Clinical trial NCT02091960
Conditions: HER2 Amplified Advanced Breast Cancer Human Epidermal Growth Factor Receptor 2 (HER2)
Keywords: Enzalutamide Trastuzumab Breast cancer HER2 Androgen receptor positive Xtandi
Sponsor: Astellas Pharma Global Development, Inc.
Start date: 2014-09-05; Completion date: 2024-01-30
Enrollment: 103 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study was to evaluate the efficacy of enzalutamide with trastuzumab in patients with HER2+ AR+ metastatic or locally advanced breast cancer.

Detailed description:

Arms: arm 1: Participants received 160 mg enzalutamide orally once daily and 6 mg/kg trastuzumab administered by intravenous infusion or subcutaneous injection every 21 days. Participants continued on treatment until disease progression, unacceptable toxicity or any other discontinuation criteria were met.
Interventions: intervention 1: Enzalutamide intervention 2: Trastuzumab
Intervention descriptions: intervention 1: Capsules for oral administration intervention 2: Intravenous infusion (IV) or subcutaneous injection if it is standard of care within a country

Protocol documents:
Prot_002.pdf: 
Sponsor: APGD 
ISN/Protocol 9785-CL-1121 
- CONFIDENTIAL - 
EudraCT number 2013-000093-29 
 
10 Jan 2023 
Astellas 
Page 1 of 96 
Version 7.1 Incorporating Nonsubstantial Amendment 2 
A Phase 2, Multicenter, Open-label Study to Assess the Efficacy 
and Safety of Enzalutamide with Trastuzumab in Subjects with 
HER2+ AR+ Metastatic or Locally Advanced Breast Cancer 
Protocol for Phase 2 Study of Enzalutamide 
ISN/Protocol 9785-CL-1121 
Version 7.1 
Incorporating Nonsubstantial Amendment 2 [See Attachment 1] 
10 Jan 2023 
 
IND 113,339 
EudraCT 2013-000093-29 
Sponsor: 
Astellas Pharma Global Development, Inc. (APGD) 
1 Astellas Way 
Northbrook, IL 60062 
 
 
 
Protocol History: 
Version 1.0 [18Dec2013] 
Version 2.0 [09Apr2014] Substantial Amendment 1 Local to Canada 
Version 3.0 [10Jun2014] Substantial Amendment 2 Local to United Kingdom 
Version 4.0 [06Oct2014] Substantial Amendment 3 Global 
Version 5.0 [10Jun2015] Substantial Amendment 4 Global 
Version 5.1 [17Apr2017] Nonsubstantial Amendment 1 Global 
Version 6.0 [09Aug2018] Substantial Amendment 5 Global  
Version 7.0 [30 Nov 2020] Substantial Amendment 6 Global 
 
-------------------------------------------------------------------------------------------------------------------------------------- 
This confidential document is the property of the Sponsor.  No unpublished information contained in this 
document may be disclosed without prior written approval of the Sponsor.  


Sponsor: APGD 
ISN/Protocol 9785-CL-1121 
- CONFIDENTIAL - 
EudraCT number 2013-000093-29 
 
10 Jan 2023 
Astellas 
Page 2 of 96 
Version 7.1 Incorporating Nonsubstantial Amendment 2 
Table of Contents 
I. 
SIGNATURES ································
································
······················
 8 
II. 
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL ····························
 10 
III. 
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS ··················
 11 
IV. 
SYNOPSIS ································
································
··························
 16 
V. 
FLOW CHART AND SCHEDULE OF ASSESSMENTS ································
· 29 
1 
INTRODUCTION ································
································
·················
 34 
1.1 
Background ································
································
····················
 34 
1.2 
Nonclinical and Clinical Data ································
·······························
 35 
1.2.1 
Nonclinical Studies ································
································
······  35 
1.2.1.1 
Pharmacology ································
································
······  35 
1.2.1.2 
Pharmacokinetics ································
································
··  36 
1.2.1.3 
Toxicology································
································
··········
 37 
1.2.2 
Clinical Studies ································
································
··········
 37 
1.2.2.1 
Pharmacokinetics ································
································
··  37 
1.3 
Summary of Key Safety Information for Study Drugs ································
···  38 
1.3.1 
Enzalutamide ································
································
·············
 38 
1.3.2 
Trastuzumab ································
································
·············
 40 
1.4 
Risk-Benefit Assessment ································
································
·····  40 
2 
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS ································
··  40 
2.1 
Study Objectives ································
································
··············
 40 
2.1.1 
Primary Objective ································
································
·······  40 
2.1.2 
Secondary Objectives ································
································
···  41 
2.1.3 
Exploratory Objectives ································
································
· 41 
2.2 
Study Design and Dose Rationale ································
···························
 41 
2.2.1 
Study Design ································
································
·············
 41 
2.2.2 
Dose Rationale ································
································
···········
 42 
2.3 
Endpoints ································
································
·······················
 42 
2.3.1 
Primary Endpoint ································
································
········  42 
2.3.2 
Secondary Endpoints ································
································
····  42 
2.3.2.1 
Efficacy Endpoints ································
································
 42 
2.3.2.2 
Safety Endpoints ································
································
···  43 
2.3.3 
Exploratory Endpoints ································
································
··  43 


Sponsor: APGD 
ISN/Protocol 9785-CL-1121 
- CONFIDENTIAL - 
EudraCT number 2013-000093-29 
 
10 Jan 2023 
Astellas 
Page 3 of 96 
Version 7.1 Incorporating Nonsubstantial Amendment 2 
2.3.3.1 
Pharmacokinetic Endpoints ································
·······················
 43 
2.3.3.2 
Pharmacodynamic Endpoints ································
····················
 43 
2.3.3.3 
··························
 43 
3 
STUDY POPULATION ································
································
··········
 44 
3.1 
Selection of Study Population ································
·······························
 44 
3.2 
Inclusion Criteria ································
································
··············
 44 
3.3 
Exclusion Criteria ································
································
·············
 46 
4 
TREATMENT(S) ································
································
··················
 48 
4.1 
Identification of Investigational Product(s) ································
················
 48 
4.1.1 
Test Drug(s) ································
································
··············
 48 
4.1.1.1 
Enzalutamide ································
································
·······  48 
4.1.1.2 
Trastuzumab ································
································
········  48 
4.1.2 
Comparative Drug(s) ································
································
····  49 
4.2 
Packaging and Labeling ································
································
······  49 
4.2.1 
Enzalutamide ································
································
·············
 49 
4.2.2 
Trastuzumab ································
································
·············
 49 
4.3 
Study Drug Handling ································
································
·········  49 
4.4 
Blinding ································
································
························
 50 
4.5 
Assignment and Allocation ································
································
··  50 
4.5.1 
Subject Registration ································
································
·····  50 
4.5.2 
Subject Enrollment ································
································
······  50 
4.5.3 
Definition of Treated Subject ································
··························
 50 
5 
TREATMENTS AND EVALUATION ································
························
 51 
5.1 
Dosing and Administration of Study Drug(s) and Other Medication(s) ················
 51 
5.1.1 
Dose/Dose Regimen and Administration Period ································
····  51 
5.1.1.1 
Enzalutamide ································
································
·······  51 
5.1.1.2 
Trastuzumab ································
································
········  51 
5.1.2 
Increase or Reduction in Dose of the Study Drug(s) ································
 51 
5.1.2.1 
Enzalutamide ································
································
·······  51 
5.1.2.2 
Trastuzumab ································
································
········  52 
5.1.3 
Previous and Concomitant Treatment (Medication and Nonmedication 
Therapy) ································
································
··················
 52 
5.1.4 
Treatment Compliance ································
································
··  53 
5.1.5 
Restrictions During the Study ································
··························
 53 
CCI


Sponsor: APGD 
ISN/Protocol 9785-CL-1121 
- CONFIDENTIAL - 
EudraCT number 2013-000093-29 
 
10 Jan 2023 
Astellas 
Page 4 of 96 
Version 7.1 Incorporating Nonsubstantial Amendment 2 
5.2 
Demographics and Baseline Characteristics ································
···············
 54 
5.2.1 
Demographics ································
································
············
 54 
5.2.2 
Medical History ································
································
··········
 54 
5.2.3 
Diagnosis of the Target Disease, Severity, and Duration of Disease ··············
 54 
5.2.4 
Androgen Receptor, Estrogen Receptor and Progesterone Receptor Status ······  54 
5.3 
Efficacy Assessment ································
································
··········
 55 
5.3.1 
Radiographic Disease Assessment ································
····················
 55 
5.3.2 
Disease Assessment Methods ································
··························
 55 
5.3.2.1 
Chest/Abdominal/Pelvic Imaging and Other Measurements ·················
 55 
5.3.2.2 
Brain Imaging ································
································
······  56 
5.3.2.3 
Bone Imaging ································
································
······  56 
5.3.2.4 
Cutaneous and Subcutaneous Lesions ································
···········
 56 
5.4 
Safety Assessment ································
································
············
 56 
5.4.1 
Height and Weight ································
································
······  56 
5.4.2 
Vital Signs ································
································
················
 56 
5.4.3 
Adverse Events ································
································
··········
 56 
5.4.3.1 
Adverse Events of Possible Hepatic Origin ································
····  56 
5.4.4 
Laboratory Assessments ································
································
 57 
5.4.5 
Physical Examination ································
································
···  57 
5.4.6 
Electrocardiogram (ECG) ································
······························
 57 
5.4.7 
Echocardiogram/MUGA ································
·······························
 57 
5.4.8 
Performance Status ································
································
······  57 
5.5 
Adverse Events and Other Safety Aspects ································
·················
 57 
5.5.1 
Definition of Adverse Events (AEs) ································
··················
 57 
5.5.2 
Definition of Serious Adverse Events································
·················
 58 
5.5.3 
Criteria for Causal Relationship to the Study Drug ································
· 59 
5.5.4 
Criteria for Defining the Severity of an Adverse Event ····························
 60 
5.5.5 
Reporting of Serious Adverse Events ································
·················
 60 
5.5.6 
Follow-up of Adverse Events ································
··························
 61 
5.5.7 
Monitoring of Common Serious Adverse Events ································
···  61 
5.5.8 
Procedure in Case of Pregnancy ································
·······················
 61 
5.5.9 
Emergency Procedures and Management of Overdose ·····························
 62 
5.5.10 
Supply of New Information Affecting the Conduct of the Study ··················
 62 
5.5.11 
Urgent Safety Measures ································
································
 63 
5.5.12 
Reporting Urgent Safety Measures ································
····················
 63 


Sponsor: APGD 
ISN/Protocol 9785-CL-1121 
- CONFIDENTIAL - 
EudraCT number 2013-000093-29 
 
10 Jan 2023 
Astellas 
Page 5 of 96 
Version 7.1 Incorporating Nonsubstantial Amendment 2 
5.6 
Test Drug Concentration ································
································
·····  63 
5.6.1 
Pharmacokinetic Assessments ································
·························
 63 
5.7 
Other Measurements, Assessments or Methods ································
···········
 64 
5.7.1 
Pharmacodynamic Assessments ································
·······················
 64 
5.7.1.1 
Endocrine and Circulating Tumor Markers ································
·····  64 
5.7.1.2 
 ································
·········  64 
5.7.2 
Sample for the Analysis of Genes Related to Pharmacokinetics, Efficacy, 
and/or Safety ································
································
·············
 64 
5.7.3 
Blood Sample for Future Pharmacogenomic Analysis (Retrospective 
Pharmacogenomic Analysis) ································
···························
 65 
5.8 
Total Amount of Blood ································
································
·······  65 
6 
DISCONTINUATION ································
································
············
 66 
6.1 
Discontinuation of Individual Subject(s) ································
···················
 66 
6.2 
Discontinuation of the Site ································
································
···  66 
6.3 
Discontinuation of the Study································
································
· 67 
7 
STATISTICAL METHODOLOGY ································
···························
 67 
7.1 
Sample Size ································
································
····················
 67 
7.2 
Analysis Set ································
································
····················
 67 
7.2.1 
Full Analysis Set (FAS) ································
································
 68 
7.2.2 
Efficacy Evaluable Set (EES) ································
··························
 68 
7.2.3 
Per Protocol Set (PPS) ································
································
··  68 
7.2.4 
Safety Analysis Set (SAF) ································
······························
 68 
7.2.5 
Pharmacokinetic Analysis Set (PKAS) ································
···············
 68 
7.2.6 
Pharmacodynamic Analysis Set (PDAS) ································
·············
 68 
7.3 
Demographics and Other Baseline Characteristics ································
········  68 
7.4 
Analysis of Efficacy ································
································
··········
 68 
7.4.1 
Analysis of Primary Endpoint ································
·························
 69 
7.4.1.1 
Primary Analysis ································
································
···  69 
7.4.1.2 
Secondary Analysis ································
································
 69 
7.4.1.3 
Subgroup Analysis ································
································
· 69 
7.4.2 
Analysis of Secondary Endpoints ································
·····················
 69 
7.4.3 
Analysis of Exploratory Endpoints ································
····················
 69 
7.5 
Analysis of Safety ································
································
·············
 69 
7.5.1 
Adverse Events ································
································
··········
 69 
CCI


Sponsor: APGD 
ISN/Protocol 9785-CL-1121 
- CONFIDENTIAL - 
EudraCT number 2013-000093-29 
 
