Clinical trial NCT01534052
Conditions: Castration-Resistant Prostate Cancer (CRPC)
Keywords: Prostate Cancer Castration-Resistant Prostate Cancer (CRPC) MDV3100 Androgen receptor signaling inhibitor
Sponsor: Astellas Pharma Inc
Start date: 2011-10-21; Completion date: 2017-04-18
Enrollment: 52 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A study to assess the safety of continued administration of MDV3100 in subjects with Prostate Cancer who have already undergone treatment with MDV3100 and showed benefit.

Detailed description:
This was a multi-center extension study in participants with prostate cancer who have completed MDV3100 treatment study to assess the long-term safety of continued administration of MDV3100, when judged by the investigator to be in the best interest of the participant. For the study duration, all participants with castration-resistant prostate cancer (CRPC) maintained androgen deprivation with a Luteinizing Hormone Releasing Hormone (LHRH) agonist/antagonist unless they underwent bilateral orchiectomy. Participants were discontinued from study drug when the continued administration of study drug was deemed to be not in the participants' best interest by the investigator based on clinical assessment. Throughout the study, safety and tolerability were assessed by the recording of adverse events, monitoring of vital signs and physical examinations, safety laboratory evaluations, and 12-lead electrocardiograms (ECGs). Participants had a safety follow-up visit 30 days after their last dose of study drug. Participants that did not meet any of the discontinuation criteria were eligible to continue to receive treatment with enzalutamide in study 9785-CL-0123 \[NCT02960022\] upon approval and activation of the study at the participating institution. Participants who enrolled in study 9785-CL-0123 \[NCT02960022\] were not required to have a safety follow-up visit.

Arms: arm 1: Participants received 160 mg enzalutamide orally once a day. Participants continued on treatment unless the dose was reduced or treatment was interrupted during the study.
Interventions: intervention 1: Enzalutamide
Intervention descriptions: intervention 1: Oral

Protocol documents:
Prot_000.pdf: 
A Phase 2 Open-label Extension Study to Assess the Safety of 
Continued Administration of MDV3100 in Subjects with Prostate 
Cancer Who Showed Benefit from Prior Exposure to MDV3100
ISN/Protocol 9785-CL-0121
Final version 5.0, dated 20-June-2016
ClinicalTrials.gov Identifier: NCT01534052
Sponsor: Astellas Pharma Europe B.V. (APEB)
Sylviusweg 62
2333 BE Leiden
The Netherlands


Sponsor: Astellas Pharma Europe B.V.
ISN/Protocol 9785-CL-0121
- CONFIDENTIAL -
20 Jun 2016
Astellas
Page 1 of 64
Version 5.0, Incorporating Substantial Amendment 4
A Phase 2 Open-label Extension Study to Assess the Safety of 
Continued Administration of MDV3100 in Subjects with Prostate 
Cancer Who Showed Benefit from Prior Exposure to MDV3100
Protocol for Phase 2 Study of MDV3100
ISN/Protocol 9785-CL-0121
Version 5.0
Incorporating Substantial Amendment 4 [See Attachment 1]
20 June 2016
EudraCT number: 2011-001576-19
IND number: 74,563
Sponsor: Astellas Pharma Europe B.V. (APEB)
Sylviusweg 62
2333 BE Leiden
The Netherlands
Document History:
Version 1.0 Original [11May2011]
Version 2.0 Incorporating Substantial Amendment 1 [10Oct2012]
Version 3.0 Incorporating Substantial Amendment 2 [10Sep2013]
Version 3.1 Incorporating Non-Substantial Amendment 1 [19Nov2013]
Version 4.0 Incorporating Substantial Amendment 3 [03Jul2014]
--------------------------------------------------------------------------------------------------------------------------------------
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 Europe B.V.
ISN/Protocol 9785-CL-0121
- CONFIDENTIAL -
20 Jun 2016
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Version 5.0, Incorporating Substantial Amendment 4
Table of Contents 
I.
SIGNATURES ······················································································ 7
II.
CONTACT DETAILS OF KEY SPONSOR'S PERSONNEL····························· 9
III.
LIST OF ABBREVIATIONS AND KEY TERMS··········································10
IV.
SYNOPSIS··························································································13
V.
SCHEDULE OF ASSESSMENTS ·····························································17
1
INTRODUCTION·················································································18
1.1
Background ····················································································18
1.2
Non-clinical and Clinical Data ······························································18
1.2.1
Non-clinical Data········································································18
1.2.2
Clinical Data ·············································································18
1.3
Summary of Key Safety Information for Study Drugs ···································19
1.4
Risk-Benefit Assessment·····································································20
2
STUDY OBJECTIVE(S), DESIGN AND ENDPOINTS···································21
2.1
Study Objectives ··············································································21
2.2
Study Design and Dose Rationale···························································21
2.2.1
Study Design·············································································21
2.2.2
Dose Rationale···········································································22
2.3
Endpoints·······················································································22
2.3.1
Primary Endpoints·······································································22
2.3.2
Secondary Endpoints····································································22
2.3.3
Exploratory Endpoints ··································································22
3
STUDY POPULATION··········································································22
3.1
Selection of Study Population ·······························································22
3.2
Inclusion Criteria··············································································22
3.3
Exclusion Criteria ·············································································23
3.4
Discontinuation Criteria for Individual Subjects ··········································24
4
TREATMENT(S)··················································································24
4.1
Identification of Investigational Product(s) ················································24
4.1.1
MDV3100 (Enzalutamide) ·····························································24
4.1.2
Comparative Drug(s)····································································24
4.2
Packaging and Labeling ······································································25


Sponsor: Astellas Pharma Europe B.V.
ISN/Protocol 9785-CL-0121
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4.3
Study Drug Handling ·········································································25
4.4
Blinding ························································································26
4.5
Assignment and Allocation ··································································26
5
TREATMENTS AND EVALUATION························································26
5.1
Dosing and Administration of Study Drugs and Other Medications····················26
5.1.1
Dose/Dose Regimen and Administration Period ····································26
5.1.2
Increase or Reduction in Dose of the Study Drugs··································26
5.1.3
Previous and Concomitant Medication (Drugs and Therapies)····················26
5.1.3.1
Previous Medication (Drugs and Therapies) ···································27
5.1.3.2
Concomitant Medication (Drugs and Therapies) ······························27
5.1.4
Treatment Compliance··································································28
5.1.5
Emergency Procedures and Management of Overdose ·····························28
5.2
Demographics and Baseline Characteristics ···············································28
5.2.1
Demographics············································································28
5.2.2
Medical History··········································································28
5.2.3
Diagnosis of the Target Disease, Severity, and Duration of Disease··············28
5.2.4
Performance Status······································································28
5.3
Pharmacokinetic Assessment ································································29
5.4
Safety Assessment ············································································29
5.4.1
Vital Signs················································································29
5.4.2
Adverse Events ··········································································29
5.4.2.1
Adverse Events of Possible Hepatic Origin ····································30
5.4.3
Laboratory Assessments································································30
5.4.3.1
Abnormal Liver Function Tests··················································30
5.4.3.2
Hematology·········································································30
5.4.3.3
Chemistry···········································································30
5.4.4
Physical Examination···································································30
5.4.5
Electrocardiogram (ECG) ······························································31
5.5
Adverse Events and Other Safety Aspects ·················································31
5.5.1
Definition of Adverse Events (AEs) ··················································31
5.5.2
Disease Progression·····································································32
5.5.3
Definition of Serious Adverse Events (SAEs) ·······································32
5.5.4
Criteria for Causal Relationship to the Study Drug ·································33
5.5.5
Criteria for Defining the Severity of an Adverse Event ····························33


Sponsor: Astellas Pharma Europe B.V.
ISN/Protocol 9785-CL-0121
- CONFIDENTIAL -
20 Jun 2016
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5.5.6
Reporting of Serious Adverse Events (SAEs) ·······································34
5.5.7
Follow-up to Adverse Events ··························································35
5.5.8
Monitoring of Common Serious Adverse Events ···································35
5.5.9
Procedure in Case of Pregnancy·······················································36
5.5.10
Supply of New Information Affecting the Conduct of the Study··················36
5.6
Study Drug Concentration ···································································36
5.7
Other Measurements, Assessments, or Methods ··········································36
5.8
Total Amount of Blood·······································································37
6
DISCONTINUATION············································································37
6.1
Discontinuation of Individual Subject(s)···················································37
6.2
Discontinuation of the Site···································································37
6.3
Discontinuation of the Study·································································37
7
STATISTICAL METHODOLOGY ···························································38
7.1
Sample Size····················································································38
7.2
Analysis Set····················································································38
7.2.1
Safety Analysis Set (SAF)······························································38
7.3
Demographics and Other Baseline Characteristics········································38
7.4
Analysis of Efficacy ··········································································38
7.5
Analysis of Safety·············································································38
7.5.1
Adverse Events ··········································································38
7.5.2
Clinical Laboratory Evaluations·······················································38
7.5.3
Physical Examination···································································39
7.5.4
Vital Signs················································································39
7.5.5
Electrocardiogram (ECG) ······························································39
7.5.6
Concomitant Medications ······························································39
7.5.7
Extent of Exposure ······································································39
7.6
Analysis of Pharmacokinetics ·······························································39
7.7
Protocol Deviations and Other Analysis ···················································39
7.8
Interim Analysis (and Early Discontinuation of the Clinical Study)····················40
7.9
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········40
7.9.1
Missing Data ·············································································40
7.9.2
Visit Windows ···········································································40
8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS ····················40


Sponsor: Astellas Pharma Europe B.V.
ISN/Protocol 9785-CL-0121
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8.1
Procedure for Clinical Study Quality Control ·············································40
8.1.1
Data Collection ··········································································40
8.1.2
Specification of Source Documents···················································40
8.1.3
Clinical Study Monitoring······························································41
8.1.4
Direct Access to Source Data/Documents············································41
8.1.5
Data Management ·······································································41
8.1.6
Protocol Deviations ·····································································42
8.1.7
End of Trial ··············································································42
8.2
Ethics and Protection of Subject Confidentiality··········································43
8.2.1
Institutional Review Board (IRB)/ Independent Ethics Committee(IEC)/ 
Competent Authorities (CA) ···························································43
8.2.2
Ethical Conduct of the Study···························································43
8.2.3
Informed Consent of Subjects ·························································43
8.2.3.1
Subject Information and Consent················································43
8.2.3.2
Supply of New and Important Information Influencing the Subject’s 
Consent and Revision of the Written Information ·····························44
8.2.4
Subject Confidentiality ·································································44
8.3
Administrative Matters ·······································································45
8.3.1
Arrangement for Use of Information and Publication of the Clinical Study ·····45
8.3.2
Documents and Records Related to the Clinical Study ·····························46
8.3.3
Protocol Amendment and/or Revision················································47
8.3.4
Insurance of Subjects and Others······················································47
8.3.5
Investigator Indemnity··································································47
8.3.6
Signatory Investigator for Clinical Study Report····································48
9
QUALITY ASSURANCE········································································48
10
STUDY ORGANIZATION······································································49
10.1
Data Monitoring Committee·································································49
10.2
Other Evaluation Committee(s) ·····························································49
10.3
Other Study Organization ····································································49
11
REFERENCES ····················································································50
12
APPENDICES ·····················································································51
12.1
Appendix 1:  Laboratory Tests ······························································51
12.2
Appendix 2:  Liver Safety Monitoring and Assessment··································52
12.3
Appendix 3:  Common Serious Adverse Events ··········································55


Sponsor: Astellas Pharma Europe B.V.
ISN/Protocol 9785-CL-0121
- CONFIDENTIAL -
20 Jun 2016
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13
ATTACHMENT 1:   SUBSTANTIAL AMENDMENT 4 ·································56
14
SPONSOR’S SIGNATURES····································································64
List of Tables
Table 1
Schedule of Assessments·····································································17
Table 2
ECOG Performance Status···································································29
Table 3
Criteria for Causal Relationship·····························································33
Table 4
Criteria for Severity of Adverse Event Terms Not Specified Within NCI-
CTCAE·························································································34


Sponsor: Astellas Pharma Europe B.V.
ISN/Protocol 9785-CL-0121
- CONFIDENTIAL -
20 Jun 2016
Astellas
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I. SIGNATURES
1.  SPONSOR’S SIGNATURES
Required signatures (e.g., protocol authors, sponsor’s reviewers and contributors) are located 
in Section 14, Sponsor’s Signatures; e-signatures (when applicable) are located at the end of 
this document.


