on all pre-disease 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 house work, 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
5
Dead


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5.5
Adverse Events and Other Safety Aspects
5.5.1
Definition of Adverse Events (AEs)
An adverse event (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 medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.
Adverse event terms should include a diagnosis, as available, in preference to the listing of 
individual signs and symptoms.
Examples of AEs include:

A change, excluding minor fluctuations, in the nature, severity, frequency, or duration of a 
pre-existing condition.

Development of an intercurrent illness during the study.

Development of symptoms which may or may not be related to the use of a concomitant 
medication or study drug.

Injury or accidents: if a medical condition is known to have caused the injury or accident, 
the medical condition and the accident should be reported as two separate medical events 
(e.g., for a fall secondary to dizziness, both “dizziness” and “fall” should be recorded 
separately).
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.
An AE does not include:

Medical or surgical procedures (e.g. surgery, endoscopy, tooth extraction, transfusion); the 
condition that leads to the procedure is an adverse event.

Pre-existing diseases or conditions present or detected prior to the start of study drug 
administration that do not worsen.

Situations where an untoward medical event has not occurred (e.g., planned hospitalization 
for an elective procedure as known at the time of signing of the informed consent; 
hospitalization for social reasons).

Overdose of either study drug or concomitant medication without any signs or symptoms.


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An adverse event observed after starting administration of the test drug/comparative drug is 
called “treatment emergent adverse event” Treatment-emergent adverse events will be 
analyzed and discussed in the clinical study report for this study.
Non-serious adverse event collection will begin at the time of signing the informed consent and 
continue through study completion. The subject will be questioned in a general way and no 
specific symptoms will be suggested. Any non-serious adverse events occurring during the 
screening period up until the initial dose of study drug should be reported on the medical 
history CRF.  
All adverse events, whether or not related to the study drug, must be fully and completely 
documented on the adverse event page of the CRF and in the subject’s clinical chart. In the 
event that a subject is withdrawn from the study because of an adverse event, this must be 
recorded on the CRFs.  
All subjects who experience an adverse event will be followed at appropriate time intervals 
until the event has resolved or until the event has stabilized and/or reached a new baseline. If 
an adverse event remains unresolved at the conclusion of the study, a clinical assessment will 
be made by the Investigator and Medical Monitor whether continued follow up of the adverse 
event is warranted.  
An event which recurs after resolution should generally be handled as a new adverse event.
However, adverse events that occur intermittently can be recorded as one adverse event.
5.5.2
Definition of Serious Adverse Events (SAEs)
An adverse event 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 adverse event 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 adverse event 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 


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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.
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 medicinal product(s)

Suspected abuse/misuse of the medicinal product(s)

Inadvertent or accidental exposure to the medicinal product(s)

Medication error involving the medicinal product(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 recorded on the (e)CRF. Any situation 
involving these events of interest that also meets the criteria for an SAE should be recorded 
on the AE page of the (e)CRF and marked ‘serious’ and the SAE worksheet.
The Sponsor has a list of events that they classify as “always serious” events.  If an adverse 
event is reported that is considered to be an event per this classification as  “always serious”, 
additional information on the event may be requested.
If the subjects died, the report should include the cause of death as the event term (with fatal 
outcome) and whether or not the death was related to study drug, as well as autopsy findings 
if available.
Serious adverse events will be collected and reported on the adverse event CRF from the time 
the subject signs the ICF until 30 days following last dose of study drug.
5.5.3
Criteria for Causal Relationship to the Study Drug
Adverse events that fall under either “Possible” or “Probable” should be defined as “adverse 
events 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 re- administration 
(rechallenge) or withdrawal (dechallenge).


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5.5.4
Criteria for Defining the Severity of an Adverse Event
Severity of adverse events (toxicity) will be graded according to the Cancer Therapy and 
Evaluation Program (CTEP) Common Terminology Criteria for Adverse Events v4.03. A 
copy of the CTC Version 4.03 can be downloaded from the CTEP homepage
(http://ctep.info.nih.gov).  
For terms not specified within NCI-CTCAE, the following guideline should be used to determine 
grade:
Table 4: Criteria for Severity of Adverse Event Terms Not Specified Within NCI-CTCAE
Grade
Description
1
Mild; asymptomatic or mild symptoms, clinical or diagnostic observations only; 
intervention not indicated.
2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living.
3
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation or hospitalization indicated; disabling; limiting self 
care activities of daily living. 
4
Life-threatening consequences; urgent intervention indicated. 
5
Death related to AE.
5.5.5
Reporting of Serious Adverse Events (SAEs)
In the case of a serious adverse event (SAE), the investigator must contact the delegated CRO
by telephone or fax 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 delegated CRO by fax immediately (within 
24 hours of awareness). If the faxing of an SAE Worksheet is not possible or is not possible 
within 24 hours, the local drug safety contact should be informed by phone.  
For contact details, see Section II Contact Details of Key Sponsor’s Personnel. Please email or 
fax the SAE Worksheet to: 
Astellas Pharma Global Development – United States
Email : Safety-us@us.astellas.com
Fax number: (847) 317-1241
If there are any questions, or if clarification is needed regarding the SAE, please contact the 
Sponsor’s Medical Director/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) as necessary.
The sponsor or sponsor’s designee will submit expedited safety reports (i.e. IND Safety 
Reports) to the regulatory agencies (i.e. FDA) as necessary, and will inform the investigators of 


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such regulatory reports. Investigators must submit safety reports as required by their 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) within timelines set by 
regional regulations (i.e. EU, (e)CTD, FDA). Documentation of the submission to and receipt 
by the IRB/IEC of expedited safety reports should be retained by the site.
You may contact the sponsor’s Medical Director/Expert for any other problem related to the 
safety, welfare, or rights of the study participant (subject/patient).
Full details of the SAE should also be recorded on the medical records and on the CRF.
The following minimum information is required:

ISN/Study number 

Subject number, sex and age

The date of report

A description of the SAE (event, seriousness of the event)

Causal relationship to the study drug
The period for SAE reporting after the last intake of the study drug should be specified.
In accordance with local regulation either sponsor will notify all investigators responsible for 
ongoing clinical studies with the study drug of all SAEs which require submission to their 
IRB/IEC / head of the study site within timelines set by regional/country regulations (by 
MHLW, European Clinical Trial Directives or FDA.
Expedited Safety Reports: An unexpected adverse event is one for which the nature or severity 
is not consistent with the current Investigator’s Brochure. The Sponsor will make this 
assessment for all reported serious adverse events. An adverse event which is serious, related, 
and unexpected may be termed a Suspected Unexpected Serious Adverse Reaction (SUSAR).
The Investigator will ensure that all relevant information is provided as soon as possible to 
Astellas in order that the Sponsor may meet their obligations to report any SUSAR. The 
Sponsor will notify all Investigators responsible for ongoing clinical studies with the study 
drug of all serious adverse events which require submission to their IRB within timelines set by 
regional regulations.
5.5.6
Follow-up to Adverse Events
All adverse events occurring during 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 adverse event follow-up, the adverse event progresses to an “SAE”, or if a subject 
experiences a new SAE, the investigator must immediately report the information to the 
sponsor. 
Please refer to Appendix 3 (Liver Safety Monitoring and Assessment) for detailed instructions 
on DILI follow-up responsibilities related to history of symptoms, concomitant drug use, 
alcohol use, and recreational drug use.


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5.5.7
Monitoring of Common Serious Adverse Events
Included in Appendix 4 (Common Serious Adverse Events) is a list of SAEs commonly 
anticipated to occur in the study population independent of drug exposure that will be 
monitored by the Sponsor 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 [Section 5.5.5].
5.5.8
Procedure in Case of Pregnancy
If during the conduct of the clinical trial, a male subject impregnates his partner, the subject 
should report the pregnancy to the investigator. The investigator should report the pregnancy to 
the sponsor as if it is an SAE. The expected date of delivery or expected date of the end of the 
pregnancy, last menstruation, estimated fertility date, pregnancy result and neonatal data etc., 
should be included in this information.
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 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.

“Normality” of the miscarried fetus is evaluated by visual examination unless test results 
which indicate a congenital anomaly are obtained prior to miscarriage.
The effect of enzalutamide in pregnant and lactating women is not known, and the exposure of 
a fetus or nursing infant is considered a potential risk. Subjects receiving enzalutamide in 
clinical trials are advised to use a double barrier method of birth control during the course of 
enzalutamide treatment and for at least three months after enzalutamide is discontinued. A 
double-barrier method of contraception involves the use of a condom in combination with one 
of the following: contraceptive sponge, diaphragm, or cervical ring with spermicidal gel or 
foam. Subjects who have had a vasectomy at least six months prior to starting enzalutamide
and those whose female sexual partner(s) are more than 55 years of age and postmenopausal 
for at least two years or surgically sterile (tubal ligation, hysterectomy, or bilateral 
oopherectomy) should use at minimum a condom.
Study subjects will be informed that abiraterone acetate may harm a developing fetus; thus, 
women who are pregnant or women who may be pregnant should not handle abiraterone 
acetate  without protection (e.g., gloves). Subjects will also be informed that it is not known 


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whether abiraterone acetate or its metabolites are present in semen and they should use a 
condom if having sex with a pregnant woman. The subject should use a condom and another 
effective method of birth control, if he is having sex with a woman of child-bearing potential. 
These measures are required during and for one week after treatment with abiraterone acetate.
5.5.9
Supply of New Information Affecting the Conduct of the Study
When new information becomes available, including “Dear Doctor Letters” but not limited to 
that, necessary for conducting the clinical study properly will lead to a protocol amendment, 
the sponsor should inform regulatory authorities, as well as all investigators involved in the 
clinical study, who will then inform the IRB/IEC of such information, and when needed, 
should amend the subject information.
5.6
Test Drug Concentration 
5.6.1
Optional PK Sample Collection for Enzalutamide and Metabolites (MDPC0001 
and MDPC0002)
A 2 mL pre-dose blood sample for PK will be collected into an EDTA tube at Day 29. 
Centrifuge the sample to yield plasma and freeze the plasma at approximately-70o C ± 10o  C . 
The sample will be packaged and shipped per sponsor instructions.
The PK samples may be assayed for study drug, metabolites, and/or concomitant medications 
at the discretion of the Sponsor using a validated analytical method.
5.6.2
Optional PK Sample Collection for Abiraterone
A 4 mL pre-dose blood sample for PK will be collected into an EDTA tube at Day 4 and Day 29. 
Centrifuge the sample within 1 hour to yield plasma and freeze the plasma at approximately
-70o C ± 10o  C. The sample will be packaged and shipped per sponsor instructions.
The PK samples may be assayed for study drug, metabolites, and/or concomitant medications 
at the discretion of the Sponsor using a validated analytical method.
5.7
Other Measurements, Assessments, or Methods
5.7.1
Bone Marrow Aspirate and Bone Marrow Biopsy
Bone marrow aspirate and biopsy will be collected at the Screening, Week 9, and at the End of 
Treatment (EOT) visits. If the End of Treatment visit falls between Week 9 and Week 13, and 
the Week 9 bone marrow biopsy and aspiration was performed, then an EOT bone marrow 
biopsy and aspiration will not be required.


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5.7.2
Urine N-telopeptide
A 30 mL random urine sample will be collected at Screening, Week 9, and at the End of 
Treatment (EOT) visits. If the End of Treatment visit falls between Week 9 and Week 13, and 
the Week 9 Urine N-telopeptide was collected, then an EOT collection will not be required.
5.7.3
Blood sample for androgen and androgen precursors levels and bone markers
A separate blood sample will be collected for measuring serum levels of androgens 
(testosterone and DHT) and androgen precursors. Bone alkaline phosphatase (a marker for 
bone metabolism) will be measured from the same tube of the chemistry parameters (see 
Appendix 2).
5.7.4
Archival Prostate Tumor Sample
Archival primary or metastatic prostate tumor tissue will be obtained at the Screening visit and 
used for molecular profiling.
5.7.5
Whole Blood Sample for Optional Genotype Analysis
A whole blood sample (5 mL) for biobanking will be collected at Day 1. In the event of 
unusual pharmacokinetic/pharmacodynamic (PK/PD) patterns or safety findings, genotype 
analysis of relevant metabolism, trans-porter, pharmacodynamic, and/or safety genes will be 
conducted. If there is no requirement for analysis, the whole blood sample will be destroyed. 
Separate subject consent is required. Samples will be collected, prepared and shipped to a 
central laboratory per vendor instructions.
Please refer to Appendix 6 (Optional Pharmacogenomic Sub-study) for detailed instructions.
5.8
Total Amount of Blood
The total amount of blood collected for each subjects will vary depending on how long the 
subjects stays on the study. The maximum amount of blood collected for a subject at each visit
point during the treatment period is approximately 50 mL. However, if a subject is found to have 
laboratory abnormalities or adverse events, additional blood may be drawn for evaluation and/or 
monitoring. Additional diagnostic blood for routine work may also be drawn.
In addition for pharmacokinetics samples the total amount of blood collected for each subject
is approximately 10 mL.
6
TERMINATION OF THE CLINICAL STUDY
When the sponsor is aware of information on matters concerning the quality, efficacy, and 
safety of the study drugs, as well as other important information that may affect proper conduct 
of the clinical study, the sponsor may discontinue the clinical study and send a written notice of 
the discontinuation along with the reasons to the investigator.


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If an investigator intends to discontinue participation in the study, the investigator must 
immediately inform the sponsor of the discontinuation and the reason for it.
For details on early discontinuation of the clinical study please refer to section 3.4.
7
STATISTICAL METHODOLOGY
The statistical analysis will be coordinated by the responsible biostatistician of Astellas. 
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 finalized before 
the database lock. Any deviations from the SAP will be justified in the clinical study report. 
Prior to database lock, a Final Review of Data and 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. 
7.1
Sample Size
A total of 60 subjects will provide sufficient data to assess the safety of the drug combination. 
The sample size and power calculation are based on the change of testosterone concentration or 
gene expressions (i.e. AR and CYP17) before and after therapy, which can be characterized 
base on effect size (i.e. mean difference of testosterone concentration or gene expression 
divided by standard deviation). Considering subjects with baseline and Week 9 laboratory 
results derived from bone marrow samples, a sample of 30 subjects provides 82% power to 
detect a change of testosterone concentration or gene expression with an effect size of at least 
0.55, using a two sided paired t-test at a 0.05 significance level. A total of 60 subjects will be
accrued to obtain at least 30 evaluable patients based on the prediction that the yield of 
evaluable bone marrow samples with prostate cancer cells is approximately 50%.   
7.2
Analysis Set
7.2.1
Safety Analysis Set (SAF)
The Safety Analysis Set will consist of all subjects who received at least one dose of any drug 
of the study combination treatment defined in section 1.3.
The SAF will be used to report all safety and efficacy analyses. 
7.2.2
Biomarker Evaluable Set
The Biomarker Evaluable Set will consist of all subjects with baseline and Week 9 laboratory 
results derived from bone marrow samples. The number of subjects with evaluable results may 
differ for each parameter.
The Biomarker Evaluable Set will be used to assess the effect of treatment on Testosterone/DHT
and androgen receptor signaling in the bone marrow.


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7.2.3
Pharmacokinetic Analysis Set (PKAS)
The PKAS will include the subjects from the SAF population for whom at least one PK pre-
dose concentration is available. Additional subjects may be excluded from the PKAS at the 
discretion of the pharmacokinetics.
The PKAS will be used for all tabular and graphical summaries of the PK data.
7.3
Demographics and Other Baseline Characteristics
Demographic information is to be obtained at screening and will include date of birth, race/
ethnicity as described by the subject, height and weight. Continuous baseline variables will be 
summarized by dose using descriptive statistics (number of observations [n], mean, standard 
deviation [SD], minimum, median, and maximum). Categorical baseline variables will be 
described using absolute and relative frequencies. Data will be listed as appropriate.
7.4
Analysis of Efficacy
All efficacy analyses are carried on secondary variables.
Unless otherwise specified, categorical variables will be summarized as counts and 
percentages, and continuous variables will be summarized using descriptive statistics, number 
of subjects, mean, standard deviation [SD], median, minimum and maximum.

Anti-tumor Activity
Summary statistics will be produced for the SAF. 
Progression-free survival is defined as the time interval from the date of starting treatment until 
the date of documented progression or death in absence of progression. Progression, as a 
composite endpoint, consisting of clinical deterioration, radiographic progression or PSA 
progression according to the PCWG2 criteria. Kaplan-Meier curves will be presented. The 
median and 25th and 75th percentiles will be tabulated, including the corresponding 95%CI 
calculated by use of the Brook Meyer and Crowley method. The number of events and subjects
at risk over time will be tabulated.
For PSA level over time, descriptive statistics including number of subjects, mean, standard 
deviation, median, minimum, and maximum will be provided for baseline value and post-
baseline values, as well as absolute and percent change from baseline. 
The objective response according to RECIST 1.1 and bone scan results will be reported 
through descriptive summaries as described by PCWG2, including the proportion of patients 
showing RECIST 1.1 objective response (partial or complete response).
Bone specific alkaline phosphatase and urine N-telopeptides will be descriptively summarized.

Androgen, androgen receptor signaling, androgen pre-cursors and other associated
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Summary statistics will be produced for the Biomarker Evaluable Set. 
The effect of enzalutamide on bone and serum biomarkers (including androgen pre-cursors and 
androgen expression signaling, androgen pre-cursors and other associated metabolites) will be 
analyzed based on change from baseline to Week 9.
For each biomarker (androgen, androgen expression signaling, androgen pre-cursors and other 
associated metabolites), descriptive statistics including number of subjects, mean, standard 
deviation, median, minimum, and maximum will be provided for baseline value, post-baseline 
value, change from baseline, and percent change from baseline. Graphical display using 
box-plot, histogram and scatter plot will be generated as appropriate.  
Biomarker results collected at baseline assessment and at each post-baseline assessment, if 
appropriate, will be compared using paired t-test to evaluate the effect of enzalutamide. The 
change from baseline in each biomarker will also be summarized by PSA response category, 
where PSA response is a function of percentage improvement from baseline to Week 13. The 
correlation between each biomarker and PSA level will be estimated using Spearman’s 
method.
7.5
Analysis of Safety
All safety analyses are carried on primary variables. Summary statistics will be produced for 
the SAF. Unless otherwise specified, categorical variables will be summarized as counts and 
percentages, and continuous variables will be summarized using descriptive statistics, number 
of subjects, mean, standard deviation [SD], median, minimum and maximum.
Descriptive statistics will be tabulated for the Adverse Events along with their severity 
evaluated by the investigator based on the NCI CTCAE (version 4.03) and coded to preferred 
term, higher level term, and system organ class using MedDRA. The number and percentage of 
subjects with adverse events will be presented by MedDRA system organ class and preferred 
term. Also safety will be assessed through summaries of laboratory evaluations, vital signs, 
physical examinations, and ECGs. Safety analyses will be based on the SAF.  
7.6
Analysis of Pharmacokinetics
Summary statistics will be presented for each pre-dose plasma concentration of abiraterone, 
and enzalutamide and its metabolites MDPC0001 and MDPC0002 by scheduled visit. 
Summary statistics for the concentration data will include number of subjects, mean, SD, 
coefficient of variation (CV), geometric mean, median, minimum and maximum. Further 
details will be specified in the SAP.
Pre-dose concentrations of abiraterone obtained on Day 4 and on Day 29 will be compared to 
assess the potential effect of enzalutamide on the PK of abiraterone. Further details will be 
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7.7
Protocol Deviations and Other Analyses
Drug exposure, including data on dose reduction will be summarized by descriptive statistics
based on study drug accountability.
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.
7.8
Interim Analysis (and Early Discontinuation of the Clinical Study)
Although no formal interim analysis is planned, safety monitoring will be conducted on 
ongoing basis during the trial conduct.
If the probability of Grade 4 due to treatment toxicity is likely to be greater than 10%, based 
on the toxicity information in a 3-month treatment time interval, the trial will be put on hold 
and the data will be reviewed. The trial can be stopped early if the risk of severe toxicity
(defined as any grade 4 toxicity that is possibly attributed to the study agents) has been 
confirmed. Formally, denoting the grade 4 toxicity probability by pTOX and assuming this 
follows a beta(1, 1) prior distribution, the trial will be held if Prob{ pTOX > 0.10 | data}> 
0.95. Following this rule, starting with the 15th subjects, the trial will be held if [# subjects 
with TOX due to treatment]/ [# subjects evaluated] is greater than or equal to 4/15, 6/30, 8/45 
or 10/60. The operating characteristics of this design based on 10,000 simulations per case 
are summarized in the following table.
True Prob(tox)
Pr(stop)
Mean # Pts
0.02
<0.001
59.9
0.05
0.01
59.7
0.10
0.13
55.8
0.20
0.75
34.3
0.30
0.98
20.7
7.9
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information
Imputations for missing data, if applicable, will be addressed 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 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 investigator or designee will enter data collected using an Electronic Data Capture (EDC) 
system.
The monitor should verify the data in the eCRFs with source documents and confirm that there 
are no inconsistencies between them. 
For screening failures, the minimum demographic data (sex, birth date or age, race and 
informed consent date) and reason for screening failure will be collected in screening failure 
log (SFL), if applicable.
8.1.2
Specification of Source Documents
Source data must be available at the site to document the existence of the study subjects and 
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 in the source medical records:

Demographic data (age, sex, race, ethnicity, height and body weight)

Inclusion and exclusion criteria details

Participation in study and signed and dated informed consent forms 

Visit dates

Medical history and physical examination details

Key efficacy and safety data, if applicable (as specified in the protocol)

Adverse events and concomitant medication (if applicable)

Results of relevant examinations (e.g., ECG charts, X-ray films etc.)