10 Jan 2023 
Astellas 
Page 6 of 96 
Version 7.1 Incorporating Nonsubstantial Amendment 2 
7.5.2 
Laboratory Assessments ································
································
 70 
7.5.3 
Vital Signs ································
································
················
 70 
7.5.4 
ECGs ································
································
······················
 70 
7.5.5 
LVEF ································
································
·····················
 70 
7.6 
Analysis of Pharmacokinetics ································
·······························
 70 
7.6.1 
Estimation of Pharmacokinetic Parameters ································
··········
 70 
7.6.2 
Concentration-Response Relationship Analysis ································
·····  70 
7.7 
Analysis of Pharmacodynamics ································
·····························
 70 
7.7.1 
Pharmacodynamic Analyses ································
···························
 70 
7.7.2 
es ································
···  71 
7.8 
Protocol Deviations and Other Analyses ································
···················
 71 
7.9 
Interim Analysis (and Early Discontinuation of the Clinical Study) ····················
 71 
7.10 
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········  71 
8 
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS ····················
 72 
8.1 
Procedure for Clinical Study Quality Control ································
·············
 72 
8.1.1 
Data Collection ································
································
··········
 72 
8.1.2 
Specification of Source Documents ································
···················
 72 
8.1.3 
Clinical Study Monitoring ································
······························
 73 
8.1.4 
Direct Access to Source Data/Documents ································
············
 74 
8.1.5 
Data Management ································
································
·······  74 
8.1.6 
Protocol Deviations ································
································
·····  74 
8.1.7 
End of Trial in All Participating Countries ································
···········
 75 
8.2 
Ethics and Protection of Subject Confidentiality ································
··········
 75 
8.2.1 
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC)/Competent Authorities (CA) ································
···················
 75 
8.2.2 
Ethical Conduct of the Study ································
···························
 75 
8.2.3 
Informed Consent of Subjects ································
·························
 76 
8.2.3.1 
Subject Information and Consent ································
················
 76 
8.2.3.2 
Supply of New and Important Information Influencing the Subject’s 
Consent and Revision of the Written Information ·····························
 76 
8.2.4 
Subject Confidentiality ································
································
· 76 
8.3 
Administrative Matters ································
································
·······  77 
8.3.1 
Arrangement for Use of Information and Publication of the Clinical Study ·····  77 
8.3.2 
Documents and Records Related to the Clinical Study ·····························
 77 
8.3.3 
Protocol Amendment and/or Revision ································
················
 78 
CCI


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8.3.4 
Insurance of Subjects and Others ································
······················
 78 
8.3.5 
Signatory Investigator for Clinical Study Report ································
····  78 
9 
QUALITY ASSURANCE ································
································
········  78 
10 
STUDY ORGANIZATION ································
································
······  79 
10.1 
Independent Data-Monitoring Committee (IDMC) | Data and Safety Monitoring 
Board (DSMB) ································
································
················
 79 
10.2 
Other Study Organization ································
································
····  79 
11 
REFERENCES ································
································
····················
 80 
12 
APPENDICES ································
································
·····················
 82 
12.1 
List of Excluded Concomitant Medications································
················
 82 
12.2 
Liver Safety Monitoring and Assessment ································
··················
 83 
12.3 
Common Serious Adverse Events ································
···························
 86 
12.4 
Retrospective Pharmacogenomic Sub-Study ································
··············
 87 
12.5 
ECOG Performance Status ································
································
···  89 
12.6 
RECIST 1.1 Criteria ································
································
··········
 90 
12.7 
Laboratory Assessments ································
································
······  93 
13 
ATTACHMENT 1:  NONSUBSTANTIAL AMENDMENT 2 ····························
 94 
14 
SPONSOR’S SIGNATURE ································
································
·····  96 
 
List of Tables 
Table 1 
Schedule of Assessments ································
································
·····  31 
Table 2 
Effect of Enzalutamide and Trastuzumab on Her2-amplified Breast Cancer Cell 
Lines ································
································
····························
 36 
Table 3 
Evaluation of Target Lesions ································
································
 91 
Table 4 
Evaluation of Nontarget Lesions ································
····························
 91 
Table 5 
Evaluation of New Lesions ································
································
··  91 
Table 6 
Time Point Response ································
································
·········  91 
Table 7 
Best Overall Response ································
································
········  92 
 


Sponsor: APGD 
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I. 
SIGNATURES 
1. 
SPONSOR’S SIGNATURES 
Required signatures (e.g., Protocol authors, Sponsor’s reviewers and contributors, etc.) are 
located in Section 14, Sponsor Signatures; e-signatures (when applicable) are located at the 
end of this document.  


Sponsor: APGD 
ISN/Protocol 9785-CL-1121 
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10 Jan 2023 
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2. 
INVESTIGATOR’S SIGNATURE 
A Phase 2, Multicenter, Open-label Study to Assess the Efficacy and Safety of 
Enzalutamide with Trastuzumab in Subjects with HER2+ AR+ Metastatic or 
Locally Advanced Breast Cancer 
ISN/Protocol 9785-CL-1121   
Version 7.1 
Incorporating Nonsubstantial Amendment 2  
10 Jan 2023 
I have read all pages of this clinical study protocol for which Astellas is the Sponsor. I agree to 
conduct the study as outlined in the protocol and to comply with all the terms and conditions set 
out therein. I confirm that I will conduct the study in accordance with International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good 
Clinical Practice (GCP) guidelines and applicable local regulations. I will also ensure that 
Subinvestigator(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  
 
Address: 
 
 
 
 
 
 
 
 
 
 
 


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II. 
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL 
24h-Contact for 
Serious Adverse 
Events (SAEs) 
 
See Section 5.5.5 
Please fax or email the SAE Worksheet to: 
Astellas Pharma Global Development, Inc.  
Product Safety & Pharmacovigilance 
Fax numbers:  
  
 
 
 
Medical Monitor/ 
Medical Expert: 
 
 
Astellas Pharma Global Development, Inc. 
 
 
Clinical Research 
Contact: 
 
 
Astellas Pharma, Inc. 
 
 
 
PPD
PPD
PPD
PPD
PPD


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III. 
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS 
List of Abbreviations 
Abbreviations 
Description of abbreviations 
AE 
Adverse event 
AI 
Adrenal insufficiency 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase (GPT) 
ANC 
Absolute neutrophil count 
APEBV 
Astellas Pharma Europe B.V. 
APGD 
Astellas Pharma Global Development, Inc. 
AR 
Androgen receptor 
AREC 
Astellas ethical committee 
AST 
Aspartate aminotransferase (GOT) 
AUC 
Area under the concentration curve 
AUST 
Astellas United States Technologies 
BORR 
Best overall response rate 
CA 
Competent authority 
CBR 
Clinical benefit rate 
CR 
Complete response 
CRO 
Contract research organization 
CRF 
Case report form 
CRPC 
Castration-resistant prostate cancer 
CSR 
Clinical study report 
CT 
Computed tomography 
Ctrough 
Trough concentration 
CTx 
Chemotherapy 
CYP 
Cytochrome P450 
D 
Day 
DHT 
Dihydrotestosterone 
DILI 
Drug-induced liver injury 
DOR 
Duration of response 
DLT 
Dose limiting toxicity 
DNA 
Deoxyribonucleic acid 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
Echo 
Echocardiogram 
ECLIA 
Electrochemiluminescence immunoassay 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
eCTD 
Electronic common technical document 
EDC 
Electronic data capture 
EDTA 
Ethylenediaminetetraacetic acid 


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Abbreviations 
Description of abbreviations 
EOT 
End of treatment 
ER 
Estrogen receptor 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FDG-PET 
Fluorodeoxyglucose positron emission tomography 
FOXA1 
Forkhead box protein A1 
FSH 
Follicle stimulating hormone 
FU 
Follow-up 
GABA 
Gamma aminobutyric acid 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practices 
GnRH 
Gonadotropin releasing hormone 
GWAS 
Genome-Wide Association Studies 
HBsAg 
Hepatitis B surface antigen 
hCG 
Human chorionic gonadotropin 
HER2  
or HER2/neu 
Human epidermal growth factor receptor 2 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH  
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IDMC 
Independent data monitoring committee 
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 
IMPD 
Investigational Medicinal Product Dossier 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRT 
Interactive response technology 
ISH 
in situ hybridization 
ISN 
International study number 
IUD 
Intrauterine device 
IUS 
Intrauterine system 
IV 
Intravenous 
J-NDA 
Japanese new drug application 
LABC 
Locally advanced breast cancer 
LA-CRF 
Liver abnormality case report form 
LC-MS/MS 
liquid chromatography – tandem mass spectrometry 
LFT 
Liver function tests or liver function testing 
LH 
Luteinizing hormone 
LHRH 
Luteinizing hormone releasing hormone 


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Abbreviations 
Description of abbreviations 
LVEF 
Left ventricular ejection fraction 
M 
Month 
MAA 
Marketing Authorisation Application 
MBC 
Metastatic breast cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
MPS 
Myocardial perfusion scintigraphy 
MRI 
Magnetic resonance imaging 
MUGA 
Multi-gated acquisition scan 
N/A 
Not applicable 
NASH 
Nonalcoholic steatohepatitis 
NCI CTCAE 
National Cancer Institute Common Toxicity Criteria for Adverse Events 
NDA 
New Drug Application 
NE 
Not evaluated 
NYHA 
New York Heart Association 
OPT 
Optional 
ORR 
Overall response rate 
PD 
Pharmacodynamic or progressive disease 
PDAS 
Pharmacodynamic analysis set 
PET 
Positron emission tomography 
PFS 
Progression free survival 
PGx 
Pharmacogenomics 
PgR 
Progesterone receptor 
PHI 
Protected health information 
PK 
Pharmacokinetic 
PKAS 
Pharmacokinetic analysis set 
PPS 
Per protocol set 
PR 
Partial response 
PT 
Preferred term 
Q 
Quarter or every 
RBC 
Red blood cell 
RECIST 
Response evaluation criteria in solid tumors 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SD 
Stable disease 
SDF-1 
Stromal cell-derived factor 1 
SHBG 
Sex hormone binding globulin 
sHER2 
Serum HER2 
SPC 
Summary of Product Characteristics 
SOC 
System organ class 
SOP 
Standard operating procedure 
T 
Testosterone 


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Abbreviations 
Description of abbreviations 
t½ 
Apparent terminal elimination half-life 
TEAE 
Treatment emergent adverse event 
TBL 
Total bilirubin 
TLF 
Tables listings figures 
tmax 
Time after dosing when Cmax occurs 
TMF 
Trial master file 
TNBC 
Triple negative breast cancer 
TTP 
Time to progression 
TTR 
Time to response 
Tx 
Treatment 
ULN 
Upper limit of normal 
UNSCH 
Unscheduled 
USM 
Urgent safety measure 
W 
Week 
WHO 
World Health Organization 
%ΔTM 
Percent change in tumor measurement 
 


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Definition of Key Study Terms 
Terms 
Definition of terms 
Baseline  
Observed values/findings which are regarded observed starting point for 
comparison. For this study, unless otherwise specified, Baseline finding are 
the findings observed just prior to the first dose of study drug (enzalutamide 
or trastuzumab). 
Enroll 
To enter into a clinical trial in order to begin treatment. Informed consent 
precedes enrollment. 
Investigational 
period 
Period of time where major interests of protocol objectives are observed, and 
where the test drug or comparative drug is usually given to a subject, and 
continues until the last assessment after completing administration of the test 
drug or comparative drug. The Investigational period for this trial is from the 
time of enrollment through the end of treatment. 
Post investigational 
period 
Period of time after the Investigational period. Follow-up observations for 
sustained adverse events and/or survival are done in this period. 
Screening period 
Period of time before entering the investigational period, usually from the 
time of starting a subject signing consent until enrollment.  
Screening 
Process for checking the eligibility of subjects usually done during the 
Screening Period and prior to Enrollment. 
Screen failure 
Subject that was screened but did not fulfill protocol inclusion and/or 
exclusion criteria and failed to receive study treatment, or decided not to 
participate anymore (withdrew consent) prior to completing 
preinvestigational period. 
Study drug 
Agents given as part of the clinical trial. In this study, enzalutamide and 
trastuzumab are study drugs. 
Study period 
Period of time beginning with the first subject consented through to the last 
observation collected for the study. 
Variable 
Any quantity, attribute, phenomenon or event that can have different 
qualitative or quantitative values. 
 


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IV. 
SYNOPSIS 
Date and Version of Protocol Synopsis: 
10 Jan 2023, Version 7.1 
Sponsor:   
Astellas Pharma Global Development Inc (APGD) 
Protocol Number:   
9785-CL-1121 
Name of Study Drugs:  
enzalutamide and trastuzumab 
Phase of Development:   
Phase 2 
Title of Study: 
A Phase 2, Multicenter, Open-label Study to Assess the Efficacy and Safety of Enzalutamide  
with Trastuzumab in Subjects with HER2+ AR+ Metastatic or Locally Advanced Breast Cancer  
Planned Study Period:  
From 2Q2014 to 1Q2025 
Study Objective(s):  
Primary Objective: 
To evaluate the efficacy of enzalutamide with trastuzumab in evaluable subjects with human 
epidermal growth factor receptor 2 positive (HER2+) and androgen receptor positive (AR+) 
metastatic or locally advanced breast cancer, as measured by Clinical Benefit Rate (CBR) (defined 
as the proportion of evaluable subjects with best objective response of confirmed CR or PR per 
RECIST 1.1, or prolonged SD (≥ 24 weeks).  
Secondary Objectives: 
● 
To evaluate the following efficacy measures: 
o Best Overall Response Rate (BORR) 
o Overall Response Rate (ORR) at 24 weeks 
o Progression Free Survival (PFS) 
o Time to Progression (TTP) 
o Duration of Response (DOR)  
o Time to Response (TTR) 
● 
To evaluate safety and tolerability. 
Exploratory Objectives: 
● 
 
  
 
  
  
 
 
 
 
Planned Total Number of Study Centers and Location(s):   
Approximately 55 centers 
North America and Europe 
Study Population:  
Female subjects with HER2+ and AR+ metastatic or locally advanced breast cancer who have 
progressed on at least 1 prior line of anti-HER2 therapy in the metastatic or advanced setting. 
Subjects may be either ER/PgR positive or negative according to the local assessment for hormone 
receptor diagnostics. A line of therapy is defined as a course of treatment at the end of which there 
CCI


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Version 7.1 Incorporating Nonsubstantial Amendment 2 
was disease progression toxicity, or in the Investigator’s opinion, maximum benefit has been 
achieved. 
 