Sponsor: Astellas Pharma Europe B.V.
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2. INVESTIGATOR’S SIGNATURE
A Phase 2 Open-label Extension Study to Assess the Safety of Continued 
Administration of MDV3100 in Subjects with Prostate Cancer Who Showed 
Benefit From Prior Exposure to MDV3100
ISN/ Protocol 9785-CL-0121 / Version 5.0
Incorporating Substantial Amendment 4 / 20 June 2016
I have read all pages of this clinical study protocol for which Astellas is the sponsor. I agree to 
conduct the study as outlined in the protocol and to comply with all the terms and conditions set out 
therein. I confirm that I will conduct the study in accordance with ICH GCP guidelines and applicable 
local regulations. I will also ensure that sub-investigator(s) and other relevant members of my staff 
have access to copies of this protocol and the ICH GCP guidelines to enable them to work in 
accordance with the provisions of these documents.
Principal Investigator:
Signature:
Printed Name:
Date (DD MMM YYYY)
Address:




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III.
LIST OF ABBREVIATIONS AND KEY TERMS
List of Abbreviations
Abbreviations
Description of Abbreviations
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase 
APEB
Astellas Pharma Europe BV
APGD
Astellas Pharma Global Development
AR
Androgen Receptor
AST
Aspartate Aminotransferase 
AT
Aminotransferase
BUN
Blood Urea Nitrogen
CA
Competent Authorities
Cmax
Maximum concentration
Cmin
Minimum concentration
CBC
Complete Blood Count
CFR
Code of Federal Regulations
CO2
Bicarbonate
CRO
Contract Research Organization
CRPC
Castration-resistant prostate cancer
CYP
Cytochrome P450
DILI
Drug Induced Liver Injury
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EDTA
Ethylenediaminetetraacetic Acid
EU
European Union
FDA
Food and Drug Administration
FU
Follow up
GnRH
Gonadotropin-releasing hormone 
GCP
Good Clinical Practice
GGT
Gamma glutamyl transferase
GMP
Good Manufacturing Practice
HCT
Hematocrit
Hgb
Hemoglobin
HIPAA
Health Insurance Portability and Accountability Act
ICF
Informed Consent Form
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IMPD
Investigational Medicinal Product Dossier
IND
Investigational New Drug
IRB
Institutional Review Board
ISN
International Study Number
LA-CRF
Liver Abnormality Case Report Form
LFT
Liver Function Tests


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Abbreviations
Description of Abbreviations
LHRH
Luteinizing Hormone Releasing Hormone
MedDRA
Medical Dictionary for Regulatory Activities
MDV3100
3-(4-cyano-3-trifluoromethylphenyl)-1-[3-fluoro-4-(methylcarbamoyl)phenyl]-
5,5-dimethyl-2-thioxoimidazolin-4-one
MAA
Marketing Authorization Application 
NASH
Non-alcoholic Steato Hepatitis
NCI-CTCAE
National Cancer Institute’s Common Terminology Criteria for Adverse Events
PB
Privacy Board
PFS
Progression-free survival
P-gp
P-glycoprotein 
PHI
Protected Health Information
PK
Pharmacokinetics
PSA
Prostate-specific antigen
RBC
Red Blood Cell
SAE
Serious Adverse Event
SAF
Safety Analysis Set
SOP
Standard Operating Procedure
TBL
Total Bilirubin
t½
Apparent Terminal Elimination Half-life
ULN
Upper Limit of Normal
WBC
White Blood Cell


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List of Key Study Terms
Terms
Definition of terms
Baseline
1) Observed values/findings which are regarded as calibrated zero status in the 
present study, 2) Time when ‘Baseline’ is observed.
Discontinuation
The act of concluding participation, prior to completion of all protocol-
required elements, in a trial by an enrolled subject. Four categories of 
discontinuation are distinguished: a) dropout: Active discontinuation by a 
subject (also a noun referring to such a discontinued subject); b) investigator-
initiated discontinuation (e.g., for cause); c) loss to follow-up: cessation of 
participation without notice or action by the subject; d) sponsor-initiated 
discontinuation. Note that subject discontinuation does not necessarily imply 
exclusion of subject data from analysis. “Termination” has a history of 
synonymous use, but is now considered non-standard.
Enroll
To register or enter into a clinical study; transitive and intransitive.  Informed 
consent precedes enrollment, which precedes or is contemporaneous with 
treatment allocation.
End of study
The end of study for this protocol is defined as Last Subject’s Last Visit.
Investigational 
Period
Period of time where major interests of protocol objectives are observed, and 
where the study drug or comparative drug is given to a subject, and continues 
until the last assessment after completing administration of the study drug or 
comparative drug.
Screening
1) Process for retrieving candidates for the study. 2) Process for checking the 
eligibility of subjects done prior to the investigational period.
Study Drug
Agents given as part of a clinical trial. In this study, MDV3100 is the study 
drug.
Study Period
Period of time beginning with the first subject consented through to the last 
observation collected for the study.
Subject
An individual who participates in a clinical trial, either as a recipient of the 
investigational product(s) or as a control.
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 Open-Label Extension Study to Assess the Safety of Continued 
Administration of MDV3100 in Subjects with Prostate Cancer who Showed 
Benefit from Prior Exposure to MDV3100 [ISN 9785-CL-0121]
Planned Study 
Period
From 3Q2011 to 1Q2017
Study Objective(s)
Primary Objective:
To follow up the long-term safety of continued administration of MDV3100 in 
prostate cancer subjects who were enrolled and completed MDV3100 
treatment period in a prior study with MDV3100.
Planned Total 
Number of Study 
Centers and 
Location
Those sites that currently have subjects actively enrolled and completed 
MDV3100 treatment in a prior study with MDV3100 may participate.  
Design and 
Methodology
This is a multi-center phase 2 open-label extension study in subjects with 
prostate cancer who have completed MDV3100 treatment in a previous study 
with MDV3100 to assess the long-term safety of continued administration of 
MDV3100, when judged by the investigator to be in the best interest of the 
subject.
For the study duration, all subjects with castration-resistant prostate cancer 
(CRPC) will have to maintain androgen deprivation with an LHRH 
agonist/antagonist unless they underwent bilateral orchiectomy.
Subjects will be discontinued from study drug when continued administration 
of study drug is deemed to be not in the subject’s best interest by the 
investigator based on clinical assessment.
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 that have not met any of the discontinuation criteria as outlined in 
Section 3.4 may be eligible to continue to receive treatment with enzalutamide 
in Study 
 upon approval and activation of this study at the 
participating institution. Subjects who enroll in Study 
 will not 
be required to have a safety follow-up visit.
Subjects who choose not to participate or are not eligible for Study 
 will complete their participation in Study 9785-CL-0121 by completing 
the safety follow-up visit upon activation of Study 
 at the 
institution.
Number of 
Subjects Planned
Subjects who were actively enrolled and have completed MDV3100 treatment 
in a previous study with MDV3100 may be eligible to participate in this study
when continuation of MDV3100 is deemed by the investigator in the best 
interest of the subjects.


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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 must be obtained from the subject or legally authorized 
representative prior to any study-related procedures (including withdrawal 
of prohibited medication, if applicable).
2.
Has completed a prior study with MDV3100, can be enrolled in this 
extension study without any interruption in study drug and in the opinion 
of the investigator would derive benefit from continuing MDV3100 
treatment.
3.
No new clinically significant abnormalities based upon physical 
examination, safety laboratory data, vital signs, ECG, and other clinical 
assessments noted from the last visit conducted during the subject’s active 
MDV3100 study prior to initiation of this study.
4.
Male subjects and their female spouses/partners who are of childbearing 
potential must be using highly effective contraception1 consisting of two 
forms of birth control (one of which must be a barrier method) starting at 
Screening and continue throughout the study period and for 3 months after 
final study drug administration. Male subjects must not donate sperm 
starting at Screening and throughout the study period and for at least 
3 months after final study drug administration. 
1Highly effective contraception is defined as: 
Established use of oral, injected or implanted hormonal methods of 
contraception. 
Placement of an intrauterine device (IUD) or intrauterine system 
(IUS).
Barrier methods of contraception: Condom or occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal form/gel/film/
cream/suppository
5.
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.
Subject has a history of seizure or any condition that may predispose to 
seizure including, but not limited to underlying brain injury, stroke, 
primary brain tumours, brain metastases, or alcoholism.
2.
Subject has a history of loss of consciousness or transient ischemic attack 
within 12 months prior to Day 1 of the completed preceding study.
3.
Use of the following prohibited medication/therapies:
Concomitant medication that likely could cause clinically relevant 
drug-to-drug interactions with MDV3100.
Other (than MDV3100) androgen-receptor (AR) antagonists 
(bicalutamide, flutamide, nilutamide).
Investigational therapy other than MDV3100 or investigational 
procedures of any kind. 


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Discontinuation 
Criteria 
Subjects will be discontinued from study drug when continued administration 
of study drug is deemed to be not in the subject’s best interest by the 
investigator based on clinical assessment. Use of other investigational drugs 
will also lead to discontinuation. It is also possible that the sponsor or the 
competent authorities (CA) request termination of the study if there are 
concerns about conduct or safety.
Astellas will be closing Study 9785-CL-0121. Subjects that have not met any 
of the discontinuation criteria as outlined in Section 3.4 may be eligible to 
continue to receive treatment with enzalutamide in Study 
 upon 
approval and activation of this study at the participating institution.
Subjects who choose not to participate or are not eligible for Study 
 will complete their participation in Study 9785-CL-0121 by completing 
the safety follow-up visit upon activation of Study 
 at the 
institution.
Test Drug Dose:
Mode of 
Administration:
Duration of 
Treatment:
Subjects will take 160 mg (4 capsules) MDV3100 once daily oral dose at the 
same time each day. 
MDV3100 can be taken with or without food. 
Subjects will receive their assigned therapy until discontinuation criteria are 
met. 
Reference Therapy
Dose:
Not applicable
Concomitant 
Medication 
The following medications are prohibited while the subject is continuing on 
study drug:
Concomitant medication that likely could cause clinically relevant drug-to-
drug interactions with MDV3100
Other than MDV3100 AR antagonists (bicalutamide, flutamide, 
nilutamide)
Investigational therapy other than MDV3100 or investigational procedures 
of any kind. 
When applicable, the following medications should be maintained during the 
investigational period at the same dosage and schedule:
LHRH agonist/antagonist.
Co-administration of a strong CYP2C8 inhibitor (e.g., gemfibrozil) increased 
the composite AUC0-inf of MDV3100 plus its active metabolite in healthy 
volunteers; therefore, co-administration of MDV3100 with strong CYP2C8 
inhibitors should be avoided, if possible. 
The effects of CYP2C8 inducers on the PK of MDV3100 have not been 
evaluated in vivo. Co-administration of MDV3100 with strong or moderate 
CYP2C8 inducers (e.g., rifampin) may decrease the plasma exposure of 
MDV3100 and should be avoided if possible. Selection of a concomitant 
medication with no or minimal CYP2C8 induction potential is recommended.
Co-administration of MDV3100 with strong CYP3A4 inducers (e.g., 
carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may 
decrease the plasma exposure of MDV3100 and should be avoided, if possible. 


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Selection of a concomitant medication with no or minimal CYP3A4 induction 
potential is recommended. Moderate CYP3A4 inducers (e.g., bosentan, 
efavirenz, etravirine, modafinil, nafcillin) and St John’s Wort may also reduce 
the plasma exposure of MDV3100 and should be avoided, if possible.
MDV3100 is a strong CYP3A4 inducer and a moderate CYP2C9 and 
CYP2C19 inducer in humans. Concomitant use of MDV3100 with narrow 
therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, 
cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, 
sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 
(e.g., S-mephenytoin) should be avoided, as MDV3100 may decrease their 
exposure. If co-administration with warfarin cannot be avoided, conduct 
additional INR monitoring.
Primary Variable
Safety parameters include clinical laboratory test, 12-lead ECGs, vital signs, 
physical examination and adverse events (AEs).  
Secondary 
Variable
Not applicable
Statistical Methods
No formal statistical analysis will be conducted. Descriptive summary 
statistics will be produced. 




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1
INTRODUCTION
1.1
Background
Enzalutamide is approved in the US, Canada and EU for patients with metastatic CRPC who
have previously received docetaxel.  Enzalutamide (formerly MDV3100) is an androgen 
receptor (AR) inhibitor that blocks multiple steps in the AR signaling pathway. Enzalutamide 
competitively inhibits binding of androgens to ARs, inhibits nuclear translocation of receptors
and inhibits the association of the AR with DNA even in the setting of AR over expression and 
in prostate cancer cells resistant to anti-androgens. By inhibiting AR signaling, enzalutamide 
elicits several downstream effects, which include reduced expression of AR-dependent genes, 
decreased growth of prostate cancer cells, induction of cancer cell death, and tumor regression.
Enzalutamide lacks agonist activities such as those that may limit the sustained efficacy of 
current anti-androgens.
The 9785-CL-0121 study is an extension to the preceding MDV3100 studies offering patients a 
possibility to continue MDV3100 medication if deemed as being of benefit to the patient by the 
investigator. The main objective of this study is to follow up the long-term safety of continued 
administration of MDV3100 in prostate cancer subjects who were enrolled and completed 
MDV3100 treatment period in prior (e.g., phase 1) studies.
1.2
Non-clinical and Clinical Data
1.2.1
Non-clinical Data
In mice, rats, and dogs, oral MDV3100 had a half-life (t1/2) of approximately 0.25 to 3 days. 
The t1/2 did not appear to be affected by the dose size; however, the bioavailability appeared to 
decrease with increasing dose size. Plasma protein binding of MDV3100 in human plasma 
ranged from 97.2% to 97.8% and was similar in mice, rats, rabbits, and dogs. In vitro drug 
metabolism studies suggest that MDV3100 undergoes very slow rates of metabolism. In vitro 
drug metabolism studies suggest that MDV3100 may have the potential to induce cytochrome 
P450 (CYP) 3A4 and to directly inhibit CYP2B6, CYP2C8, CYP2C9, and CYP2C19. In 
consideration of time-dependent inhibition data, a metabolite of MDV3100 may inhibit 
CYP1A2 [Investigator’s Brochure].
1.2.2
Clinical Data
A clinical drug-drug interaction study in 41 healthy volunteers (9785-CL-0006) revealed that 
CYP2C8 plays an important role in the elimination of MDV3100 and the formation of the 
active metabolite. Following oral administration of the strong CYP2C8 inhibitor gemfibrozil 
(600 mg twice daily) to healthy male subjects the AUC of MDV3100 increased 4.26-fold, 
while Cmax decreased by 18%; the AUC and Cmax of the active metabolite decreased by 25% 
and 44% respectively. CYP3A4 plays a minor role in the metabolism of MDV3100. Following 
oral administration of CYP3A4 inhibitor itraconazole (200 mg once daily), the AUC of 
MDV3100 increased by 1.41-fold while the Cmax was essentially unaffected (decreased by
2%); the AUC of the active metabolite increased 1.21-fold while the Cmax decreased by 14%.