Laboratory printouts (if applicable)

Dispensing and return of study drug detail

Reason for premature discontinuation (if applicable)

Randomization number (if applicable)
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 


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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 Global Data Science Department of the sponsor 
in accordance with the standard operating procedures (SOPs) for data management. All study 
specific processes and definitions will be documented by Data Management. CRF completion
and correction process will be referenced in the CRF instructions. Coding of medical terms will 
be performed using MedDRA. 
The study database will be soft-locked when all data that are specified in the study protocol to 
be collected have been received and cleaned according to applicable SOPs. It will be hard-
locked when a data review meeting has been held, and all data related decisions have been 
made and reflected in the database.
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 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. 
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 


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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 (TMF).  
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)
The investigator shall make accurate and adequate written progress reports to the IRB at 
appropriate intervals, not exceeding one year. The 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, or for APEB/APEL-sponsored studies within one year after last patient out 
(LPO) or termination of the study.
8.2.2
Ethical Conduct of the Study
The investigator(s) and all parties involved in this study should conduct the study in adherence 
to GCP, ICH Guidelines and the applicable laws and regulations.
8.2.3
Informed Consent of Subjects
8.2.3.1 Subject Information and Consent
Prior to execution of the clinical study, the investigator should prepare the written informed 
consent form and other written information in collaboration with the sponsor and revise the 
information whenever necessary. The written informed consent form and any other written 
information should be submitted to the sponsor and be subject to prior approval by the 
Institutional Review Board/Independent Ethics Committee (IRB/IEC).

The investigator/sub-investigator is responsible for explaining the nature and purpose of 
the study as well as other study-related matters to subjects, using the written information, 
and for obtaining their full understanding and written consent to participate in the study 
of their own free will.


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
The investigator or other responsible personnel who provided explanations (including 
collaborators who gave supportive information, if applicable) and the subject should sign 
and date the written information, or write down his/her name, and date the form.

Informed consent must be obtained by the time that the first observations / examinations 
of the pre-investigational period are performed. Guardian consent should be obtained 
from the proxy consenter, before start of pre-investigational period.

The investigator or other responsible personnel must give a copy of the signed consent 
form to the subject and store the original appropriately in accordance with the rules at the 
study site concerned. 

The investigator or other responsible personnel should note the following when 
obtaining consent from subjects:
・No subject may be subjected to undue influence, such as compulsory enrollment into 
a study.
・The language and expressions used in the written information should be as plain and 
understandable as possible. Subjects should be given the opportunity to ask questions 
and receive satisfactory answers to the inquiry, and should have adequate time to 
decide whether or not to participate in the study. Written information should not 
contain any language or contents that causes the subject to waive or appears to waive 
any legal rights, or that releases/mitigates or appears to release/mitigate the study site, 
the investigator/sub-investigator, collaborators, or the sponsor from liability for 
negligence.
The signed consent forms will be retained by the investigator and made available (for review 
only) to the study monitor and auditor 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/sub-investigator 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 participation in the study (e.g., report of 
serious adverse drug reactions). The communication should be documented in the
subject's medical records, and it should be confirmed whether the subject is willing to 
remain in the study or not. 
2. If the investigator recognizes the necessity to revise the written information in the terms 
and conditions applicable to paragraph 1, the written information should be revised 
immediately based upon the newly available information, and be re-approved by the 
IRB/IEC. 
3. The investigator/sub-investigator should obtain written informed consent to continue 
participation with the revised written information defined in paragraph 2, even if subjects 
are already informed of the relevant information orally. The investigator or other 
responsible personnel who provided explanations (including collaborators who gave 
supportive information, if applicable) and the subject should sign and date the informed 
consent form, or write down his/her name and date the form. The investigator or other 


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responsible personnel should give a copy of the signed informed consent form to the 
subject who had given consent with the written information and store the original 
appropriately as done for the previous informed consent.
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 (PHI) 
obtained during a research study complies with the federal and/or regional legislation related to 
the privacy and protection of personal information (i.e. HIPAA).
For US sites, the HIPAA Privacy Rule provides federal protection for the privacy of PHI by 
implementing standards to protect and guard against the misuse of individually identifiable 
health information of subjects participating in sponsored clinical trials. "Authorization" is 
required from each research subject, i.e. specific permission granted by an individual to a 
covered entity for the use or disclosure of an individual's PHI. A valid authorization must meet 
the implementation specifications under the HIPAA Privacy Rule. Authorization may be 
combined into the Informed Consent document (approved by the IRB/IEC) or it may be a 
separate document (approved by the IRB/IEC or designed PB) or provided by the investigator 
or sponsor (without IRB/IEC or PB approval). It is the responsibility of the investigator and 
institution to obtain such waiver/authorization in writing from the appropriate individual.
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 


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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.
The study will be considered for publication or presentation at (scientific) symposia and 
congresses. The investigator will be entitled to publish or disclose the data generated at their 
respective study site only after submission to the sponsor all transcripts, texts of presentations, 
and abstracts related to the study at least 90 days prior to the intended submission for 
publication or any other disclosure for API and/or APEB/APEL-sponsored studies or 30 days 
prior for APGD-sponsored studies. This is necessary to confirm whether any inventive 
knowledge should be protected by a patent or not and to prepare and file a patent application 
accordingly. In addition this is in no way intended to restrict publication of facts or opinions 
formulated by the investigator. The sponsor will inform the investigator in writing of any 
objection or question arising within 30 days of receipt of the proposed publication material.
8.3.2
Documents and Records Related to the Clinical Study
The sponsor will provide the investigator and/or institution with the following:

Study protocol (and amendments, as applicable)

Investigator’s Brochure (and amendments, as applicable)

CRFs and SAE Report Worksheet

Study drug with all necessary documentation

Study contract
In order to start the study, the investigator and/or study site is required to provide the following 
documentation to the sponsor: 

Financial disclosure in compliance with federal regulation 21CFR Part 54

Signed Investigator's Statement in this protocol

Executed Research Agreement

Signed and dated FDA form 1572

Copy of the approved ICF and separate authorization form, if appropriate.

Independent Ethics Committee/IRB approval of the protocol, protocol amendments 
(if applicable) and ICF (and separate authorization form, if appropriate), stating 
clearly the sponsor's name, study number and study drug, including a membership list 
with names and qualifications.

Current Curricula Vitae of all investigators (signed and dated)

Laboratory normal reference ranges (if applicable, signed and dated by the 
responsible laboratory employee)

Medical/Laboratory/Technical procedures/tests certifications or accreditations or 
established quality control or other validation, where required.
At the end of the study, the sponsor is responsible for the collection of:

Unused CRFs and other study documentation,

Unused study drug


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The investigator will archive all study data (e.g., Subject Identification Code List, source data, 
CRFs, 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 NDA or discontinuation of the IND). It is recommended, however, that records 
be retained for at least five years in the event follow-up is necessary to help determine any 
potential hazards to subjects who took part in the study. The sponsor will notify the
site/investigator if the NDA is approved or if the IND is discontinued. The investigator agrees 
to obtain the sponsor's agreement prior to disposal, moving, or 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 CRFs supplied for 
each subject. 
Data may be transcribed legibly on CRFs supplied for each subject or directly inputted into an 
electronic system or any combination thereof.
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 amendments and/or non-substantial amendments. Depending 
on the nature of the amendment, either IRB/IEC Competent Authority approval or notification 
is 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
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


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Principal Investigator(s) will be selected from the participating investigators by the Sponsor 
prior to database lock.
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 
(record), and reported in compliance with the protocol, GCP, and applicable regulatory 
requirement(s).
The Sponsor or Sponsor's designee may arrange to inspect/audit the clinical study at any or all 
investigational sites. The auditor is independent from the clinical monitoring and project 
management team at the Sponsor. 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) ׀Data Monitoring 
Committee (DMC) 
Not applicable.
10.2
Other Evaluation Committee(s)
Not applicable.
10.3
Other Study Organization
Not applicable.


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11
REFERENCES
Abiraterone acetate, ZYTIGA (Package Insert). Horsham, PA: Centocor Ortho Biotech Inc.; April 2011.  
de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, et al. Abiraterone and increased survival 
in metastatic prostate cancer. N Engl J Med 2011; 346, 21.
Duc I, Bonnet P, Duranti V, Cardinali S, Rivière A, De Giovanni A, et al. In vitro and in vivo models for 
the evaluation of potent inhibitors of male rat 17α -hydroxylase/C17,20 lyase. J Steroid Biochem 
Mol Biol 2003; 84(5):537-42.
Efstathiou E, Titus M, Tsavachidou D, Vassiliki Tzelepi, Wen S, Hoang A, et al. Effects of Abiraterone 
Acetate on Androgen Signaling in Castrate-Resistant Prostate Cancer in Bone. J Clin Oncol 2011.
Efstathiou E, Logthetis CJ. A New Therapy Paradigm for Prostate Cancer Founded on Clinical 
Observations. Clin Cancer Res 2010; 16(4):1100-1107.
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-
247.
Foster WR, Car BD, Shi H et al. Drug safety is a barrier to the discovery and development of new 
androgen receptor antagonists. Prostate 2011; 71(5):480-488.
Haidar S, Ehmer PB, Barassin S, Batzl-Hartmann C, Hartmann RW . Effects of novel 17α-hydroxylase/
C17, 20 lyase (P45017α, CYP 17) inhibitors on androgen biosynthesis in vitro and in vivo. J 
Steroid Biochem Mol Biol 2003; 84(5):555-62.
Ideyama Y, Kudoh M, Tanimoto K, Susaki Y, Nanya T, Nakahara T, et al. Novel nonsteroidal inhibitor 
of cytochrome P45017α) (17α -hydroxylase/C17-20 lyase), YM116, decreased prostatic weights 
by reducing serum concentrations of testosterone and adrenal androgens in rats. Prostate 1998;
37(1):10-8. 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity And 
Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5:649-
655.
Prednisolone 5 mg (Package Insert). Devon, UK: Actavis UK Ltd.; July 2011.  
Scher HI, Beer TM, Higano CS, Anand A, Taplin ME, Efstathiou E, et al. Antitumor activity of 
MDV3100 in castration-resistant prostate cancer: a phase 1–2 study. Lancet 2010; 375: 1437–46.
Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, et al. Design and end points of 
clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: 
recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol 2008; 
26:1148-5.
Company Reports
Investigator’s Brochure. MDV3100 for the treatment of cancer. 5th edition. Medivation, Inc., 
23 March 2012.


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12
APPENDICES
12.1
Appendix 1:   List of  Excluded Concomitant Medication
Prohibited drugs 
cyproterone acetate
flutamide
nilutamide
bicalutamide
finasteride
dustasteride
estrogens
megestrol
medroxyprogesterone 
DES
cyproterone
spirinolactone
testosterone 
dehydroepiandrosterone
ketoconazole
saw Palmetto
Note that this drug list is not all inclusive, please contact the Medical Monitor with questions.
Please reference section 5.1.3.


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12.2
Appendix 2:   Laboratory Tests
Test
Visit
Collecting Tube
Parameters to be Analyzed
Hematology
All visits, except Day 4
EDTA tube 
Hemoglobin
Hematocrit
Erythrocytes (RBC)
Leukocytes (WBC) 
Differential WBC
Platelets
PT/PTT & INR
All visits, except Day 4
Citrate tube
PT/PTT & INR
Chemistry
All visits, except Day 4
Serum tube 
Sodium
Potassium
Calcium
Chloride
Magnesium
Phosphorus
Glucose
Creatinine
Alkaline phosphatase
LDH
AST
ALT
Direct bilirubin
Total bilirubin
Total protein
Albumin
CO2
BUN
Bone alkaline phosphatase
PSA
All visits, except for Day 4
Serum tube 
PSA
Urine N-
telopeptide
Screening, Week 9 and at 
the end of treatment (ET). If 
the ET visit falls between 
Week 9 and Week 13, and 
the Week 9 Urine N-
telopeptide was collected, 
then an ET collection will 
not be required.
30 mL random urine 
sample
Urine N-telopeptide
Androgen, 
androgen 
expression 
signaling, 
androgen pre-
cursors and other 
associated 
metabolites
Screening, Week 9 and at 
the end of treatment (ET). If 
the ET visit falls between 
Week 9 and Week 13, and 
the Week 9 samplewas 
collected, then an ET 
collection will not be 
required.
Serum tube (red top, 
no additive), Sodium 
Heparin tube
androgen, androgen expression 
signaling, androgen pre-cursors 
and other associated metabolites
Blood sample for 
genotype analysis
Day 1
K3EDTA tube
Genotype analysis
Blood sample for 
PK analysis
Day 4 and Week 5
K2EDTA tube
PK analysis


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12.3
Appendix 3:  Liver Safety Monitoring and Assessment
If laboratory testing for a subject enrolled in study and receiving study drug reveals an increase 
of serum aminotransferases (AT) to > 3X ULN, or bilirubin > 2X ULN, at least all four of the 
usual serum hepatic measures (ALT, AST, ALP, and TBL) should be repeated. Testing should 
be repeated within 48-72 hours of notification of the test results. For studies for which a central 
laboratory is used, alerts will be generated by the central lab regarding moderate and marked 
liver abnormality to inform the investigator, study monitor and study team. Subjects should be 
asked if they have any symptoms suggestive of hepatobiliary dysfunction.
Definition of Liver Abnormalities
Confirmed abnormalities will be characterized as moderate and marked where ULN:
ALT or AST
Total Bilirubin
Moderate
> 3 x ULN
or
> 2 x ULN
Marked
> 3 x ULN
and
> 2 x ULN
In addition, the subject should be considered to have marked hepatic abnormalities for any of 
the following:

ALT or AST > 8X ULN

ALT or AST > 5X ULN for more than 2 weeks

ALT or AST > 3X ULN and INR > 1.5

ALT or AST > 3X ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%). 
The investigator may determine that abnormal liver function results, other than as described 
above, may qualify as moderate or marked abnormalities and require additional monitoring and 
follow-up.
Follow-up Procedures
Confirmed moderate and marked abnormalities in hepatic functions should be thoroughly 
characterized by obtaining appropriate expert consultations, detailed pertinent history, physical 
examination and laboratory tests. The site should complete the Liver Abnormality Case Report 
Form (LA-CRF) or an appropriate document. Subjects with confirmed abnormal liver function 
testing should be followed as described below. 
Confirmed moderately abnormal LFTs should be repeated 2-3 times weekly then weekly or 
less if abnormalities stabilize or the study drug has been discontinued and the subject is 
asymptomatic.  
Marked hepatic liver function abnormalities, in the absence of another etiology, may be 
considered an important medical event and reported as a Serious Adverse Event (SAE). The 
sponsor should be contacted and informed of all subjects for whom marked hepatic liver 
function abnormalities possibly attributable to study drug are observed.


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To further assess abnormal hepatic laboratory findings, the investigator is expected to:

Obtain a more detailed history of symptoms and prior or concurrent diseases. Symptoms 
and new onset-diseases should be recorded as ’adverse events’ on the AE page of CRF. 
Illnesses and conditions such as hypotensive events, and decompensated cardiac disease 
that may lead to secondary liver abnormalities should be noted. Non-alcoholic 
steatohepatitis (NASH) is seen in obese hyperlipoproteinemic, and/or diabetic patients 
and may be associated with fluctuating aminotransferase levels. The investigator should 
ensure that the medical history form captures any illness that pre-dates study enrollment 
that may be relevant in assessing hepatic function. 

Obtain a history of concomitant drug use (including non-prescription medication, 
complementary and alternative medications), alcohol use, recreational drug use, and 
special diets. Medications, including dose, should be entered on the concomitant 
medication page of CRF. Information on alcohol, other substance use, and diet should be 
entered on the LA-CRF or an appropriate document.

Obtain a history of exposure to environmental chemical agents

Based on the subject’s history, other testing may be appropriate including: 
1. acute viral hepatitis (A,B, C, D, E or other infectious agents). 
2. ultrasound or other imaging to assess biliary tract disease
3. other laboratory tests including INR, direct bilirubin

Consider gastroenterology or hepatology consultations

Submit results for any additional testing and possible etiology on the LA-CRF or an 
appropriate document.
Study Discontinuation
In the absence of an explanation for increased LFTs, such as viral hepatitis, pre-existing or 
acute liver disease or exposure to other agents associated with liver injury, the subject may be 
discontinued from the study. The investigator may determine that it is not in the subject’s 
best interest to continue study enrollment. 
Discontinuation of treatment must occur if:

ALT or AST > 8X ULN

ALT or AST > 5X ULN for more than 2 weeks

ALT or AST > 3X ULN and (TBL > 2X ULN or INR > 1.5)
Discontinuation of treatment should be considered if:
ALT or AST > 3X ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%).
In addition, if close monitoring for a subject with moderate or marked hepatic laboratory tests 
is not possible, drug should be discontinued.
Reference
Guidance for Industry titled “Drug-Induced Liver Injury: Premarketing Clinical Evaluation” 
issued by FDA on July 2009.


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12.4
Appendix 4:  Common Serious Adverse Events
The following is a list of serious adverse events that the Sponsor considers to be associated 
with the disease state being studied. The list does NOT change your reporting obligations or 
prevent the need to report an adverse event 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 you that some events reported as SAEs may not require expedited reporting to the 
regulatory authorities based on the classification of “common serious adverse events”. You are 
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 indicate they occur more 
frequently with study drug, an expedited IND safety report may be submitted to the FDA.  

Anemia 

Anorexia 

Asthenia / Fatigue

Back pain 

Bone pain

Catheter related infection 

Dyspnea

Haematuria 

Hydronephrosis 

Metastases to bone 

Metastases to central nervous system 

Nausea 

Obstructive uropathy 

Pain 

Prostate cancer metastatic 

Renal failure 

Renal failure acute 

Spinal compression fracture 

Spinal cord compression 

Urinary retention 

Urinary tract infection 

Urinary tract obstruction 

Vomiting


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12.5
Appendix 5:  Soft Tissue Assessment (RECIST 1.1)
Reproduced from: Eisenhauer EA, Therasse P, Bogaerts J et al. New response 
evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J 
Cancer 2009; 45:228-247.