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Number of Subjects to be Enrolled/Randomized:   
Approximately 80 subjects were planned to be enrolled to reach 66 evaluable AR+ subjects. 
103 subjects were actually enrolled in the study. 
Study Design Overview:   
This is a multinational, multicenter, open-label, single-arm, 2-stage, Phase 2 study evaluating the 
efficacy, safety, and tolerability of enzalutamide with trastuzumab. A Simon’s 2-stage design is 
implemented to allow for early termination if < 3 of 21 evaluable AR+ subjects show clinical 
benefit [confirmed complete response (CR), partial response (PR) according to Response 
Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria or prolonged stable disease (SD) 
≥ 24weeks] at the analysis of the first stage. If ≥ 3 of 21 evaluable AR+ subjects show clinical 
benefit, then a second stage will continue to enroll a total of 66 evaluable AR+ subjects.  
Subjects will enter the screening period up to 28 days prior to treatment start. Subjects will be 
allowed to prescreen under a separate consent form to enable testing of archival tissue for AR 
expression before initiation of other screening activities. After completion of screening 
assessments, eligible subjects will enter into the treatment phase to receive enzalutamide with 
trastuzumab. Study visits will take place every 3 weeks until week 16, then at weeks, 25, 34, 40, 
and 49, and then every 12 weeks thereafter until the subject meets discontinuation criteria or the 
study ends. Tumor assessments will be performed every 8 weeks up to week 49, and then every 
12 weeks thereafter. Subjects will continue on treatment until disease progression, unacceptable 
toxicity, or any other discontinuation criteria are met.  
Upon discontinuation of study drug, subjects will enter the follow-up period. An end of treatment 
visit will be performed within 7 days of the last dose of enzalutamide. The Follow-up Visit will be 
performed approximately 30 days after the last dose of enzalutamide or before initiation of 
subsequent treatment (whichever is first); this visit may be conducted by phone call if the subject is 
unable to return to the clinic. The treatment emergent period will be defined as the period of time 
from the first dose date of study drug to 30 days after the last dose date of study drug or the start of 
subsequent treatment (whichever occurs first). All adverse events (AEs) that occur during the 
collection period are to be followed until resolved or judged to be no longer clinically significant, 
or until they become chronic to the extent that they can be fully characterized. 
If the study is terminated early for reasons other than safety, and the subject is receiving clinical 
benefit per Investigator’s judgment, the subject may continue on study medication until they have 
disease progression as defined per RECIST. 
Inclusion/Exclusion Criteria:   
Inclusion: 
1. The subject has consented and signed an Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) approved written Informed Consent and privacy language as per national 
regulations (e.g., Health Insurance Portability and Accountability Act [HIPAA] for U.S. sites) 
prior to any study-related procedures (including withdrawal of prohibited medication, if 
applicable). 
2. The subject is a female ≥ 18 years of age. 
3. The subject has histologically or cytologically proven adenocarcinoma of the breast that is 
HER2+ defined as a score of 3+ for staining by immunohistochemistry (IHC), or IHC 2+ with 
HER2 gene amplification as determined by a locally approved in situ hybridization (ISH) 
assay, or (for patients without IHC data) HER2 gene amplification. 
 


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Inclusion continued 
4. The subject has AR+ breast cancer, which is defined as any tumor cells with nuclear AR 
staining by immunohistochemistry (IHC). Enrollment may be based on the local pathologist’s 
findings; however, tissue will be sent to a central pathology laboratory for assessment. NOTE: 
If a subject is enrolled in the study based on local pathologist results, but subsequent central 
assessment cannot confirm AR+ disease, the subject may remain in the study.    
5. The subject has metastatic disease or has locally advanced disease that is not amendable to 
curative treatment. 
6. The subject has measurable disease or nonmeasurable, evaluable disease per RECIST 1.1 
(NOTE:  pleural effusions, ascites or other third fluid space are not evaluable diseases per 
RECIST 1.1).  
7. The subject has received at least 1 line of therapy in the metastatic or locally advanced disease 
setting:    
● A line of therapy is defined as a course of treatment at the end of which there was 
disease progression, toxicity, or in the Investigator’s opinion, maximum benefit has 
been achieved. If the subject discontinued therapy due to any other reason but 
progressed without receiving other treatment, this would be considered a line of 
therapy.  
● The subject has been documented to have progressed by determination of the 
Investigator on a regimen containing an anti-HER2 agent (includes trastuzumab 
emtansine in countries where it is not approved) as the most recent regimen or the most 
recent anti-HER2 regimen was discontinued for any toxicity, with the exception of a 
cardiotoxicity.  
● Subjects who received < 28 days of therapy in the most recent regimen may be eligible 
upon approval from the medical monitor.     
● The subject progressed on a trastuzumab containing regimen. If progression occurred 
within 12 months after completing trastuzumab-containing adjuvant treatment, this 
counts as having received trastuzumab but not as a line of therapy.  
8. The subject has adequately recovered from toxicities due to prior therapy. 
9. The subject has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 at 
Screening and Day 1. 
10. The subject has available at the site a representative, formalin-fixed, paraffin-embedded, 
tumor specimen that enabled the definitive diagnosis of breast cancer with adequate viable 
tumor cells in a tissue block (preferred) or ≥ 10 (20 preferred) freshly cut, unstained, serial 
slides and the associated pathology report: 
● Archival tissue from the most recent biopsy available is preferred. 
● For subjects who are known AR+ per local pathology report, a fresh biopsy can be 
done per Investigator’s discretion, to obtain tissue for central AR confirmation if the 
archival specimen is insufficient or unavailable.  
● Cytological or fine-needle aspiration samples are not acceptable. 
11. The subject has an estimated life expectancy of at least 6 months at Day 1, in the opinion of 
the Investigator. 


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Inclusion continued 
12. The subject is either: 
● Of nonchildbearing potential: 
o postmenopausal (defined as no spontaneous menses for at least 12 months prior 
to Screening with FSH > 40 IU/L for women < 55 years of age at Screening),  
o documented surgically sterile or status post hysterectomy (at least 1 month prior 
to Screening), or  
● Or, if of childbearing potential,  
o must agree to not try to become pregnant during the study and for 5 half-lives 
(29 days) after the final study drug administration  
o must have a negative urine pregnancy test at Screening and at Day 1 before the 
first dose of study drug is administered, 
o must use 2 acceptable methods of birth control starting at Screening and through 
6 months after the final study drug administration. 
The 2 acceptable methods of birth control are as follows or per local guidelines where these 
require additional description of contraceptive methods: 
● A barrier method (e.g., condom by a male partner) is required;  
AND 
● One of the following is required: 
o Placement of an intrauterine device (IUD) or intrauterine system (IUS);  
o Additional barrier method including occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/suppository; 
o Vasectomy or other surgical castration at least 6 months before Screening. 
13. The subject must not be breastfeeding at Screening or during the study period, and for 6 
months after the final study drug administration. 
14. The subject must be able to swallow enzalutamide and comply with study requirements.  
15. The subject agrees not to participate in another interventional study while on treatment 
Waivers to the inclusion criteria will NOT be allowed. 
Exclusion: 
Subject will be excluded from participation if any of the following apply: 
1. The subject has a severe concurrent disease, infection, or comorbidity that, in the judgment of 
the Investigator, would make the subject inappropriate for enrollment. 
2. The subject has current or previously treated brain metastasis or active leptomeningeal disease. 
Brain imaging is required during screening in all subjects to exclude the presence of 
unequivocal central nervous system disease. 
3. The subject has a history of a nonbreast cancer malignancy with the following exceptions:  
● The subject with a previous history of a noninvasive carcinoma is eligible if in the 
opinion of the Investigator he/she has had successful curative treatment any time prior 
to Screening. 
● For all other malignancies, the subject is eligible if they have undergone potentially 
curative therapy and they have been considered disease free for at least 5 years prior to 
Screening. 


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Exclusion continued 
4. The subject has inadequate marrow, hepatic, and/or renal function at the Screening Visit 
defined as: 
● Absolute neutrophil count < 1.5 x109/L (< 1500 cells/mm3) 
● Platelet count < 75 x109/L (< 75,000 cells/mm3) 
● Hemoglobin < 5.6 mmol/L (< 9 g/dL) 
● Total bilirubin > 1.5 x Upper Limit of Normal (ULN) unless there is an alternate 
nonmalignant etiology (e.g., Gilbert’s syndrome). 
● Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 x ULN (or > 5 
x ULN if hepatic metastasis is present). 
● Creatinine > 1.5 x ULN or Glomerular Filtration Rate (eGFR)/Creatinine Clearance 
(CrCL) < 30 mL/min, whichever is more restrictive. 
● NOTE:  May not have received any growth factors or blood transfusions within 7 days 
before the hematology values obtained at screening 
5. The subject has a history of seizure or any condition that may predispose to seizure (e.g., prior 
cortical stroke, significant brain trauma). 
6. The subject has a history of loss of consciousness, cerebrovascular accident or transient 
ischemic attack within 12 months before the Day 1 visit. 
7. The subject has had a hypoglycemic episode requiring medical intervention while on insulin (or 
other anti-diabetic) treatment within 12 months before Day 1. 
8. The subject has clinically significant cardiovascular disease including: 
● Myocardial infarction within 6 months before the Day 1 visit.  
● Uncontrolled angina within 6 months before the Day 1 visit. 
● Congestive heart failure New York Heart Association (NYHA) Class III or IV or history  
of congestive heart failure NYHA Class III or IV in the past, unless a screening echo-
cardiogram, myocardial perfusion scintigraphy (MPS), or multi-gated acquisition scan 
performed within 3 months before the Day 1 visit reveals a left ventricular ejection 
fraction that is ≥ 50%. 
● History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, 
ventricular fibrillation, Torsade de Pointes). 
● History of Mobitz II second degree or third degree heart block without a permanent 
pacemaker in place. 
● Hypotension as indicated by systolic blood pressure < 86 mmHg on 2 consecutive 
measurements at the Screening visit. 
● Bradycardia (in the presence of known cardiovascular disease) as indicated by a heart 
rate of < 50 beats per minute on the Screening electrocardiogram (ECG) recording. 
● Uncontrolled hypertension as indicated by systolic blood pressure > 170 mmHg or 
diastolic blood pressure > 105 mmHg on 2 consecutive measurements at the Screening 
visit. 
9. The subject has significant respiratory disease, including severe dyspnea at rest due to 
complications of advanced malignancy or requiring supplementary oxygen therapy.  
10. The subject has an active gastrointestinal disorder affecting absorption (e.g., gastrectomy, 
active peptic ulcer disease) within the 3 months prior to the Day 1 visit. 
11. The subject had a major surgical procedure, substantial open biopsy, or significant traumatic 
experience within 28 days before the Day 1 visit, or anticipation of need for major surgical 
procedure during the course of the study. 


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12. The subject has had palliative radiation therapy to bone metastases within 14 days prior to the 
Day 1 visit (side effects from radiation must be resolved). 
 
Exclusion continued 
13. The subject has received chemotherapy, immunotherapy, or any other systemic anti-cancer 
therapy, with the exception of anti-HER2 therapy (e.g., trastuzumab and trastuzumab 
emtansine), within 14 days prior to the Day 1 visit.  
14. The subject has been treated with any investigational drugs within 14 days prior to the Day 1 
visit. 
15. The subject has received treatment with any approved or investigational agent that either 
blocks androgen synthesis or targets the AR (e.g., abiraterone acetate, bicalutamide, 
enzalutamide, TAK-448, TAK-683, TAK-700, ARN-509, ODM-201, BMS-641988). Subjects 
who received treatment for < 28 days or placebo on an investigational study are acceptable. 
16. The subject would, in the Investigator’s opinion, benefit from estrogen receptor targeted 
therapy while on study.  
17. The subject has used any of the following within 28 days before the Day 1 visit: 
● 5-α reductase inhibitors 
● Systemic androgens and estrogens 
18. The subject has a known history of positive test for Hepatitis B surface antigen (HBsAg) or 
hepatitis C antibody or history of positive test for Human Immunodeficiency Virus (HIV). 
19. The subject has shown a hypersensitivity reaction to the active pharmaceutical ingredient or 
any of the enzalutamide capsule components, including Labrasol, butylated hydroxyanisole 
and butylated hydroxytoluene. 
20. The subject has had a severe infusion reaction to trastuzumab or hypersensitivity to 
trastuzumab, and excipients including murine proteins, L-histidine, L-histidine hydrochloride 
monohydrate, α,α-trehalose dehydrate, L-methionine, and polysorbate. 
21. The subject has any other condition or reason that, in the opinion of the Investigator, would 
make the subject ineligible to receive trastuzumab, interferes with the ability of the subject to 
participate in the trial, places the subject at undue risk, or complicates the interpretation of 
safety data.  
Waivers to the exclusion criteria will NOT be allowed. 
Investigational Product(s): 
Enzalutamide 40 mg soft gelatin capsules 
Trastuzumab 150 mg lyophilized sterile powder 
Dose(s):   
Enzalutamide 160 mg/day. 
Trastuzumab infusion: 6 mg/kg every 21 days. For subjects whose last dose of anti-HER2 antibody 
was greater than 21 days prior to Day 1 or for subjects who were on weekly trastuzumab for 
≤ 2 weeks, a loading dose of 8 mg/kg will be administered on Day 1, followed by 6 mg/kg every 
21 days thereafter. 
Trastuzumab subcutaneous: 600mg/5mL q3 weeks 
Mode of Administration: 
Enzalutamide capsules are administered orally with or without food. 