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A clinical drug-drug interaction study in 14 patients with castration resistant prostate cancer 
(9785-CL-0007) indicated that MDV3100 (160 mg once daily to steady state) has no 
clinically relevant effect on CYP2C8, is a moderate inducer of CYP2C19 and CYP2C19, and 
is a strong inducer of CYP3A4, based on changes in plasma AUC0-inf for single doses of the 
sensitive substrates pioglitazone, S-warfarin, omeprazole and midazolam respectively.
The PK of MDV3100 were examined in subjects with baseline mile (n=6) or moderate (n=8) 
hepatic impairment (Child-Pugh Class A and B, respectively) and in 14 matched control 
subjects with normal hepatic function (9785-CL-0009). Following a single 160 mg dose of 
MDV3100, exposure parameters of MDV3100 increased by approximately 24% and 29% in 
subject with mild and moderate hepatic impairment, respectively, compared to healthy control 
subjects. Hepatic impairment had similar minimal effects on the exposure parameters of the 
active metabolite.
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 protocol pre-specified 
interim analysis after 520 deaths showed a statistically significant superiority in overall 
survival in patients treated with MDV3100 compared to placebo. Interim data revealed that the 
estimated median overall survival in man who had received MDV3100 was about 18.4 months 
compared with 13.6 months for the placebo group. An overall survival difference of 4.8 
months and a 37% reduction of risk of death were observed. This benefit was sufficiently 
compelling to stop the patient study early and switch men who had taken placebo over to 
MDV3100.
Please see the most current version of the IB for additional details.
1.3
Summary of Key Safety Information for Study Drugs
More than 4900 subjects and patients have been enrolled worldwide in completed and 
ongoing clinical trials evaluating enzalutamide of whom, approximately 3200 received at 
least 1 dose of enzalutamide (MDV3100).
In the phase 3 study CRPC2 (AFFIRM; N = 1199), a randomized, double-blind, 
placebo-controlled, efficacy and safety study of enzalutamide (160 mg daily) in patients with 
progressive CRPC previously treated with docetaxel-based chemotherapy, the most common 
adverse drug reactions (³ 5%) in patients treated with enzalutamide (N = 800) were 
asthenia/fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal 
pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower 
respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, 
paresthesia, anxiety, and hypertension. Discontinuations due to adverse events were reported 
for 16% of enzalutamide-treated patients and 18% of placebo-treated patients. The most 
common adverse reaction leading to treatment discontinuation was seizure, which occurred in 
0.9% of the enzalutamide-treated patients and none (0%) of the placebo-treated patients.


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In the phase 3 study MDV3100-03 (PREVAIL; N = 1717), a multinational, randomized, 
double-blind, placebo-controlled, efficacy and safety study of enzalutamide in 
chemotherapy-naïve patients with progressive metastatic prostate cancer who have failed 
androgen deprivation therapy, enzalutamide was generally well tolerated with an overall 
safety profile consistent with that observed in AFFIRM, with a lower seizure rate observed in 
PREVAIL (1 patient [0.1%] each in the enzalutamide and placebo treatment groups).
Additional information on the clinical experience with enzalutamide is provided in the most 
current edition of the MDV3100 Investigator’s Brochure.
1.4
Risk-Benefit Assessment 
MDV3100 is a novel small molecule designed to have an increased affinity for the androgen 
receptor and more effective suppression of the androgen pathway in the setting of androgen 
over expression [Tran et al, 2009]. MDV3100 has a higher binding affinity to the AR 
(8-10 times greater), has no agonist activity, and has demonstrated superior AR downstream 
effects compared to bicalutamide in pre-clinical studies. In a clinical trial (phase 1-2) involving 
140 castrate subjects with progressive prostate cancer who have either failed androgen 
deprivation therapy or chemotherapy, MDV3100 has shown strong anti-tumor effects. These 
effects include reduction of PSA, prolonged time to radiographic and PSA progression and 
CTC conversion from unfavorable to favorable status. 
Commonly used androgen receptor antagonists are flutamide, bicalutamide and
nilutamide. The endocrine effects of antiandrogens usually include significant increases in LH, 
Follicle Stimulating Hormones, Testosterone and Estradiol .Common adverse effects resulting 
from androgen receptor blockade are to be expected. For these compounds the most common 
side effects are known and include breast pain, gynecomastia, hot flushes, back pain, asthenia, 
and constipation.
It has now been shown in phase1-3 clinical trials that MDV3100 demonstrates a similar 
endocrine response profile (hypergonado-tropic hypergonadism) as other marketed AR 
antagonists. Given the strong in vitro data showing superiority to bicalutamide, the 
nonclinical data demonstrating few toxicities, robust clinical data from the phase 1-3 showing 
anti-tumor effect, the favorable overall safety profile of MDV3100 in the phase 1-3 
completed and ongoing  studies, together with the manageable safety profile , the benefits of 
studying MDV3100 outweigh the risks involved. Patients with locally advanced or metastatic 
prostate cancer may benefit from a compound that offers improved efficacy to traditional 
anti-androgens coupled with a less unfavorable side effect profile when compared to LHRH 
analogues. The proposed total daily dosage (160 mg) in the proposed study seems to be 
acceptable in light of the safety and efficacy data obtained to date. The identified risk of 
seizure and potential risks described for currently approved anti-androgens will be monitored 
through clinical follow-up and by routine laboratory assessments. The FDA’s guidance for 
Drug-Induced Liver Injury (DILI) will also be followed. In summary, the benefit risk profile 
for patients participating in the study that will be treated with MDV3100 is considered to be 
favorable as potential benefits exceed identified and potential risks. Please refer to the most 


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current edition of the MDV3100 Investigator’s Brochure for complete information on 
risk/benefit.
The 9785-CL-0121 is an extension study to prior MDV3100 studies and subjects will only 
participate in this extension study if they have been actively enrolled and have completed 
MDV3100 treatment in the prior MDV3100 study and when administration of MDV3100 is 
deemed by the investigator/treating physician to be in the patient’s best interest. Routine 
subject disease management will assess the risks and benefits of the continued use of 
MDV3100. The possibility of offering patients who benefit from MDV3100 in the preceding
study continuous medication within the boundaries of an extension study is in compliance with 
the ethical principles for oncology phase 1 studies.
2
STUDY OBJECTIVE(S), DESIGN AND ENDPOINTS
2.1
Study Objectives
The main objective of this study is to follow up the long-term safety of continued 
administration of MDV3100 in prostate cancer subjects who were enrolled and completed 
MDV3100 treatment period in prior (e.g., phase 1) studies.
The long-term safety will be determined by:
●
Adverse Events
●
Vital Signs
●
12-lead ECGs
●
Physical Examination
●
Safety laboratory evaluation
●
ECOG performance status.
2.2
Study Design and Dose Rationale
2.2.1
Study Design
This is a multi-center phase 2, open-label extension study in prostate cancer subjects who 
have completed MDV3100 treatment in a prior MDV3100 study.  In order to participate in 
this study, the subjects must have completed the prior study with MDV 3100, be in the state 
of at least stable disease and in the opinion of the investigator would derive benefit from 
continuing MDV3100 treatment.  The final visit in the prior MDV3100 study, in which the 
subject is taking study drug, will serve as the initial visit for this extension study.
This protocol’s baseline, for comparison purposes, will be considered the original baseline 
from the previous MDV3100 study. In addition, all ongoing concomitant medications and 
AEs from the previous study will be transferred onto the appropriate case report forms 
(eCRFs) for this study.
All subjects will take 160 mg (4 capsules) MDV3100 once daily oral dose at the same time 
each day. MDV3100 can be taken with or without food.


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Subjects will be discontinued from study drug when continued administration of study drug 
is deemed to be not in the subject’s best interest by the investigator based on clinical 
assessments. Use of other investigational drugs will also lead to discontinuation.    
Throughout the study, safety and tolerability will be assessed by the recording of AEs, 
monitoring of vital signs and physical examinations, safety laboratory evaluations, and 
12-lead electrocardiograms (ECGs).  
Subjects that have not met any of the discontinuation criteria as outlined in Section 3.4 may 
be eligible to continue to receive treatment with enzalutamide in Study 
 upon 
approval and activation of this study at the participating institution. Subjects who enroll in 
Study 
 will not be required to have a safety follow-up visit.
Subjects who choose not to participate or are not eligible for Study 
 will 
complete their participation in Study 9785-CL-0121 by completing the safety follow-up visit 
upon activation of Study 
 at the institution.
See Section V, Table 1, Schedule of Assessments for an outline of study procedures.
2.2.2
Dose Rationale
Subjects enrolled into this extension study will continue to receive 160 mg/day of MDV3100 
until the investigator and/or sponsor feels that continued use of MDV3100 is not beneficial to 
the subject, or the subject withdraws consent.
2.3
Endpoints
2.3.1
Primary Endpoints
Safety, as measured by adverse events, vital signs, 12-lead ECGs, physical examination and 
safety laboratory evaluation. 
2.3.2
Secondary Endpoints
Not applicable.
2.3.3
Exploratory Endpoints
Not applicable.
3
STUDY POPULATION
3.1
Selection of Study Population
Subjects actively enrolled and completed MDV3100 treatment in prior studies, are eligible to 
participate in this study.
3.2
Inclusion Criteria
Subject is eligible for the study if all of the following apply:


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1.
Institutional Review Board (IRB)-/Independent Ethics Committee (IEC)-approved 
written Informed Consent and privacy language as per national regulations must be 
obtained from the subject or legally authorized representative prior to any study-related
procedures (including withdrawal of prohibited medication, if applicable).
2.
Has completed a prior study with MDV3100, can be enrolled in this extension study 
without any interruption in study drug, and in the opinion of the investigator would derive 
benefit from continuing MDV3100 treatment.
3.
No new clinically significant abnormalities based upon physical examination, safety 
laboratory data, vital signs, ECG, and other clinical assessments noted from the last visit 
conducted during the subject’s active MDV3100 study prior to initiation of this study.
4.
Male subjects and their female spouses/partners who are of childbearing potential must be 
using highly effective contraception1 consisting of two forms of birth control (one of 
which must be a barrier method) starting at Screening and continue throughout the study 
period and for 3 months after final study drug administration. Male subjects must not 
donate sperm starting at Screening and throughout the study period and for at least 3 
months after final study drug administration. 
5.
Subject agrees not to participate in another interventional study while on treatment.
1Highly effective contraception is defined as: 
• Established use of oral, injected or implanted hormonal methods of contraception. 
• Placement of an intrauterine device (IUD) or intrauterine system (IUS).
•
Barrier methods of contraception: Condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal form/gel/film/cream/suppository
Waivers to the inclusion criteria will NOT be allowed.
3.3
Exclusion Criteria
Subject will be excluded from participation if any of the following apply:
1. Subject has a history of seizure or any condition that may predispose to seizure including, 
but not limited to underlying brain injury, stroke, primary brain tumours, brain 
metastases, or alcoholism.
2. Subject has a history of loss of consciousness or transient ischemic attack within 12 
months prior to Day 1 of the completed preceding study.
3. Use of the following prohibited medication/therapies:
•
Concomitant medication that likely could cause clinical relevant drug-to-drug 
interactions with MDV3100
•
Other (than MDV3100) androgen-receptor antagonists (bicalutamide, flutamide, 
nilutamide) 
•
Investigational therapy other than MDV3100 or investigational procedures of any 
kind. 


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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 drug is terminated 
for any reason.  
The subject is free to withdraw from the study treatment and/or study for any reason and at any 
time without giving reason for doing so and without penalty or prejudice. The investigator is 
also free to terminate a subject's involvement in the study at any time if the subject's clinical 
condition warrants it.
Subjects will be discontinued from study drug when continued administration of study drug is 
deemed to be not in the subject’s best interest by the investigator based on clinical assessments. 
Use of other investigational drugs will also lead to discontinuation. It is also possible that the 
sponsor or the competent authorities (CA) request termination of the study if there are concerns 
about conduct or safety.
Unless the 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 MDV3100. For subjects who 
enroll into Study 
, a safety follow-up visit is not required. For these subjects, the 
final visit for Study 9785-CL-0121 will serve as Day 1 for Study 
 (±7 days).
Individual subjects may discontinue the study in case of:
1.
Not fulfilling inclusion or exclusion criteria
2.
Adverse event
3.
Lack of efficacy
4.
Withdrawal of consent
5.
Subject lost to follow-up
6.
Protocol violation.
4
TREATMENT(S)
4.1
Identification of Investigational Product(s)
4.1.1
MDV3100 (Enzalutamide)
MDV3100 has the chemical name 3-(4-cyano-3-trifluoromethylphenyl)-1-[3-fluoro-4-
(methylcarbamoyl) phenyl]-5, 5-dimethyl-2-thioxoimidazolin-4-one.It is a white to off-white 
solid that is insoluble in water and no salt forms are available at approximately pH 2 to 10.  
The drug substance is formulated in the surfactant, Labrasol, to create a self-emulsifying (or 
microemulsifying) dosage form. The product will be supplied as liquid-filled soft gelatin 
capsules containing 40 mg of MDV3100.  
4.1.2
Comparative Drug(s)
Not applicable.