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12.6
Appendix 6: Optional Pharmacogenomic Sub-study
INTRODUCTION
Pharmacogenomics research aims to provide medical information regarding how variations in a
subject’s gene function and/or expression based on their genetic polymorphism may impact what
treatment options are best suited for that subject. Through investigation of pharmacogenomics
via such technologies as gene sequencing, statistical genetics and gene expression analysis, the
relationship between gene profiles and a drug’s efficacy or toxicity may be better understood.
Because many diseases may develop as a result of one or more genetic mutations, pharmaco-
genomics research may identify the genes that are involved in determining whether a subject
may or may not respond to a drug.
STUDY OBJECTIVES
The pharmacogenomic research that will be conducted in the future with acquired blood 
samples is exploratory. The objective of this research is to comprehensively analyze:

Suspected disease-related genes;

Genes of relevance to clinical response, pharmacokinetics, and toxicity/safety issues, 
to be identified in a precautionary/retrospective setting.
By analyzing differing genetic polymorphisms, it may be possible to predict genetic effect on 
an individual subject’s response to enzalutamide.
STUDY POPULATION
Subjects who have consented to participate in the 9785-CL-0011 study may also participate in
this optional sub-study. As part of this sub-study, subjects must provide written consent prior 
to providing any blood samples that will be used at a later time for the genetic analysis.
SITE SAMPLE COLLECTION
Subjects who consent to participate in this sub-study will provide one 5 mL sample of whole
blood on visit Day 1 per vendor preparation instructions. Each sample will be identified with a
unique subject identifier. Sample will be shipped to a Sponsor designated central laboratory.
Samples will be anonymized prior to analysis.
CENTRAL LABORATORY AND PHARMACOGENOMIC RESEARCH
LABORATORY PROCESSING AND STORAGE / SAMPLE ANONYMIZATION
Upon receipt, the central laboratory will identify each sample by subject number and initials
utilizing the shipment documents accompanying each sample. Samples will be stored frozen
until prompted by Astellas. When prompted, the central laboratory will ship the samples to a
separate laboratory for prolonged storage.
When samples are shipped from the central laboratory to the prolonged storage laboratory, they
will be identified solely by subject number. Once received at the prolonged storage laboratory,


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the samples will be assigned a unique sample code and stored frozen. A table linking the 
subject number with newly-assigned sample code will be provided to the Astellas’ code 
administrator.
Once the table is provided to Astellas and receipt acknowledged, the link between the subject
number and sample code held at the prolonged storage laboratory will be broken.
ASSOCIATING CLINICAL DATA WITH SAMPLE CODES
Before the pharmacogenomics research begins, the Astellas’ code administrator will provide
Astellas with the linkage table. Astellas will associate clinical data related to finding with each
subject number and corresponding sample code. The clinical data with the corresponding 
sample codes (without associated subject numbers) will be provided to the Astellas Research 
Laboratory, who will be responsible for the genetic analysis. After which, the original linkage 
table and any copies containing the subject number and sample code provided to Astellas will 
be destroyed by Astellas. No pharmacogenomics data will be traceable back to the original 
subject number.
PHARMACOGENOMIC ANALYSIS
The detailed content of the pharmacogenomic analysis has not been determined. Astellas will
initiate the pharmacogenomic research after the targeted genes have been identified. In the 
event of unusual PK/PD patterns or safety findings, genotype analysis or relevant metabolism, 
transporter, pharmacodynamic and/or safety genes will be conducted. If there is no requirement 
for analysis, the whole blood sample will be destroyed.
DISPOSAL OF PHARMACOGENOMIC SAMPLES/DATA
All collected pharmacogenomic samples will be maintained for a period of up to 15 years
following database hardlock. In addition, the Astellas Research Laboratory will retain all raw
data and records pertaining to the study for the period of at least 15 years or unless otherwise
notified by the Sponsor. At the conclusion of the retention period, Astellas will instruct the
central or pharmacogenomics research laboratory to destroy all remaining samples, data and
records.
SUBJECT INFORMED CONSENT
This pharmacogenomic sub-study is independent of the clinical study. Each subject 
participating in the clinical study may choose whether or not to consent to provide pharmaco-
genomic blood samples. Refusal to consent to the pharmacogenomic research or withdrawal of 
pharmacogenomic consent will not result in any penalty in regards to participation in the 
clinical study or further treatment received.
Prior to providing any blood samples as part of the pharmacogenomic sub-study, separate 
written informed consent must be obtained. A subject has the irrevocable right to withdraw 
consent from solely the pharmacogenomic research at any point during or after completion of 
the clinical study. Once pharmacogenomic consent is withdrawn, the subject’s samples will be 


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destroyed. However, any genetic analysis data which had been obtained from the subject’s 
analyzed samples at the time of withdrawal may be used after withdrawal.
INFORMATION DISCLOSURE TO THE SUBJECTS
The exploratory pharmacogenomics research will be conducted following the conclusion of the
clinical study. The results of the genetic analysis will not be provided to any Investigators or
subjects nor can the results of the genetic analysis be requested at a later date. Any information 
that is obtained from the pharmacogenomic research in relation to the contents of the 
pharmacogenomic research protocol, results of the correlation between genetic data and subject 
response or toxicity, etc. belong to Astellas.
SITE PARTICIPATION IN THE PHARMACOGENOMICS SUB-STUDY
Participation in the pharmacogenomic sub-study at a given site is contingent on the site’s
Institutional Review Board/Ethics Committee/Regulatory Authority approval and on specific
local regulations when applicable. If a site’s IRB/EC/Regulatory Authority does not approve 
the sampling for the pharmacogenomic research, this section will not be applicable to that site.


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13
ATTACHMENT 1: SUBSTANTIAL AMENDMENT 2
I.  The purpose of this amendment is:
Substantial Changes
1.  Secondary Variables
DESCRIPTION OF CHANGE:
Re-organized the presentation of the secondary variables into groups and added variables that 
will that will be included in the analysis.
RATIONALE:
To provide clarification on the secondary variables in the analysis.
2.  Statistical Methods
DESCRIPTION OF CHANGE:
Reclassified the testosterone and DHT as androgens and added androgen pre-cursors and 
other associated metabolites to the efficacy analysis.
RATIONALE:
To provide details on the efficacy analysis and align with the changes in the secondary 
variables. 
3.  Description of the Study Drug
DESCRIPTION OF CHANGE:
Amended the description of the study drug to include the capsules that are marked with 
“ENZ”.
RATIONALE:
To update the description of the study drug.
Non-Substantial Changes
1.  Update Contact Details of Key Sponsor’s Personnel
DESCRIPTION OF CHANGE:
Contact information of the Clinical Research Contact and Medical Monitor are updated
RATIONALE:
To update Sponsor personnel assigned to the study and to update Medical Monitor’s contact 
information.


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2.  Update Planned Study Period
DESCRIPTION OF CHANGE:
The planned study period used projected quarter and is being modified to use the actual study 
start date and a planned completion date.
RATIONALE:
To update the study period to reflect current estimates.
3.  Add Footnote to Table 2
DESCRIPTION OF CHANGE:
Added a footnote to the table instructing the reader to refer to the Investigator’s Brochure for 
up to date information.
RATIONALE:
To provide a reference to the Investigator’s Brochure for the current safety information.
4.  Update Study Design
DESCRIPTION OF CHANGE:
Removed the statement that subjects with only PSA progression will not be removed from 
the study  
RATIONALE:
To allow subjects with only PSA progression to discontinue from the study if it is in their 
best interest.
5.  Update Exploratory Variables
DESCRIPTION OF CHANGE:
Added a statement that other variables that have not been identified yet may be explored 
during the study.
RATIONALE:
To provide flexibility in the options for performing exploratory analyses.
6.  Update Discontinuation Criteria
DESCRIPTION OF CHANGE:
Removed the word “either” from the first discontinuation criteria.
RATIONALE:
To correct the grammatical error.


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7.  Change in Adverse Event Reporting
DESCRIPTION OF CHANGE:
The statement on the adverse event reporting period was modified to including the reporting 
of adverse events for 30 days post last dose of study drug.  Duplicate and incorrectly placed 
information was also deleted or moved to an appropriate section.
RATIONALE:
To clarify the adverse event reporting period.
8.  Change to Adverse Events of Possible Hepatic Origin
DESCRIPTION OF CHANGE:
Moved the reference to Appendix 12.3, Liver Safety Monitoring and Assessment, to this 
section of the protocol.
RATIONALE:
To place the reference in a more appropriate location
9.  Definition of Serious Adverse Events
DESCRIPTION OF CHANGE:
Clarified the reporting period of SAEs by removing the term “termination of the study” and 
replacing it with a more specific description.
RATIONALE:
To clarify the SAE reporting period.
10.  Procedure in Case of Pregnancy
DESCRIPTION OF CHANGE:
Removed the incorrect reference that the pregnancy should be reported within 30 days of 
discontinuing study drug.
RATIONALE:
To correct the reporting period for a pregnancy.
11.  Blood Sample for Androgen Levels
DESCRIPTION OF CHANGE:
Added a reference to testing the blood for androgen precursors.
RATIONALE:
To align the text with the new secondary variables.


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12.  Analysis of Efficacy
DESCRIPTION OF CHANGE:
The text was revised to match the changes in the secondary variables by adding angrogen, 
androgen precursors, and associated metabolites.  References to testosterone and DHT was 
removed since they are covered under the term androgen. Other small changes were made to 
fix grammatical error
RATIONALE:
To align the analysis with the new secondary variable and to correct grammatical errors
13.  Laboratory Tests  
DESCRIPTION OF CHANGE:
Replaced references to testosterone and DHT with Androgen, androgen expression signaling, 
androgen pre-cursors and other associated metabolites.
RATIONALE:
To align the laboratory test descriptions with the new secondary variables.
14. Common Adverse Events
DESCRIPTION OF CHANGE:
Added text based on standards to further describe the process for handling common serious 
adverse events
RATIONALE:
To update the text to reflect standard language.
15. Other Minor Administrative-type Corrections
DESCRIPTION OF CHANGE:
Include minor administrative corrections, e.g., spelling, grammar, consistency.
RATIONALE:
To ensure accuracy and clear understanding of protocol content.




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IS AMENDED TO:
From 10 July 20122Q2012 to 17 June 20144Q2013
IV.  SYNOPSIS, Secondary Variables
Page 19
WAS:

Testosterone concentration in bone marrow aspirate and blood

DHT concentration in bone marrow aspirate and blood

Expression and localization of AR

Splice variants

CYP17 expression

PSA levels

Progression Free Survival (PFS)

Objective response according to RECIST 1.1

Bone scan results

Markers of bone metabolism (bone specific alkaline phosphatase and urine N-
telopep`tides)
IS AMENDED TO:

Androgen receptor signaling
o
Expression and localization of AR 
o
CYP17 expression
o
Splice variants

Pathways linked with non-classical AR signaling & Bone development
Androgens 
o
Testosterone concentration in bone marrow aspirate and blood
o
DHT concentration in bone marrow aspirate and blood

Androgen pre-cursors and other associated metabolites.  For example:
o
Cortisol
o
Androstenedione
o
Pregnenolone
o
Progesterone

PSA levels

Progression-free Survival (PFS)

Objective response according to RECIST 1.1

Bone scan results

Markers of bone metabolism (bone specific alkaline phosphatase and urine N-
telopep`tides)

Testosterone concentration in bone marrow aspirate and blood

DHT concentration in bone marrow aspirate and blood

Expression and localization of AR

Splice variants

CYP17 expression


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IV.  SYNOPSIS, Statistical Methods
Page 20
WAS:
Efficacy analysis will be conducted on all enrolled subjects who received any amount of 
study drug. Progression free survival (PFS) is defined as the time interval from the date of 
starting treatment until the date of documented progression or death in absence of 
progression. PFS will be reported using Kaplan-Meier methods, including the median and its 
95% CI. PSA and PSA change from baseline over time will be descriptively summarized. 
Proportion of patients showing RECIST 1.1 objective response (partial or complete 
response) will be descriptively summarized. Bone specific alkaline phosphatase and urine N-
telopeptides will be descriptively summarized.
Proportion of patients showing RECIST 1.1 objective response (partial or complete 
response) will be descriptively summarized. Bone specific alkaline phosphatase and urine N-
telopeptides will be descriptively summarized.

Testosterone/DHT and Androgen Receptor Signaling
Considering subjects with baseline and Week 9 laboratory results derived from bone marrow 
samples, testosterone, DHT, and androgen receptor signaling will be summarized by 
descriptive statistics and a paired t-test at a 0.05 level of significance will be performed on 
the change from baseline at Week 9.
IS AMENDED TO:
Efficacy analysis will be conducted on all enrolled subjects who received any amount of 
study drug. Progression-free survival (PFS) is defined as the time interval from the date of 
starting treatment until the date of documented progression or death in absence of 
progression. PFS will be reported using Kaplan-Meier methods, including the median and its 
95% CI. PSA and PSA change from baseline over time will be descriptively summarized. 
Proportion of patients showing RECIST 1.1 objective response (partial or complete 
response) will be descriptively summarized. Bone specific alkaline phosphatase and urine N-
telopeptides will be descriptively summarized.
Proportion of patients showing RECIST 1.1 objective response (partial or complete 
response) will be descriptively summarized. Bone specific alkaline phosphatase and urine N-
telopeptides will be descriptively summarized.

Androgens, Testosterone/DHT and Androgen Receptor Signaling, Androgen pre-
cursors and other associated metabolites
Considering subjects with baseline and Week 9 laboratory results derived from bone marrow 
samples, testosterone, DHT androgens, and androgen receptor signaling, androgen pre-
cursors and other associated metabolites will be summarized by descriptive statistics and, 
if appropriate, a paired t-test at a 0.05 level of significance will be performed on the change 
from baseline at Week 9.


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1.3.1 Enzalutamide
Page 29
WAS:
Table 2: Summary of Study Drug Exposure, Adverse Events, and Deaths (CRPC2)
Treated (Safety Population)
enzalutamide 
(n = 800)
Placebo 
(n = 399)
Discontinued Treatment
569 (71.1%)
380 (95.2%)
Treatment Duration (median months)
8.3
3.0
Patients with ≥ 1 Treatment Emergent Adverse Event 
785 (98.1%)
390 (97.7%)
Patients with ≥ 1 Treatment Emergent Adverse Event  (Grade 3 or 
Higher)
362 (45.3%) 
212 (53.1%)
Patients with ≥1 Serious Treatment Emergent Adverse Event
268 (33.5%)
154 (38.6%)
Patients with an Adverse Event Leading to Death
23 (2.9%)
14 (3.5%)
Patients with Adverse Events Leading to Study Drug Discontinuation
61 (7.6%)
39 (9.8%)
SUSARs (all in unique patients)
10
6
Deaths
308 (38.5%)
212 (53.1%)
IS AMENDED TO:
Table 2: Summary of Study Drug Exposure, Adverse Events, and Deaths (CRPC2)*
Treated (Safety Population)
enzalutamide 
(n = 800)
Placebo 
(n = 399)
Discontinued Treatment
569 (71.1%)
380 (95.2%)
Treatment Duration (median months)
8.3
3.0
Patients with ≥ 1 Treatment Emergent Adverse Event 
785 (98.1%)
390 (97.7%)
Patients with ≥ 1 Treatment Emergent Adverse Event  (Grade 3 or 
Higher)
362 (45.3%) 
212 (53.1%)
Patients with ≥1 Serious Treatment Emergent Adverse Event
268 (33.5%)
154 (38.6%)
Patients with an Adverse Event Leading to Death
23 (2.9%)
14 (3.5%)
Patients with Adverse Events Leading to Study Drug Discontinuation
61 (7.6%)
39 (9.8%)
SUSARs (all in unique patients)
10
6
Deaths
308 (38.5%)
212 (53.1%)
*For up to date study information refer to the current edition of the Investigator’s Brochure


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1.3.2 Abiraterone Acetate
Page 31, Paragraph 4
WAS:
Hepatotoxicity:  Increases in liver enzymes have lead to drug interruption, dose modification 
and/or discontinuation. Liver function should be monitored and modify, interrupt, or 
discontinue abiraterone acetate dosing as recommended. Study subjects will have liver 
function tests (including alkaline phosphatase, AST, ALT, direct and total bilirubin, and 
LDH) every 2 weeks for the first 12 weeks of treatment.
IS AMENDED TO:
Hepatotoxicity:  Increases in liver enzymes have leadled to drug interruption, dose 
modification and/or discontinuation. Liver function should be monitored and modify, 
interrupt, or discontinue abiraterone acetate dosing as recommended. Study subjects will 
have liver function tests (including alkaline phosphatase, AST, ALT, direct and total 
bilirubin, and LDH) every 2 weeks for the first 12 weeks of treatment.
2.2.1 Study Design
Page 34
WAS:
This is an open label study to determine the safety and tolerability of enzalutamide in 
combination with abiraterone acetate plus prednisone in CRPC subjects with bone metastases 
by clinical evaluations at protocol specified intervals. The study will also determine the 
modulation of androgen receptor (AR) signaling in bone marrow biopsy and androgen levels 
as measured by testosterone concentration in bone marrow aspirate and blood by Liquid 
Chromatography Mass spectrometry, expression of AR and its subcellular localization by 
immunohistochemistry (IHC), presence of known and assessable splice variants and CYP17 
expression in epithelial and host compartment of the cancer by IHC. Tumor tissue will be 
collected to determine AR signaling and candidate pathways that may be part of a signaling 
network implicated in therapy resistance. The baseline determination and subsequent 
assessment of AR signaling will be correlated with progression free survival (radiographic 
progression, PSA progression, and/or clinical deterioration).
Approximately 60 subjects will receive enzalutamide 160 mg daily, abiraterone acetate 
1,000 mg daily, and prednisone 5 mg twice daily to be taken orally. 
Throughout the study, safety and tolerability will be assessed by the recording of adverse 
events, monitoring of vital signs and physical examinations, safety laboratory evaluations,
and 12-lead electrocardiograms (ECGs).
The occurrence of an adverse event or toxicity, where continued administration of study drug 
is deemed to be not in the subject’s best interest by the investigator and/or the sponsor, will
result in the removal of the subject from therapy.  
For the study duration, all subjects will maintain androgen deprivation with an GnRH agonist 
or antagonist or orchiectomy. 


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IS AMENDED TO:
This is an open label study to determine the safety and tolerability of enzalutamide in 
combination with abiraterone acetate plus prednisone in CRPC subjects with bone metastases 
by clinical evaluations at protocol specified intervals. The study will also determine the 
modulation of androgen receptor (AR) signaling in bone marrow biopsy and androgen levels 
as measured by testosterone concentration in bone marrow aspirate and blood by Liquid 
Chromatography Mass spectrometry, expression of AR and its subcellular localization by 
immunohistochemistry (IHC), presence of known and assessable splice variants and CYP17 
expression in epithelial and host compartment of the cancer by IHC. Tumor tissue will be 
collected to determine AR signaling and candidate pathways that may be part of a signaling 
network implicated in therapy resistance. The baseline determination and subsequent 
assessment of AR signaling will be correlated with progression-free survival (radiographic 
progression, PSA progression, and/or clinical deterioration).
Approximately 60 subjects will receive enzalutamide 160 mg daily, abiraterone acetate 
1,000 mg daily, and prednisone 5 mg twice daily to be taken orally. 
Throughout the study, safety and tolerability will be assessed by the recording of adverse 
events, monitoring of vital signs and physical examinations, safety laboratory evaluations,
and 12-lead electrocardiograms (ECGs).
The occurrence of an adverse event or toxicity, where continued administration of study drug 
is deemed to be not in the subject’s best interest by the investigator and/or the sponsor, will
result in the removal of the subject from therapy.  
For the study duration, all subjects will maintain androgen deprivation with an GnRH agonist 
or antagonist or orchiectomy. 
2.3.2 Secondary Variables
Page 36
WAS:

Testosterone concentration in bone marrow aspirate and blood

DHT concentration in bone marrow aspirate and blood

Expression and localization of AR

Splice variants

CYP17 expression

PSA levels

Progression Free Survival (PFS)

Objective response according to RECIST 1.1

Bone scan results

Markers of bone metabolism (bone specific alkaline phosphatase and urine N-telopep`tides)
IS AMENDED TO:

Androgen receptor signaling
o
Expression and localization of AR 
o
CYP17 expression
o
Splice variants


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
Pathways linked with non-classical AR signaling & Bone development

Androgens 
o
Testosterone concentration in bone marrow aspirate and blood
o
DHT concentration in bone marrow aspirate and blood

Androgen pre-cursors and other associated metabolites.  For example:
o
Cortisol
o
Androstenedione
o
Pregnenolone
o
Progesterone

PSA levels

Progression-free Survival (PFS)

Objective response according to RECIST 1.1

Bone scan results

Markers of bone metabolism (bone specific alkaline phosphatase and urine N-
telopeptides)

Testosterone concentration in bone marrow aspirate and blood

DHT concentration in bone marrow aspirate and blood

Expression and localization of AR

Splice variants

CYP17 expression
2.3.3 Exploratory Variables
Page 36
WAS:
Pre-dose concentrations of abiraterone on Day 4 and Day 29 (optional).
IS AMENDED TO:
Pre-dose concentrations of abiraterone on Day 4 and Day 29 (optional). Other variables 
may be explored.
3.4 Discontinuation Criteria for Individual Subjects
Page 39
WAS:
Subject develops disease progression defined as a composite endpoint, consisting of either 
clinical deterioration, radiographic progression or PSA progression according to the PCWG2 
criteria. Subject with PSA progression alone will not be withdrawn from the study.
IS AMENDED TO:
Subject develops disease progression defined as a composite endpoint, consisting of either
clinical deterioration, radiographic progression or PSA progression according to the PCWG2 
criteria. Subject with PSA progression alone will not be withdrawn from the study.