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Trastuzumab Infusion: Intravenous (IV) infusion is given over 30-90 minutes. For a loading dose, a 
90 minute IV infusion is given or per local label. 
Sub-cutaneous: subcutaneous injections should be given per local label. 
 
Comparative Drug(s): 
Not applicable. 
Dose(s): 
Not applicable. 
Mode of Administration: 
Not applicable. 
Concomitant Medication Restrictions or Requirements: 
Medications taken within 14 days before the Screening visit and up to the 30 Day Follow-Up visit 
will be documented on the appropriate case report form as concomitant medication.  
All concomitant medication(s) must be reported on the appropriate case report form. Prior and 
concomitant medications include all vitamins, herbal remedies, over the counter, and prescription 
medications.  
Concomitant administration of bisphosphonates or bone targeting agents are acceptable if the 
subject is on a stable regimen (per Investigator’s judgement) prior to Day 1. The Investigator 
should consult with Medical Monitor if new use of bone-targeting agents is deemed necessary 
during the study. 
Concomitant administration of enzalutamide with strong cytochrome P450 (CYP)2C8 inhibitors, 
strong or moderate CYP2C8 inducers, strong or moderate CYP3A4 inducers should be avoided. 
Concomitant use of enzalutamide with narrow therapeutic index drugs that are metabolized by 
CYP3A4, CYP2C9, and CYP2C19 should be avoided. 
Subjects should avoid use of any herbal medications or dietary supplements including products 
containing Hypericum perforatum (e.g., St. John’s Wort). 
The following medications or therapies are prohibited during the receipt of study drug: 
● Medications, including herbal therapies, with an antitumor effect (medications used to induce 
menopause in women of child-bearing potential and are permitted). 
● Any investigational agent 
● AR antagonists (e.g., bicalutamide, flutamide, nilutamide) 
● 5-α reductase inhibitors (e.g., finasteride, dutasteride) 
● Systemic androgens and estrogens (vaginal estrogen creams are allowed) 
● Megestrol acetate for appetite stimulation may be used at Investigator’s discretion.  
If it is anticipated that the subject may require radiation (e.g., painful boney metastases), 
Investigators are encouraged to have subjects complete any radiation therapy prior to entering the 
study, as concomitant radiation therapy may be cause for discontinuation from the study. During 
the course of the study the Medical Monitor must be contacted for approval prior to initiation of 
any radiation. 
Duration of Treatment:   
Until disease progression, unacceptable toxicity, or any other discontinuation criteria are met. 
Formal Stopping Rules: 
A Simon’s 2-stage design is implemented to allow for termination if < 3 of 21 evaluable AR+ 
subjects show clinical benefit (defined as subjects with best objective response of confirmed CR or 


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PR per RECIST 1.1, or prolonged SD (≥ 24 weeks). If ≥ 3 of 21 evaluable AR+ subjects show 
clinical benefit, approximately 45 additional evaluable AR+ subjects will be enrolled, for a total of 
66 evaluable AR+ subjects. Recruitment in Stage 1 will not be suspended to evaluate interim data.   


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Endpoints for Evaluation:   
Primary 
CBR defined as the proportion of evaluable subjects with best objective response of confirmed CR 
or PR per RECIST 1.1 criteria, or prolonged SD (≥ 24 weeks). 
Secondary 
Efficacy Endpoints: 
● ORR (CR+PR) at 24 weeks according to RECIST 1.1 criteria. 
● BORR according to RECIST 1.1.  
● PFS is defined as the time from the date of first dose of enzalutamide (Study Day 1) until the 
date of disease progression per RECIST 1.1or death from any cause on study, whichever 
occurs first.  
● TTP is defined as the time from the first date of enzalutamide treatment until the date of 
disease progression per RECIST 1.1.  
● DOR is defined as the time from the date first documentation of response (CR or PR) until the 
date of disease progression per RECIST 1.1. 
● TTR is defined as the time from the first date of enzalutamide treatment to initial CR or PR. 
Safety Endpoints: 
Safety will be assessed on an ongoing basis by physical examination, measurement of vital signs, 
laboratory assessments, 12-lead ECGs, LVEF by echocardiogram or multi-gated acquisition scan 
(MUGA), and evaluation of AEs/serious adverse events. 
Exploratory 
 
 
 
 
 
 
 
  
 
 
 
 
Statistical Methods: 
Sample Size Justification:  
The sample size is sufficient to determine the absence or presence of an efficacy signal. The sample 
sizes for the first and second stage were determined using Simon’s 2-stage design. The null 
hypothesis that the true CBR is 10% will be tested against a 1-sided alternative at a 5% significance 
level. In the first stage, 21 evaluable AR+ subjects will be evaluated; the study will stop if < 3 
evaluable subjects show confirmed CR or PR per RECIST 1.1, or prolonged SD (≥ 24 weeks). 
Otherwise, the study will continue to enroll up to 66 evaluable AR+ subjects. This design has a 
statistical power of 90% when the true CBR is 25%. To illustrate the precision with a total of 66 
subjects: if the observed CBR is 40%, then the 90% confidence interval will be within the 30% to 
50% range. 
CCI


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Taking into account an anticipated number of nonevaluable subjects, approximately 80 subjects 
were planned to be enrolled to achieve a data set with at least 66 evaluable AR+ subjects.  
 
Efficacy:   
The Efficacy Evaluable Set (EES) is a subset of the FAS defined as all enrolled subjects who have 
centrally assessed AR+ (defined as > 10% of tumor cells with nuclear expression), received at least 
1 dose of study drug, and have at least 1 available post baseline tumor assessment. 
The primary analyses will be done in the EES, while all efficacy analyses will be done in both the 
EES and Full Analysis Set (FAS). If more than 5 subjects are enrolled into the study but had less 
than 10% of tumor cells with nuclear expression, and received at least 1 dose of study drug, the 
efficacy analyses will also be conducted in this subset of FAS. Further details will be presented in 
the statistical analysis plan. Subjects whose disease is not confirmed to be AR+ upon central 
review may stay on study; however, they will not contribute to the primary and secondary efficacy 
analyses. 
All variables will be presented as descriptive statistics. CBR, ORR, and BORR will be summarized 
including 95% 2-sided confidence intervals. 
Kaplan-Meier methods will be used to estimate PFS, TTP, TTR, and DOR. 
Pharmacokinetics:   
PK analyses will be conducted using the pharmacokinetic analysis set (PKAS). The PKAS is 
defined as the subset of the safety analysis set (SAF) population for which at least 1 quantifiable 
enzalutamide N-desmethyl enzalutamide, or trastuzumab concentration value after Week 4 is 
available.  
The enzalutamide, N-desmethyl enzalutamide, and trastuzumab concentration-time data will be 
summarized by descriptive statistics at each visit. Additional model-based analyses may be 
performed but will be reported separately. 
Pharmacodynamics: 
Pharmacodynamic: 
Circulating hormones and protein markers will be expressed as the change in absolute value and 
percent change from baseline at each visit and presented using descriptive statistics. 
Additional model-based analyses to explore PK-PD relationships may be performed. 
 
 
 
 
 
 
 
Safety: 
Safety analyses will be conducted using the Safety Analysis Set (SAF). The SAF is defined as all 
subjects who have received at least partial or full dose of study drug. The treatment emergent 
period will be defined as the period of time from the first dose date of study drug to 30 days after 
the last dose date of study drug or the start of subsequent treatment (whichever is first). Safety will 
be assessed through descriptive statistics for the frequency of AEs by system organ class (SOC), 
preferred term (PT), and National Cancer Institute Common Terminology Criteria for Adverse 
CCI


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Events (NCI CTCAE) grade, the frequency of treatment discontinuations due to AEs, vital signs, 
ECG, LVEF, and laboratory evaluations.  


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The severity of all AEs is to be evaluated by the Investigator based on the NCI CTCAE, version 
4.03. All AEs will be coded to preferred term and system organ class using Medical Dictionary for 
Regulatory Activities (MedDRA). The number and percentage of subjects with treatment emergent 
adverse events will be presented by MedDRA system organ class and preferred term, relationship 
to study treatment, and NCI CTCAE grade. A subject reporting the same AE more than once is 
counted once and at the maximum severity or strongest relationship to study drug treatment, when 
calculating incidence.  
Laboratory data consist of hematology, chemistry, coagulation, and urine dipstick laboratory test 
results. Where applicable, NCI CTCAE version 4.03 will be used to categorize toxicity grades for 
the laboratory parameters. Laboratory shift tables compared to baseline results for each subsequent 
visit will be produced. For each laboratory parameter, the baseline laboratory value is defined as 
the last laboratory value collected on or prior to the first dose date of enzalutamide. 
Interim Analyses:  
Recruitment will continue if there are 3 or more subjects with clinical benefit in the first 21 
evaluable AR+ subjects from the evaluable set. If there are less than 3 subjects who demonstrate 
confirmed CR or PR per RECIST 1.1, or prolonged SD ≥ 24 weeks (using all available data), 
recruitment will be stopped.  
 


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V. 
FLOW CHART AND SCHEDULE OF ASSESSMENTS 
Flow Chart  
 
Footnotes appear on next page 


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AR+ = androgen receptor positive, BORR = best overall response rate, CBR = clinical benefit rate, CT = computed tomography, CTx = chemotherapy, D = day,  
DOR = duration of response, Echo = echocardiogram, EOT = end of treatment, HER2+ = human epithelial growth factor receptor positive, LABC = locally advanced breast cancer, M 
= month, MBC = metastatic breast cancer, MPS= Myocardial Perfusion Scintigraphy, MRI = magnetic resonance imaging, MUGA = multi-gated acquisition scan, ORR = overall 
response rate, PFS = progression free survival, PK = pharmacokinetics, Q = every, TTP = time to progression, Tx = treatment,  
W = week, %ΔTM = percent change in tumor measurements. 


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Table 1 
Schedule of Assessments 
Assessments 
Prescreen 
Screen 
Treatment 
Follow-up 
Study Week/Visit 
Prior to 
screen 
-4  
to -1 
1 
4 
7 
10 
13 
16 
25  
34 
40 
49 and 
Q12W 
UNSCH 
EOT 
30D FU1 
Study Day 
N/A 
-28  
to -1 
1 
22 
43 
64 
85 
106 
169 
232 
274 
337+ 
N/A 
≤ 7D after 
last dose 
30D after 
last dose 
Window (days) 
N/A 
N/A 
0 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
N/A 
N/A 
+7 
Informed Consent 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Initial AR expression testing2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Return and/or Dispense Enzalutamide 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X [OPT] 
X 
 
Trastuzumab administration 
 
 
To be administered Q3W 
 
 
 
Concomitant Medications3 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Demographics, Medical and Disease 
History  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Radiographic Disease Assessment4 
 
X 
To be performed Q8W (+/- 10 D) 
X 
X [OPT] 
 
 
Brain Imaging5 
 
X 
 
 
 
 
 
X [OPT] 
 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
X 
 
 
 
X 
 
X 
X 
X 
X 
X [OPT] 
X 
 
Vital Signs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X [OPT] 
X 
 
Adverse Events6 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Laboratory Tests7 
 
X8 
X9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X [OPT] 
X 
 
Urine Pregnancy Test10 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X [OPT] 
X 
X 
Physical Examination11 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-Lead ECG12 
 
X 
To be performed Q12W (+/- 14D) or according to local guidelines 
X [OPT] 
X 
 
Echocardiogram/MUGA/MPS 
 
X 
To be performed Q12W (+/- 14D) or according to local guidelines 
X [OPT] 
 
 
ECOG PS 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X [OPT] 
X 
 
Circulating Endocrine and Other 
Protein Markers13 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
PK Samples14 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Dosing Diary Review15 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Tumor Tissue Collection for Central 
Testing16 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Sample for Genotype Analysis17 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Optional PGx Sample18 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Footnotes appear on next page 


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Abbreviations: CT = computed tomography, D = day, DOR = duration of response, Echo = echocardiogram, ECG = electrocardiogram, EOT = end of treatment,  
FU = follow-up, MPS= Myocardial Perfusion Scintigraphy, MRI = magnetic resonance imaging, MUGA = multi-gated acquisition scan, N/A = not applicable,  
OPT = optional, PGx = pharmacogenomic, PK = pharmacokinetic, Q = every, UNSCH = unscheduled, W = week 
1. Phone call may be conducted only if subject is unable to return to the clinic. Follow-up visit should occur approximately 30 days following the last dose of study drug, or 
before initiation of subsequent treatment (whichever is first).  
2. Testing of archival tissue for AR expression can be done before initiation of other screening activities under a separate prescreen consent form. Results for AR expression 
from local pathology can be used for enrollment.   
3. Medications taken within 14 days before the Screening visit and up to 30 Day-Follow-up visit will be collected.  
4. CT/MRI of the chest/abdomen/pelvis as well as any other anatomical region appropriate for that subject’s disease must be performed within 28 days prior to day 1. Results 
from CT/MRI assessments performed prior to consent and within 28 days of day 1 may be used for screening if available. All subjects should have bone imaging to assess 
metastasis to the bone within 6 months prior to the Day 1 visit. Thereafter, subjects without bone metastasis will have bone scans only if clinically indicated. PR and CR 
require confirmation with equivalent or improved assessment no less than 4 weeks after the date of scan that PR or CR was first observed. 
a. Subjects with suspected bone-only, measurable lesions must have bone lesions assessed by CT with bone windows or by MRI within 12 weeks before Day 1. 
Thereafter, measureable lytic lesions should be followed as target lesions according to RECIST 1.1 using the same method. 
b. Subjects with suspected bone-only, nonmeasurable disease should have had a bone assessment (e.g., scintigraphy or skeletal survey) performed within 12 weeks 
before Day 1. 
c. Imaging of nonmeasurable, evaluable disease should be performed as clinically indicated, with a required assessment at Week 24. 
d. Cutaneous and subcutaneous lesions should be assessed by physical examination with digital photographs that must include a metric ruler in the image. Photographs 
should be obtained in such a manner to protect subject privacy. 
5. Brain imaging is required at Screening for all subjects to rule out central nervous system disease. A brain MRI with contrast enhancement is required unless it cannot be 
performed within 2 weeks prior to Day 1 due to feasibility or subject-specific contraindications. A head CT may be performed in these situations after discussion with the 
medical monitor or designee. Results from brain imaging performed prior to consent and within 28 days of Day 1 may be used for screening if available. Additional 
imaging to rule out CNS metastases should be performed as clinically indicated. 
6. Adverse Events will be collected from the time of informed consent through 30 days following last dose of study drug or through the day prior to initiation of alternate 
treatment (whichever occurs first).  
7. Clinical Laboratory Assessments include hematology, chemistry, and local urine dipstick. Coagulation panel will be performed at Screening for all subjects and only at 
each visit if subject is on anti-coagulant therapy. 
8. Local FSH testing is required at screening for postmenopausal women who are < 55 years of age. 
9. Day 1 clinical laboratory tests do not need to be repeated if Screening labs were performed within 7 days prior to Day 1. 
10. Urine pregnancy test will be performed in women of child-bearing potential. Testing at treatment visits must occur prior to study drug administration.  
11. Physical exam performed prior to ICF and within 7 days of the screening visit may be used for screening if available. 
Footnotes continued on next page 