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4.2
Packaging and Labeling
All medication used in this study will be prepared, packaged, and labeled under the 
responsibility of a qualified person (QP) at Astellas Pharma Europe BV (APEB) or at 
sponsor’s designee in accordance with APEB or sponsor’s designee Standard Operating 
Procedures (SOPs), Good Manufacturing Practice (GMP) guidelines, International Conference 
on Harmonization for Good Clinical Practice (ICH GCP) guidelines, and applicable local 
laws/regulations.
The Investigational Medicinal Product (IMP) will be labeled according to the requirements as 
published in Annex 13 of the GMP guidelines and/or local requirements. The labels will be 
approved by a local representative and finally released by the head of quality control or 
sponsor’s designee. A Qualified Person (from APEB) or sponsor’s designee will release the 
final IMP according to the requirements of EU Directive 2003/94/EG and/or local 
laws/regulations.
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 study 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 by the sponsor or 


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representative, 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 study drug not destroyed at the site must be returned to 
the sponsor or designee at the end of the study or upon expiration.
4.4
Blinding
Not applicable. This is an open-label study. 
4.5
Assignment and Allocation
Subjects will be assigned to a subject number at study entry (signing of Informed Consent 
Form). 
5
TREATMENTS AND EVALUATION
5.1
Dosing and Administration of Study Drugs and Other Medications
5.1.1
Dose/Dose Regimen and Administration Period
In this study, subjects will continue to receive 160 mg/day of MDV3100 until the investigator 
feels that continued use of MDV3100 is not beneficial to the subject, or the subject withdraws 
consent.
Since Astellas will close Study 9785-CL-0121, subjects that have not met any of the 
discontinuation criteria as outlined in Section 3.4 may be eligible to continue to receive treatment 
with enzalutamide in Study 
 upon approval and activation of this study at the 
participating institution.
Subjects who choose not to participate or are not eligible for Study 
 will 
complete their participation in Study 9785-CL-0121 by completing the safety follow-up visit 
upon activation of Study 
 at the institution.
Study drug should be taken as close to the same time each day as possible. Study drug can be 
taken with or without food. If dosing is missed on one day for any reason, double-dosing 
should not occur the following day.
5.1.2
Increase or Reduction in Dose of the Study Drugs 
Subjects who experience a grade 3 or greater toxicity 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 restarted on study 
drug at a reduced dose with the written approval of the sponsor. An increase in dose is not 
permitted.
5.1.3
Previous and Concomitant Medication (Drugs and Therapies)
All ongoing concomitant medications will be transcribed from the subject’s previous MDV3100 
study onto the appropriate eCRF for this study.


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5.1.3.1 Previous Medication (Drugs and Therapies)
Not applicable as the subject is continuing from a prior MDV3100 study.
5.1.3.2 Concomitant Medication (Drugs and Therapies)
The following medications are prohibited while the subject is continuing on study drug:
●
Concomitant medication that likely could cause clinical relevant drug-to-drug interactions 
with MDV3100
●
Other (than MDV3100) AR antagonists (bicalutamide, flutamide, nilutamide) 
●
Investigational therapy other than MDV3100 or investigational procedures of any kind.
When applicable, the following medications should be maintained during the investigational 
period at the same dosage and schedule:
●
LHRH agonist/antagonist.
Precautions Regarding Concomitant Medications
Please refer to the following links for an up-to-date list of CYP inhibitors, inducers, and 
substrates.  
●
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Drug
InteractionsLabeling/ucm093664.htm#potency;
●
http://medicine.iupui.edu/clinpharm/ddis/table.asp
Effects of MDV3100 on Exposure to Other Drugs
Clinical data indicate that MDV3100 is a strong inducer of CYP3A4 and a moderate inducer of 
CYP2C9 and CYP2C19.  Drugs with a narrow therapeutic index that are metabolized by 
CYP3A4 (e.g., alfentanil, cyclosporine, pimozide, quinidine, sirolimus, tacrolimus), CYP2C9 
(e.g., phenytoin, warfarin), and CYP2C19 (e.g., S-mephenytoin) should be used with caution 
and may require dose adjustment as co-administration with MDV3100 may result in decreased 
exposure. If MDV3100 is co-administered with warfarin, conduct additional INR monitoring.
In consideration of the long half-life of MDV3100 (approximately 1 week), effects on 
enzymes may persist for 1 month or longer after stopping MDV3100.
Drugs That May Affect Exposure to MDV3100
Drugs that Inhibit or Induce CYP2C8
Co-administration of a strong CYP2C8 inhibitor (e.g., gemfibrozil) increased the composite 
AUC0-inf of MDV3100 plus its active metabolite in healthy volunteers; therefore, 
co-administration of MDV3100 with strong CYP2C8 inhibitors should be avoided, if possible. 
The effects of CYP2C8 inducers on the PK of MDV3100 have not been evaluated in vivo. 
Co-administration of MDV3100 with strong or moderate CYP2C8 inducers (e.g., rifampin) may 
decrease the plasma exposure of MDV3100 and should be avoided if possible. Selection of a 
concomitant medication with no or minimal CYP2C8 induction potential is recommended.


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Drugs that Induce CYP3A4
The effects of CYP3A4 inducers on the PK of MDV3100 have not been evaluated in vivo. 
Co-administration of MDV3100 with strong CYP3A4 inducers (e.g., carbamazepine, 
phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure 
of MDV3100 and should be avoided if possible. Selection of a concomitant medication with 
no or minimal CYP3A4 induction potential is recommended. Moderate CYP3A4 inducers 
(e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) and St John’s Wort may also 
reduce the plasma exposure of MDV3100 and should be avoided if possible.
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 and all study drug 
packaging at each study visit for drug accountability.
5.1.5
Emergency Procedures and Management of Overdose
Neither the effects of overdose of MDV3100 nor an antidote to overdose are known. In case 
of overdose of MDV3100, symptomatic treatment with frequent monitoring is recommended. 
5.2
Demographics and Baseline Characteristics
5.2.1
Demographics
Demographic information (date of birth, ethnicity, race as described by the subject and 
height) will be collected at screening of the prior study with MDV3100 and will be 
transcribed onto the appropriate eCRF for this study. Weight will be measured at every clinic 
visit including the safety follow-up visit.
5.2.2
Medical History
Medical history, to include any significant conditions or diseases other than prostate cancer 
that stopped at or prior to screening, will be recorded at screening of the prior study with 
MDV3100 and will be transcribed onto the appropriate eCRF for this study.
5.2.3
Diagnosis of the Target Disease, Severity, and Duration of Disease
Medical history of the target disease will be recorded at screening of the prior study with 
MDV3100 and will be transcribed onto the appropriate eCRF for this study.
5.2.4
Performance Status
The ECOG scale [Oken et al, 1982] will be used to assess performance status.


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Table 2
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.
ECOG score will be collected at every clinic visit including the safety follow-up visit, see 
also the Schedule of Assessments (Section V, Table 1).
5.3
Pharmacokinetic Assessment
No PK assessment involved.
5.4
Safety Assessment
Please review the requirements related to the evaluation, reporting and analysis of Drug-
Induced Liver Injury (DILI) information found in Appendix 2 (Liver Safety Monitoring and 
Assessment). In the event of a confirmed, marked hepatic abnormality as defined in 
Appendix 2 (Liver Safety Monitoring and Assessment), it is the investigator’s responsibility 
to ensure contact with the sponsor/delegated CRO by telephone or fax immediately (i.e. 
within 24 hours of awareness).
5.4.1
Vital Signs
Vital signs including blood pressure, pulse rate, respiration rate, and temperature will be 
assessed prior to study drug administration, after the subject has rested for at least 5 minutes 
in the supine position, at every clinic visit while on study drug and at the safety follow-up 
visit (see also the Schedule of Assessments, Section V, Table 1).
5.4.2
Adverse Events
Adverse event collection will begin at the time of visit Day 1 and continue for 30 days after 
last dose of study drug. AEs will be documented at each clinic visit per the Schedule of 
Assessments. See Section 5.5 for details on AE collection.
Please refer to Appendix 2 (Liver Safety Monitoring and Assessment) for DILI adverse event 
assessment.


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5.4.2.1 Adverse Events of Possible Hepatic Origin
Subjects with AEs of hepatic origin accompanied by Liver Function Test (LFT)
abnormalities should be carefully monitored.
5.4.3
Laboratory Assessments
Please refer to Appendix 2 (Liver Safety Monitoring and Assessment) for additional DILI 
laboratory testing requirements and timing. Routine laboratory assessments for hematology
and chemistry will be collected and analyzed at the local laboratory. Laboratory assessments 
will be assessed at every clinic visit including the safety follow-up visit, see also the 
Schedule of Assessments (Section V, Table 1). A maximum of 18 mL of blood will be taken 
at every visit. See also 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.
Any changes in laboratory values will be evaluated by the investigator. Clinically important 
changes from the time of signing the informed consent will be reported as AEs.
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) to > 3x ULN, or bilirubin > 2x ULN, at least all 
four of the usual serum measures (ALT, AST, ALP, and total bilirubin [TBL]) should be 
repeated within 48 - 72 hours of notification of the test results. See Appendix 2 (Liver Safety 
Monitoring and Assessment) for additional information on monitoring and assessment of 
abnormal liver function tests.
Laboratory assessments must be obtained prior to study drug administration.
5.4.3.2 Hematology
Analytes to be tested include complete blood count (CBC), red blood cell count (RBC), 
hemoglobin (Hgb), hematocrit (HCT), white blood cell count (WBC), platelets, and WBC 
differential.
5.4.3.3 Chemistry
Analytes to be tested include sodium, potassium, calcium, chloride, magnesium, phosphate, 
glucose, creatinine, alkaline phosphatase, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), gamma-glutamyl transferase (GGT), total bilirubin, total protein, 
albumin, bicarbonate (CO2), blood urea nitrogen (BUN).
5.4.4
Physical Examination 
Standard, full physical examinations will be performed to assess weight, general appearance, 
skin, eyes, ears, nose, throat, neck, cardiovascular, chest and lungs, abdomen, 
musculoskeletal, neurologic status, mental status, lymphatic, genitourinary, and rectal 


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systems. Any abnormalities will be collected as medical history or AEs. Physical 
examination and weight will be recorded at every clinic visit including the safety follow-up 
visit, see also the Schedule of Assessments (Section V, Table 1).
5.4.5
Electrocardiogram (ECG) 
The 12-lead ECG measurements will be performed at every time point according to the 
Schedule of Assessments after the subject has been in supine position for 5 minutes.
The investigator will review, sign and date the ECGs immediately after recording to ensure the 
subject’s safety. The time and heart rate of the ECG, as well as an overall conclusion, will be 
recorded in the eCRF. This overall conclusion will be recorded as normal, abnormal not 
clinically significant, or abnormal clinically significant.  If the overall conclusion is abnormal, 
the applicable abnormality code (provided in the eCRF) must be recorded in the eCRF.
Per time point, the ECG will be stored electronically, printed (photocopied to prevent fading 
of original print outs) and timely reviewed by the investigator. The original printout will be 
stored with the subject’s source data. ECGs that have technical failures will not be stored.
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.
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 drug
●
The abnormality or investigational value is clinically significant in the opinion of the 
investigator.
An AE observed after starting administration of the study drug is called a "treatment 
emergent adverse event" and usually summed up as the AEs in the clinical study report. If a 
diagnosis is made from the sign and/or symptom, the diagnosis should be recorded in 
preference to the listing of individual signs and symptoms. If not, the investigator should 
record each sign and symptom as an individual AE. 
All AEs occurring after visit Day 1 should be recorded in the eCRF. All observed or 
spontaneously reported AEs will be recorded in the eCRF. Data to be recorded include a 


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description of the event, date and time of onset and end of the event, severity, action with 
respect to study drug, treatment required, relationship to study drug, and outcome of the 
event. All subjects who experience an AE will be followed up at appropriate time intervals 
until resolved or stabilized to the satisfaction of the investigator.
If an event recurs after it had resolved, it should be handled as a new AE. However, AEs that 
occur intermittently can be recorded as one AE. When the severity of an AE increases, the 
worst severity of that AE should be recorded for the entire duration.
5.5.2
Disease Progression 
It is anticipated that a proportion of subjects will experience disease progression. Disease 
progression should not be reported as an AE. Clinical signs and symptoms due to disease 
progression will be collected as AEs. Individual signs and symptoms will be listed rather than 
the term “disease progression” with the following exception: if disease progression is the 
cause of death, this event may be recorded as an AE with “disease progression” as the 
reported term.
5.5.3
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 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 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 a Sponsor medicinal product that may require expedited reporting 
and/or safety evaluation include, but are not limited to:


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●
Overdose of a Sponsor medicinal product
●
Suspected abuse/misuse of a Sponsor medicinal product
●
Inadvertent or accidental exposure to a Sponsor medicinal product
●
Medication error involving a Sponsor product (with or without subject exposure to the 
Sponsor medicinal product, e.g., name confusion)
All of the events of interest noted above should be recorded on the eCRF. Any situation 
involving these events of interest that also meets the criteria for an SAE should be recorded 
on the AE page of the eCRF 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.
5.5.4
Criteria for Causal Relationship to the Study Drug
Adverse events that fall under either "Possible" or "Probable" should be defined as "AEs
whose relationship to the study drugs could not be ruled out". The following table describes 
the criteria for determining causal relationship of AEs.
Table 3
Criteria for Causal Relationship
Causal relationship
to the study drug
Criteria for casual 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).
5.5.5
Criteria for Defining the Severity of an Adverse Event 
Severity of AEs will be graded according to the Common Terminology Criteria for Adverse 
Events (CTCAE) v. 4.0 of the National Cancer Institute (NCI) Cancer Therapy Evaluation 
Program (CTEP). For terms not specified within NCI-CTCAE, the following guideline should 
be used to determine grade as below in Table 4


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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
5.5.6
Reporting of Serious Adverse Events (SAEs)
In the case of a serious adverse event (SAE), the investigator must contact the Sponsor by 
telephone or fax immediately (within 24 hours of awareness). The investigator should complete 
and submit a report/report form containing all information that is required by the Regulatory 
Authorities to the Sponsor by fax immediately (within 24 hours of awareness). If the faxing of
the report/report form or an SAE Worksheet is not possible or is not possible within 24 hours, 
the 24h contact for SAEs 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,
Product Safety and Pharmacovigilance
Fax number: 
Email: 
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 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).