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4.1.1 Enzalutamide
Page 40, Paragraph 2
WAS:
Enzalutamide capsules are white to off-white oblong capsules, printed with “MDV” in black 
ink. The soft gelatin capsules are filled with a clear, yellowish solution which contains the 
two antioxidants, butylated hydroxyanisole, and butylated hydroxytoluene , and 
enzalutamide active ingredient (40 mg), all dissolved in the non-ionic surfactant, Labrasol® 
(Caprylocaproyl Polyoxylglycerides). Enzalutamide capsules are provided in white, opaque, 
high-density polyethylene (HDPE) bottles with child-resistant induction seal closure.
IS AMENDED TO:
Enzalutamide capsules are white to off-white oblong capsules, printed with either “MDV”
or “ENZ” in black ink. The soft gelatin capsules are filled with a clear, yellowish solution 
which contains the two antioxidants, butylated hydroxyanisole, and butylated 
hydroxytoluene , and enzalutamide active ingredient (40 mg), all dissolved in the non-ionic 
surfactant, Labrasol® (Caprylocaproyl Polyoxylglycerides). Enzalutamide capsules are
provided in white, opaque, high-density polyethylene (HDPE) bottles with child-resistant 
induction seal closure.
5.1.2 Reduction in Dose or Discontinuation of the Study Drugs
Page 44, Paragraph 5
WAS:
Subjects should be able to take all three study drugs (enzalutamide, abiraterone acetate and 
prednisone) to participate in the study. Interruptions of one of these drugs is allowed as per 
instruction above. Permanent discontinuation of one of the drugs, while continuing the two 
other drugs, is not allowed.
IS AMENDED TO:
Subjects should be able to take all three study drugs (enzalutamide, abiraterone acetate and 
prednisone) to participate in the study. An interruption Interruptions of one of these drugs 
is allowed as per instruction above. Permanent discontinuation of one of the drugs, while 
continuing the two other drugs, is not allowed.
5.4.1 Adverse Events
Page 48
WAS:
Adverse events will be assessed regularly as per schedule of assessments.
Adverse event collection will begin at the time the informed consent form is signed and 
continue through to the last assessments.
Baseline conditions that worsen during the study will be recorded as adverse events. 
Adverse events beginning after subjects have completed end of study procedures will be 


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Version 3.0  Incorporating Substantial Amendment  2
recorded up to 30 days following last dose of study drug.
Adverse events ongoing at the final visit will be followed up for as long as necessary to 
adequately evaluate the subject’s safety or until the event stabilizes. 
Please refer to Appendix 3 (Liver Safety Monitoring and Assessment) for DILI adverse 
event assessment.
IS AMENDED TO:
Adverse events will be assessed regularly as per schedule of assessments.
Adverse event collection will begin at the time the informed consent form is signed and 
continue up to 30 days following last dose of study drug continue through to the last 
assessments.
Baseline conditions that worsen during the study will be recorded as adverse events.  
Adverse events beginning after subjects have completed end of study procedures will be 
recorded up to 30 days following last dose of study drug.
Adverse events ongoing at the final visit will be followed up for as long as necessary to 
adequately evaluate the subject’s safety or until the event stabilizes.
Please refer to Appendix 3 (Liver Safety Monitoring and Assessment) for DILI adverse 
event assessment.
5.4.4.1 Adverse Events of Possible Hepatic Origin
Page 49
WAS:
Subjects with AE’s of hepatic origin accompanied by Liver Function Test (LFT)
abnormalities should be carefully monitored.
IS AMENDED TO:
Subjects with AE’s of hepatic origin accompanied by Liver Function Test (LFT)
abnormalities should be carefully monitored. See Appendix 12.3 Liver Safety Monitoring 
and Assessment for detailed information on liver abnormalities, monitoring and 
assessment.
5.5.2 Definition of Serious Adverse Events (SAEs)
Page 53, Paragraph 7
WAS:
Serious adverse events will be collected and reported on the adverse event CRF from the 
time the subject signs the ICF until termination from the study.
IS AMENDED TO:
Serious adverse events will be collected and reported on the adverse event CRF from the 
time the subject signs the ICF until 30 days following last dose of study drug termination 
from the study.


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5.5.8 Procedure in Case of Pregnancy
Page 56, Paragraph 1
WAS:
If during the conduct of the clinical trial, a male subject impregnates his partner, the subject 
should report the pregnancy to the investigator. The investigator should report the 
pregnancy to the sponsor as an SAE within 30 days from discontinuation of dosing. The 
expected date of delivery or expected date of the end of the pregnancy, last menstruation, 
estimated fertility date, pregnancy result and neonatal data etc., should be included in this 
information.
IS AMENDED TO:
If during the conduct of the clinical trial, a male subject impregnates his partner, the subject 
should report the pregnancy to the investigator. The investigator should report the 
pregnancy to the sponsor as if it is an SAE within 30 days from discontinuation of dosing. 
The expected date of delivery or expected date of the end of the pregnancy, last 
menstruation, estimated fertility date, pregnancy result and neonatal data etc., should be 
included in this information.
5.7.3 Blood sample for androgen levels and bone markers
Page 58
WAS:
5.7.3 Blood sample for androgen levels and bone markers
A separate blood sample will be collected for measuring serum levels of androgens 
(testosterone and DHT). Bone alkaline phosphatase (a marker for bone metabolism) will be 
measured from the same tube of the chemistry parameters (see Appendix 2).
IS AMENDED TO:
5.7.3 Blood sample for androgen and androgen precursors levels and bone markers
A separate blood sample will be collected for measuring serum levels of androgens 
(testosterone and DHT) and androgen precursors. Bone alkaline phosphatase (a marker for 
bone metabolism) will be measured from the same tube of the chemistry parameters (see 
Appendix 2).
7.4 Analysis of Efficacy
Page 60
WAS:
Progression free survival is defined as the time interval from the date of starting treatment 
until the date of documented progression or death in absence of progression. Progression, as 
a composite endpoint, consisting of either clinical deterioration, radiographic progression or 
PSA progression according to the PCWG2 criteria. Subjects with PSA progression alone 
will not be withdrawn from the study. Kaplan-Meier curves will be presented. The median 
and 25% and 75% percentiles will be tabulated, including the corresponding 95%CI 


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calculated by use of the Brook Meyer and Crowley method. The number of events and 
subjects at risk over time will be tabulated.
For PSA level over time, descriptive statistics including number of subjects, mean, standard 
deviation, median, minimum, and maximum will be provided for baseline value and post-
baseline values, as well as absolute and percent change from baseline. 
The objective response according to RECIST 1.1 and bone scan results will be reported 
through descriptive summaries as described by PCWG2, including the proportion of patients 
showing RECIST 1.1 objective response (partial or complete response).
Bone specific alkaline phosphatase and urine N-telopeptides will be descriptively 
summarized.

Testosterone/DHT and Androgen Receptor Signaling
Summary statistics will be produced for the Biomarker Evaluable Set. 
The effect of enzalutamide on bone and serum biomarkers (including androgen expression 
signaling) will be analyzed based on change from baseline to Week 9. 
For each biomarker (testosterone, DHT and androgen receptor signaling), descriptive 
statistics including number of subjects, mean, standard deviation, median, minimum, and 
maximum will be provided for baseline value, post-baseline value, change from baseline, 
and percent change from baseline. Graphical display using box-plot, histogram and scatter 
plot will be generated as appropriate.  
Biomarker results collected at baseline assessment and at each post-baseline assessment will 
be compared using paired t-test to evaluate the effect of enzalutamide. The change from 
baseline in each biomarker will also be summarized by PSA response category, where PSA 
response is a function of percentage improvement from baseline to Week 13. The 
correlation between each biomarker and PSA level will be estimated using Spearman’s 
method.
IS AMENDED TO:
Progression-free survival is defined as the time interval from the date of starting treatment 
until the date of documented progression or death in absence of progression. Progression, as 
a composite endpoint, consisting of either clinical deterioration, radiographic progression or 
PSA progression according to the PCWG2 criteria.Subjects with PSA progression alone 
will not be withdrawn from the study. Kaplan-Meier curves will be presented. The median 
and 25th% and 75th% percentiles will be tabulated, including the corresponding 95%CI 
calculated by use of the Brook Meyer and Crowley method. The number of events and 
subjects at risk over time will be tabulated.
For PSA level over time, descriptive statistics including number of subjects, mean, standard 
deviation, median, minimum, and maximum will be provided for baseline value and post-
baseline values, as well as absolute and percent change from baseline. 
The objective response according to RECIST 1.1 and bone scan results will be reported 
through descriptive summaries as described by PCWG2, including the proportion of patients 
showing RECIST 1.1 objective response (partial or complete response).
Bone specific alkaline phosphatase and urine N-telopeptides will be descriptively 
summarized.


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Version 3.0  Incorporating Substantial Amendment  2

Androgen, Testosterone/DHT and  Aandrogen Rreceptor Ssignaling, androgen pre-
cursors and other associated metabolites
Summary statistics will be produced for the Biomarker Evaluable Set. 
The effect of enzalutamide on bone and serum biomarkers (including androgen pre-
cursors and androgen expression signaling, androgen pre-cursors and other associated 
metabolites) will be analyzed based on change from baseline to Week 9. 
For each biomarker (androgen, androgen expression signaling, androgen pre-cursors 
and other associated metabolitestestosterone, DHT and androgen receptor signaling), 
descriptive statistics including number of subjects, mean, standard deviation, median, 
minimum, and maximum will be provided for baseline value, post-baseline value, change 
from baseline, and percent change from baseline. Graphical display using box-plot, 
histogram and scatter plot will be generated as appropriate.  
Biomarker results collected at baseline assessment and at each post-baseline assessment, if 
appropriate, will be compared using paired t-test to evaluate the effect of enzalutamide. 
The change from baseline in each biomarker will also be summarized by PSA response 
category, where PSA response is a function of percentage improvement from baseline to 
Week 13. The correlation between each biomarker and PSA level will be estimated using 
Spearman’s method.
12.2 Appendix 2:   Laboratory Tests
Page 73
WAS:
Testosterone and 
DHT
Screening, Week 9 and 
at the end of treatment 
(ET). If the ET visit 
falls between Week 9 
and Week 13, and the 
Week 9 DHT and 
Testosterone was 
collected, then an ET 
collection will not be 
required.  
Serum tube (red 
top, no additive), 
Sodium Heparin 
tube
Testosterone and DHT
IS AMENDED TO:
Androgen, androgen 
expression signaling, 
androgen pre-
cursors and other 
associated 
metabolites
Testosterone and 
DHT
Screening, Week 9 and 
at the end of treatment 
(ET). If the ET visit 
falls between Week 9 
and Week 13, and the 
Week 9 sample DHT 
and Testosteronewas 
collected, then an ET 
collection will not be 
required.  
Serum tube (red 
top, no additive), 
Sodium Heparin 
tube
androgen, androgen 
expression signaling, 
androgen pre-cursors and 
other associated 
metabolites Testosterone 
and DHT


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12.4 Appendix 4:  Common Serious Adverse  
Page 76
WAS:
The following list of serious adverse events are considered common for the study population
defined in this protocol and should be reported by the investigator as described in Section 
5.5. For IND safety reporting, single occurrences of the following events may be excluded 
from expedited reporting. If aggregate analysis of these events indicates they occur more 
frequently with study drug, an expedited IND safety report may be submitted to FDA. 
IS AMENDED TO:
The following list of serious adverse events are considered common for the study population 
defined in this protocol and should be reported by the investigator as described in Section 
5.5. For IND safety reporting, single occurrences of the following events may be excluded 
from expedited reporting. If aggregate analysis of these events indicates they occur more 
frequently with study drug, an expedited IND safety report may be submitted to FDA.
The following is a list of serious adverse events that the Sponsor considers to be 
associated with the disease state being studied. The list does NOT change your 
reporting obligations or prevent the need to report an adverse event 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 you that some events reported as SAEs may 
not require expedited reporting to the regulatory authorities based on the classification 
of “common serious adverse events”. You are 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 indicate 
they occur more frequently with study drug, an expedited IND safety report may be 
submitted to the FDA.  


Sponsor: APGD
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18 Jun 2014
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Version 3.0, Incorporating Substantial Amendment 2
[GPF V3.0]
14
SPONSOR’S SIGNATURES







SAP_001.pdf: 
A Phase 2 Study Determining Safety and Tolerability of 
Enzalutamide (Formerly MDV3100) in Combination With 
Abiraterone Acetate in Bone Metastatic Castration-resistant 
Prostate Cancer Patients
ISN/Protocol 9785-CL-0011
ClinicalTrials.gov Identifier: NCT01650194
Date of Statistical Analysis Plan Final Version 2.0:
04 Jan 2016
Sponsor: Astellas Pharma Global Development, Inc. (APGD)
Research & Development
3 Parkway North
Deerfield, IL 60015


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 2.0
ISN/Protocol 9785-CL-0011
04-Jan-2016
Astellas
Page 1 of 46
STATISTICAL ANALYSIS PLAN
Final Version 2.0, dated 04-JAN-2016
A Phase 2 Study Determining Safety and Tolerability of
Enzalutamide (formerly MDV3100) in Combination with
Abiraterone Acetate in Bone Metastatic Castration-Resistant
Prostate Cancer Patients
ISN/Protocol: 9785-CL-0011
IND number: 74,563
Astellas Pharma Global Development, Inc.
(APGD) Research & Development
3 Parkway North
Deerfield, IL 60015
-------------------------------------------------------------------------------------------------------------
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 Global Development, Inc.
SAP Final Version 2.0
ISN/Protocol 9785-CL-0011
04-Jan-2016
Astellas
Page 2 of 46
Table of Contents
I.
LIST OF ABBREVIATIONS AND KEY TERMS··········································· 5
1
INTRODUCTION·················································································· 8
2
FLOW CHART AND SCHEDULE OF ASSESSMENTS ·································· 9
3
STUDY OBJECTIVES AND DESIGN························································12
3.1
Study Objectives ··············································································12
3.1.1
Primary Objective ·······································································12
3.1.2
Secondary Objectives ···································································12
3.1.3
Exploratory Objective···································································12
3.2
Study Design···················································································12
3.3
Randomization·················································································13
4
SAMPLE SIZE·····················································································13
5
ANALYSIS SETS ·················································································13
5.1
Safety Analysis Set (SAF) ···································································14
5.2
Biomarker Evaluable Set (BES)·····························································14
5.3
Plasma Evaluable Set (PES) ·································································14
5.4
Pharmacokinetics Analysis Set (PKAS)····················································14
5.5
Protocol Deviations ···········································································14
6
ANALYSIS VARIABLES ·······································································15
6.1
Efficacy Variables·············································································15
6.1.1
Overview ·················································································15
6.1.2
Androgen and Androgen Pre-cursors ·················································16
6.1.3
Expression and Localization of AR ···················································16
6.1.4
Splice Variants and CYP17 Expression ··············································16
6.1.5
PSA Levels···············································································16
6.1.6
RECIST and Bone Scan Results·······················································17
6.1.7
Progression Free Survival ······························································18
6.1.8
Markers of Bone Metabolism, Bone specific Alkaline Phosphatase and 
Urine N-telopeptide ·····································································19
6.2
Safety Variables ···············································································20
6.2.1
Overview ·················································································20
6.2.2
Adverse Events (AEs) ··································································20
6.2.3
Clinical Laboratory······································································21


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6.2.4
Vital Signs················································································21
6.2.5
12-lead ECG ·············································································21
6.2.6
Physical Examination···································································22
6.2.7
Other Safety Variables··································································22
6.3
Exploratory Pharmacokinetic Variables····················································22
6.4
Other Variables················································································22
7
STATISTICAL METHODOLOGY ···························································22
7.1
General Considerations·······································································22
7.2
Study Population ··············································································23
7.2.1
Disposition of Subjects ·································································23
7.2.2
Protocol Deviations ·····································································23
7.2.3
Demographics and Other Baseline Characteristics··································24
7.2.4
Previous and Concomitant Medications ··············································24
7.2.5
Medical History··········································································24
7.3
Study Drugs····················································································25
7.4
Analysis of Efficacy ··········································································25
7.5
Analysis of Safety·············································································27
7.5.1
Adverse Events ··········································································27
7.5.2
Clinical Laboratory Evaluation ························································28
7.5.3
Vital Signs················································································28
7.5.4
12- Lead ECG············································································29
7.5.5
Physical Examination···································································29
7.6
Analysis of Pharmacokinetics and/or Pharmacodynamics ·······························29
7.6.1
PK Concentrations ······································································29
7.7
Other Analyses ················································································30
7.8
Interim Analysis (and Early Discontinuation of the Clinical Study)····················30
7.9
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········30
7.9.1
Missing Data ·············································································30
7.9.2
Missing Adverse Event Dates··························································30
7.9.3
Baseline Assessments···································································31
7.9.4
Visit Windows ···········································································31
7.9.5
Outliers ···················································································31
7.9.6
Values Below LOQ in PK Data ·······················································31
8
DOCUMENT REVISION HISTORY ·························································32


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9
REFERENCES ····················································································32
10
APPENDICES ·····················································································33
10.1
Appendix 1: Laboratory Tests ·······························································33
10.2
Appendix 2: Liver Function Test····························································34
10.3
Appendix 3: Common Terminology Criteria for Adverse Events (CTCAE) ··········35
10.4
Appendix 4: Review and Approval Signatures ············································46
List of In-text Tables
Table 1
Schedule of Assessments·····································································10
Table 2
RECIST Overall Responses for All Possible Combinations of Tumor Responses 
in Target and Non-target Lesions With or Without The Appearance of New 
Lesions ·························································································18
Table 3
Vital Signs Reference Ranges ·······························································29


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I.
LIST OF ABBREVIATIONS AND KEY TERMS
List of Abbreviations
Abbreviations
Description of abbreviations
AE
Adverse Event
ALT
Alanine Aminotransferase
APGD
Astellas Pharma Global Development
AR
Androgen Receptor
ASCM
Analysis Set Classification Meeting
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutical Classification
BES
Biomarker Evaluable Set
BID
Twice a Day
BMI
Body Mass Index
CAT (CT scan)
Computed Axial Tomography
CFR
Code of Federal Regulations
CI
Confidence Interval
CM
Concomitant Medication
CR
Complete Response
CRPC
Castration-Resistant Prostate Cancer
CTCAE
Common Terminology Criteria for Adverse Events
CYP
Cytochrome P450
CXR
Chest x-ray
CV
Coefficient of Variation
DHT
Dihydrotestosterone
DRM
Data Review Meeting
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG PS
Eastern Cooperative Oncology Group Performance Status
eCRF
Electronic Case Report Form
EOT
End of Treatment
ESV
End of Study Visit
ET
End of Treatment
GM
Geometric Mean
GnRH
Gonadotropin Releasing Hormone
ICH
International Conference on Harmonisation
IHC
Immunohistochemistry
IND
Investigational New Drug (Application)
INR
International Normalized Ratio
ISN
International Study Number
LDH
Lactate Dehydrogenase
LOQ
Limit of Quantitation
LLOQ
Lower Limit of Quantitation
LVEF
Left Ventricle Ejection Fraction
K-M
Kaplan-Meier
MedDRA
Medical Dictionary for Regulatory
mg
Milligram
mmHg
Millimeters of Mercury