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12. All on-treatment ECGs will be obtained prior to drug administration. In addition, whenever a study procedure coincides with the scheduled time point for an ECG, the 
study activities should be undertaken in a fixed sequence if possible: ECGs first, vital signs second, and any type of blood draw as the last assessment. 
13. Blood samples to measure circulating endocrine levels and other protein markers will be obtained. Blood sample should be obtained prior to study drug administration at 
the Day 1 visit and at approximately the same time of day at each following visit. 
14. Predose plasma PK samples will be collected prior to enzalutamide intake and will be analyzed for enzalutamide and N-desmethyl enzalutamide. Predose serum PK 
samples will be collected prior to the start of the trastuzumab infusion and will be analyzed for trastuzumab. Enzalutamide and trastuzumab will be administered in clinic 
on PK days.  
15. A dosing diary will be dispensed to the subject on Day 1. Date and time of enzalutamide dose will be recorded in the diary by the subject for the 2 days prior to each PK 
sample. 
16. All subjects are required to have tissue sample available to send for central lab confirmation of AR expression at screening visit.  
17. A blood sample is taken to allow evaluation of potential AR mutations and another sample is taken to allow for genotype analysis of relevant metabolism, transporter, PD, 
and/or safety genes, in the event of unusual PK/PD patterns or safety findings. 
18. Optional exploratory retrospective, PGx for those subjects who consent to the sub-study. 


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1 
INTRODUCTION 
1.1 
Background 
Breast cancer is one of the most frequently diagnosed malignancies and the second most 
common cause of cancer deaths in women, despite improvements in screening and treatment 
regimens. According to the American Cancer Society, about 1.4 million women are 
diagnosed with breast cancer annually worldwide and about 458,400 will die from the 
disease [American Cancer Society, 2011]. In the United States, approximately 1 in 8 women 
(12%) will develop invasive breast cancer over their lifetimes, and about 39,510 women 
annually will die from the disease [Siegel et al, 2011].  
Breast cancer is genetically heterogeneous and biologically diverse and it is no longer 
considered a single disease. The long recognized clinical and phenotypic differences have 
been shown to correlate with differences at the gene expression level [Sørlie et al, 2004; 
Perou et al, 2000]. Five distinct breast cancer molecular subtypes are defined by hierarchical 
cluster analyses of array gene expression data; they include luminal A, luminal B, human 
epidermal growth factor receptor 2 (HER2) amplified, basal-like and normal-like [Goldhirsch 
et al, 2011]. 
Approximately 20% of all breast cancers have gene amplification or overexpression (or both) 
of human epidermal growth factor receptor 2 (HER2), a tyrosine kinase transmembrane 
receptor, resulting in a more aggressive phenotype and a poor prognosis. Treatment with the 
anti-HER2 humanized monoclonal antibody trastuzumab in addition to chemotherapy, as 
compared with chemotherapy alone, significantly improves progression-free and overall 
survival among patients with HER2-positive metastatic breast cancer. Trastuzumab binds to 
subdomain intravenous (IV) infusion of the HER2 extracellular domain and exerts its 
antitumor effects by blocking HER2 cleavage, stimulating antibody-dependent, cell-mediated 
cytotoxicity and inhibiting ligand-independent, HER2-mediated mitogenic signaling. 
However, in most patients with HER2-positive metastatic breast cancer, the disease 
progresses, highlighting the need for new targeted therapies for advanced disease [Baselga et 
al, 2012] 
Expression of the androgen receptor (AR) has been observed in the majority of breast cancer 
specimens. In studies evaluating over 3,000 breast tumor specimens, AR expression was 
observed in 77% of invasive breast tumors and its expression was observed across all 
molecular phenotypes [Collins et al, 2011; Goldhirsch et al, 2011; Niemeier et al, 2010]. In 
invasive carcinomas, AR expression was identified in 89% of luminal A, 66% of luminal B, 
54% of HER2 amplified, 31% of triple negative breast cancer (TNBC) and 35% of 
unclassified breast cancers [Collins et al, 2011; Niemeier et al, 2010]. The role of AR 
signaling in patients with AR-positive (AR+) breast cancer remains to be elucidated through 
well conducted studies using selective and potent AR signaling inhibitors. 
AR expression has been identified in over 50% of patients with HER2 positive/hormone 
receptor negative disease [Hu et al, 2011; Park et al, 2010]. An evaluation of published 
microarray data from 3 patient sets demonstrated that AR gene expression levels correlated 


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with HER2 amplification/ overexpression [Ni et al, 2011]. This is consistent with 
immunohistochemistry (IHC) observations of AR expression correlating with HER2 
overexpression [Niemeier et al, 2010; Park et al, 2010; Agoff et al, 2003]. Prolonged AR 
stimulation in an AR+ cell line where ER is absent and HER2 is expressed but not amplified 
(MDA-MB-453) resulted in activation of HER2/HER3 signaling. Bicalutamide reversed this 
activation via reduction of total and phosphorylated HER3 protein and inhibited growth.  The 
combination of lapatinib (a tyrosine kinase inhibitor with activity against HER1 and HER2) 
and bicalutamide was more active than either agent alone [Brown, 2011]. In vivo, 
dihydro-testosterone (DHT) enhanced tumor growth while bicalutamide caused tumor 
regression [Ni et al, 2011].  A similar mechanism of action may be occurring in AR+/ER- 
cell lines where HER2 is amplified.  In BT474 cells (AR+/ER-/HER2+amplified), DHT 
treatment increases both total and phospho-HER3 protein [Richer AACR Advances in Breast 
Cancer meeting, 03 Oct, 2013].  In addition, the combination of enzalutamide and 
trastuzumab can reverse HER3 activation better than either agent alone and reduce cell 
growth [Richer AACR Advances in Breast Cancer meeting, 03 Oct, 2013] 
Clinical evaluations of agents that interfere with HER2/HER3 crosstalk in patients with 
HER2 amplified breast cancer have yielded promising results [Baselga et al, 2012]. The 
combination of pertuzumab plus trastuzumab plus docetaxel, as compared with placebo plus 
trastuzumab plus docetaxel, when used as first-line treatment for HER2-positive metastatic 
breast cancer, significantly prolonged progression-free survival, with no increase in cardiac 
toxic effects. The median progression-free survival was 12.4 months in the control group, as 
compared with 18.5 months in the pertuzumab group. The interim analysis of overall survival 
showed a strong trend in favor of pertuzumab plus trastuzumab plus docetaxel.  Median 
overall survival was 37.6 months in the placebo group but had not been reached in the 
pertuzumab group [Swain et al, 2013]. Taken together, these data warrant further clinical 
investigation of a possible link between AR and growth factor pathways in AR+/HER2+ 
breast cancer. The primary pharmacodynamic (PD) effect of enzalutamide is inhibition of the 
AR signaling pathway. Medivation and APGD are in a partnership to co-develop 
enzalutamide for the treatment of breast cancer.  
1.2 
Nonclinical and Clinical Data 
1.2.1 
Nonclinical Studies 
1.2.1.1 Pharmacology 
The primary PD effect of enzalutamide is inhibition of the AR signaling pathway. Primary 
PD has been defined in experiments that demonstrated inhibition of AR binding, inhibition of 
AR nuclear translocation, inhibition of AR chromatin association, inhibition of AR-
dependent transcription and cancer cell proliferation, induction of cell death and tumor 
regression, and lack of agonist activity. On the whole, nonclinical data on the primary PD of 
enzalutamide shows that it is a potent AR inhibitor, and further that it is distinct from other 
anti-androgens in affecting multiple points in the AR signaling pathway. 


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A major human metabolite of enzalutamide, N-desmethyl enzalutamide, demonstrated key 
primary PD of similar potency to the parent molecule.  
Two luminal AR+ and ER+ breast cancer cell lines, MCF7 and BCK4, were shown to 
proliferate in response to AR stimulation with DHT. Enzalutamide inhibited DHT-mediated 
cell growth in both cell lines. Enzalutamide also inhibited estradiol-mediated cell growth of 
MCF7 and BCK4 cells. In contrast, bicalutamide did not inhibit estradiol-mediated cell 
growth of MCF7 cells. Consistent with the inhibitory effect on estradiol-induced cell growth, 
enzalutamide also blocked estradiol-stimulated expression of 3 genes: Stromal Cell-Derived 
Factor-1 (SDF-1), the progesterone receptor (PgR), and the AR. As enzalutamide does not 
block binding of estradiol to the ER, these data suggest that AR and ER crosstalk, and AR 
signaling inhibition with enzalutamide has a dominant negative role on ER signaling. In 
AR+, ER-negative (ER-) breast cancer cells (MDA-kb2), enzalutamide inhibits DHT-induced 
viability at 10 μM.  
The effect of enzalutamide on several Her2-amplified cell lines was evaluated in vitro. In 
some cases, DHT could enhance the growth of these cell lines. In the cell lines tested, either 
enzalutamide or trastuzumab inhibited cell growth in the presence or absence of DHT. In the 
cases where DHT was present, enzalutamide reduced cell number below nonDHT-treated 
levels. A similar observation was made with trastuzumab.  When cells were treated with both 
agents, a further reduction in cell number was observed. The results are summarized in the 
table below. 
Table 2 
Effect of Enzalutamide and Trastuzumab on Her2-amplified Breast 
Cancer Cell Lines 
Cell line 
Receptor Status 
Stimulated by DHT 
Enz 
Tras 
Enz + Tras 
SK-BR-3 
ER-/PgR- 
NT 
R 
R 
E 
SUM225* 
ER-/PgR- 
Y 
R 
R 
E 
ZR-75-30* 
ER+/PgR- 
N 
R 
R 
E 
UACC812 
ER+/PgR+ 
NT 
R 
NT 
NT 
BT-474* 
ER+/PgR+ 
Y 
R 
R 
E 
*Tested in the presence of DHT, Enz-enzalutamide, Tras-trastuzumab, R-reduced cell number, E-enhanced 
reduction in cell number beyond Enz or Tras alone, NT-not tested 
Please refer to the Investigator’s Brochure for more information. 
1.2.1.2 Pharmacokinetics 
Following oral administration in animals, enzalutamide is eliminated slowly from plasma 
with a long t1/2 across species. In vitro studies show that enzalutamide is metabolized by 
human recombinant cytochrome P450 (CYP) isoenzymes CYP2C8 and CYP3A4/5. 
Enzalutamide and/or its major human metabolites caused direct in vitro inhibition of multiple 
CYP enzymes including CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4/5; 
however, subsequent clinical data showed that enzalutamide is an inducer of CYP2C9, 
CYP2C19 and CYP3A4/5 and had no clinically meaningful effect on CYP2C8 (see 
Section 1.2.2.1). In vitro, enzalutamide caused time-dependent inhibition of CYP1A2. Based 


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on in vitro data, enzalutamide is a potential inducer of CYP3A4 and is not expected to induce 
CYP1A2 at therapeutically relevant concentrations. 
In vitro data show that enzalutamide and its active metabolite N-desmethyl enzalutamide are 
potential inhibitors, but not substrates, of the efflux transporter P-glycoprotein (P-gp).  
Please refer to the Investigator’s Brochure for more information. 
1.2.1.3 Toxicology  
The species included in the toxicity program were mice, rats, dogs and cynomolgus monkeys.  
Electrocardiogram (ECG) and cardiovascular assessments in a toxicity study in dogs showed 
no treatment related effects. In vivo and in vitro safety pharmacology studies also 
demonstrated the absence of cardiovascular enzalutamide-related effects. 
Enzalutamide was non mutagenic in bacteria, nonclastogenic in mammalian cells and non 
genotoxic in vivo in mice. The 2 major human metabolites (N-desmethyl enzalutamide and 
an inactive carboxylic acid derivative) and a minor metabolite (M6) were negative for 
mutagenicity in the bacterial reverse mutation assay (Ames). 
Overall, enzalutamide was generally well tolerated in pivotal nonclinical studies with rats and 
dogs with the most prominent effects occurring in reproductive and hormone-sensitive 
tissues. 
Please refer to the Investigator’s Brochure for more information. 
1.2.2 
Clinical Studies 
1.2.2.1 Pharmacokinetics 
The pharmacokinetics (PK) of oral enzalutamide is being investigated in a Phase 1 study in 
women with advanced breast cancer (MDV3100-08, NCT01597193). Preliminary data 
demonstrate similar PK of enzalutamide and N-desmethyl enzalutamide in women relative to 
men with CRPC. 
The PK and metabolism of enzalutamide have been evaluated in more than 2500 patients 
with prostate cancer and in more than 200 volunteers, including healthy male subjects and 
subjects with mild or moderate hepatic impairment. Individual daily doses have ranged from 
30 to 600 mg.  
Oral absorption of enzalutamide, whether administered as single or multiple doses, is rapid 
and independent of dose. Peak concentration of enzalutamide is generally achieved 1 to 
2 hours post dose in both patients and healthy subjects. Enzalutamide is well absorbed 
(estimated bioavailability based on mass balance data ≥ 84.2%). The mean t1/2 is 5.8 days, 
and does not appear to be affected by dose. With daily administration, it takes approximately 
1 month to reach steady state. The accumulation ratio is 8.3-fold. At steady state, 
enzalutamide shows approximately dose proportional PK over the range of 30 to 600 mg/day. 
A mass balance and biotransformation study in healthy male volunteers showed that 
enzalutamide is primarily eliminated by hepatic metabolism.  