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Full details of the SAE should also be recorded on the medical records and on the eCRF
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.
SAEs will be collected from the time of study drug administration on Day 1 through 30 days 
after the last dose of study drug.
The Sponsor will notify all investigators responsible for ongoing clinical studies with the
study drug of all SAEs which require submission to their IRB/IEC within timelines set by
regional/country regulations.
The investigators should provide written documentation of IRB/IEC notification for each 
report to the Sponsor.
For Suspected Unexpected Serious Adverse Reactions (SUSAR) from a blinded trial, 
unblinded CIOMS-I report will be submitted to the authorities and IRB/IEC where required. 
All SAEs recorded up to 30 days after the last study drug intake should be reported, i.e. even 
if they occur after the end of study visit.
5.5.7
Follow-up to Adverse Events
All adverse events occurring during treatment 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 (all follow-up results are to be reported to the sponsor or delegated 
CRO).
For those subjects that transition to Study 
, it is not needed to collect AEs and 
SAEs after the last dose within this study, as these will be collected as part of the extension 
study.
For subjects who do not transition to Study 
, any adverse event that 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 2 (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.
5.5.8
Monitoring of Common Serious Adverse Events
Included in Appendix 3 (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. 


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Any changes to this list will be communicated to the participating investigational sites. 
Investigators must report individual occurrences of these events [Section 0].
5.5.9
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 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.
The investigator will follow the medical status of the mother, as well as the fetus, as if the 
pregnancy is an SAE and will report the outcome to the sponsor.
When the outcome of the pregnancy falls under the criteria for SAEs [spontaneous abortion, 
induced abortion, stillbirth, death of newborn, congenital anomaly (including anomaly in a 
miscarried fetus)], the investigator should respond in accordance with the report procedure 
for SAEs. Additional information regarding the outcome of a pregnancy (which is 
categorized as an SAE) is mentioned below.
●
"Spontaneous abortion" includes 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.
5.5.10
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
Study Drug Concentration 
None.
5.7
Other Measurements, Assessments, or Methods 
None.


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5.8
Total Amount of Blood
The total amount of blood for each subject will vary depending on how long they stay on 
treatment. The maximum amount of blood collected at each clinic visit is approximately 18 ml.
Furthermore, if any laboratory abnormalities are found for a subject, additional blood may be 
drawn for monitoring.
6
DISCONTINUATION
6.1
Discontinuation of Individual Subject(s)
A discontinuation is a subject who enrolled in the study and for whom study treatment is 
permanently discontinued prematurely for any reason. 
A safety follow-up visit will be performed approximately 30 days after the last dose of study 
drug, or prior to the initiation of another anti-neoplastic therapy, whichever occurs first.
For subjects who enroll into Study 
, a safety follow-up visit is not required.
For these subjects, the final visit for Study 9785-CL-0121 will serve as Day 1 for Study 
 (±7 days).
The subject is free to withdraw from the study treatment and/or study for any reason and at 
any time without giving reason for doing so and without penalty or prejudice. The 
investigator is also free to terminate a subject's involvement in the study at any time if the 
subject's clinical condition warrants it.
If a subject is discontinued from the study with an ongoing adverse event or an unresolved 
laboratory result that is significantly outside of the reference range, the investigator will attempt 
to provide follow-up until the condition stabilizes or no longer is clinically significant. 
Subjects who choose not to participate or are not eligible for Study 
 will 
complete their participation in Study 9785-CL-0121 by completing the safety follow-up visit 
upon activation of Study 
 at the institution.
6.2
Discontinuation of the Site
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.
6.3
Discontinuation of the Study
The Sponsor may terminate this study prematurely, either in its entirety or at any study site, 
for reasonable cause provided that written notice is submitted in advance of the intended 
termination. Advance notice is not required if the study is stopped due to safety concerns. If 
the Sponsor terminates the study for safety reasons, the Sponsor will immediately notify the 
investigator and subsequently provide written instructions for study termination.


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7
STATISTICAL METHODOLOGY
This is a phase 2, open-label, extension study for subjects who are benefiting from administration 
of MDV3100 in a prior named study. No formal statistical analyses will be conducted. 
Descriptive summary statistics will be produced for all parameters. 
7.1
Sample Size
Subjects who were actively enrolled and have completed MDV3100 treatment in prior named
studies are eligible to participate in this study when continuation of MDV3100 is deemed by 
the investigator in the best interest of the subjects.
There is no statistically determined sample size for this safety follow-up study.
7.2
Analysis Set
7.2.1
Safety Analysis Set (SAF)
The SAF is defined as all subjects who have taken at least one dose of study drug in this 
extension study. 
7.3
Demographics and Other Baseline Characteristics
Descriptive summary statistics will be produced for all parameters. 
7.4
Analysis of Efficacy 
Not applicable.
7.5
Analysis of Safety
Descriptive summary statistics will be produced for all parameters. Safety analyses will be 
conducted using the SAF.  
7.5.1
Adverse Events
Treatment-emergent adverse events (TEAE) will be presented within each system organ class 
by preferred term, by relationship to study drug and by severity (NCI-CTCAE grade). AEs 
leading to permanent discontinuation of study drug, SAEs, and SAEs by NCI-CTCAE grade 
will be summarized. AEs will also be summarized by NCI-CTCAE grade and relationship to 
study drug jointly.
AEs will be coded to system organ class and preferred term using the Medical Dictionary for 
Regulatory Authorities (MedDRA) and graded using NCI-CTCAE. Listings of deaths, SAEs, 
and withdrawals due to AEs will be presented.
7.5.2
Clinical Laboratory Evaluations
Clinical laboratory evaluations (including hematology and serum chemistry) will be 
summarized for each visit using descriptive statistics. Change from baseline will also be 


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summarized. Shift analysis tables will present shift from baseline to the same visits using the 
NCI-CTCAE grade and laboratory reference range indicator. All clinically significant 
abnormal laboratory values will be recorded as AEs and graded using NCI-CTCAE 
guidelines.
7.5.3
Physical Examination
All clinically significant abnormal findings will be recorded as medical history or AEs and 
graded using NCI-CTCAE guidelines.
7.5.4
Vital Signs
Descriptive statistics will be presented for each vital sign measurement at each visit. Change 
from baseline will also be summarized.
7.5.5
Electrocardiogram (ECG)
Overall ECG interpretation will be summarized for each visit. A shift analysis table showing 
shifts from baseline to each visit in overall ECG interpretation (normal, abnormal not 
clinically significant, and abnormal clinically significant) will be provided.
7.5.6
Concomitant Medications
The frequency of concomitant medications (prescription, over-the-counter, and nutritional 
supplements) will be summarized by preferred term. Medications will be coded using the 
World Health Organization (WHO) drug dictionary. Medications will be counted by the 
number of subjects who took each medication. A subject taking the same medication multiple 
times will only be counted once for that medication. Medications will be presented in 
decreasing order of frequency based on the total number of subjects who took each medication.
7.5.7
Extent of Exposure
Duration of treatment and total dose administered will be summarized. 
7.6
Analysis of Pharmacokinetics
None.
7.7
Protocol Deviations and Other Analysis
Protocol deviations as defined in Section 8.1.6 will be summarized for all subjects and 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,


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PD4 – Received excluded concomitant treatment
Descriptive summary statistics will be produced for ECOG. 
7.8
Interim Analysis (and Early Discontinuation of the Clinical Study)
An interim analysis will be performed when deemed to be necessary (e.g. as part of a 
submission).
7.9
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information
7.9.1
Missing Data
Imputations for missing data, if applicable, will be addressed in the statistical analyses plan. 
7.9.2
Visit Windows
Visit windows are allowed for certain visits per the schedule of procedures. Subject data will 
not be excluded from analyses due to the subject’s failure to comply with the visit schedule.
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. 
Laboratory tests are performed at the local laboratory.
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 (but is not limited to) in the source medical 
records:
●
Demographic data (age, sex, race, ethnicity, weight and height)
●
Records to support inclusion and exclusion criteria details


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●
Participation in study and signed and dated informed consent form
●
Visit dates
●
Disease and prior treatment history. Photocopies or fax documents of original records are 
acceptable if obtained from an outside institution
●
Medical history
●
Physical examination details
●
Key safety data as specified in the protocol
●
Adverse events and concomitant medication
●
Results of protocol specified evaluations (laboratory, ECG)
●
Dispensing, destruction, and return of study drug details
●
Reason for discontinuation
●
Subject number
●
Staff notes and phone records 
●
Medical records from other departments or hospitals, including discharge summaries, 
correspondence, etc., at which the subject received treatment. Photocopies or fax 
documents of original records are acceptable if obtained from an outside institution.
8.1.3
Clinical Study Monitoring
The sponsor or delegated CRO is responsible for monitoring the clinical study to ensure that 
subject's human rights, safety, and well-being are protected, that the study is properly 
conducted in adherence to the current protocol and GCP, and study data reported by the 
investigator/sub-investigator are accurate and complete and that they are verifiable with study-
related records such as source documents. The sponsor is responsible for assigning study 
monitor(s) to this study for proper monitoring. They will monitor the study in accordance with 
planned monitoring procedures.
8.1.4
Direct Access to Source Data/Documents
The investigator and the study site must accept monitoring and auditing by the sponsor or 
delegated CRO as well as inspections from the IRB/IEC and relevant regulatory authorities. 
In these instances, they must provide all study-related records, such as source documents 
(refer to Section 8.1.2 "Specification of Source Documents") when they are requested by the 
sponsor monitors and auditors, the IRB/IEC, or regulatory authorities. The confidentiality of 
the subject's identities shall be well protected consistent with local and national regulations 
when the source documents are subject to direct access.
8.1.5
Data Management
Data management will be overseen by the responsible department at the sponsor in 
accordance with the standard operating procedures for data management. All study specific 
processes and definitions will be documented by Data Management. eCRF retrieval and 
correction process will be referenced in the eCRF instructions. Coding of medical terms will 
be performed using MedDRA.


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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 systemic 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 purpose 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 
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
The end of trial in all participating countries is defined as the Last Patient’s Visit.


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8.2
Ethics and Protection of Subject Confidentiality
8.2.1
Institutional Review Board (IRB)/ Independent Ethics Committee(IEC)/ 
Competent Authorities (CA)
The clinical study may begin after acquisition of a written approval from the Institutional 
Review Board/Independent Ethics Committee/ Competent Authorities of record for that site 
and study.
The protocol and the required supporting documents will be submitted to the CA according to 
the national laws. Prior to starting the study, approval must be obtained in writing, where 
applicable. 
The investigator shall make accurate and adequate written progress reports to the IRB/IEC 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.
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 
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.
●
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:


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o
No subject may be subjected to undue influence, such as compulsory enrollment 
into a study.
o
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 
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.