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Abbreviations
Description of abbreviations
MRI
Magnetic Resonance Imaging
MUGA
Multi-Gated Acquisition
NCI
National Cancer Institute
NYHA
New York Heart Association
PCWG2
Prostate Cancer Clinical Trials Working Group 2
PD
Progressive Disease
PES
Plasma Evaluable Set
PFS
Progression Free Survival
PK
Pharmacokinetics
PKAS
Pharmacokinetic Analysis Set
PR
PR Interval
PR
Partial Response
PSA
Prostate-Specific Antigen
PT
Prothrombin Time
PT
Preferred Term
PTT
Partial Thromboplastin Time
QD
Once Daily
QRS
QRS Interval
QTcB
QTC Bazett Calculator
QTcF
QTC Fridericia Calculator
RECIST
Response Evaluation Criteria In Solid Tumors
SAF
Safety Analysis Set
SAP
Statistical Analysis Plan
SD
Standard Deviation
SD
Stable Disease
SOC
System Organ Class
TEAE
Treatment Emergent Adverse Event
WHO-DRL
World Health Organization-Drug Reference List


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List of Key Terms
Terms
Definition of terms
Adverse Event
An adverse event with an onset date on or after starting administration of the
study drug or any ongoing AE on the date of first dose that has worsened in 
severity after administration of the study drug. All adverse events collected that 
begin within 30 days of taking the last dose of study drug will also be counted 
as TEAE.
Baseline
A period that begins at the Screening visit where all initial subject assessments
and findings will be obtained prior to study drug administration on Day 1.
Discontinuation
A discontinuation is a subject who is enrolled in the study and for whom study
drug is terminated for any reason.
Enroll
To register or enter into the study following the signing of informed consent.
Investigational
Period
Period of time between Day 1 to Safety F/U.
Screening failure
Screened subject, but did not fulfill protocol inclusion and/or exclusion criteria
and failed to receive open label study treatment, or decided not to participate 
anymore (withdrew consent) prior to completing pre- investigational period.
Screening period
Period of time between Day -28 and Day -1.
Study Drug
Agents given as part of a clinical trial. In this study, enzalutamide, abiraterone
acetate and prednisone are the study drugs.
Subject
An individual who participates in this clinical trial, and will be a recipient of the
study drug.
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 variables and other data.
The SAP is finalized and signed before the database soft lock at the latest. Any deviations 
from the SAP will be justified in the Clinical Study Report (CSR).
Prior to Database Lock, a Final Review of Data and Tables, 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.
This SAP is created to accommodate the production of a Clinical Study Report based on the 
final efficacy evaluation of the data from the study. Only data from visits which took place 
on or before the cutoff date will be included in this report. Subjects still in the study at the 
data cutoff date will be censored based on the data cutoff date if appropriate.


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2
FLOW CHART AND SCHEDULE OF ASSESSMENTS
Flow Chart


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Table 1
Schedule of Assessments
Study Day
Screening
Visit
1
4
29
57
85
113
141
169
ET
Safety F/U
Week
−4 to −1 
(28 days)
1
1
5
9
13
17
21
25 and every 
subsequent
12 weeks
End of
Treatment
30 Days after 
last dosee
Window (days)
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
Informed Consent
X
Medical History
X
Inclusion/Exclusion Criteria
X
X
Vital Signsa
X
X
X
X
X
X
X
X
X
X
Physical Examination, Weight, Height j
X
Xd
Xn
Xn
Xn
Xn
Xn
Xn
Xn
Xn
12-Lead ECG
X
Xd
Xr
Xr
Xr
Xr
Xr
Xr
Xr
Xr
PT/PTT b
X
Xd
X
X
X
X
X
X
X
X
Clinical Labs b
Including liver function test c
X
X
d
X
X
X
X
X
X
X
X
PK of Abiraterone l
X
X
PK of enzalutamide m
X
PSA
X
Xd
X
X
X
X
X
X
X
X
Urine N-telopeptide
X
X
Xg
Blood testosterone and DHT levels q
X
X
Xg
CT/MRI and Bone Scan
Xi
X
X
X
CXR or Chest CT
Xk
Xk
Xk
MUGA or ECHO f
X
ECOG Performance Status
X
X
X
X
X
X
X
X
X
X
Bone Marrow Aspirate and Biopsy
Xh
X
Xg
Archival Tumor Tissue o
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
Previous & Concomitant Medications
X
X
X
X
X
X
X
X
X
X
Study Drug Dispensing
X
X
X
X
X
X
X
Study Drug Treatment
X
X
X
X
X
X
X
Blood Sample for Genotypingp
X
a. Vital signs will be obtained prior to study drug administration and 1-2 hours after study drug administration.
b. Clinical labs (hematology and chemistry) and, PT/PTT, will be obtained prior to study drug administration. Day 1 chemistry and hematology do not need to be completed if the 
screening assessments were completed within 3 days prior to Day 1.
c. Subjects will have liver function tests (including alkaline phosphatase, AST, ALT, direct and total bilirubin, and LDH) every 2 weeks for the first 12 weeks of treatment. 
Footnotes continued on next page


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d. If Day 1 visit occurs within 72 hours after screening, these assessments do not need to be repeated.
e. Safety follow-up visit will occur after 30 days following the last dose of study drug.
f. A MUGA scan or echocardiogram showing LVEF ≥ 45% is required for subjects with a history of anthracycline or anthracenedione (mitoxantrone) treatment, or if the subjects has
Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or subjects with history of congestive heart failure NYHA class 3 or 4 in the past.
g. Blood sample for testosterone and DHT and urine sample for N-telopeptide will be collected if not obtained at Week 9 (Day 57) or if subject terminates study drug or study prior to
Week 9 (Day 57).
h. Bone marrow aspirate and biopsy should be taken between screening and prior to first dose of study drug.
i. Subjects must be assessed with CT/MRI and bone scan within 6 weeks prior to study drug administration (Day 1). 
j.
Height will be recorded at the screening visit only.
k. At screening a chest X-ray will be performed. A chest CT is required if the screening chest X-ray demonstrates metastatic chest disease. In this case, additional chest CT’s should be
performed as follow up at Week 13 (Day 85) and end of treatment (ET) visit.
l.
Optional PK blood sample for determination of plasma concentrations of abiraterone will be obtained predose on Day 4 and Day 29.
m. Optional PK blood sampling for determination of plasma concentrations of enzalutamide and its metabolites MDPC0001 and MDPC0002 will be obtained predose on week 5 
(Day 29).
n. Only weight to be measured.
o. Archival tumor tissue will be obtained any time prior to Day 1.
p. Sample for optional genotyping sub-study will be collected prior to Day 1 dosing.
q. Blood sample testosterone and DHT should be collected within 2 hours of bone marrow biopsy and aspirate.
r. ECG must be performed prior to dosing.


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3
STUDY OBJECTIVES AND DESIGN
3.1
Study Objectives
3.1.1
Primary Objective
To explore the safety, and tolerability of enzalutamide in combination with abiraterone 
acetate plus prednisone.
3.1.2
Secondary Objectives
●
To explore the effect of enzalutamide in combination with abiraterone acetate plus 
prednisone on androgen receptor signaling and androgen levels.
●
To explore the antitumor activity of enzalutamide in combination with abiraterone
●
acetate plus prednisone as assessed by serum prostate-specific antigen (PSA), imaging of 
soft tissue and bone metastases, and markers of bone metabolism.
3.1.3
Exploratory Objective
To measure pre-dose concentrations of abiraterone on Day 4 and Day 29 (optional).
3.2
Study Design
This is an open label study to determine the safety and tolerability of enzalutamide in 
combination with abiraterone acetate plus prednisone in castration-resistant prostate cancer 
(CRPC) subjects with bone metastases by clinical evaluations at protocol specified intervals.
The study will also determine the modulation of androgen receptor (AR) signaling in bone 
marrow biopsy and androgen levels as measured by testosterone concentration in bone 
marrow aspirate and blood by Liquid Chromatography Mass spectrometry, expression of AR 
and its subcellular localization by immunohistochemistry (IHC), presence of known and 
assessable splice variants and CYP17 expression in epithelial and host compartment of the 
cancer by IHC. Tumor tissue will be collected to determine AR signaling and candidate 
pathways that may be part of a signaling network implicated in therapy resistance.
Approximately 60 subjects will receive enzalutamide 160 mg daily, abiraterone acetate
1000 mg daily, and prednisone 5 mg twice daily to be taken orally. Subjects will be unable to 
continue in the study if one of the above study drugs is discontinued.
Throughout the study, safety and tolerability will be assessed by the recording of adverse 
events, monitoring of vital signs and physical examinations, safety laboratory evaluations, 
and 12-lead electrocardiograms (ECGs). Subjects will have a safety follow-up visit 30 days 
after their last dose of study drug.
The occurrence of an adverse event or toxicity, where continued administration of study drug 
is deemed to be not in the subject’s best interest by the investigator and/or the sponsor, will 
result in the removal of the subject from therapy.
For the study duration, all subjects will maintain androgen deprivation with an GnRH agonist 
or antagonist or orchiectomy.


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Study drug will be administered until disease progression. Disease progression is defined as a 
composite endpoint, consisting of either clinical deterioration, radiographic progression or 
PSA progression according to the prostate cancer clinical trials working group 2 (PCWG2) 
criteria. Subjects with PSA progression alone will not be withdrawn from the study.
The following assessments of prostate cancer status will be collected during the course of the 
trial: soft tissue disease on computed tomography (CT) scan or on magnetic resonance 
imaging (MRI), bone disease on radionuclide bone scans, and PSA.
Study films (abdominopelvic CT/MRI [lung when applicable] and bone scan) should be read 
on site.
Optional pharmacokinetics (PK) blood samples for determination of plasma concentrations of 
abiraterone will be collected pre-dose on Day 4 and Day 29. In addition optional PK blood 
sampling for determination of plasma concentrations of enzalutamide and its metabolites 
MDPC0001 and MDPC0002 will be collected on Day 29.
Archival tumor tissue samples will be collected to allow for tumor profiling. Samples will be 
obtained and stored until qualified assays become available.
3.3
Randomization
This is an open-label study, subjects who meet all inclusion criteria and no exclusion criteria
are assigned to begin study treatment. Registration must occur following informed consent 
process and prior to initiation of investigational therapy. A unique subjects/treatment number 
is assigned to each subjects enrolled in the study. Discontinued subjects are not replaced.
4
SAMPLE SIZE
A total of 60 subjects will provide sufficient data to assess the safety of the drug 
combination. The sample size and power calculation are based on the change of testosterone 
concentration or gene expressions (i.e., AR and CYP17) before and after therapy, which can 
be characterized based on effect size (i.e., mean difference of testosterone concentration or 
gene expression divided by standard deviation). Considering subjects with baseline and 
Week 9 laboratory results derived from bone marrow samples, a sample of 30 subjects 
provides 82% power to detect a change of testosterone concentration or gene expression with 
an effect size of at least 0.55, using a two sided paired t-test at a 0.05 significance level. A 
total of 60 subjects will be accrued to obtain at least 30 evaluable patients based on the 
prediction that the yield of evaluable bone marrow samples with prostate cancer cells is 
approximately 50%.
5
ANALYSIS SETS
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. In 
accordance with ICH recommendations in guidelines E3 and E9, the following analysis sets 
will be used for the analyses.


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Four populations will be used for the analyses; the Safety Analysis Population (SAF), the 
Biomarker Evaluable Set (BES), Plasma Evaluable Set (PES), and the Pharmacokinetic 
Analysis Set (PKAS). However the number of subjects with evaluable biomarker parameter 
results may differ, resulting in several Biomarker and Plasma Evaluable Sets. If case-by-case 
review is required to allocate subjects to analysis sets then this will be determined at the 
Analysis Set Classification Meeting (ASCM) prior to database hard lock.
5.1
Safety Analysis Set (SAF)
The Safety Analysis Set will consist of all subjects who received at least one dose of any 
drug of the study combination treatment (i.e., enzalutamide, abiraterone acetate, and 
prednisone).
The SAF will be used to report all safety and efficacy analyses.
5.2
Biomarker Evaluable Set (BES)
The Biomarker Evaluable Set (BES) will consist of all subjects with baseline and Week 9 
laboratory results derived from bone marrow samples. The number of subjects with evaluable 
results may differ for each parameter:
●
Biomarker <parameter> Evaluable Set: Subjects from the SAF population with bone 
marrow results at baseline and at Week 9 assessments for the following parameters: 
Testosterone (BTES), Cortisol (BCES), Androstenedione (BAOS), Progesterone 
(BOES), and Pregnenolone (BEES).
5.3
Plasma Evaluable Set (PES)
The Plasma Evaluable Set (PES) will consist of all subjects with baseline and Week 9 
assessment of testosterone and DHT results derived from plasma samples. The number of 
subjects with evaluable results may differ for each parameter:
●
Plasma <parameter> Evaluable Set: Subjects from the SAF population with blood 
testosterone results at baseline and at Week 9 assessments for the following parameters: 
Testosterone (PTES), Cortisol (PCES), Androstenedione (PAOS), Progesterone (POES), 
and Pregnenolone (PEES).
5.4
Pharmacokinetics Analysis Set (PKAS)
The Pharmacokinetic Analysis Set will include the subjects from the SAF population for 
whom at least one PK pre-dose concentration is available. Additional subjects may be 
excluded from the PKAS at the discretion of the pharmacokineticist.
The PKAS will be used for all tabular and graphical summaries of the PK data.
5.5
Protocol Deviations
All protocol deviations and whether they lead to the exclusion of the subject from the SAF, 
any of the Biomarker Evaluable Sets and/or PKAS will be listed. Additional other protocol 
deviations that are identified during the ASCM will also be presented.


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The following protocol deviations will be defined:
●
Subjects who entered the study even though they did not satisfy the entry criteria
●
Subjects who developed withdrawal criteria during the study but were not withdrawn
●
Subject who received the wrong treatment or incorrect dose
●
Subjects who received an excluded concomitant medication
●
Other:

The actual PK sampling time deviates from the planned sampling day or time

(e.g., post-dose instead of pre-dose)

Visit outside protocol visit windows

Further protocol deviation may be determined by the team during the ASCM
Subjects with protocol deviations will not be excluded from the analyses of the safety data
(except in the case of subjects with all post-baseline safety data missing). The PK specialist 
will be consulted whether there are any protocol deviations which lead to exclusion of 
subjects or plasma concentrations at single time-points from the PK analysis.
6
ANALYSIS VARIABLES
6.1
Efficacy Variables
All efficacy analyses will be carried out on secondary variables.
6.1.1
Overview
The efficacy of the treatment combination will be assessed by:
●
Androgens

Testosterone concentration in bone marrow aspirate and blood
●
Androgen pre-cursors and other associated metabolites. For example:

Cortisol

Androstenedione

Pregnenolone

Progresterone
●
Androgen receptor signaling

Expression and localization of AR

CYP17 expression

Splice variant
●
Pathways linked with non-classical AR signaling & Bone development
●
Anti-tumor activity

PSA levels

Objective response according to Response Evaluation Criteria In Solid Tumors
(RECIST) 1.1

Bone scan results

Progression Free Survival (PFS)
●
Markers of bone metabolism

Bone specific alkaline phosphatase


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
Urine N-telopeptides
6.1.2
Androgen and Androgen Pre-cursors
Bone marrow aspirate and blood measuring androgen and androgen pre-cursors will be 
collected at the Screening visit and Week 9, and at the end of treatment if the sample was not 
obtained at Week 9, or subject terminates study drug or study prior to Week 9 bone marrow 
assessment.
Baseline value will be defined as the screening value prior to first dose of study drug. Change 
from baseline and percent change from baseline will be calculated as (Week 9 – Baseline)
and ((Week 9 – Baseline)/Baseline)*100, respectively.
6.1.3
Expression and Localization of AR
The study will also determine the modulation of AR signaling in and its subcellular 
localization in bone marrow biopsy by IHC as described per the schedule of assessment 
[Table 1].
It will be collected at the Screening visit and Week 9, and at the end of treatment if the 
sample was not obtained at Week 9, or subject terminates study drug or study prior to Week 9 
bone marrow assessment.
For purposes of this report the variables related to expression and localization of Androgen
Receptors will only be listed in the report and no further analyses will be performed.
6.1.4
Splice Variants and CYP17 Expression
The study will determine the presence of known and assessable splice variants and CYP17 
expression in epithelial and host compartment of the cancer by IHC as described per the 
schedule of assessment [Table 1].
It will be collected at the Screening visit and Week 9, and at the end of treatment if the 
sample was not obtained at Week 9, or subject terminates study drug or study prior to Week 9 
bone marrow assessment.
For purposes of this report the variables related to Splice Variants and CYP17 expression will
only be listed in the report and no further analyses will be performed.
6.1.5
PSA Levels
Samples for PSA will be collected and analyzed at the local laboratory. Prostate-specific 
antigen testing will be performed as per the schedule of assessment [Table 1]. The PSA test 
performed at the Screening visit does not need to be repeated on Day 1 if the Day 1 visit 
occurs within 72 hours of screening.
Baseline value will be defined as the latest value prior to first dose of study drug. For the 
PSA levels the following variables will be derived and summarized:
●
PSA response is the change from baseline and percent change from baseline that will be 
calculated as (Post-baseline – Baseline) and ((Post-baseline – Baseline)/Baseline)*100, 
respectively.