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A food-effects study showed that food does not have a clinically relevant effect on AUC of 
enzalutamide or N-desmethyl enzalutamide; therefore, enzalutamide can be taken with or 
without food. 
A hepatic impairment study showed that the composite area under the curve (AUC) of 
enzalutamide plus N-desmethyl enzalutamide after single-dose enzalutamide was similar in 
subjects with baseline mild or moderate hepatic impairment (Child-Pugh Class A and B, 
respectively) relative to subjects with normal hepatic function, and no starting dose 
adjustment is needed.  
A clinical drug-drug interaction study showed that enzalutamide can affect exposures to other 
co-medications. At steady state, enzalutamide did not have a clinically significant effect on 
exposure to pioglitazone (CYP2C8 substrate). Steady-state enzalutamide reduced the AUC of 
midazolam (CYP3A4 substrate), S-warfarin (CYP2C9 substrate) and omeprazole (CYP2C19 
substrate) by 86%, 56% and 70%, respectively. Therefore, enzalutamide is a strong CYP3A4 
inducer and a moderate CYP2C9 and CYP2C19 inducer. Substrates of CYP3A4, CYP2C9 
and CYP2C19 with a narrow therapeutic index are to be avoided, as enzalutamide may 
decrease plasma exposure of these drugs.  
Another clinical drug-drug interaction study showed that concomitant medications can affect 
exposure to enzalutamide. Coadministration of gemfibrozil (a strong CYP2C8 inhibitor) 
increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold; 
therefore, strong CYP2C8 inhibitors are to be avoided. If coadministration with a strong 
CYP2C8 inhibitor is necessary, the dose of enzalutamide is to be reduced to 80 mg once 
daily. Coadministration of itraconazole (strong CYP3A4 inhibitor) increased the composite 
AUC of enzalutamide plus N-desmethyl enzalutamide by 1.3-fold; as this small change is not 
clinically meaningful, no starting dose adjustment is needed when coadministering 
enzalutamide with CYP3A4 inhibitors.  
Strong or moderate inducers of CYP3A4 or CYP2C8 are to be avoided as they can alter the 
plasma exposure to enzalutamide plus N-desmethyl enzalutamide. 
1.3 
Summary of Key Safety Information for Study Drugs 
1.3.1 
Enzalutamide 
To date, limited safety data are available from the ongoing Phase 1 study of enzalutamide in 
women with breast cancer (MDV3100-08, NCT01597193). The dose-escalation portion of the 
study evaluated 80 and 160 mg/day, and 160 mg/day was determined to be the recommended 
Phase 2 dose. The dose-expansion portion of this study is evaluating enzalutamide at 
160 mg/day as a single agent in women with AR+ breast cancer, and enzalutamide at 
160 mg/day in combination with either anastrozole or exemestane in women with ER+ breast 
cancer. Preliminary data suggest a similar safety profile to that observed in men.  In addition, 
enzalutamide is being evaluated in a Phase 2, single-arm, open-label study in AR+ TNBC 
patients, MDV3100-11 (NCT01889238), and in a Phase 2, randomized, double-blind, 
placebo-controlled study in combination with exemestane in ER+/PgR+ HER2-normal breast 
cancer patients, MDV3100-12.  


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As of 28 Feb 2015, over 3000 patients with prostate cancer, over 300 women with breast 
cancer and over 250 subjects with no known cancer, including healthy male subjects and 
subjects with hepatic impairment, have received at least 1 dose of enzalutamide in completed 
and ongoing clinical studies.  
Enzalutamide 160 mg daily was generally well-tolerated in subjects with CRPC. The adverse 
events (AEs) occurring in at least 5% of the enzalutamide group and at an incidence at least 
2% greater than in the placebo group included fatigue (37% vs. 30%), arthralgia (21% vs. 
17%), diarrhea (20% vs. 18%), hot flush (20% vs. 10%), peripheral edema (16% vs. 13%), 
musculoskeletal pain (14% vs. 12%), headache (12% v 6%), muscular weakness (9% vs. 
7%), insomnia (9% vs. 6%), hematuria (7% vs. 5%), hypertension (6% vs. 3%) and 
pollakiuria (5% vs. 3%). 
Other AEs reported less commonly than 5% but that may be associated with enzalutamide 
treatment after careful assessment of the AEs include: falls (4.5% vs. 1.3%), nonpathologic 
facture (4.0% vs. 0.8%), dry skin (3.6% vs. 1.3%) and pruritus (3.3% vs. 1.3%). A possible 
cognitive effect of enzalutamide was observed with a greater proportion of patients in the 
enzalutamide-treated group (4.5% vs. 1.8%) reporting the following AE terms: memory 
impairment, cognitive disorder, amnesia, disturbance of attention and dementia. In addition, 
event terms related to hallucination (visual hallucination, tactile hallucination, hallucination) 
were reported more frequently in the enzalutamide-treated group (1.6% vs. 0.3%). 
In clinical studies, seizure was identified as a risk associated with enzalutamide treatment. In 
the controlled clinical study CRPC2, seizures occurred in 0.9% (7/800) of patients receiving 
enzalutamide 160 mg daily, whereas no seizures occurred in patients treated with placebo. 
Confounding factors may have contributed to the occurrence of seizures in several of these 
cases. Dose appears to be an important predictor of seizure, with a greater risk of seizure at 
daily doses higher than 160 mg. In a dose escalation study involving 140 patients, no patients 
experienced seizures at or below daily doses of 240 mg, whereas 3 seizures were reported, 
1 each at 360, 480 and 600 mg/day. Caution should be used in administering enzalutamide to 
patients with a history of seizures or other predisposing factors including, but not limited to, 
underlying brain injury, stroke, primary brain tumors or brain metastases or alcoholism. In 
addition, the risk of seizure may be increased in patients receiving concomitant medications 
that may lower the seizure threshold. Enzalutamide should be permanently discontinued in 
patients who have a seizure while on treatment. 
Enzalutamide should not be administered to any patient who has shown a hypersensitivity 
reaction to the active pharmaceutical ingredient or any of the enzalutamide capsule 
components, including Labrasol, butylated hydroxyanisole and butylated hydroxytoluene. 
Concomitant administration of enzalutamide with strong CYP2C8 inhibitors, strong or 
moderate CYP2C8 inducers, strong or moderate CYP3A4 inducers should be avoided. 
Concomitant use of enzalutamide with narrow therapeutic index drugs that are metabolized 
by CYP3A4, CYP2C9, and CYP2C19 should be avoided. Subjects should avoid use of any 
herbal medications or dietary supplements including products containing Hypericum 
perforatum (e.g., St. John’s Wort). 


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Food has no clinically significant effect on the extent of absorption. Enzalutamide may be 
taken with or without food. 
1.3.2 
Trastuzumab 
Signs and symptoms of cardiotoxicity and cardiac dysfunction have been observed in patients 
treated with Trastuzumab, especially when used concurrently with anthracyclines. 
Please refer to local prescribing information for key safety information. 
1.4 
Risk-Benefit Assessment 
Although new therapies are available for patients with metastatic HER2+ breast cancer, this 
still remains an unmet medical need as patients will eventually progress on their treatments 
[Lin et al, 2004]. 
Enzalutamide given at 160 mg/day has been evaluated and found to be well tolerated in a 
Phase 3 study in men with prostate cancer. It is the dose approved by the Food and Drug 
Administration (FDA) and European Medicinal Agency (EMA) for use in men with 
castration-resistant prostate cancer after chemotherapy.  
A Phase 1 dose escalation study in women with Stage IV and locally advanced unresectable 
breast cancer is ongoing. The dose of 160 mg daily has been found tolerable according to the 
protocol dose escalation criteria. To date, enzalutamide has been generally safe and well 
tolerated in breast cancer subjects. 
This Phase 2 study represents a proof-of-concept study in women with HER2+/AR+ breast 
cancer. The patient population selected for this study is a standard population for the 
assessment of safety, tolerability, PK and anti-tumor activity in a Phase 2 breast cancer 
setting.  
Restricting the HER2+ population to AR+ patients is to minimize exposure to potential 
toxicities in patients least likely to benefit from enzalutamide. Moreover, this study will 
enroll subjects who would be receiving a HER2-targeting agent (e.g., trastuzumab 
monotherapy) as part of their standard of care treatment. 
2 
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS 
2.1 
Study Objectives 
2.1.1 
Primary Objective 
To evaluate the efficacy of enzalutamide with trastuzumab in evaluable subjects with human 
epidermal growth factor receptor 2 positive (HER2+) and androgen receptor positive (AR+) 
metastatic or locally advanced breast cancer, as measured by Clinical Benefit Rate (CBR) 
[defined as the proportion of evaluable subjects with best objective response of confirmed CR 
or PR per RECIST 1.1, or prolonged SD (≥ 24 weeks)].   


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2.1.2 
Secondary Objectives 
● 
To evaluate the following efficacy measures: 
o 
Best Overall Response Rate (BORR) 
o 
Overall Response Rate (ORR) at 24 weeks 
o 
Progression Free Survival (PFS) 
o 
Time to Progression (TTP) 
o 
Duration of Response (DOR)  
o 
Time to Response (TTR) 
● 
To evaluate safety and tolerability. 
2.1.3 
Exploratory Objectives 
 
 
  
 
 
  
 
 
 
 
2.2 
Study Design and Dose Rationale 
2.2.1 
Study Design 
This is a multinational, multicenter, open-label, single-arm, 2-stage, Phase 2 study evaluating 
the efficacy, safety, and tolerability of enzalutamide with trastuzumab. The study population 
includes female subjects with HER2+ and AR+ metastatic or locally advanced breast cancer 
who have progressed on at least 1 prior line of anti-HER2 therapy in the metastatic or 
advanced setting. Subjects may be either ER/PgR positive or negative according to the local 
assessment for hormone receptor diagnostics. A line of therapy is defined as a course of 
treatment at the end of which there was disease progression, toxicity, or in the Investigator’s 
opinion, maximum benefit has been achieved. Approximately 55 centers in North America 
and Europe will conduct the study. Approximately 80 subjects were planned to be enrolled to 
reach 66 evaluable AR+ subjects. 103 subjects were actually enrolled in the study. 
A Simon’s 2-stage design is implemented to allow for early termination if < 3 of 21 evaluable 
AR+ subjects show clinical benefit [confirmed complete response (CR), partial response (PR) 
according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, criteria or 
prolonged stable disease (SD) ≥ 24 weeks] at the analysis of the first stage. If ≥ 3 of 
21 evaluable AR+ subjects show clinical benefit, then a second stage will continue to enroll a 
total of 66 evaluable AR+ subjects. 
Subjects will enter the screening period up to 28 days prior to treatment start. Subjects will be 
allowed to prescreen under a separate consent form to enable testing of archival tissue for AR 
expression before initiation of other screening activities. After completion of screening 
assessments, eligible subjects will enter into the treatment phase to receive enzalutamide with 
trastuzumab. Study visits will take place every 3 weeks until week 16, then at weeks 25, 34, 
CCI


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40, and 49, and then every 12 weeks thereafter until the subject meets discontinuation criteria 
or the study ends.  Tumor assessments will be performed every 8 weeks through week 49, 
and then every 12 weeks thereafter. Subjects will continue on treatment until disease 
progression, unacceptable toxicity, or any other discontinuation criteria are met. Upon 
discontinuation of study drug, subjects will enter the follow-up period. An end of treatment 
visit will be performed within 7 days of the last dose of enzalutamide. The Follow-up Visit 
will be performed 30 days after the last dose of enzalutamide or before initiation of 
subsequent treatment (whichever occurs first); this visit may be conducted by phone call if 
the subject is unable to return to the clinic. The treatment emergent period will be defined as 
the period of time from the first dose date of study drug to 30 days after the last dose date of 
study drug or the start of subsequent treatment (whichever occurs first). All AEs that occur 
during the collection period are to be followed up until resolved or judged to be no longer 
clinically significant, or until they become chronic to the extent that they can be fully 
characterized. 
If the study is terminated early for reasons other than safety, and the subject is receiving 
clinical benefit per Investigator’s judgment, the subject may continue on study medication 
until they have disease progression as defined per RECIST. 
2.2.2 
Dose Rationale 
Enzalutamide given at 160 mg/day has been approved by the FDA and EMA for use in men 
with castration-resistant prostate cancer after docetaxel chemotherapy.  
A Phase 1 dose escalation study in women with breast cancer (MDV3100-08) has identified 
the 160 mg/day dose as the recommended dose in women. 
Trastuzumab will be given per local guidelines. Trastuzumab given as an 8mg/kg loading 
dose followed by 6 mg/kg every 21 days has been evaluated in numerous studies and remains 
standard of care treatment after first line therapy for advanced metastatic or locally advanced 
disease [NCCN, 2012; Cardoso et al, 2012]. Trastuzumab given every 21 days is preferred 
over the weekly schedule for subject convenience with similar safety and efficacy observed 
[Leyland-Jones et al, 2003]. 
2.3 
Endpoints  
2.3.1 
Primary Endpoint 
CBR defined as the proportion of evaluable subjects with best objective response of confirmed 
CR or PR per RECIST 1.1 or prolonged SD (≥ 24 weeks) criteria.  
2.3.2 
Secondary Endpoints 
2.3.2.1 Efficacy Endpoints 
Efficacy Endpoints include: 
● 
Overall response rate (CR+PR) at 24 weeks according to RECIST 1.1 criteria. 
● 
Best overall response rate according to RECIST 1.1.  