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The sponsor, its board members and its personnel 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). 
If applicable, 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 Privacy Board [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 
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 allowing the sponsor to review 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 Astellas Pharma sponsored studies. This 


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is necessary to prevent premature disclosure of trade secrets or patent-protected information 
and 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)
●
eCRFs and SAE Report Form
●
Investigator’s File
●
Study drug with all necessary documentation
●
Study contract
●
Approval of regulatory authority and all documents related to submission
●
Investigational Medicinal Product Dossier (IMPD) (if applicable per local regulations)
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
●
Submission letter to IRB/IEC
●
Signed confidentiality agreement
●
Signed Investigator's Statement in this protocol
●
Executed Study Contract
●
Signed and dated FDA form 1572, if applicable
●
Copy of the approved ICF and separate authorization form, if appropriate.
●
IEC/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, brief and in English)
●
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:
●
Study documentation, forms etc.
●
Unused study drug
The investigator will archive all study data (e.g., Subject Identification Code List, source data, 
eCRFs, and Investigator's File) and relevant correspondence. These documents are to be kept 
on file for the appropriate term determined by local regulation. 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 


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the investigator if the Marketing Authorization Application (MAA) is approved or if the IMPD 
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 eCRFs supplied for 
each subject. 
The investigator and sponsor will mutually agree upon the storage format for the retention of 
electronic data.
8.3.3
Protocol Amendment and/or Revision
Any changes to the study that arise after approval of the protocol must be documented as 
protocol amendments: substantial amendments and/or administrative changes/non-substantial 
amendments. Depending on the nature of the amendment and/or administrative change, either 
IRB/IEC 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/national regulation.
8.3.4
Insurance of Subjects and Others
The sponsor, Astellas Pharma Europe B.V., has covered this study by means of an insurance 
of the study according to national requirements. The name and address of the relevant 
insurance company, the certificate of insurance, the policy number and the sum insured are 
provided in the Investigator's File. 
8.3.5
Investigator Indemnity 
The sponsor agrees to, and does hereby, indemnify, defend and hold the investigator harmless 
from and against all claims, demands, actions, and proceedings which may be brought or 
asserted against the investigator to recover damages and losses for or attributable to bodily 
injury, sickness, disease, or death arising from or alleged to arise from or be reasonably 
attributable to this study.
Notwithstanding the foregoing, the sponsor does not, however, agree to indemnify, defend or 
hold the investigator harmless from claims, demands, actions, proceedings or damages 
resulting or claimed to have resulted from:


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●
Failure of the investigator to evaluate or properly interpret available information that is 
relevant to this study, and for independent decisions made as the result of such failure;
●
Failure of the investigator to adhere to all provisions of the protocol for this study and to 
written recommendations and written instructions delivered to the investigator by the 
sponsor concerning the administration and use of drug substances, including the placebo, 
involved in this study;
●
Failure of the investigator to render professional service or to conduct this study in a 
normal, prudent manner.
A condition of this indemnity obligation is that, whenever the investigator has information 
from which it may be reasonably concluded that an incident of bodily injury, sickness, 
disease or death has occurred, the investigator shall immediately give notice to the sponsor of 
all pertinent data surrounding any such incident, and, in the event a claim is made or a suit is 
brought, the investigator shall assist the sponsor and cooperate in the gathering of 
information with respect to the time, place, and circumstances and in obtaining the names and 
addresses of the injured parties and available witnesses. The investigator shall not, except at 
his own cost, voluntarily make any payment or incur any expense in connection with any 
such claim or suit without the prior written consent of the sponsor.
8.3.6
Signatory Investigator for Clinical Study Report
ICH E3 guidelines recommend and EU Directive 2001/83/EC requires that a final study report 
which forms part of a marketing authorization application be signed by the representative for 
the Coordinating Investigator(s) or the Principal Investigator(s). The representative for the 
Coordinating Investigator(s) or the Principal Investigator(s) will have the responsibility to 
review the final study results to confirm to the best of his/her knowledge it accurately describes 
the conduct and results of the study. The representative for Coordinating Investigator(s) or the 
Principal Investigator(s) will be selected from the participating investigators by the Sponsor
prior to database lock.
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.


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10
STUDY ORGANIZATION
10.1
Data Monitoring Committee 
Not applicable.
10.2
Other Evaluation Committee(s)
Not applicable.
10.3
Other Study Organization
Not applicable.


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11
REFERENCES
Chen CD, Welsbie DS, Tran C et al. Molecular determinants of resistance to ant androgen therapy. Nat 
Med 2004; 10(1):33-39.
deBono JS, Oudard S, Ozguroglu M, Hansen S, Machiels J-P, Kocak I, Gravis G, Bodrogi I, Mackenzie 
MJ, Shen L, Roessner M, Gupta S, Sartor AO.  Prednisone plus Cabazitaxel or mitoxantrone for 
metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised 
open-label trial. Lancet 2010; 376: 1147-1154.
Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, Redfern CH, Ferrari AC, 
Dreicer R, Sims RB, Xu Y, Frohlich MW, Schellhammer PF. Sipuleucel-T immunotherapy for 
castration-resistant prostate cancer. N Engl J Med 2010; 363: 411-422.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. 1982;6:649-655.
Sartor Sartor AO, Tangen CM, Hussain MHA, Eisenberger MA, Parab M, Fontana JA, Chapman RA, 
Mills GM, Raghavan D, Crawford ED.  Anti androgen withdrawal in castrate-refractory prostate 
cancer.  Cancer 2008; 112(11): 2393-2400.
Scher HI, Buchanan G, Gerald W, Butler LM, Tilley WD. Targeting the androgen receptor: improving 
outcomes for castration-resistant prostate cancer. Endocr Relat Cancer 2004; 11(3):459-476.
Tannock IF, de WR, Berry WR et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for 
advanced prostate cancer. N Engl J Med 2004; 351(15):1502-1512.
Tran C, Ouk S, Clegg NJ et al. Development of a second-generation antiandrogen for treatment of 
advanced prostate cancer. Science 2009; 324(5928): 787-790.
http://medicine.iupui.edu/clinpharm/ddis/table.asp
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLa
beling/ucm093664.htm#potency
Company Reports
Protocol 9785-CL-0007. Current version
Protocol 9785-CL-0003. Current version
Investigator’s Brochure. MDV3100 for the treatment of cancer. Current edition.


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12
APPENDICES
12.1
Appendix 1:  Laboratory Tests
Test type
Visit
Parameters to be analyzed
Hematology
All visits
Hemoglobin (Hgb)
Hematocrit (HCT)
Complete Cell Count (CBC)
Red Blood Cells (RBC)
White blood cells (WBC) 
Differential WBC
Platelets
Biochemistry
All visits
sodium
potassium
calcium 
chloride 
magnesium 
phosphate
glucose
creatinine
alkaline phosphatase
alanine aminotransferase (ALT) 
aspartate aminotransferase (AST)
gamma-glutamyl transferase (GGT)
total bilirubin
total protein
albumin
bicarbonate (CO2) 
blood urea nitrogen (BUN)


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12.2
Appendix 2:  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 bilirubin [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. Discontinuation of treatment must occur if subject has marked abnormalities. In 
addition, if closed monitoring for a subject with moderate hepatic laboratory tests is not 
possible, drug should be discontinued.
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 liver function tests (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 


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sponsor should be contacted and informed of all subjects for whom marked hepatic liver 
function abnormalities possibly attributable to study drug are observed.
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 eCRF. 
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 eCRF.  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: 
o
acute viral hepatitis (A,B, C, D, E or other infectious agents) 
o
ultrasound or other imaging to assess biliary tract disease
o
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.


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Reference
Guidance for Industry titled “Drug-Induced Liver Injury: Premarketing Clinical Evaluation” 
issued by FDA on July 2009.


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12.3
Appendix 3:  Common Serious Adverse Events
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 0. 
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. 
●
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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13
ATTACHMENT 1:  SUBSTANTIAL AMENDMENT 4
I.  The purpose of this amendment is:
Substantial Changes
1.
Revise Study Design 
DESCRIPTION OF CHANGE:
Subjects who are continuing to derive clinical benefit from treatment with enzalutamide 
based on the investigator’s medical opinion and have not met any of the discontinuation 
criteria as outlined in Section 3.4 of the protocol may be eligible to continue to receive 
treatment with enzalutamide in Study 
 upon approval of the protocol and 
activation of this study at the participating institution. 
Subjects who choose not to participate or are not eligible for Study 
 will 
complete their participation in Study 9785-CL-0121 by completing the safety follow-up visit 
upon activation of Study 
 at the institution.  
RATIONALE:
Astellas will close Study 9785-CL-0121 and allow subjects who are continuing to derive 
clinical benefit from treatment with enzalutamide to enroll in Study 
. 
Study
 allows investigators to follow their subjects per standard of care while 
still providing treatment with enzalutamide for their prostate cancer.
Nonsubstantial Changes
1.
Update Sponsor contact information
DESCRIPTION OF CHANGE: 
Change of Astellas Medical Expert/Medical Monitor.
RATIONALE:
Key sponsor personnel change.
2.
Revise planned study period
DESCRIPTION OF CHANGE: 
Change planned study period to indicate an end date of first quarter 2017.
RATIONALE:
The planned study period is updated to reflect the most current information.


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II.  Amendment Summary of Changes:
IV Synopsis, Design and Methodology and 2 Study Objective(s), Design and Endpoints
2.2.1 Study Design
WAS:
This is a multi-center phase 2 open-label extension study in subjects with prostate cancer who 
have completed MDV3100 treatment in a previous study with MDV3100 to assess the long-
term safety of continued administration of MDV3100, when judged by the investigator to be 
in the best interest of the subject.
For the study duration, all subjects with castration-resistant prostate cancer (CRPC) will have 
to maintain androgen deprivation with an LHRH agonist/antagonist unless they underwent 
bilateral orchiectomy.
Subjects will be discontinued from study drug when continued administration of study drug 
is deemed to be not in the subject’s best interest by the investigator based on clinical 
assessment. 
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.
IS AMENDED TO:
This is a multi-center phase 2 open-label extension study in subjects with prostate cancer who 
have completed MDV3100 treatment in a previous study with MDV3100 to assess the long-
term safety of continued administration of MDV3100, when judged by the investigator to be 
in the best interest of the subject.
For the study duration, all subjects with castration-resistant prostate cancer (CRPC) will have 
to maintain androgen deprivation with an LHRH agonist/antagonist unless they underwent 
bilateral orchiectomy.
Subjects will be discontinued from study drug when continued administration of study drug 
is deemed to be not in the subject’s best interest by the investigator based on clinical 
assessment.
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 from their last dose of study drug.
Subjects that have not met any of the discontinuation criteria as outlined in Section 3.4 
may be eligible to continue to receive treatment with enzalutamide in Study 
 upon approval and activation of this study at the participating institution. Subjects 
who enroll in Study 
 will not be required to have a safety follow- up visit.
Subjects who choose not to participate or are not eligible for Study 
 will 
complete their participation in Study 9785-CL-0121 by completing the safety follow-up 
visit upon activation of Study 
 at the institution.


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IV Synopsis, Discontinuation Criteria
ADDED:
Astellas will be closing Study 9785-CL-0121. Subjects that have not met any of the 
discontinuation criteria as outlined in Section 3.4 may be eligible to continue to receive 
treatment with enzalutamide in Study 
 upon approval and activation of 
this study at the participating institution.
Subjects who choose not to participate or are not eligible for Study 
 will 
complete their participation in Study 9785-CL-0121 by completing the safety follow-up 
visit upon activation of Study 
 at the institution.
V Schedule of Assessments
Table 1: Schedule of Assessments 
WAS:
Study Day
-32 
to -1
1a
29
85
every 
12 
weeks 
up to 
week 
85
every 
24 
weeks 
from 
week 
85
Safety FU
Week
1
5
13
30 days 
after last 
dose of 
MDV 3100
Window (days)
NA
± 3
± 7
± 7
± 7
± 7
Informed Consent
Xb
Inclusion/Exclusion Criteria
X
Medical History
X
Vital Signsc
X
X
X
X
X
X
Physical Examination 
X
X
X
X
X
X
Weight
X
X
X
X
X
X
12-lead ECG
X
X
X
X
X
X
Clinical laboratory testsd
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
MDV3100 Dispensing
X
X
X
X
X
g.
The final visit of the prior study with MDV3100 in which the subject is taking study drug and all 
assessments done during this visit, will serve as the initial visit (day 1) and visit assessments for 
this extension study.  
h.
To ensure that MDV3100 is taken continuously without interruption, the subjects will be 
informed about the extension study at any of the visits during the previous study and sign ICF 
prior to visit on day 1 of this study.  
i.
Vital signs (blood pressure, pulse rate, respiration rate, and temperature) will be obtained prior to 
study drug administration.


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IS AMENDED TO:
Study Day
-32 
to -1
1a
29
85
every 
12 
weeks 
up to 
week 85
every
24d
weeks 
from 
week 
85
Safety FUe, 
f
Week
1
5
13
30 days 
after last 
dose of 
MDV 
3100
Window (days)
NA
± 3
± 7
± 7
± 7
± 7
Informed Consent
Xb
Inclusion/Exclusion Criteria
X
Medical History
X
Vital Signsc
X
X
X
X
X
X
Physical Examination 
X
X
X
X
X
X
Weight
X
X
X
X
X
X
12-lead ECG
X
X
X
X
X
X
Clinical laboratory testsd
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
MDV3100 Dispensing
X
X
X
X
X
a)
The final visit of the prior study with MDV3100 in which the subject is taking study drug and all 
assessments done during this visit, will serve as the initial visit (day 1) and visit assessments for 
this extension study.  
b) To ensure that MDV3100 is taken continuously without interruption, the subjects will be 
informed about the extension study at any of the visits during the previous study and sign ICF 
prior to visit on day 1 of this study.  
c)
Vital signs (blood pressure, pulse rate, respiration rate, and temperature) will be obtained prior to 
study drug administration.
d) If the subject is eligible to continue in extension Study 
, the final visit of 
Study 9785-CL-0121 will serve as the initial visit (day 1) for extension Study 
. 
Subjects who enroll in Study 
 will not be required to have a safety follow-up 
visit.
e)
If a new cytotoxic or investigational anticancer treatment is initiated before 30 days after 
last dose, then safety follow-up for Study 9785-CL-0121 should occur immediately before 
starting the new treatment.
f)
Subjects who choose not to participate or are not eligible for Study 
 will 
complete their participation in Study 9785-CL-0121 by completing the safety follow-up 
visit upon activation of Study 
 at the institution.