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●
The best PSA response is the largest decline in PSA, expressed as the percentage change 
from baseline, that occurs at any point after treatment start. For subjects with no 
decrease, the best PSA response is the smallest increase in PSA.
The following time intervals will be used for the best PSA response:

over the first 12 weeks on treatment

up to and including the end of treatment (EOT) visit but excluding the end of 
study visit (ESV)

up to and including the end of study visit (ESV)
●Proportion of subjects with a decline from baseline in PSA blood concentrations of
≥30%, ≥50% and ≥90% observed at every visit as well as the proportion of 
subjects with the largest decline in PSA from baseline (Nadir), ≥30%, 50% and 
≥90%.
6.1.6
RECIST and Bone Scan Results
The overall objective response assessment is based on RECIST version 1.1 for soft tissue 
lesion on CT/MRI and the PCWG2 guidelines for bone lesions on bone scans. The baseline is 
the last assessment prior to the first drug intake.
All assessments will be done by the investigator, no independent central review.
TimePointResponsefortargetlesionsandnon-targetlesions.
Response assessments for target and non-target lesions are reported in the eCRF by the 
investigator at each of the time-points mentioned in the schedule of assessments [Table 1
above], to one of the following categories:
●
CR = complete response
●
PR = partial response (Target only)
●
SD = stable disease (Target only)
●
PD = progressive disease
●
Non CR/non PD= not complete response rate and not progressive disease (Non-Target 
only)
●
NE = not evaluable
●
NA= not applicable
TimePointResponseforbonelesions.
Response assessments for bone lesions are reported in the eCRF by the investigator at each of 
the time-points mentioned in the schedule of assessments to one of the following categories:
●
CR = complete response
●
PD = progressive disease
●
PDu = unconfirmed progressive disease
●
Non CR/non PD= not complete response rate and not progressive disease
●
NE = not evaluable
●
NA = not applicable


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OverallTimePointResponse
In the CRF the Overall Time Point Response assessment reported by the investigator 
incorporates both the RECIST overall time point response assessment for soft tissue lesions 
by CT/MRI [see Table 2 and Table 3 below] and the response assessment on bone lesion 
according to PCWG2.
The following categories have been used:
●
CR = complete response
●
PR = partial response
●
SD = stable disease
●
PD = progressive disease
●
Non CR/non PD= not complete response rate and not progressive disease
●
NE= not evaluated
All the above parameters will be summarized by visit.
RESISTOverallTimePointResponse
At each time point, the RECIST overall time point response in patients with measurable soft 
tissue lesions at study entry can be derived according to RECIST for all possible 
combinations [Table 2] of tumor response assessments in target and non-target lesions in soft 
tissues with or without appearance of new unequivocal lesions.
Table 2
RECIST Overall Responses for All Possible Combinations of Tumor 
Responses in Target and Non-target Lesions With or Without The 
Appearance of New Lesions
Target lesions
Non-Target lesions
New Lesions*
Overall response
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-CR/Non-PD
No
PR
PR
Not evaluated
No
PR
SD
Non-CR/Non-PD
No
SD
SD
Not evaluated
No
SD
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Not evaluated
Non-CR/Non-PD
No
NE
*Any unequivocal new lesions
Based on the methodology described in [Table 2] above, the best overall response per
RECIST 1.1, during the entire investigational period will be derived and summarized.
6.1.7
Progression Free Survival
Progression free survival (PFS) will be measured as time from the date of first dose of any 
drug of the study combination treatment until the first evidence of documented progression (a
composite endpoint consisting of radiographic progression or PSA progression by PCWG2 or 
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last known to be progression free. In other words, PFS is the time interval (in days) between 
the earliest date among the date of first evidence of PD (radiographic progression or PSA 
progression by PCWG2 or clinical deterioration) or the date of death in absence of 
progression or the date last known to be progression free and the date of first dose of any 
drug of the study combination plus1.
Definition radiographic progression
Radiographic progression is defined as either a progression in soft tissue on CT/MRI 
according to RECIST 1.1, and/or a progression in bone lesions on the bone scan (when a 
minimum of two new lesions are observed). In the CRF, at each time-point, radiographic 
disease progression has been assessed by the investigator as progression based on both 
RECIST (for soft tissue) and bone lesions. In the absence of bone lesion unequivocal 
progression based on bone scan, the radiographic progression assessment will correspond to 
the RECIST overall response assessment if available; if not available radiographic 
progression is considered absent. In the presence of a bone lesion unequivocal progression or 
a new bone lesion on bone scan, which leads to treatment discontinuation, radiographic 
progression is considered present, whatever the RECIST overall tumor response assessment 
is.
Definition clinical progression (deterioration)
Clinical progression will be defined based on the observation of clinical signs and symptoms 
due to disease progression, assessed by the investigator and reported in the eCRF, as AEs at 
any time during the course of the study. Adverse event with “disease progression” as the 
reported term, corresponding to disease progression as the cause of death will also be 
considered as clinical progression.
Definition PSA progression
Prostate-specific antigen progression by PCWG2 is defined as a PSA increase 25% and
2 ng/ml above the post-baseline nadir, and which is confirmed by the first subsequent value 
of 3 or more weeks later. The date of the PSA progression is the date the first evidence of 
PSA progression is documented.
6.1.8
Markers of Bone Metabolism, Bone specific Alkaline Phosphatase and Urine 
N-telopeptide
Bone alkaline phosphatase will be measured from the same serum tube of the chemistry 
parameters as per the schedule of assessment [Table 1]. The lab test performed at the 
Screening visit does not need to be repeated on Day 1 if the Day 1 visit occurs within
72 hours of screening.
A 30 mL random urine sample will be collected for measurement of urine N-telopeptide at 
the Screening visit and Week 9, and at the end of treatment if the sample was not obtained at 
Week 9, or subject terminates study drug or study prior to Week 9 bone marrow assessment.


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Baseline value will be defined as the screening value prior to first dose of study drug. Change 
from baseline and percent change from baseline will be calculated as (Week 9 – Baseline)
and ((Week 9 – Baseline)/Baseline)*100, respectively.
6.2
Safety Variables
All safety analyses will be carried on primary variables.
6.2.1
Overview
The safety of the treatment combination will be assessed by:
●
Nature, frequency and severity of adverse events
●
Safety laboratory tests: chemistry and hematology
●
Vital signs (blood pressure, pulse rate and temperature)
●
12 Lead electrocardiogram (ECG) parameters
●
Physical examination results.
6.2.2
Adverse Events (AEs)
Adverse events (AEs) will be assessed regularly as per schedule of assessments [Table 1]. 
Adverse event collection will begin at the time the informed consent form is signed and 
continue through to the last assessments.
For purposes of safety assessment in this study, recorded AEs will be classified as either 
treatment emergent adverse events (TEAEs) or pre-treatment adverse events.
Adverse events which started or worsened during the pre-investigational period (i.e., during 
the period from obtaining informed consent to the start and prior to administration of study 
drug) will be considered as pre-treatment AEs.
An adverse event whose onset date is on the first day of drug intake and ‘onset after first dose 
of study drug’ is marked as ‘yes’ by the investigator in the eCRF or whose onset date is after 
the first dose of any study drug of the study combination treatment will be considered as 
TEAE. If a subject experiences an event both during the pre-investigational period and during 
the investigational period, the event will be considered as TEAE only if it has worsened in 
severity (i.e., it is reported with a new start date). Severity of AEs is reported by the 
investigator using the NCI (National Cancer Institute) CTCAE (Common Terminology 
Criteria for Adverse Events) Version 4.03. For AEs with incomplete or missing start date 
and/or time, a worst-case scenario will be used to determine treatment emergence of this 
adverse event (see algorithm in Section 7.9.2).
The duration of each adverse event will be calculated as the difference between the onset date 
and the end date, and presented in days. Section 7.9.2 contains an elaboration on how to deal 
with missing dates.
The following counting rules for AEs are used:
●
A subject having experienced the same event (i.e., same preferred term) more than once 
will be counted only once in the number of subjects experiencing AEs.


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●
When the table counts AEs only by severity, then only the most severe severity will be 
counted for each event.
●
When the table counts AEs only by relationship (by study drug), then only the most 
related AE will be counted for each event.
Adverse events whose relationship to study drug is assessed as “possible” or “probable” by 
the investigator, or whose relationship to study drug is missing on the eCRF will be defined 
as “treatment related AE”.
AEs with a start data after the data cutoff date will be excluded
6.2.3
Clinical Laboratory
Routine laboratory assessments for hematology, chemistry and PT/PTT will be collected and 
analyzed at the local laboratory and will be obtained as per schedule of assessment. The 
laboratory assessments performed at the Screening visit do not need to be repeated on Day 1
if the Day 1 visit occurs within 3 days of screening. Laboratory assessments must be obtained 
prior to study drug administration. Laboratory test specifications can be found in Section 10.1
Appendix 1.
If the results of clinical laboratory tests are outside the normal range and considered clinically
significant, the investigator may decide to repeat tests on new samples.
Liver function tests (including alkaline phosphatase, AST, ALT, direct and total bilirubin, 
and LDH) will be assessed every 2 weeks for the first 12 weeks of treatment. See
Section 10.2 Appendix 2 for liver function test and abnormalities.
Severity of each clinical laboratory parameter will be calculated using the NCI CTCAE 
Version 4.03 (see Section 10.3 Appendix 3).
Baseline lab value will be defined as the latest value prior to first dose of study drug. Change 
from baseline will be calculated as (Post-baseline – Baseline) respectively.
6.2.4
Vital Signs
Vital signs including blood pressure, pulse rate, and temperature will be assessed at
Screening, at every clinic visit while on study drug, and at the safety follow-up visit.
Per schedule of assessment vital signs will be obtained prior to and 1 to 2 hours after study 
drug administration. Subjects should withhold dosing of study medication on clinic visit 
days. Study drug will be administered in clinic.
Vital signs should be assessed after 3 minutes rest, preferably supine position or in 
semirecumbent, if supine is not tolerated.
6.2.5
12-lead ECG
A standard 12-lead ECG will be performed on all subjects at Screening, Day1, and at every 
clinic visit while on study drug, and at the safety follow-up visit. The ECG test performed at 
the Screening visit does not need to be repeated on Day 1 if the Day 1 visit occurs within
72 hours of screening. All ECGs will be performed prior to study drug administration. The 


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subject should have rested in supine position (or semirecumbent, if supine is not tolerated) 
for 5-10 minutes.
Electrocardiogram parameters including heart rate, PR interval, RR interval, QRS interval, 
QT interval (QTcF and QTcB) as well as an overall conclusion will be collected on the
eCRF. The overall conclusion will be recorded as normal, abnormal not clinically significant, 
or abnormal clinically significant.  If the overall conclusion is abnormal, the abnormality 
recorded by the investigator on the CRF (provided in the eCRF) will be reported.
6.2.6
Physical Examination
Standard, full physical examinations will be performed to assess weight, general appearance, 
head, eyes, ears, nose, throat, neck, cardiovascular, chest and lungs, abdomen, 
musculoskeletal, neurologic status, mental status, lymphatic, and genitourinary system. Any 
clinically significant abnormalities will be collected as medical history (for baseline 
assessment) or adverse events (for post dose assessments). Weight will be recorded at each 
visit. Height will be recorded at the screening visit only. The physical examination performed 
at the screening visit does not need to be repeated on Day 1 if the Day 1 visit occurs within
72 hours of Screening visit.
6.2.7
Other Safety Variables
Other safety variables, such as ECOG, will be listed only.
6.3
Exploratory Pharmacokinetic Variables
Pre-dose concentrations of abiraterone on Day 4 and Day 29 (optional) as well as pre-dose 
concentration of enzalutamide on Day 29 will be collected.
6.4
Other Variables
Time of discontinuation
For subjects that did not complete the study, the time of discontinuation is calculated as: 
(withdrawal date – date of first intake of study drug) + 1
7
STATISTICAL METHODOLOGY
7.1
General Considerations
All statistical analyses and summary information are to be generated according to this 
analysis plan. Any deviation from this plan will be documented in the clinical study report.
All data processing, summarization, and analyses will be performed using SAS® Version 9.1 
or higher on Unix. Specifications for table, figures, and data listing formats can be found in 
the TLF (Tables, Listings and Figures) specifications for this study.
All subject data collected in the eCRF for patient exposed to study drug will be listed. In data 
listings, baseline values will be flagged.
For continuous variables, descriptive statistics will include the number of subjects (N), mean, 
standard deviation (SD), median (MED), minimum (MIN), and maximum (MAX). In


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addition to the above for plasma concentration data, the coefficient of variation (CV), 
geometric mean (GM) will also be calculated.
For categorical variables, frequencies and percentages will be presented. Percentages by 
categories will be based on the number of subjects with no missing data, i.e., will add up to
100%.
All statistical testing (e.g., t-test) will be 2-sided at the nominal alpha 5% level. Kaplan-
Meier (KM) method will be used to summarize time-to-event analysis.
Data summaries and analyses will be presented for enzalutamide and by visit, where multiple 
visit assessments are available for a given parameter. Visits will be presented as Baseline, 
Weeks 5, 9, 13,…, 25, 25+12 week repeats, …, End of Treatment, and 30 Days After Last 
Dose.
Prior to database lock, a Final Review of Data and 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.
7.2
Study Population
7.2.1
Disposition of Subjects
The following subject data will be summarized:
●
Number and percentage of subjects in SAF, BES, PES, and PKAS for all enrolled 
subjects. For each biomarker parameter (testosterone, cortisol, androstenedione, 
progresterone, pregenelone, AR, Splice Variants, and CYP17) the corresponding BES 
will consist of the number of subjects who had both baseline and Week 9 bone marrow 
samples of the biomarker. Also for blood testosterone, cortisol, androstenedione, 
progresterone and pregenelone the corresponding PES will consist of the number of 
subjects who had both baseline and Week 9 blood samples of the biomarker.
●
Number and percentage of subjects who completed the study or prematurely 
discontinued from the investigational period by reasons for discontinuation, will be 
tabulated for each analysis set
●
Number and percentage of subjects who prematurely discontinued treatment during the 
investigational period by reasons for discontinuation, will be tabulated for each analysis 
set
7.2.2
Protocol Deviations
A summary table of the number (and percentage) of SAF subjects with protocol deviations 
will be presented. All protocol deviations will be listed as well as subjects or data that are 
excluded from the PKAS along with the reason for their exclusion will also be listed.
Subjects with protocol deviations will not be excluded from the analyses of the safety data 
(except in the case of subjects with all post-baseline safety data missing); such subjects may 
be excluded from the analysis of the PK data at the discretion of the responsible 
pharmacokineticist.


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7.2.3
Demographics and Other Baseline Characteristics
Demographic information collected at Screening and other baseline characteristics will be 
summarized and presented using descriptive statistics (for continuous variables), frequencies 
and percentages (for categorical variables).
Age (years), Sex, weight (kg), height (cm) at Screening, and body mass index (BMI) where 
BMI (kg/m2) = weight (kg) / [height (m) * height (m)] will be presented using descriptive 
statistics. Frequency (%) tabulations for race and ethnicity as described by the subject will be 
presented. In addition, frequency (%) tabulation will also be presented for age categories:
<55, 55 to <65, 65 to <75, & ≥75 years.
Summaries will be based on SAF, BES, PES and PKAS. The summaries for BES, PES and 
PKAS will not be created if the number of subjects in SAF and BES/PES/PKAS are
identical. All data will be provided in subject data listings.
7.2.4
Previous and Concomitant Medications
Previous medications or therapies are those with a start date between four weeks prior to 
Sreening and Day 1. Concomitant medications are those medications or therapies taken after 
the first dose of study drug during the investigational period.
Previous, concomitant medications and non-medication therapies will be coded with World 
Health Organization Drug Reference List (WHO-DRL) and summarized by anatomical 
therapeutical classification (ATC, 4th level, chemical subgroup) and coded term for the SAF. 
Subjects taking the same medication multiple times will be counted once per medication and 
treatment period.
A summary table and listing of all previous and concomitant medications used will be 
presented. The listing will include the days/time of start and stop of administration and time 
since study drug administration will be presented.
Medications with a start date after the data cutoff date will be excluded. A summary of 
non-medication therapies will also be provided.
7.2.5
Medical History
Medical history will include any significant conditions or diseases other than prostate cancer 
that occurred prior to informed consent.
A complete disease history of the target disease will be recorded at Screening. This includes 
documenting the subject’s initial diagnosis of prostate cancer, Gleason score at time of 
diagnosis dates and other disease specific information as designated in the eCRF, as well as 
prior therapy for treatment of prostate cancer (prior radiotherapy, prior procedures and 
prior/current drug therapy).
Medical history will be coded in Medical Dictionary for Regulatory Activities (MedDRA)
and will be provided in a summary tables as well as a listing.


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7.3
Study Drugs
Compliance with the dosing regimen in terms of study drug exposure of enzalutamide 
(160mg/QD/oral), abiraterone acetate (1000mg/QD/oral), and prednisone (5mg/BID/oral) 
will be presented descriptively for the number of days on the study drug, the cumulative 
number of doses received during the study period, the average dose per day and the average 
dose per day in percentage of the planned study drug exposure of enzalutamide (defined as 
treatment compliance in the summary table) (160mg/QD/oral), abiraterone acetate 
(1000mg/QD/oral), and prednisone (5mg/BID/oral).
Number (%) of subjects with a dose reductions and interruptions in abiraterone acetate and in 
enzalutamide will also be presented.
Summaries of study drug exposure, dose reduction and dose interruptions will be presented 
for SAF. Study drug dosing data will also be provided in subject data listings.
Exposure to the data cutoff date only.
7.4
Analysis of Efficacy
●
Bone marrow androgens, summaries and analyses will be presented for the 
corresponding biomarker parameter evaluable set.
For each biomarker (e.g., testosterone, cortisol, androgestenedione, pregenelone and 
progesterone), descriptive statistics including number of subjects, mean, standard 
deviation, median, minimum, and maximum will be provided for baseline, Week 9, 
change from baseline, percent change from baseline. The effect size (i.e., the mean 
difference divided by the SD) will also be displayed. Summaries of change and percent 
change from baseline to EOT will be presented for BES subjects who also had an EOT 
assessment of the corresponding biomarker parameter sample.
Baseline and post-baseline biomarker results will also be presented graphically using 
waterfall plots (per subject, the largest reduction or smallest increase in case of no 
reduction).
Biomarker results collected at baseline and at Week 9 will be compared using the paired
t-test to evaluate the effect of enzalutamide*. The following generic SAS code for paired 
t-test can be used:
proc ttest data=pairedsample;
paired baseline * week_9;
ods output ttests=ttest;
run
* If warranted the wilcoxon-signed rank test can be used instead.
For each biomarker, summaries of baseline, post-baseline, change from baseline, and 
percent change from baseline will be also presented by PSA response category, where 


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PSA response is defined as at least 50% reduction (improvement) in PSA from baseline 
to Week 9 in SAF. The correlation between each biomarker and PSA level at baseline 
and at Week 9 will be estimated using Spearman’s method. The following generic
SAS code for Spearman’s correlation coefficient can be used:
proc corr data=corr outp=spearmancorr1 spearman;
var variable1 variable2;
ods output spearmancorr=spearmancorr2;
run;
●
Blood androgens, summaries and analyses will be presented for the corresponding 
plasma parameter evaluable set.
Analyses and summaries of blood testosterone, cortisol, androgestenedione, pregenelone 
and progesterone will be conducted and presented similar to the bone marrow 
testosterone, cortisol, androgestenedione, pregenelone and progesterone as stated above.
Following secondary endpoints will be presented for SAF:
●
Baseline, post-baseline, change from baseline, and percent change from baseline values 
of PSA measurements will be summarized descriptively.
The largest decline from baseline in PSA blood concentrations

over the first 12 weeks on treatment

up to and including EOT but excluding ESV

up to and including ESV
will be summarized descriptively.
The number (%) of subjects with a ≥30%, ≥50% and ≥90% decline from baseline as well 
as undetectable values in PSA blood concentration will be tabulated per visit over time. 
Also the number (%) of subjects with the largest decline in PSA from baseline (Nadir),
≥30%, ≥50% and ≥90%, will be provided.
●
Baseline, post-baseline, change from baseline, and percent change from baseline values 
in bone specific alkaline phosphatise (ug/L) and in urine N-telopeptides 
(nmolBCE/mmol) will be summarized descriptively.
●
Number (%) of subjects with tumor identification results (i.e., target, non-target, new, 
bone) and lesion location (e.g., bone, breast, colorectal, kidney, etc) will be summarized.
●
Subjects without radiologic PD or clinical PD or PSA progression or death will be 
censored at the last known date to be alive and progression free. Subjects still PSA 
progression free as of the data cutoff date will be right censored. Kaplan-Meier method 
will be used to draw the survival curve. Also the median, 25%, and 75% percentile of 
survival time will be tabulated, including the corresponding 95% confidence interval 
(CI) using a robust non-parametric method due to Brookmeyer and Crowley. The 
number of events and subjects at risk over time (at visit dates) will also be tabulated.