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● 
PFS is defined as the time from the date of first dose of enzalutamide (Study Day 1) until 
the date of disease progression per RECIST 1.1, or death from any cause on study, 
whichever occurs first.  
● 
TTP is defined as the time from the first date of enzalutamide treatment until the date of 
disease progression per RECIST 1.1.  
● 
DOR is defined as the time from the date of first documentation of response (CR or PR) 
until the date of disease progression per RECIST 1.1. 
● 
TTR is defined as the time from the first date of enzalutamide treatment to initial CR or PR. 
2.3.2.2 Safety Endpoints 
Safety will be assessed on an ongoing basis by physical examination, measurement of vital 
signs, laboratory assessments, 12-lead ECGs, left ventricular ejection fraction (LVEF) by 
echocardiogram, myocardial perfusion scintigraphy (MPS) or multi-gated acquisition scan 
(MUGA), and evaluation of AEs/serious adverse events (SAEs). 
2.3.3 
Exploratory Endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
CCI


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3 
STUDY POPULATION 
3.1 
Selection of Study Population  
Subjects will be selected based on Inclusion and Exclusion Criteria listed. Waivers to eligibility 
criteria will not be allowed. 
3.2 
Inclusion Criteria 
Subject is eligible for the study if all of the following apply: 
1. The subject has consented and signed an Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC) approved written Informed Consent and privacy language as per 
national regulations (e.g., Health Insurance Portability and Accountability Act [HIPAA] 
for U.S. sites) prior to any study-related procedures (including withdrawal of prohibited 
medication, if applicable). 
2. The subject is a female ≥ 18 years of age. 
3. The subject has histologically or cytologically proven adenocarcinoma of the breast that 
is HER2+ defined as a score of 3+ for staining by IHC, or IHC 2+ with HER2 gene 
amplification as determined by a locally approved in situ hybridization (ISH) assay, or 
(for patients without IHC data) HER2 gene amplification. 
4. The subject has AR+ breast cancer, which is defined as any tumor cells with nuclear AR 
staining by IHC. Enrollment may be based on the local pathologist’s findings; however, 
tissue will be sent to a central pathology laboratory for assessment. NOTE: If a subject is 
enrolled in the study based on local pathologist results, but subsequent central 
assessment cannot confirm AR+ disease, the subject may remain in the study. 
5. The subject has metastatic disease or has locally advanced disease that is not amendable 
to curative treatment. 
6. The subject has measurable disease or nonmeasurable, evaluable disease per RECIST 1.1 
(NOTE:  pleural effusions, ascites or other third fluid space are not evaluable diseases per 
RECIST 1.1). 
7. The subject has received at least 1 line of therapy in the metastatic or locally advanced 
disease setting: 
● A line of therapy is defined as a course of treatment at the end of which there was 
disease progression, toxicity, or in the Investigator’s opinion, maximum benefit has 
been achieved. If the subject discontinued therapy due to any other reason but 
progressed without receiving other treatment, this would be considered a line of 
therapy. 
● The subject has been documented to have progressed by determination of the 
Investigator on a regimen containing an anti-HER2 agent (includes trastuzumab 
emtansine in countries where it is not approved) as the most recent regimen or the 
most recent anti-HER2 regimen was discontinued for any toxicity, with the 
exception of a cardiotoxicity.  


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● Subjects who received < 28 days of therapy in the most recent regimen may be 
eligible upon approval from the medical monitor. 
● The subject has progressed on a trastuzumab containing regimen. If progression 
occurred within 12 months after completing trastuzumab-containing adjuvant 
treatment, this counts as having received trastuzumab but not as a line of therapy.  
8. The subject has adequately recovered from toxicities due to prior therapy.  
9. The subject has an Eastern Cooperative Oncology Group performance (ECOG) status ≤ 1 
at Screening and Day 1. 
10. The subject has available at the site a representative, formalin-fixed, paraffin-embedded, 
tumor specimen that enabled the definitive diagnosis of breast cancer with adequate 
viable tumor cells in a tissue block (preferred) or ≥ 10 (20 preferred) freshly cut, 
unstained, serial slides and the associated pathology report: 
● Archival tissue from the most recent biopsy available is preferred. 
● For subjects who are known AR+ per local pathology report, a fresh biopsy can be 
done, per Investigator’s discretion, to obtain tissue for central AR confirmation if 
the archival specimen is insufficient or unavailable.  
● Cytological or fine-needle aspiration samples are not acceptable. 
11. The subject has an estimated life expectancy of at least 6 months at Day 1, in the opinion 
of the Investigator. 
12. The subject is either: 
● Of nonchildbearing potential: 
▪ postmenopausal (defined as no spontaneous menses for at least 12 months prior 
to Screening with FSH > 40 IU/L at Screening for women < 55 years of age),  
▪ documented surgically sterile or status post hysterectomy (at least 1 month prior 
to Screening), 
● Or, if of childbearing potential,  
▪ must agree to not try to become pregnant during the study and for 5 half-lives 
(29 days) after the final study drug administration  
▪ must have a negative urine pregnancy test at Screening and at Day 1 before the 
first dose of study drug is administered, 
▪ must use 2 acceptable methods of birth control starting at Screening and through 
6 months after the final study drug administration. 
The 2 acceptable methods of birth control are as follows or per local guidelines where 
these require additional description of contraceptive methods: 
● A barrier method (e.g., condom by a male partner) is required; AND 
● One of the following is required: 
o Placement of an intrauterine device (IUD) or intrauterine system (IUS);  
o Additional barrier method including occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/suppository; 
o Vasectomy or other surgical castration at least 6 months before Screening. 


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13. The subject must not be breastfeeding at Screening or during the study period, and for  
6 months after the final study drug administration. 
14. The subject must be able to swallow study drug and comply with study requirements.  
15. The subject agrees not to participate in another interventional study while on treatment. 
Waivers to the inclusion criteria will NOT be allowed. 
3.3 
Exclusion Criteria 
Subject will be excluded from participation if any of the following apply: 
1. The subject has a severe concurrent disease, infection, or comorbidity that, in the 
judgment of the Investigator, would make the subject inappropriate for enrollment. 
2. The subject has current or previously treated brain metastasis or active leptomeningeal 
disease. Brain imaging is required during screening in all subjects to exclude the 
presence of unequivocal central nervous system disease. 
3. The subject has a history of a nonbreast cancer malignancy with the following 
exceptions:  
● The subject with a previous history of a noninvasive carcinoma is eligible if in the 
opinion of the Investigator he/she has had successful curative treatment any time 
prior to Screening. 
● For all other malignancies, the subject is eligible if they have undergone potentially 
curative therapy and they have been considered disease free for at least 5 years prior 
to Screening. 
4. The subject has inadequate marrow, hepatic, and/or renal function at the Screening Visit 
defined as:  
● Absolute neutrophil count < 1.5 x109/L (< 1500 cells/mm3) 
● Platelet count < 75 x109/L (< 75,000 cells/mm3) 
● Hemoglobin < 5.6 mmol/L (< 9 g/dL) 
● Total bilirubin > 1.5 x Upper Limit of Normal (ULN) unless there is an alternate 
nonmalignant etiology (e.g., Gilbert’s syndrome). 
● AST or alanine aminotransferase (ALT) > 3 x ULN (or > 5 x ULN if hepatic 
metastasis is present). 
● Creatinine > 1.5 x ULN or Glomerular Filtration Rate (eGFR)/Creatinine Clearance 
(CrCL) < 30 mL/min, whichever is more restrictive. 
● NOTE: May not have received any growth factors or blood transfusions within 
7 days before the hematology values obtained at screening. 
5. 
The subject has a history of seizure or any condition that may predispose to seizure 
(e.g., prior cortical stroke, significant brain trauma). 
6. The subject has a history of loss of consciousness, cerebrovascular accident, or transient 
ischemic attack within 12 months before the Day 1 visit. 


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7. The subject has had a hypoglycemic episode requiring medical intervention while on 
insulin (or other anti-diabetic) treatment within 12 months before Day 1. 
8. The subject has clinically significant cardiovascular disease including: 
● Myocardial infarction within 6 months before the Day 1 visit.  
● Uncontrolled angina within 6 months before the Day 1 visit. 
● Congestive heart failure New York Heart Association (NYHA) Class III or IV or 
history of congestive heart failure NYHA Class III or IV in the past, unless a 
screening echo-cardiogram, myocardial perfusion scintigraphy (MPS) , or multi-
gated acquisition scan performed within 3 months before the Day 1 visit reveals a 
left ventricular ejection fraction that is  
≥ 50%. 
● History of clinically significant ventricular arrhythmias (e.g., ventricular 
tachycardia, ventricular fibrillation, Torsade de Pointes). 
● History of Mobitz II second degree or third degree heart block without a permanent 
pacemaker in place. 
● Hypotension as indicated by systolic blood pressure < 86 mmHg on 2 consecutive 
measurements at the Screening visit. 
● Bradycardia (in the presence of known cardiovascular disease) as indicated by a 
heart rate of < 50 beats per minute on the Screening ECG recording. 
● Uncontrolled hypertension as indicated by systolic blood pressure > 170 mmHg or 
diastolic blood pressure > 105 mmHg on 2 consecutive measurements at the 
Screening visit. 
9. The subject has significant respiratory disease, including severe dyspnea at rest due to 
complications of advanced malignancy or requiring supplementary oxygen therapy.  
10. The subject has an active gastrointestinal disorder affecting absorption (e.g., 
gastrectomy, active peptic ulcer disease) within the 3 months prior to the Day 1 visit. 
11. The subject had a major surgical procedure, substantial open biopsy, or significant 
traumatic experience within 28 days before the Day 1 visit, or anticipation of need for 
major surgical procedure during the course of the study. 
12. The subject has had palliative radiation therapy to bone metastases within 14 days prior 
to the Day 1 visit (side effects from radiation must be resolved). 
13. The subject has received chemotherapy, immunotherapy, or any other systemic anti-
cancer therapy, with the exception of anti-HER2 therapy (e.g., trastuzumab), within  
14 days prior to the Day 1 visit.  
14. The subject has been treated with any investigational drugs within 14 days prior to the 
Day 1 visit. 
15. The subject has received treatment with any approved or investigational agent that either 
blocks androgen synthesis or targets the AR (e.g., abiraterone acetate, bicalutamide, 
enzalutamide, TAK-448, TAK-683, TAK-700, ARN-509, ODM-201, BMS-641988). 


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Subjects who received treatment for < 28 days or placebo on an investigational study are 
acceptable. 
16. The subject would, in the Investigator’s opinion, benefit from estrogen receptor targeted 
therapy while on study.  
17. The subject has used any of the following within 28 days before the Day 1 visit: 
● 5-α reductase inhibitors 
● Systemic androgens and estrogens 
18. The subject has a known history of positive test for Hepatitis B surface antigen (HBsAg) 
or hepatitis C antibody or history of positive test for Human Immunodeficiency Virus 
(HIV). 
19. The subject has shown a hypersensitivity reaction to the active pharmaceutical ingredient 
or any of the enzalutamide capsule components, including Labrasol, butylated 
hydroxyanisole and butylated hydroxytoluene. 
20. The subject has had a severe infusion reaction to trastuzumab or hypersensitivity to 
trastuzumab, and excipients including murine proteins, L-histidine, L-histidine 
hydrochloride monohydrate, α,α-trehalose dehydrate, L-methionine, and polysorbate. 
21. The subject has any other condition or reason that, in the opinion of the Investigator, 
would make the subject ineligible to receive trastuzumab, interferes with the ability of 
the subject to participate in the trial, places the subject at undue risk, or complicates the 
interpretation of safety data. 
Waivers to the exclusion criteria will NOT be allowed. 
4 
TREATMENT(S) 
4.1 
Identification of Investigational Product(s) 
4.1.1 
Test Drug(s) 
Enzalutamide and trastuzumab are components of the study regimen.   
4.1.1.1 Enzalutamide 
Enzalutamide is an opaque white to off-white oblong liquid filled soft gelatin capsule for oral 
administration. Each capsule contains 40 mg enzalutamide.  
4.1.1.2 Trastuzumab 
Trastuzumab may be given by IV infusion or sub-cutaneous injection.   
IV infusion; Trastuzumab is a sterile, white to pale yellow, preservative-free, lyophilized 
powder for reconstitution to solution for IV infusion. Trastuzumab is supplied as vials 
containing 440 mg or 150 mg lyophilized powder. Please refer to the local prescribing 
information for specific information on identification [Herceptin Product Monograph, 2012; 
Herceptin Prescribing Information, 2010; Herceptin Summary of Product Characteristics, 
2010]. 