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3 Study Population
3.4 Discontinuation Criteria for Individual Subjects
WAS:
Unless the 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 MDV3100.  
IS AMENDED TO:
Unless the 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 MDV3100.  For subjects 
who enroll into Study 
, a safety follow-up visit is not required. For these 
subjects the final visit for Study 9785-CL-0121 will serve as Day 1 for Study 
 (±7 days).
5 Treatments and Evaluation
5.1.1 Dose/Dose Regimen and Administration Period 
WAS:
In this study, subjects will continue to receive 160 mg/day of MDV3100 until the investigator 
feels that continued use of MDV3100 is not beneficial to the subject, or the subject 
withdraws consent.
Study drug should be taken as close to the same time each day as possible. Study drug can be 
taken with or without food. If dosing is missed on one day for any reason, double-dosing 
should not occur the following day.
IS AMENDED TO:
In this study, subjects will continue to receive 160 mg/day of MDV3100 until the investigator 
feels that continued use of MDV3100 is not beneficial to the subject, or the subject 
withdraws consent.
Since Astellas will close Study 9785-CL-0121, subjects that have not meet any of the 
discontinuation criteria as outlined in Section 3.4 may be eligible to continue receive 
treatment with enzalutamide in Study 
 upon approval and activation of 
this study at the participating institution.
Subjects who choose not to participate or are not eligible for Study 
 will 
complete their participation in Study 9785-CL-0121 by completing the safety follow-up 
visit upon activation of Study
 at the institution.
Study drug should be taken as close to the same time each day as possible. Study drug can be 
taken with or without food. If dosing is missed on one day for any reason, double-dosing 
should not occur the following day.


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5 Treatments and Evaluation
5.5.7 Follow-up of Adverse Events
WAS:
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 (all follow-up results are to be reported to the sponsor or delegated 
CRO).
Since it is unpredictable how long such a follow-up will take, data from this follow-up 
generated after the subject's end of the study visit will be recorded by the investigator. Full 
details regarding this follow-up will be described in the study report, whenever necessary.
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 2 (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.
IS AMENDED TO:
All adverse events occurring during the study treatment 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 (all follow-up results are to be reported to the sponsor or 
delegated CRO).
Since it is unpredictable how long such a follow up will take, data from this follow up 
generated after the subject's end of the study visit will be recorded by the investigator. Full 
details regarding this follow up will be described in the study report, whenever necessary.
For those subjects that transition to Study 
, it is not needed to collect new 
AEs and SAEs after the last dose within this study, as these will be collected as part of 
the extension study. 
If during adverse event follow up, the For subjects who do not transition to Study 
 any adverse event that 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 2 (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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6 Discontinuation
6.1 Discontinuation of Individual Subject(s)
WAS:
A discontinuation is a subject who enrolled in the study and for whom study treatment is 
permanently discontinued 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. The 
investigator is also free to terminate a subject's involvement in the study at any time if the 
subject's clinical condition warrants it.
If a subject is discontinued from the study with an ongoing adverse event or an unresolved 
laboratory result that is significantly outside of the reference range, the investigator will 
attempt to provide follow-up until the condition stabilizes or no longer is clinically significant. 
IS AMENDED TO:
A discontinuation is a subject who enrolled in the study and for whom study treatment is 
terminated discontinued prematurely for any reason.  
A safety follow-up visit will be performed approximately 30 days after the last dose of 
study drug, or prior to the initiation of another anti-neoplastic therapy, whichever 
occurs first.
For subjects who enroll into Study 
, a safety follow-up visit is not 
required. For these subjects, the final visit for Study 9785-CL-0121 will serve as Day 1 
for Study
 (±7 days).
The subject is free to withdraw from the study treatment and/or study for any reason and at 
any time without giving reason for doing so and without penalty or prejudice. The 
investigator is also free to terminate a subject's involvement in the study at any time if the 
subject's clinical condition warrants it.
If a subject is discontinued from the study with an ongoing adverse event or an unresolved 
laboratory result that is significantly outside of the reference range, the investigator will 
attempt to provide follow-up until the condition stabilizes or no longer is clinically 
significant. 
Subjects who choose not to participate or are not eligible for Study 
 will 
complete their participation in Study 9785-CL-0121 by completing the safety follow-up 
visit upon activation of Study 
 at the institution.




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14
SPONSOR’S SIGNATURES 


 
S-1 
ELECTRONIC SIGNATURE PAGE 
Document Type :  
Document Control Number :  
Amendment Number :  
International Study Number :  
Departmental Study Number :  
Actual Version Number :  
Document Version :  
Nonclinical Initial SD Approved Date (UTC) :  
Date (UTC) 
Signed by 
Sign Off Meaning 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
 
Full Name / Legal Name 
 
 
 
 
 
 
Full Name / Legal Name 
 
*UTC: Coordinated Universal Time 
06/23/2016 07:43:11
Clinical Study Protocol
Study Manager Approval
Principal Reviewer Approval
06/22/2016 15:49:20
Reissue v5.0, 20Jun2016
Study Physician Approval
N/A
06/22/2016 15:23:15
N/A
MGC1600636
9785-CL-0121
2.0
N/A

SAP_001.pdf: 
A Phase 2 Open-label Extension Study to Assess the Safety of 
Continued Administration of MDV3100 in Subjects with Prostate 
Cancer Who Showed Benefit from Prior Exposure to MDV3100
ISN/Protocol 9785-CL-0121
Final version 1.0, dated 08-April-2015
ClinicalTrials.gov Identifier: NCT01534052
Sponsor: Astellas Pharma Europe B.V. (APEB)
Sylviusweg 62
2333 BE Leiden
The Netherlands


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STATISTICAL ANALYSIS PLAN
Final version 1.0, dated 08-April-2015
A Phase 2 open-label extension study to assess the safety of 
continued administration of MDV3100 in subjects with Prostate 
Cancer who showed benefit from prior exposure to MDV3100
Protocol Version 4.0, 03-July-2014
Phase 2 Study of MDV3100
Astellas Pharma Europe B.V. (APEB)
Sylviusweg 62
2333 BE Leiden
The Netherlands
----------------------------------------------------------------------------------------------------------------
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.
LIST OF ABBREVIATIONS AND KEY TERMS ············································· 4
1
INTRODUCTION··················································································· 5
2
VISIT SCHEDULE·················································································· 5
3
STUDY OBJECTIVE(S), DESIGN ······························································· 6
3.1
Study Objectives ··············································································· 6
3.2
Study Design···················································································· 6
3.3
Assignment and Allocation ··································································· 6
3.4
Transfer of data from prior study····························································· 7
4
SAMPLE SIZE······················································································· 7
5
ANALYSIS SETS ··················································································· 7
5.1
Safety Analysis Set (SAF) ···································································· 7
6
ANALYSIS VARIABLES ········································································· 8
6.1
Efficacy Variables ············································································· 8
6.2
Safety Variables················································································ 8
6.3
Pharmacokinetics··············································································· 8
7
STATISTICAL METHODOLOGY······························································· 8
7.1
General Considerations········································································ 8
7.2
Study Population ··············································································· 8
7.2.1
Disposition of Subjects ·································································· 8
7.2.2
Protocol Deviations ······································································ 9
7.2.3
Demographics and Other Baseline Characteristics··································· 9
7.2.4
Medical History··········································································· 9
7.2.5
Concomitant Medications ······························································· 9
7.3
Study Drug·····················································································10
7.4
Analysis of Efficacy ··········································································10
7.5
Analysis of Safety·············································································11
7.5.1
Adverse Events ··········································································11
7.5.2
Clinical Laboratory Evaluations·······················································11
7.5.3
Physical Examination···································································11
7.5.4
Vital Signs················································································11
7.5.5
Electrocardiogram (ECG) ······························································12


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7.6
Analysis of Pharmacokinetics ·······························································12
7.7
Other Analyses ················································································12
7.8
Interim Analysis (and Early Discontinuation of the Clinical Study)····················12
7.9
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········12
7.9.1
Missing Data ·············································································12
7.9.2
Visit Windows ···········································································13
8
REFERENCES······················································································14
9
APPENDICES ······················································································15
9.1
Appendix 1: Signatures·······································································15


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I.
LIST OF ABBREVIATIONS AND KEY TERMS
List of Abbreviations
Abbreviations
Description of abbreviations
AE
Adverse Event
BMI
Body Mass Index
CA
Competent Authority
CRF
Case Report Form
CT
Computed Tomography
CV
Coefficient of Variation
CXR
Chest X Ray
CYP
Cytochrome P450
DRM
Data Review Meeting
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
e.g. 
Exempli Gratia (for example) 
ESV
End of Study Visit
EudraCT
European Union Drug Regulating Authorities Clinical Trials
ICF
Informed Consent Form
ISN
International Study Number
LLOQ
Lower Limit of Quantification
MDV3100
Study Drug
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
MRI
Magnetic Resonance Imaging
NCI-CTCAE
National Cancer Institute’s Common Terminology Criteria for Adverse Events
PK
Pharmacokinetic
PSA
Prostate-specific Antigen
PT
Preferred Term
s
Second
SAF
Safety Analysis Set
SAP
Statistical Analysis Plan
SD
Standard Deviation
SOC 
System Organ Class
TEAE
Treatment Emergent Adverse Event
WHO-DRL
World Health Organization Drug Reference list


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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 prior to hard lock of the database.
2
VISIT SCHEDULE
Table 1
Schedule of Assessments
Study Day
-32 to -1
1a
29
85
every 12 weeks 
up to week 85
every 24 weeks 
from week 85
Safety FU
Week
1
5
13
30 days after last 
dose of MDV 
3100
Window (days)
NA
± 3
± 7
± 7
± 7
± 7
Informed Consent
Xb
Inclusion/Exclusion Criteria
X
Medical History
X
Vital Signsc
X
X
X
X
X
X
Physical Examination 
X
X
X
X
X
X
Weight
X
X
X
X
X
X
12-lead ECG
X
X
X
X
X
X
Clinical laboratory testsd
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
MDV3100 Dispensing
X
X
X
X
X
a.
The final visit of the prior study with MDV3100 in which the subject is taking study drug and all assessments done during this visit, will serve as the initial visit (day 1) and visit 
assessments for this extension study.
b.
To ensure that MDV3100 is taken continuously without interruption, the subjects will be informed about the extension study at any of the visits during the previous study and sign 
ICF prior to visit on day 1 of this study.
c.
Vital signs (blood pressure, pulse rate, respiration rate, and temperature) will be obtained prior to study drug administration.
d.
Clinical laboratory tests, hematology and chemistry, will be obtained prior to study drug administration.


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3
STUDY OBJECTIVE(S), DESIGN
3.1
Study Objectives
The main objective of this study is to follow up the long-term safety of continued 
administration of MDV3100 in prostate cancer subjects who were enrolled and completed 
MDV3100 treatment period in prior (e.g., phase 1) studies.
The long-term safety will be determined by:

Adverse Events

Vital Signs

12-lead ECGs

Physical Examination

Safety laboratory evaluation

ECOG performance status.
3.2
Study Design
This is a multi-center phase 2, open-label extension study in prostate cancer subjects who 
have completed MDV3100 treatment in a prior study.  In order to participate in this study, 
the subjects must have completed the prior study with MDV 3100, be in the state of at least 
stable disease and in the opinion of the investigator would derive benefit from continuing 
MDV3100 treatment.  The final visit in the prior MDV3100 study, in which the subject is 
taking study drug, will serve as the initial visit for this extension study.
The extension protocol’s baseline, for comparison purposes, will be a baseline from the prior
MDV3100 study.  In addition, all ongoing concomitant medications and AEs from the prior
study will be transferred onto the appropriate case report forms (eCRFs) for this study.
All subjects will take 160 mg (4 capsules) MDV3100 once daily oral dose at the same time 
each day. MDV3100 can be taken with or without food.
Subjects will be discontinued from study drug when continued administration of study drug 
is deemed to be not in the subject’s best interest by the investigator based on clinical 
assessments. Use of other investigational drugs will also lead to discontinuation.
Throughout the study, safety and tolerability will be assessed by the recording of AEs,
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.
3.3
Assignment and Allocation
Subjects will be assigned to a subject number at study entry (signing of Informed Consent 
Form).