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●
Time to study drug discontinuation will be calculated as the number of days from start 
of study drug to date of last dose of study drug using the safety populations. Subjects 
still on study drug as of the data cutoff date will be right censored. Kaplan-Meier 
method will be used to draw the survival curve. Also the median, 25%, and 75%
percentile of survival time will be tabulated, including the corresponding 95% 
confidence interval (CI) using a robust non-parametric method due to Brookmeyer and 
Crowley. The number of events and subjects at risk over time (at visit dates) will also 
be tabulated.
●
Number (%) of subjects for the time point response variables (soft tissue and bone) will 
be tabulated per visit over time. Also the number (%) of subjects with the the best 
overall response per RECIST 1.1, during the entire investigational period will be 
derived and summarized. In addition to that, number (%) subjects with objective 
response (CR or PR) will be summarized.
7.5
Analysis of Safety
All safety and tolerability data will be summarized using descriptive statistics and will be 
listed and summarized in tabular and/or graphical form. No formal statistical testing will be 
performed on these data.
7.5.1
Adverse Events
All summaries of adverse events (AEs), unless otherwise stated, will include TEAEs only. 
All AEs will be coded into system organ class (SOC) and preferred term (PT) using
MedDRA. Severity of AEs will be coded using NCI (National Cancer Institute) CTCAE
(Common Terminology Criteria for Adverse Events) Version 4.03. The following TEAEs 
summaries will be provided by SOC and PT:
●
Number of reported TEAEs (= actual events)
●
Number (%) of subjects reporting at least one TEAEs
●
Number (%) of subjects reporting at least one TEAEs by maximum severity of NCI 
CTCAE grade
●
Number (%) of subjects reporting at least one TEAEs of NCI CTCAE grade 3, 4, or 5
●
Number (%) of subjects with at least one enzalutamide related TEAE by maximum 
severity of NCI CTCAE grade
●
Number (%) of subjects with at least one abiraterone related TEAE by maximum 
severity of NCI CTCAE grade
●
Number (%) of subjects with at least one prednisone related TEAE by maximum severity 
of NCI CTCAE grade
●
Number of reported serious TEAEs (= actual events)
●
Number (%) of subjects with at least one enzalutamide related serious TEAEs
●
Number (%) of subjects with at least one abiraterone related serious TEAEs
●
Number (%) of subjects with at least one prednisone related serious TEAEs
●
Incidence of TEAE leading to permanent discontinuation
●
Incidence of enzalutamide related TEAE leading to permanent discontinuation of 
enzalutamide


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●
Incidence of abiraterone related TEAE leading to permanent discontinuation of 
abiraterone
●
Incidence of prednisone related TEAE leading to permanent discontinuation of 
prednisone
●
Incidence of deaths
All AEs recorded on the CRF will be presented in data listing.
A listing of subjects with NCI CTCAE grade 3, 4 or 5 TEAEs will be provided separately. 
Adverse events with a start date after the data cutoff date will be excluded.
7.5.2
Clinical Laboratory Evaluation
All clinical laboratory values will be summarized using international system of units (SI). 
Quantitative clinical laboratory variables, i.e., hematology, biochemistry, coagulation and
liver function tests will be summarized descriptively by visit. Additionally, a within-subject
change from baseline will be summarized for each post-baseline visit.
Each quantitative laboratory result will be classified as low (L), normal (N), or high (H) at 
each visit according to the laboratory supplied reference ranges. Values equal to the limits of 
the normal range are still considered normal. The incidence (and percentage) of subjects with 
these classifications will be displayed by laboratory parameter and visit as a shift table from 
baseline to each particular post-baseline visit.
In addition, a summary table of each quantitative laboratory variable classified by CTCAE 
severity will be produced. The incidence (and percentage) of subjects with these 
classifications will be displayed by laboratory parameter and time-point.
A listing of all laboratory measurements, including the derived outcomes, will be made; all 
quantitative laboratory values outside of the normal range will be flagged as high or low on 
the listing and the CTCAE grade will be specified. Baseline records will be flagged.
A separate listing of all values which fall outside of the respective normal range will also be 
produced for each laboratory test along with the CTCAE grade. A listing of subjects with 
CTCAE grade 4 laboratory values will be provided separately.
Clinically significant values in liver function test and their shift from baseline will be 
summarized.
Laboratory assessments with a collection date after the data cutoff date will be excluded.
7.5.3
Vital Signs
Vital signs which include systolic blood pressure (mmHg), diastolic blood pressure (mmHg), 
pulse rate (bpm) and body temperature (◦C) will be summarized descriptively by visit. 
Additionally, a within-subject change from baseline will be summarized by visit.
For all parts figures will be made of the mean change from baseline over time, by visit. Each 
vital signs result will be classified as low (L), normal (N), or high (H) at each visit according 
to the vital signs reference ranges mentioned in [Table 3]. Shift tables indicating shifts 
between baseline and post-baseline measurements will be displayed by visit.


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Table 3
Vital Signs Reference Ranges
Low
Normal
High
Pulse (bpm) 
<40
40-100
>100
DBP (mm Hg)
≤100
>100
SBP (mm Hg)
≤160
>160
Source: Adapted from “The seventh report of the Joint National Committee on prevention, detection, evaluation 
and treatment of high blood pressure” 2004, [Table 3]
A listing of all vital signs outcomes, including any derived measurements, will be presented. 
A listing of subjects with SBP >160 mmHg or DBP >100 mmHg and also a listing of 
subjects with pulse rate <40 bpm (bradycardia) or pulse rate >100 bpm (tachycardia) will be 
provided separately.
Vital Signs assessments with a collection date after the data cutoff date will be excluded.
7.5.4
12- Lead ECG
A standard 12-lead ECG will be performed on all subjects prior to dosing at each visit. The 
ECG parameters including hear rate (bpm), PR interval (ms), RR interval (ms), QRS interval 
(ms), QT interval (ms), QTcF interval (ms), QTcB interval (ms) will be collected on the
eCRF. Baseline, post-baseline, and their changes from baseline in ECG values will be 
presented using descriptive statistics.
Also overall ECG interpretation (i.e. normal, abnormal-not clinically significant, and 
abnormal-clinically significant) as reported by the investigator will be tabulated by visit. 
Shift tables indicating shifts between baseline and post-dose measurements will be displayed 
by visit.
A listing of all ECG outcomes will be presented. A separate listing of subjects with CTCAE 
grade 3 or 4 based on prolonged QTc (i.e., QTc>0.5 second; life threatening signs or 
symptoms (e.g., arrthythmia, chronic hear failure, hypotension, shock, syncope); torsade de 
pointes) will also be provided.
ECG assessments with a collection date after the data cutoff date will be excluded.
7.5.5
Physical Examination
Body mass index over time will be calculated using the weight at the given visit and the 
height at screening. Physical examination findings will only be listed within the medical 
history or adverse event listings as appropriate.
7.6
Analysis of Pharmacokinetics and/or Pharmacodynamics
7.6.1
PK Concentrations
Individual and mean pre-dose plasma concentration of abiraterone, and enzalutamide and its 
metabolities MDPC0001 and MDPC0002 will be summarized by scheduled visit using mean 
(arithmetic and geometric), standard deviation, minimum, maximum, median, and coefficient 
of variation. Values below the lower limit of quantitation (LLOQ) will be set to 0 for 
calculation of descriptive statistics.


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Descriptive statistics will not be calculated if all values are LLOQ. In cases where more than 
half of the individual data are LLOQ, SD and CV will not be calculated. If one or more 
values are LLOQ, the geometric mean will not be calculated.
7.7
Other Analyses
Not applicable.
7.8
Interim Analysis (and Early Discontinuation of the Clinical Study)
The interim analysis as defined in Section 7.8 of the protocol will not be subject of this SAP. 
A separate “Charter for Interim Safety Review” has been written for this purpose. This 
internal document was finalized and signed on January 10th, 2013.
7.9
Handling of Missing Data, Outliers, Visit Windows, and Other
Information
7.9.1
Missing Data
As a general rule, missing data will not be imputed. Exceptions include the imputation of 
(partly) missing onset and end dates of AE and the computation of “Time since study drug” 
for AEs.
7.9.2
Missing Adverse Event Dates
If a subject experiences an event both during the pre-investigational period and during the 
investigational period, the event will be considered as TEAE only if it has worsened in 
severity (i.e., it is reported with a new start date). For AEs with incomplete or missing start 
date, a worst-case scenario will be used to determine treatment emergence of this adverse 
event:
●
If the investigator has ticked the box that AE onset was after the first dose of study drug 
then the AE will be considered TEAE.
●
If the AE onset date is the same day as the study drug start date or if the onset date is 
incomplete and the investigator has not ticked the box that the onset was before the first 
dose of study drug AND:

if the AE start date is non-missing and equal or greater the date of treatment dose 
then the AE will be considered TEAE;

if the AE day is missing, then if the AE month is equal or greater the month in 
which treatment was administered then the AE will be considered TEAE;

if the AE month is missing and the AE year is equal or greater the year in which 
treatment was administered then the AE will be considered TEAE;

if the AE year is missing then the AE will be considered TEAE;

for TEAEs with partial dates the AE will be allocated to the treatment period using 
the available partial information, without imputations.
●
Other cases of incomplete onset date of an AE will be addressed prior to or during the 
data review meeting (DRM) in order to determine whether the AE must be considered 
treatment emergent or not.


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Listings will always show the original date information without imputation, but derived 
parameters (TEAE indicator and duration of AEs) would be flagged.
7.9.3
Baseline Assessments
Baseline will be defined as the latest (non-missing) assessment taken prior to study drug 
administration on Day 1. If all pre-dose measurements are missing then baseline will be
considered as missing, and no changes from baseline and no percentage reduction from 
baseline will be computed.
7.9.4
Visit Windows
The following analysis visit windows will be used for safety and efficacy analyses for the 
week visits in terms of study days:
Week (Planned Study Day)
Visit Window
1 (Day 4)
4
5 (Day 29)
16 to 43
9 (Day 57)
44 to 71
13…25 (Day xa)
Day xa-13 to Day xa+14
25+12 Weeks * i Repeats,
Where i= 1, 2, 3,…
169+12*i±3,
Where i=1, 2, 3
End of Treatment
End of Treatment±3
Safety F/U
Safety F/U
a. See [Table 1] Schedule of Assessments for the corresponding planned study days.
7.9.5
Outliers
All values will be included in the analyses.
7.9.6
Values Below LOQ in PK Data
For the purpose of summary statistics, graphs and statistical analyses of PK data, values 
below the LOQ will be set to 0. For laboratory safety data, values recorded as “<X” or “>Y” 
will be imputed by “X” and “Y” respectively for descriptive statistics, graphs and inferential 
statistics. This will be documented in a footnote to all summary tables and all output where 
such a replacement was performed.


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8
DOCUMENT REVISION HISTORY 
Version
Date
Changes
Comment/rationale for change
1.00
02-OCT-2014
NA
Document finalized
2.00
14-DEC-2015
Deleted reference to 
specific 01JUL2014 
cutoff date
Cutoff date was delayed until complete bone 
marrow was in-house, more efficient to use a 
general data cut reference.
2.00
14-DEC-2015
Added document 
revision history section, 
needed to change 
relevant TOC and body 
of document section 
numbers
Needed to track revisions to SAP
2.00
14-DEC-2015
Added new study 
statistician and medical 
monitor for signoff
Sign off to reflect current study team 
members.
9
REFERENCES
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; 45:228-247.
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)
Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, et al. Design and end points 
of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: 
recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol 
2008;26:1148-5
The seventh report of the Joint National Committee on prevention, detection, evaluation and treatment 
of high blood pressure. 2004; [Table 3]


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10
APPENDICES
10.1
Appendix 1: Laboratory Tests
Test
Visit
Collecting Tube
Parameters to be Analyzed
Hematology
All visits, except
Day 4
EDTA tube
Hemoglobin
Hematocrit Erythrocytes (RBC) 
Leukocytes (WBC) Differential WBC 
Platelets
PT/PTT
All visits, except
Day 4
Citrate tube
PT/PTT
Chemistry
All visits, except
Day 4
Serum tube
Sodium
Potassium Calcium Chloride Magnesium 
Phosphorus Glucose Creatinine
Alkaline phosphatase
LDH AST ALT
Direct bilirubin Total bilirubin Total
protein
Albumin
CO2
BUN
Bone alkaline phosphatase
PSA
Screening, Week 5
and every 
subsequent
4 weeks and end 
of treatment.
Serum tube
PSA
Urine N-telopeptide
Screening, Week 9
and at the end of 
treatment if the 
sample was not 
obtained at
Week 9
30 mL random urine
sample
Urine N-telopeptide
Testosterone and
DHT
Screening, Week 9
and at the end of 
treatment if the 
sample was not 
obtained at
Week 9
Serum tube
Testosterone and DHT
Blood sample for
genotype analysis
Day 1
K3EDTA tube
Genotype analysis
Blood sample for
PK analysis
Day 4 and Week 5
K2EDTA tube
PK analysis


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10.2
Appendix 2: Liver Function Test
If laboratory testing for a subject enrolled in study and receiving study drug reveals an 
increase of serum aminotransferases (AT) to > 3X ULN, or bilirubin > 2X ULN, at least all 
four of the usual serum hepatic measures (ALT, AST, ALP, and TBL) should be repeated. 
Testing should be repeated within 48-72 hours of notification of the test results. For studies 
for which a central laboratory is used, alerts will be generated by the central lab regarding 
moderate and marked liver abnormality to inform the investigator, study monitor and study
team. Subjects should be asked if they have any symptoms suggestive of hepatobiliary 
dysfunction.
DefinitionofLiverAbnormalities
Confirmed abnormalities will be characterized as moderate and marked where ULN:
ALT or AST
Total Bilirubin
Moderate
Marked
> 3 x ULN
> 3 x ULN
or
and
> 2 x ULN
> 2 x ULN
In addition, the subject should be considered to have marked hepatic abnormalities for any of 
the following:
●
ALT or AST > 8X ULN
●
ALT or AST > 5X ULN for more than 2 weeks
●
ALT or AST > 3X ULN and INR > 1.5
●
ALT or AST > 3X ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%).
The investigator may determine that abnormal liver function results, other than as described 
above, may qualify as moderate or marked abnormalities and require additional monitoring 
and follow-up.


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10.3
Appendix 3: Common Terminology Criteria for Adverse Events (CTCAE)
CTCAE v4.0
SOC
CTCAE v4.0 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.0 AE Term
Definition
Errata
Blood and
Anemia
Hemoglobin (Hgb)
Hgb <10.0 - 8.0 g/dL;
Hgb <8.0 g/dL; <4.9
Life-threatening
Death
A disorder characterized by
lymphatic
<LLN - 10.0 g/dL;
<6.2 - 4.9 mmol/L;
mmol/L; <80 g/L;
consequences; urgent
an reduction in the amount
system
<LLN - 6.2 mmol/L;
<100 - 80g/L
transfusion indicated
intervention indicated
of hemoglobin in 100 ml of
disorders
<LLN - 100 g/L
blood. Signs and symptoms
of anemia may include
pallor of the skin and
mucous membranes,
shortness of breath,
palpitations of the heart,
soft systolic murmurs,
lethargy, and fatigability.
Blood and
Bone marrow
Mildly hypocellular or
Moderately
Severely hypocellular
Aplastic persistent for
Death
A disorder characterized by
lymphatic
hypocellular
<=25% reduction
hypocellular or
or >50 - <=75%
longer than 2 weeks
the inability of the bone
system
from normal
>25 - <50% reduction
reduction cellularity
marrow to produce
disorders
cellularity for age
from normal 
cellularity for age
from normal for age
hematopoietic elements.
Blood and
Disseminated
-
Laboratory findings
Laboratory findings
Life-threatening
Death
A disorder characterized by
lymphatic
intravascular
with no bleeding
and bleeding
consequences; urgent
systemic pathological
system
coagulation
intervention indicated
activation of blood clotting
disorders
mechanisms which results
in clot formation
throughout the body. There
is an increase in the risk of
hemorrhage as the body is
depleted of platelets and
coagulation factors.
Blood and
Febrile neutropenia
-
-
ANC <1000/mm3 with
Life-threatening
Death
A disorder characterized by
lymphatic
a single temperature of
consequences; urgent
an ANC <1000/mm3 and a
system
>38.3 degrees C
intervention indicated
single temperature of
disorders
(101 degrees F) or a
>38.3 degrees C
sustained temperature
(101 degrees F) or a
of >=38 degrees C
sustained temperature of
(100.4 degrees F) for
>=38 degrees C
more than one hour
(100.4 degrees F) for more
thanonehour
Table continued on next page


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CTCAE v4.0
SOC
CTCAE v4.0 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.0 AE Term
Definition
Errata
Blood and
Hemolysis
Laboratory evidence
Evidence of hemolysis
Transfusion or
Life-threatening
Death
A disorder characterized by
lymphatic
system
of hemolysis only(e.g., 
direct antiglobulin test;
and >=2 gm decrease 
in hemoglobin
medical intervention
indicated
consequences; urgent
intervention indicated
laboratory test results that
indicate widespread
disorders
DAT; Coombs';
(e.g., steroids)
erythrocyte cell membrane
schistocytes;
destruction.
decreased
haptoglobin)
Blood and
Hemolytic uremic
Evidence of RBC
-
Laboratory findings
Life-threatening
Death
A disorder characterized by
lymphatic
syndrome
destruction
with clinical
consequences, (e.g.,
a form of thrombotic
system
(schistocytosis)
consequences
CNS hemorrhage or
microangiopathy with renal
disorders
without clinical
(e.g., renal
thrombosis/embolism
failure, hemolytic anemia,
consequences
insufficiency, petechiae)
or renal failure)
and severe thrombocytopenia.
Blood and
Leukocytosis
-
-
>100,000/mm3
Clinical
Death
A disorder characterized by
lymphatic
manifestations of
laboratory test results that
system
leucostasis; urgent
indicate an increased
disorders
intervention indicated
number of white blood cells
in the blood.
Blood and
Thrombotic
Evidence of RBC
-
Laboratory findings
Life-threatening
Death
A disorder characterized by
lymphatic
thrombocytopenic
destruction
with clinical
consequences,
the presence of
system
purpura
(schistocytosis)
consequences
(e.g., CNS
microangiopathic hemolytic
disorders
without clinical
(e.g., renal
hemorrhage or
anemia, thrombocytopenic
consequences
insufficiency,
thrombosis/embolism
purpura, fever, renal
petechiae)
or renal failure)
abnormalities and
neurological abnormalities
such as seizures,
hemiplegia, and visual
disturbances. It is an acute
or subacute condition.
Cardiac
Acute coronary
-
Symptomatic,
Symptomatic, unstable
Symptomatic,
Death
A disorder characterized by
disorders
syndrome
progressive angina;
angina and/or acute
unstable angina
signs and symptoms related
cardiac enzymes
myocardial infarction,
and/or acute
to acute ischemia of the
normal;
cardiac enzymes
myocardial infarction,
myocardium secondary to
hemodynamically 
stable
abnormal,
hemodynamically
cardiac enzymes
abnormal, 
coronary artery disease. The
clinical presentation
stable
hemodynamically
covers a spectrum of
unstable
heart diseases
from unstable angina to
myocardialinfarction.
Table continued on next page


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CTCAE v4.0
SOC
CTCAE v4.0 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.0 AE Term
Definition
Errata
Cardiac
Myocardial 
-
Asymptomatic and
Severe symptoms;
Life-threatening
Death
A disorder characterized by
disorders
infarction
cardiac enzymes
cardiac enzymes
consequences;
gross necrosis of the
minimally abnormal
abnormal;
hemodynamically
myocardium; this is due to
and no evidence of
hemodynamically
unstable
an interruption of blood
ischemic ECG 
changes
stable; ECG changes
consistent with
supply to the area.
infarction
Investigations
Activated partial
>ULN - 1.5 x ULN
>1.5 - 2.5 x ULN
>2.5 x ULN;
-
-
An abnormal laboratory test
thromboplastin time
hemorrhage
result in which the partial
prolonged
thromboplastin time is
found to be greater than the
control value. As a possible
indicator of coagulopathy, a
prolonged partial
thromboplastin time (PTT)
may occur in a variety of
diseases and disorders, both
primary and related to
treatment.
Investigations
Alanine
>ULN - 3.0 x ULN
>3.0 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
-
A finding based on
aminotransferase
laboratory test results that
increased
indicate an increase in the
level of alanine
aminotransferase (ALT or
SGPT) in the blood
specimen.
Investigations
Alkaline phosphatase
>ULN - 2.5 x ULN
>2.5 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
-
A finding based on
increased
laboratory test results that
indicate an increase in the
level of alkaline
phosphatase in a blood
specimen.
Investigations
Aspartate
>ULN - 3.0 x ULN
>3.0 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
-
A finding based on
aminotransferase
laboratory test results that
increased
indicate an increase in the
level of aspartate
aminotransferase (AST or
SGOT) in a blood specimen.
Table continued on next page