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3.4
Transfer of data from prior study
Relevant data from the prior study has been transcribed to the eCRF of this study. This is 
done on the basis of specific instructions by the Investigators involved.
Demographic information (date of birth, ethnicity, race as described by the subject and 
height) collected at screening of the prior study with MDV3100 has been transcribed onto the 
appropriate eCRF for this study.
Medical history, as well as non prostate cancer medical history that stopped at or prior to 
screening,  recorded at screening of the prior study with MDV3100 has been transcribed onto 
the appropriate eCRF for this study.
Medical history and disesase history of the target disease recorded at screening of the prior 
study with MDV3100 has been transcribed onto the appropriate eCRF for this study.
As stated earlier, in addition, all ongoing concomitant medications (including non-medication 
therapies) and AEs from the prior study have been transferred onto the appropriate case 
report forms (eCRFs) for this study.
Further details can be found in the Investigators EDC Instruction Manual (see references).
Because of the transfer of all relevant data from the prior study, the reporting of the extension 
study will be exclusively based on the data available in the database of this extension study. 
The only exception is that for a number of safety assessments (Laboratory data, Vital signs, 
ECG data and the ECOG scale) as baseline the last assessment before the first MDV3100 
intake of the prior study will be used.
4
SAMPLE SIZE
Subjects who were actively enrolled and have completed MDV3100 treatment in prior named 
studies, are eligible to participate in this study when continuation of MDV3100 is deemed by 
the investigator in the best interest of the subjects. There is no statistically determined sample 
size for this safety follow up study.
5
ANALYSIS SETS
In accordance with ICH recommendations in guidelines E3 and E9, the following analysis 
sets will be used for the analyses.
5.1
Safety Analysis Set (SAF)
Only one analysis set is defined for this study. The Safety Analysis Set (SAF) is defined as 
all subjects who have taken at least one dose of study drug in this extension study.


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6
ANALYSIS VARIABLES
6.1
Efficacy Variables
Not applicable.
6.2
Safety Variables
Safety will be assessed by evaluation of the following variables:

Treatment-emergent adverse events (TEAEs; frequency, seriousness, severity 
(NCI-CTCAE grade) and relationship to study drug)

Safety laboratory variables (hematology and biochemistry)

Vital signs (blood pressure, pulse rate, respiration rate, temperature and body weight)

Physical examination

12-lead electrocardiogram (ECG)
TEAE: An adverse event observed after starting administration of study drug during the 
extension study. If a subject experiences an event during the prior study with MDV3100 
which continues during this extension study, the event will be considered as TEAE only if it 
has worsened in severity (i.e. it is reported with a new start date during the extension period) 
All adverse events collected that begin within 30 days of taking the last dose of study drug 
will also be counted as TEAE.
6.3
Pharmacokinetics
No PK assessment involved.
7
STATISTICAL METHODOLOGY
7.1
General Considerations
No inferential statistical analyses will be conducted. Descriptive statistics including the number 
of subjects (n), mean, standard deviation (SD), median, minimum and maximum will be used to 
summarize continuous variables. Number (n) and percentage (%) of subjects in each category 
will be used to summarize categorical variables. All data processing, summarization, and 
analyses will be performed using SASVersion 9.1 or higher on Unix. Specifications for table, 
graphs and data listing formats can be found in the TLF specifications for this study.
7.2
Study Population
7.2.1
Disposition of Subjects
The subject disposition will be summarized and presented for the safety analysis set (SAF):

Number and percentage of subjects enrolled in study;

Number and percentage of subjects who stayed on study medication for the complete 
duration of the study* or discontinued from the study by reason of discontinuation.
*this extension study is open ended in the sense that no maximum duration is defined.
  The study will end when all subjects on medication have discontinued treatment or 
  the sponsor makes the decision to terminate the study.


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7.2.2
Protocol Deviations
Protocol deviations will be assessed for all subjects allocated to treatment.
The number and percentage of subjects meeting any criteria will be summarized for each 
criterion and overall, by total as well as by study site. Subjects deviating from a criterion 
more than once will be counted once for the corresponding criterion. Any subjects who have
more than one protocol deviation will be counted once in the overall summary. A data listing 
will be provided by site and subject.
The protocol deviation 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.
7.2.3
Demographics and Other Baseline Characteristics
Descriptive summary statistics will be produced for all parameters. For the calculation of age 
the initial visit of the extension study (Day 1) will be used as the reference date. For weight 
and BMI the data assessed at the baseline of the prior study will be used.
Demographic data and other baseline characteristics will be provided in a listing.
7.2.4
Medical History
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and will be obtained at screening visit (see section 3.4).
Non-prostate cancer related medical history data will be summarized by presenting the 
number and percentage on the SAF. The summary table will be presented alphabetically by 
system organ class and by decreasing order of frequency of preferred terms within each 
system organ class.
Cancer history will be summarized by presenting the number and percentage of subjects for 
tumor and lymph node stages, Gleason scores, incidence of metastases and previous therapies 
on the FAS. The duration of prostate cancer will be calculated as (Date of first MDV3100 
intake in the prior study – Date of Initial Diagnosis) + 1. Descriptive statistics will be used to 
summarize the duration of disease.
A listing of medical history will be provided.
7.2.5
Concomitant Medications
Concomitant medications (prescription, over-the-counter, and nutritional supplements) will 
be coded using the World Health Organization (WHO) drug dictionary and will be 
summarized by preferred WHO name and reported term. Medications will be counted by the 
number of subjects who took each medication. A subject taking the same medication multiple 


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times will only be counted once for that medication. Medications will be presented in 
decreasing order of frequency based on the total number of subjects who took each 
medication.
All concomitant medication data will be provided in a listing.
Concomitant medications are those medications or therapies with at least one dose taken 
between the date of first MDV3100 intake in the 121 study (inclusive) and the date of last 
MDV3100 dose (inclusive) and up to the end of the study. 
7.3
Study Drug
Duration of treatment and total dose will be summarized in two ways:

Descriptive statistics of MDV3100 exposure in Days

Exposure time will be categorized according to the following categories:
o
<2 months
o
≥2 – <6 months*
o
≥6 – <12 months*
o
≥12 months
*The following convention will be applied: 2 months = 60 days; 6 months = 180 days and 
12 months = 365 days.
Counts and percentage of subjects in each of these categories will be summarized.
The duration of exposure (number of days) to study medication will be summarized using 
descriptive statistics on the SAF, where the duration of exposure to MDV3100 is defined as 
the last known date that subject took MDV3100 during this study – the first dose date in this 
study + 1 day. Dose interruptions will be ignored in the calculation.
Also a summary of average daily dose during the extension period will be provided. The 
daily dose received by a subject is collected for each CRF visit. Changes in dose are also 
collected. The daily dose will be assumed the same between 2 CRF visits if no change in 
dose is recorded.
In addition information on MDV3100 compliance will be summarized via descriptive 
statistics and via categories (<80%, ≥80%). Percentage compliance is defined as the total 
number of capsules taken divivded by the total number of capsules that should have be taken:
[Total number of tablets consumed]
------------------------------------------------------------------------------- x 100
[(‘Date last dose of study drug’ - ‘Date first dose’) + 1] * 4
where, total number of capsules consumed will be calculated as:
(total number of capsules dispensed) – (total number of capsules returned).
All study drug dosing information will be provided in a listing
7.4
Analysis of Efficacy
Not applicable


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7.5
Analysis of Safety
Safety analyses will be conducted using the SAF.
7.5.1
Adverse Events
AEs will be coded to system organ class and preferred term using the Medical Dictionary for 
Regulatory Authorities (MedDRA) and graded using NCI-CTCAE.
Treatment-emergent adverse events (TEAE) will be presented within each system organ class 
by preferred term, by relationship to study drug and by severity (NCI-CTCAE grade). AEs 
leading to dose reduction or temporary discontinuation of study drug, AEs leading to 
permanent discontinuation of study drug, SAEs, and SAEs by NCI-CTCAE grade will be 
summarized. AEs will also be summarized by NCI-CTCAE grade and relationship to study 
drug jointly.
All AEs data will be displayed in listings. In addition listings of deaths, SAEs, drug related 
AEs, AEs leading to dose reduction or temporary discontinuation of study drug and AEs 
leading to permanent discontinuation of study drug will be presented.
7.5.2
Clinical Laboratory Evaluations
Clinical laboratory evaluations (including hematology and serum chemistry) will be 
summarized for each visit using descriptive statistics. Change from baseline will also be 
summarized. As a baseline the last assessment before the first day of MDV3100 intake from 
the prior study will be used. Shift analysis tables will present shift from baseline to the same 
visits using the NCI-CTCAE grade and laboratory reference range indicator. All clinically 
significant abnormal laboratory values will be recorded as AEs and graded using NCI-
CTCAE guidelines.
Laboratory data will be listed for each test. Each laboratory result will be flagged as low (L), 
normal, or high (H) at each visit according to laboratory reference ranges. In addition a 
listing will be presented with the indicated subset of laboratory parameters,  if at least one of 
the following criteria is fulfilled:  ALT or AST >= 3xULN or Bilirubin >= 2.0 mg/dL 
(34.2 μmol/L) or Creatinine > 352 μmol/L (4.0 mg/dL).
7.5.3
Physical Examination
All clinically significant abnormal findings will be recorded as medical history or AEs and 
graded using NCI-CTCAE guidelines.
7.5.4
Vital Signs
Descriptive statistics will be presented for each vital sign measurement at each visit. Change 
from baseline will also be summarized. In addition for weight a frequency table indicating 
percentage change from baseline by category* will be provided. As a baseline the last 
assessment before the first day of MDV3100 intake from the prior study will be used.
Vital signs data will be provided in a data listing.


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*The percentage change will be categorized in 7 different categories, from loss >=20% up to 
gain >=20% (see TLF specifications for the other categories )
7.5.5
Electrocardiogram (ECG)
Overall ECG interpretation will be summarized for each visit. A shift analysis table showing 
shifts from baseline to each visit in overall ECG interpretation (normal, abnormal not 
clinically significant, and abnormal clinically significant) will be provided. As a baseline the 
last assessment before the first day of MDV3100 intake from the prior study will be used.
ECG data will be provided in a data listing.
7.6
Analysis of Pharmacokinetics
Not applicable.
7.7
Other Analyses
The Eastern Cooperative Oncology Group (ECOG) scale categorized as grade scores 0-5 will 
be used to assess performance status. The higher grade score of ECOG indicates the worse of 
the patient’s performance. Number and percentage of subjects with grade scores 0-5 will be 
tabulated at scheduled visits. A shift analysis table showing shifts from baseline to each 
scheduled visit in ECOG PS grade will be provided. In addition a shift analysis table showing 
shift from baseline to the highest ECOG PS grade during the extension study will be 
provided. As a baseline the last assessment before the first day of MDV3100 intake from the 
prior study will be used.
The ECOG performance status will be provided in a data listing
7.8
Interim Analysis (and Early Discontinuation of the Clinical Study)
Not applicable
7.9
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information
7.9.1
Missing Data
As a general principle, no imputations of missing data will be done. Exceptions are the 
following:

Partially missing date of initial diagnosis will be imputed to get the duration of 
prostate cancer. For an incomplete initial diagnosis date, the first day of the month 
and/or the 1st month of the year will be used.

The worst case scenario will be used in the estimation of partial dates for adverse 
events and concomitant medication. That is, for an incomplete start date the first day 
of the month or the first month of the year will be used (unless this leads to an 
estimated date before the date of first dose of study drug, which will be used in these 
cases) and for an incomplete stop date the last day of the month or the last month of 
the year will be used in order to assess whether an adverse event should be analyzed 


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as a TEAE or whether a medication should be analyzed as concomitant medication. 
Completely missing start or stop dates will not be estimated. Adverse events or 
medications with completely missing start date will be assumed to be non TEAEs or 
not concomitant, respectively.  Any stop date that is derived to be after death date or 
last observed date in the study (e.g. date of lost to follow up) will be set to the date of 
death or last observed date, respectively. The corresponding listings will always show 
the original date and time information.
7.9.2
Visit Windows
Visit windows are allowed for certain visits per the schedule of assessments. Subject data 
will not be excluded from analyses due to the subject’s failure to comply with the visit 
schedule. The visit windows for safety variables are described in the following table.
Table 2
Analysis visit window
Visit day interval
Scheduled visit
Analysis visit
Baseline
Baseline prior study
Baseline
Day 1*
Week 1
Day 1
Day 2 – Day 57
Week 5
Week 5 (Day 29)
Day 58 – Day 127
Week 13
Week 13 (Day 85)
Day 128 – Day 211
Week 25
Week 25 (Day 169)
Day 212 – Day 295
Week 37
Week 37 (Day 253)
Day 296 – Day 379
Week 49
Week 49 (Day 337)
Day 380 – Day 463
Week 61
Week 61 (Day 421)
Day 464 – Day 547
Week 73
Week 73 (Day 505)
Day 548 – Day 673
Week 85
Week 85 (Day 589)
Day 674 – Day 841
Week 109
Week 109 (Day 757) 
Day 842 – Day 1009   
Week 133
Week 133 (Day 925)
Similarly for follow-up visits
*Day 1 of extension; all day numbers are relative to day 1 of the extension study
In the case of multiple observations at a specific visit, the observation which is closest to the 
target date will be used.  If the observations have the same distance to the target visit, the 
latest one will be used.
All visit dates and times of dosing will be provided in a listing for each study period.


Sponsor: Astellas Pharma Europe B.V. (APEB)
SAP Final Version 1.0
ISN/Protocol  9785-CL-0121
08-Apr-2015
Astellas
Page 14 of 15
8
REFERENCES
ICH Harmonized Tripartite Guideline E 3. Structure and Content of Clinical Study Reports, 
November 1995. (www.ich.org; Guidelines; "Efficacy" Topics)
ICH Harmonized Tripartite Guideline E 9. Statistical Principles for Clinical Trials, February 1998. 
(www.ich.org; Guidelines; "Efficacy" Topics)
Investigators EDC Instruction Manual for protocol 9785-CL-0121; Internal Astellas document