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CTCAE v4.0
SOC
CTCAE v4.0 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.0 AE Term
Definition
Errata
Investigations
Blood antidiuretic
Asymptomatic;
Symptomatic; medical
Hospitalization
-
-
A finding based on
hormone abnormal
clinical or diagnostic 
observations only;
intervention indicated
indicated
laboratory test results that 
indicate abnormal
intervention not 
indicated
levels of antidiuretic 
hormone in the
blood specimen.
Investigations
Blood bilirubin
>ULN - 1.5 x ULN
>1.5 - 3.0 x ULN
>3.0 - 10.0 x ULN
>10.0 x ULN
-
A finding based on
increased
laboratory test results that 
indicate an abnormally
high level of bilirubin in
the blood. Excess
bilirubin is associated
with jaundice.
Investigations
Blood corticotrophin
Asymptomatic;
Symptomatic; medical
Hospitalization
-
-
A finding based on
decreased
clinical or diagnostic 
intervention indicated
indicated
laboratory test results that
observations only;
indicate an decrease in
intervention not
levels of corticotrophin in a
indicated
blood specimen.
Investigations
Blood gonadotrophin
Asymptomatic;
Symptomatic; medical
Severe symptoms;
-
-
A finding based on
abnormal
clinical or diagnostic 
observations only;
intervention indicated; 
limiting instrumental
limiting self care ADL
laboratory test results that 
indicate abnormal levels of
intervention not
ADL
gonadotrophin hormone in
indicated
a blood specimen.
Investigations
Blood prolactin
Asymptomatic;
Moderate symptoms;
-
-
-
A finding based on
abnormal
clinical or diagnostic
limiting instrumental
laboratory test results that
observations only;
ADL
indicate abnormal levels of
intervention not
indicated
prolactin hormone in a blood 
specimen.
Investigations
Carbon monoxide
3 - 5 units below
6 - 8 units below LLN;
Asymptomatic
-
-
A finding based on
diffusing capacity 
decreased
LLN; for follow-up, a 
decrease of 3 - 5 units
for follow-up, an
asymptomatic
decrease of >8 units 
drop;  >5 units drop
lung function test results that 
indicate a decrease in 
(ml/min/mm Hg) 
decrease of >5 - 8 units
along with the
the lung capacity to absorb
below the baseline
(ml/min/mm Hg)
presence of pulmonary
carbon monoxide.
value
below
symptoms (e.g.,
the baseline value
>Grade 2  hypoxia or
>Grade 2 or higher
dyspnea)
Table continued on next page


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CTCAE v4.0
SOC
CTCAE v4.0 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.0 AE Term
Definition
Errata
Investigations
Cardiac troponin I
Levels above the
-
Levels consistent with
-
-
A laboratory test result
increased
upper limit of normal
myocardial infarction
which indicates increased
and below the level of
myocardial infarction
as defined by the 
manufacturer
levels of cardiac troponin I 
in a biological
as defined by the
specimen.
manufacturer
Investigations
Cardiac troponin T
Levels above the
-
Levels consistent with
-
-
A laboratory test result
increased
upper limit of normal
myocardial infarction
which indicates increased
and below the level of
myocardial infarction
as defined by the 
manufacturer
levels of cardiac troponin T 
in a biological
as defined by the
specimen.
manufacturer
Investigations
CD4 lymphocytes
decreased
<LLN - 500/mm3;
<LLN - 0.5 x 109 /L
<500 - 200/mm3; <0.5
-0.2 x 109 /L
<200 - 50/mm3; <0.2 x 
0.05 - 109 /L
<50/mm3; <0.05 x 109
/L
-
A finding based on
laboratory test results
that indicate an decrease
in levels of CD4
lymphocytes
in a blood specimen.
Investigations
Cholesterol high
>ULN - 300 mg/dL;
>300 - 400 mg/dL;
>400 - 500 mg/dL;
>500 mg/dL; >12.92
-
A finding based on
>ULN - 7.75 mmol/L
>7.75 - 10.34 mmol/L
>10.34 - 12.92 mmol/L
mmol/L
laboratory test results that 
indicate higher than normal
levels of cholesterol in a
blood specimen.
Investigations
CPK increased
>ULN - 2.5 x ULN
>2.5 x ULN - 5 x ULN
>5 x ULN - 10 x ULN
>10 x ULN
-
A finding based on
laboratory test results that
indicate an increase in
levels of creatine
phosphokinase in a blood
specimen.
Investigations
Creatinine increased
>1 - 1.5 x baseline;
>1.5 - 3.0 x baseline;
>3.0 baseline; >3.0 -
>6.0 x ULN
-
A finding based on
>ULN - 1.5 x ULN
>1.5 - 3.0 x ULN
6.0 x ULN
laboratory test results that 
indicate increased
levels of creatinine in
a biological specimen.
Investigations
Fibrinogen decreased
<1.0 - 0.75 x LLN  or
<0.75 - 0.5 x LLN or 25
<0.5 - 0.25 x LLN or
<0.25 x LLN  or 75%
-
A finding based on
<25% decrease from
- <50% decrease from
50 - <75% decrease
decrease from
laboratory test results that
baseline
baseline
from baseline
baseline or absolute
indicate an decrease in
value <50 mg/dL
levels of fibrinogen in a 
bloodspecimen.
Table continued on next page


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SAP Final Version 2.0
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14-Dec-2015
Astellas
Page 40 of 46
CTCAE v4.0
SOC
CTCAE v4.0 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.0 AE Term
Definition
Errata
Investigations
GGT increased
>ULN - 2.5 x ULN
>2.5 - 5.0 x ULN
>5.0 - 20.0 x ULN
>20.0 x ULN
-
A finding based on
laboratory test results that
indicate higher than normal
levels of the enzyme
gamma-glutamyltransferase
in the blood specimen.
GGT (gamma-
glutamyltransferase )
catalyzes the transfer of a
gamma glutamyl group
from a gamma glutamyl
peptide to another peptide,
amino acids or water.
Investigations
Growth hormone
Asymptomatic;
Symptomatic; medical
-
-
-
A finding based on
abnormal
clinical or diagnostic
intervention indicated;
laboratory test results that
observations only;
limiting instrumental
indicate abnormal levels of
intervention not
ADL
growth hormone in a
indicated
biological specimen.
Investigations
Haptoglobin decreased
<LLN
-
-
-
-
A finding based on
laboratory test results that
indicate an decrease in
levels of haptoglobin in a
blood specimen.
Investigations
Hemoglobin increased
Increase in >0 - 2
Increase in >2 - 4
Increase in >4 gm/dL
-
-
A finding based on
gm/dL above ULN or
gm/dL above ULN or
above ULN or above
laboratory test results that
above baseline if
above baseline if
baseline if baseline is
indicate increased levels of
baseline is above
baseline is above ULN
above ULN
hemoglobin in a biological
ULN
specimen.
Investigations
INR increased
>1 - 1.5 x ULN; >1 -
>1.5 - 2.5 x ULN; >1.5
>2.5 x ULN; >2.5
-
-
A finding based on
1.5 times above
- 2.5 times above
times above baseline if
laboratory test results that
baseline if on
baseline if on
on anticoagulation
indicate an increase in the
anticoagulation
anticoagulation
ratio of the patient's
prothrombin time to a
control sample in the blood.
Investigations
Lipase increased
>ULN - 1.5 x ULN
>1.5 - 2.0 x ULN
>2.0 - 5.0 x ULN
>5.0 x ULN
-
A finding based on
laboratory test results that
indicate an increase in the
level of lipase in a biological
specimen.
Table continued on next page


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 2.0
ISN/Protocol 9785-CL-0011
14-Dec-2015
Astellas
Page 41 of 46
CTCAE v4.0
SOC
CTCAE v4.0 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.0 AE Term
Definition
Errata
Investigations
Lymphocyte count
<LLN - 800/mm3;
<800 - 500/mm3; <0.8
<500 - 200/mm3; <0.5
<200/mm3; <0.2 x
-
A finding based on
decreased
<LLN - 0.8 x 109/L
-0.5 x 109 /L
- 0.2 x 109 /L
109 /L
laboratory test results that
indicate a decrease in
number of lymphocytes in a
blood specimen.
Investigations
Lymphocyte count
-
>4000/mm3 -
>20,000/mm3
-
-
A finding based on
increased
20,000/mm3
laboratory test results that
indicate an abnormal
increase in the number of
lymphocytes in the blood,
effusions or bone marrow.
Investigations
Neutrophil count
<LLN - 1500/mm3;
<1500 - 1000/mm3;
<1000 - 500/mm3;
<500/mm3; <0.5 x
-
A finding based on
decreased
<LLN - 1.5 x 109 /L
<1.5 - 1.0 x 109 /L
<1.0 - 0.5 x 109 /L
109 /L
laboratory test results that
indicate a decrease in
number of neutrophils in a
blood specimen.
Investigations
Pancreatic enzymes
<LLN and
Increase in stool
Sequelae of absorption
-
-
A finding based on
decreased
asymptomatic
frequency, bulk, or
deficiency
laboratory test results that
odor; steatorrhea
indicate an decrease in
levels of pancreatic
enzymes in a biological
specimen.
Investigations
Platelet count 
decreased
<LLN - 75,000/mm3; 
<LLN - 75.0 x 109 /L
<75,000 -
50,000/mm3; <75.0 -
50.0 x 109 /L
<50,000 - 25,000/mm3;
<50.0 - 25.0 x 109 /L
<25,000/mm3; <25.0 x 
109 /L
-
A finding based on 
laboratory test results that 
indicate a decrease in 
number of platelets in a 
blood specimen.
Investigations
Serum amylase
>ULN - 1.5 x ULN
>1.5 - 2.0 x ULN
>2.0 - 5.0 x ULN
>5.0 x ULN
-
A finding based on
increased
laboratory test results that
indicate an increase in the
levels of amylase in a serum 
specimen.
Investigations
White blood cell
<LLN - 3000/mm3;
<3000 - 2000/mm3;
<2000 - 1000/mm3;
<1000/mm3; <1.0 x
-
A finding based on
decreased
<LLN - 3.0 x 109 /L
<3.0 - 2.0 x 109 /L
<2.0 - 1.0 x 109 /L
109 /L
laboratory test results that
indicate an decrease in
number of white blood cells
in a bloodspecimen.
Table continued on next page


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 2.0
ISN/Protocol 9785-CL-0011
14-Dec-2015
Astellas
Page 42 of 46
CTCAE v4.0
SOC
CTCAE v4.0 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.0 AE Term
Definition
Errata
Metabolism and
nutrition
Acidosis
pH <normal, but
>=7.3
-
pH <7.3
Life-threatening
consequences
Death
A disorder characterized by
abnormally high acidity
disorders
(high hydrogen-ion
concentration) of the blood
and other body tissues.
Metabolism and
nutrition
Alkalosis
pH >normal, but
<=7.5
-
pH >7.5
Life-threatening
consequences
Death
A disorder characterized by
abnormally high alkalinity
disorders
(low hydrogen-ion
concentration) of the blood
and other body tissues.
Metabolism and
Hypercalcemia
Corrected serum
Corrected serum
Corrected serum
Corrected serum
Death
A disorder characterized by
nutrition
calcium of >ULN -
calcium of >11.5 - 12.5
calcium of >12.5 -
calcium of >13.5
laboratory test results that
disorders
11.5 mg/dL; >ULN -
mg/dL; >2.9 - 3.1
13.5 mg/dL;>3.1 - 3.4
mg/dL; >3.4 mmol/L;
indicate an elevation in the
2.9 mmol/L;  Ionized
mmol/L;  Ionized
mmol/L;  Ionized
Ionized calcium  >1.8
concentration of calcium
calcium >ULN - 1.5
calcium >1.5 - 1.6
calcium  >1.6 - 1.8
mmol/L; life-
(corrected for albumin) in
mmol/L
mmol/L; symptomatic
mmol/L; hospitalization
threatening
blood.
indicated
consequences
Metabolism and
Hyperglycemia
Fasting glucose value
Fasting glucose value
>250 - 500 mg/dL;
>500 mg/dL; >27.8
Death
A disorder characterized by
nutrition
>ULN - 160 mg/dL;
>160 - 250 mg/dL;
>13.9 - 27.8 mmol/L;
mmol/L; life-
laboratory test results that
disorders
Fasting glucose value
Fasting glucose value
hospitalization
threatening
indicate an elevation in the
>ULN - 8.9 mmol/L
>8.9 - 13.9 mmol/L
indicated
consequences
concentration of blood
sugar. It is usually an
indication of diabetes
mellitus or glucose
intolerance.
Metabolism and
Hyperkalemia
>ULN - 5.5 mmol/L
>5.5 - 6.0 mmol/L
>6.0 - 7.0 mmol/L;
>7.0 mmol/L; life-
Death
A disorder characterized by
nutrition
hospitalization
threatening
laboratory test results that
disorders
indicated
consequences
indicate an elevation in the
concentration of potassium
in the blood; associated
with kidney failure or
sometimes with the use of
diuretic drugs.
Metabolism and
Hypermagnesemia
>ULN - 3.0 mg/dL;
-
>3.0 - 8.0 mg/dL;
>8.0 mg/dL; >3.30
Death
A disorder characterized by
nutrition
>ULN - 1.23 mmol/L
>1.23 - 3.30 mmol/L
mmol/L; life-
laboratory test results that
disorders
threatening
indicate an elevation in the
consequences
concentration of
magnesiumintheblood.
Table continued on next page


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 2.0
ISN/Protocol 9785-CL-0011
14-Dec-2015
Astellas
Page 43 of 46
CTCAE v4.0
SOC
CTCAE v4.0 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.0 AE Term
Definition
Errata
Metabolism and
Hypernatremia
>ULN - 150 mmol/L
>150 - 155 mmol/L
>155 - 160 mmol/L;
>160 mmol/L; life-
Death
A disorder characterized by
nutrition
hospitalization
threatening
laboratory test results that
disorders
indicated
consequences
indicate an elevation in the
concentration of sodium in
the blood.
Metabolism and
Hypertriglyceridemia
150 mg/dL - 300
>300 mg/dL - 500
>500 mg/dL - 1000
>1000 mg/dL; >11.4
Death
A disorder characterized by
nutrition
mg/dL; 1.71 mmol/L -
mg/dL; >3.42 mmol/L
mg/dL; >5.7 mmol/L
mmol/L;  life-
laboratory test results that
disorders
3.42 mmol/L
- 5.7 mmol/L
- 11.4 mmol/L
threatening
indicate an elevation in the
consequences
concentration of
triglyceride concentration in
the blood.
Metabolism and
Hyperuricemia
>ULN - 10 mg/dL
-
>ULN - 10 mg/dL
>10 mg/dL; >0.59
Death
A disorder characterized by
nutrition
(0.59 mmol/L)
(0.59 mmol/L) with
mmol/L; life-
laboratory test results that
disorders
without physiologic
physiologic
threatening
indicate an elevation in the
consequences
consequences
consequences
concentration of uric acid.
Metabolism and
Hypoalbuminemia
<LLN - 3 g/dL; <LLN
<3 - 2 g/dL; <30 - 20
<2 g/dL; <20 g/L
Life-threatening
Death
A disorder characterized by
nutrition
- 30 g/L
g/L
consequences; urgent
laboratory test results that
disorders
intervention indicated
indicate a low concentration
of albumin in the blood.
Metabolism and
Hypocalcemia
Corrected serum
Corrected serum
Corrected serum
Corrected serum
Death
A disorder characterized by
nutrition
calcium of <LLN -
calcium of <8.0 - 7.0
calcium of <7.0 - 6.0
calcium of <6.0
laboratory test results that
disorders
8.0 mg/dL; <LLN -2.0 
mmol/L; Ionized
mg/dL; <2.0 - 1.75
mmol/L; Ionized
mg/dL; <1.75 - 1.5
mmol/L;  Ionized
mg/dL; <1.5 mmol/L;
Ionized calcium  <0.8
indicate a low concentration
of calcium (corrected for
calcium  <LLN - 1.0
calcium  <1.0 - 0.9
calcium  <0.9 - 0.8
mmol/L; life-
albumin) in the blood.
mmol/L
mmol/L; symptomati
mmol/L; hospitalization
threatening
c
indicated
consequences
Metabolism and
Hypoglycemia
<LLN - 55 mg/dL;
<55 - 40 mg/dL; <3.0
<40 - 30 mg/dL; <2.2
<30 mg/dL; <1.7
Death
A disorder characterized by
nutrition
<LLN - 3.0 mmol/L
-2.2 mmol/L
- 1.7 mmol/L
mmol/L; life-
laboratory test results that
disorders
threatening
consequences;
indicate a low concentration
seizures
of glucose in the blood.
Metabolism and
Hypokalemia
<LLN - 3.0 mmol/L
<LLN - 3.0 mmol/L;
<3.0 - 2.5 mmol/L;
<2.5 mmol/L; life-
Death
A disorder characterized by
nutrition
symptomatic;
hospitalization
threatening
laboratory test results that
disorders
intervention indicated
indicated
consequences
indicate a low concentration
ofpotassiumintheblood
Table continued on next page


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 2.0
ISN/Protocol 9785-CL-0011
14-Dec-2015
Astellas
Page 44 of 46
CTCAE v4.0
SOC
CTCAE v4.0 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.0 AE Term
Definition
Errata
Metabolism and
nutrition
Hypomagnesemia
<LLN - 1.2 mg/dL;
<LLN - 0.5 mmol/L
<1.2 - 0.9 mg/dL; <0.5 
-0.4 mmol/L
<0.9 - 0.7 mg/dL; <0.4
-0.3 mmol/L
<0.7 mg/dL; <0.3
mmol/L; life-
Death
A disorder characterized by
laboratory test results that
disorders
threatening
indicate a low
concentration
consequences
of magnesium in the blood.
Metabolism and
Hyponatremia
<LLN - 130 mmol/L
-
<130 - 120 mmol/L
<120 mmol/L; life-
Death
A disorder characterized by
nutrition
threatening
laboratory test results that
disorders
consequences
indicate a low concentration
of sodium in the blood.
Metabolism and
nutrition
Hypophosphatemia
<LLN - 2.5 mg/dL;
<LLN - 0.8 mmol/L
<2.5 - 2.0 mg/dL; <0.8 
0.6 mmol/L -
<2.0 - 1.0 mg/dL; <0.6
-0.3 mmol/L
<1.0 mg/dL; <0.3
mmol/L; life-
Death
A disorder characterized by
laboratory test results that
disorders
threatening
indicate a low
consequences
concentration
of phosphates in the blood.
Metabolism and
Iron overload
-
Moderate symptoms;
Severe symptoms;
Life-threatening
Death
A disorder characterized by
nutrition
intervention not
intervention indicated
consequences; urgent
accumulation of iron in the
disorders
indicated
intervention indicated
tissues.
Renal and
Acute kidney injury
Creatinine level
Creatinine 2 - 3 x above
Creatinine >3 x
Life-threatening
Death
A disorder characterized by
urinary
increase of >0.3
baseline
baseline or >4.0
consequences;
the acute loss of renal
disorders
mg/dL; creatinine 1.5
mg/dL; hospitalization
dialysis indicated
function and is traditionally
- 2.0 x above baseline
indicated
classified as pre-renal (low
blood flow into kidney),
renal (kidney damage) and
post-renal causes (ureteral
or bladder outflow
obstruction).
Renal and
Chronic kidney disease eGFR (estimated
eGFR or CrCl 59 - 30
eGFR or CrCl 29 - 15
eGFR or CrCl <15
Death
A disorder characterized by
urinary
Glomerular Filtration
ml/min/1.73 m2
ml/min/1.73 m2
ml/min/1.73 m2;
gradual and usually
disorders
Rate) or CrCl
dialysis or renal
permanent loss of kidney
(creatinine clearance)
transplant indicated
function resulting in renal
<LLN - 60 
ml/min/1.73 m2 or
failure.
proteinuria 2+
present; urine
protein/creatinine
>0.5
Table continued on next page


Sponsor: Astellas Pharma Global Development, Inc.
SAP Final Version 2.0
ISN/Protocol 9785-CL-0011
14-Dec-2015
Astellas
Page 45 of 46
CTCAE v4.0
SOC
CTCAE v4.0 Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
CTCAE v4.0 AE Term
Definition
Errata
Renal and
Proteinuria
1+ proteinuria;
Adults: 2+ proteinuria;
Adults: urinary protein
-
-
A disorder characterized by
urinary disorders
urinary protein <1.0
g/24 hrs
urinary protein 1.0 -
3.4 g/24 hrs; Pediatric:
>=3.5 g/24 hrs;
Pediatric: urine P/C
laboratory test results that
indicate the presence of
urine P/C
>1.9
excessive protein in the
(Protein/Creatinine)
urine. It is predominantly
ratio0.5-1.9
albumin,butalsoglobulin.