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4.1.2 
Comparative Drug(s)  
Not applicable. 
4.2 
Packaging and Labeling 
4.2.1 
Enzalutamide 
Enzalutamide is supplied by APGD. Enzalutamide will be packaged in high-density polyethylene 
bottles with child-resistant induction seal closure. There are 124 capsules per bottle. 
Enzalutamide will be prepared, packaged, and labeled under the responsibility of qualified 
staff at APGD-Astellas United States Technologies (AUST) or Sponsor’s designee in 
accordance with APGD-AUST or Sponsor’s designee Standard Operating Procedures 
(SOPs), Good Manufacturing Practice (GMP) guidelines, ICH GCP guidelines, and 
applicable local laws/regulations. 
Each bottle will bear a label conforming to regulatory guidelines, Good Manufacturing 
Practice and local laws and regulations which identifies the contents as investigational drug. 
A qualified person of Astellas Pharma Europe B.V. (APEBV) or Sponsor’s designee will 
perform the final release of the medication according to Directive 2003/94/EC annex 13. 
4.2.2 
Trastuzumab 
Trastuzumab will be supplied by the responsible site pharmacy of each investigational site or 
by the sponsor if applicable. If trastuzumab is supplied by the sponsor, trastuzumab used in 
the study will be labeled under the responsibility of AUST/APGD Standard Operating 
Procedures (SOPs), Good Manufacturing Practice (GMP) guidelines, ICH GCP guidelines, 
and applicable local laws/regulations.   
4.3 
Study Drug Handling  
Enzalutamide will be stored in a secure location with limited access at 20°C to 25°C (68°F to 
77°F) with excursions permitted to 15°C to 30°C (59°F to 86°F). Subjects will be instructed 
to store study drug at room temperature and out of the reach of children. 
Trastuzumab must be stored according to the product label. If provided by APGD, trastuzumab 
will be stored at 2-8°C (36-46°F) prior to reconstitution. 
Current ICH GCP Guidelines require the Investigator to ensure that enzalutamide and 
trastuzumab (if supplied by APGD), deliveries from the Sponsor are received by the 
Investigator/or designee and 
● 
that such deliveries are recorded, 
● 
that study drug is handled and stored according to labeled storage conditions, 
● 
that study drug with appropriate expiry/retest and is only dispensed to study subjects in 
accordance with the protocol, and 
● 
that any unused study drug is returned to the Sponsor. 
 
 


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Drug inventory and accountability records for enzalutamide and trastuzumab (if supplied by 
APGD), will be kept by the Investigator/or designee. Enzalutamide accountability throughout 
the study must be documented and reconciled. The following guidelines are therefore 
pertinent:  
● 
The Investigator agrees not to supply enzalutamide to any persons except the eligible 
subjects in this study in accordance with the protocol. 
● 
The Investigator or designee will keep the enzalutamide in a pharmacy or other locked 
and secure storage facility under controlled storage conditions, accessible only to those 
authorized by the Investigator to dispense enzalutamide. 
● 
A study drug inventory will be maintained by the Investigator or designee. The inventory 
will include details of material received and a clear record of when it was dispensed and 
to which subject. 
● 
At the conclusion or termination of this study, the Investigator or designee agrees to 
conduct a final drug supply inventory and to record the results of this inventory on the 
Drug Accountability Record. It must be possible to reconcile delivery records with those 
of used and/or returned medication. Any discrepancies must be accounted for and 
documented. Appropriate forms of deliveries and returns must be signed by the site staff 
delegated this responsibility. 
● 
The site must return enzalutamide and trastuzumab (if supplied by APGD) to the 
Sponsor or designee at the end of the study or upon expiration. 
4.4 
Blinding 
This section is not applicable as this is an open-label study.  
4.5 
Assignment and Allocation 
All subjects will receive the same treatment. An Interactive Response Technology (IRT) 
system will be used to register subjects and to assign specific enzalutamide containers by 
packaging lot to subjects. Specific procedures for the IRT are contained in a separate IRT 
procedures manual. 
4.5.1 
Subject Registration 
Subjects will be registered using the IRT at the time of informed consent signature for the 
main study. A subject number will be assigned and will be used throughout the study for that 
subject.  Prescreen subjects should not be called into the IRT system. 
4.5.2 
Subject Enrollment 
Subjects who are found to be eligible for treatment will be enrolled using the IRT at the 
Day 1 visit.  
4.5.3 
Definition of Treated Subject 
Subjects will be considered as having entered treatment on Day 1 upon initiation of dosing 
with enzalutamide. 


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5 
TREATMENTS AND EVALUATION 
5.1 
Dosing and Administration of Study Drug(s) and Other Medication(s) 
5.1.1 
Dose/Dose Regimen and Administration Period 
5.1.1.1 Enzalutamide 
Enzalutamide will be given as 160 mg/day (4 x 40 mg capsules) each day by mouth until any 
of the discontinuation criteria are met. Enzalutamide may be administered with or without 
food, and should be given around the same time each day. 
Enzalutamide will be self-administered at home by the subject, except for visit days where 
PK samples are collected. On visit days with PK sampling, enzalutamide will be 
administered in clinic after the PK sample is collected. Subjects will keep a diary to record 
the date and time of enzalutamide dose on the 2 days before PK visit days.  
Subjects should not make up missed or vomited doses; dosing should resume on the next 
calendar day unless otherwise instructed.  For the purposes of this study, a “missed dose” is 
considered a dose not administered within 4 hours of the regular dosing time. 
5.1.1.2 Trastuzumab 
Trastuzumab should be administered as approved per local guidelines (IV infusion or 
subcutaneous injection). 
Trastuzumab for infusion is typically given at a dose of 6 mg/kg every 21 days. For subjects 
whose last dose of anti-HER2 antibody was greater than 21 days prior to Day 1 (or for 
subjects who were on weekly trastuzumab for ≤ 2 weeks), a loading dose of 8 mg/kg will be 
administered on Day 1, followed by 6 mg/kg every 21 days thereafter until any of the 
discontinuation criteria are met. 
Trastuzumab is given as an IV infusion over 30-90 minutes. For a loading dose, a 90 minute 
IV infusion is given or per local label. Premedication per institutional guidelines is permitted. 
If trastuzumab is given via sub-cutaneous injection, local guidelines should be followed. 
Refer to the package insert for specific preparation instructions. 
5.1.2 
Increase or Reduction in Dose of the Study Drug(s) 
5.1.2.1 
Enzalutamide 
Enzalutamide treatment may be interrupted for subjects who experience a Grade ≥3 toxicity 
that is attributed to enzalutamide and cannot be ameliorated with adequate medical 
intervention. Enzalutamide may be resumed at the original dose (160 mg/day) or at a reduced 
dose (80 mg/day or 120 mg/day), per Investigator’s discretion. Treatment interruption for 
> 2 weeks must be discussed with the Medical Monitor. If the treatment interruption occurs for 
4 weeks, the Medical Monitor must be contacted again for approval.  Interruption of 
enzalutamide dosing for more than 4 weeks must be approved by the Medical Monitor, 
otherwise the subject will be discontinued. A dose adjustment should also be considered in 
subjects with Grade 2 toxicities that interfere with quality of life. 


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If coadministration with a strong CYP2C8 inhibitor is necessary, reduce the dose of 
enzalutamide to 80 mg once daily. If coadministration with the strong CYP2C8 inhibitor is 
discontinued, the enzalutamide dose should be returned to the dose used prior to initiation of 
the CYP2C8 inhibitor, or to 160 mg once daily if the subject was on the CYP2C8 inhibitor at 
the start of study treatment. 
5.1.2.2 
Trastuzumab 
5.1.2.2.1 
Dose Modification for Infusion Reaction 
Infusion reactions will be managed according to the institution standard. 
5.1.2.2.2 
Dose Modification for Cardiomyopathy 
Trastuzumab will be withheld for at least 4 weeks if either of the following occurs: 
≥ 16 % absolute decrease in LVEF from baseline value 
LVEF below institutional limit of normal and ≥ 10% absolute decrease in LVEF from 
baseline value 
Trastuzumab may be resumed if, within 4 to 8 weeks, the LVEF returns to normal limit and 
the absolute decrease from baseline is ≤ 15%. Trastuzumab should be discontinued for a 
persistent (> 8 weeks) LVEF decline or for suspension of dosing on more than 3 occasions 
for cardiomyopathy and the subject should be withdrawn from the study. 
5.1.2.2.3 
Dose Modification for All Other Toxicities 
If a subject experiences an intolerable side effect, trastuzumab dosing may be held for up to 
4 weeks or until symptoms improve. If the treatment interruption will occur for more than 
4 weeks, the Medical Monitor must be contacted for approval.  Interruption of trastuzumab 
dosing for more than 4 weeks for toxicity (other than for cardiomyopathy, see 
Section 5.1.2.2.2) must be approved by the Medical Monitor, otherwise the subject will be 
discontinued.  
5.1.3 
Previous and Concomitant Treatment (Medication and Nonmedication 
Therapy) 
Medications taken within 14 days before the Screening visit up to the Study 30-Day 
Follow-up visit will be documented on the appropriate case report form as concomitant 
medication.  
All concomitant medication(s) must be reported on the appropriate case report form. Prior 
and concomitant medications include all vitamins, herbal remedies, over the counter, and 
prescription medications.  
Concomitant administration of bisphosphonates or bone-targeting agents are acceptable if the 
subject is on a stable regimen (per Investigator judgement) prior to Day 1. The Investigator 
should consult with Medical Monitor if new use of bone-targeting agents is deemed 
necessary during the study. 


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Concomitant administration of enzalutamide with strong CYP2C8 inhibitors, strong or 
moderate CYP2C8 inducers, strong or moderate CYP3A4 inducers should be avoided. Please 
see Section 5.1.2.1 for enzalutamide dose modifications when taking concomitant CYP2C8 
inhibitors. Concomitant use of enzalutamide with narrow therapeutic index drugs that are 
metabolized by CYP3A4, CYP2C9, and CYP2C19 should be avoided. If enzalutamide is 
coadministered with warfarin (CYP2C9 substrate), additional international normalized ratio 
(INR) monitoring is to be conducted.  
Subjects should avoid use of any herbal medications or dietary supplements including 
products containing Hypericum perforatum (e.g., St. John’s Wort). 
The following medications or therapies are prohibited during the receipt of study drug: 
● 
Medications, including herbal therapies, with an antitumor effect (medications used to 
induce menopause in women of child-bearing potential are permitted). 
● 
Any investigational agent 
● 
AR antagonists (e.g., bicalutamide, flutamide, nilutamide) 
● 
5-α reductase inhibitors (e.g., finasteride, dutasteride) 
● 
Systemic androgens and estrogens (vaginal estrogen creams are allowed) 
● 
Megestrol acetate for appetite stimulation may be used at Investigator’s discretion  
5.1.4 
Treatment Compliance 
Study subjects should be counseled on the need to meet 100% compliance with study drug.  
Investigator or designee should ensure that study subjects meet this goal throughout the study 
period.  
Treatment compliance should be monitored closely; sites will perform accountability of 
enzalutamide doses dispensed and returned, and deviations in overall compliance < 80% 
should be reported to the Sponsor.  Greater than 1 consecutive missed cycle of Trastuzamab 
for reasons other than an adverse reaction should be reported to the Sponsor. 
5.1.5 
Restrictions During the Study 
Subjects of childbearing potential must use 2 acceptable methods of birth control starting at 
Screening and through 6 months after the final study drug administration. 
The 2 acceptable methods of birth control are as follows, or per local guidelines where these 
require additional description of contraceptive methods: 
● 
A barrier method (e.g., condom by a male partner) is required; AND 
● 
One of the following is required: 
o Placement of an IUD or intrauterine system IUS;  
o Additional barrier method including occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/suppository; 
o Vasectomy or other surgical castration at least 6 months before Screening. 
Subjects must not breastfeed from screening through 6 months after the last dose of study 
drug.   


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5.2 
Demographics and Baseline Characteristics 
5.2.1 
Demographics 
Demographic information will be collected for all subjects and will include initials, age or 
date of birth, sex, race, and ethnicity, as local regulations allow. 
5.2.2 
Medical History 
Medical history includes all significant medical conditions that have occurred or are currently 
ongoing. The condition, onset date, and recovery date will be collected. National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) grade will be 
collected for conditions that are ongoing at the time of consent. 
5.2.3 
Diagnosis of the Target Disease, Severity, and Duration of Disease 
Breast cancer diagnosis and studies related to breast cancer classification will be collected 
and will include date of diagnosis, histopathology, HER2+ status and testing method, ER and 
PgR status, details on prior therapies, and response to prior therapies. 
5.2.4 
Androgen Receptor, Estrogen Receptor and Progesterone Receptor Status 
Subjects should have known ER and PgR status prior to screening for the study.  Results for 
AR expression will be required for eligibility assessment. Enrollment may be based on the 
local pathologist’s findings; however, tissue will be sent to a central pathology laboratory for 
confirmation. AR+ breast cancer for eligibility is defined as any tumor cell(s) with nuclear 
AR staining. If a subject is enrolled in the study based on local pathologist results, but 
subsequent central assessment cannot confirm AR+ disease, the subject may remain in the 
study per Investigator judgment.  If sufficient tissue is available, expression levels of nuclear 
ER and PgR in tumor cells using standard assays will also be assessed.  
A formalin-fixed paraffin-embedded tumor tissue block from the most recent biopsy 
available is preferred. If the archival specimen is insufficient or unavailable and the subject is 
known to be AR+ by local pathology report, a fresh biopsy can be done to obtain tissue for 
central AR confirmation. Tissue used for central confirmation will be shipped to and 
analyzed by a Sponsor-designated analytical laboratory. The laboratory will prepare slides for 
analysis, and then return the block to the Investigator. Tissue processing, storage, and 
shipment instructions are provided in the lab manual. If a tissue block is unavailable, then a 
minimum of 10 (preferably 20) unstained slides freshly prepared by the Institution will be 
sent to the Sponsor-designated analytical laboratory. The slides will not be returned.  
Prescreening AR Assessment  
Subjects with HER2+ breast cancer may be approached before screening for consent to 
submit archival tissue to test for AR expression. A separate prescreening consent will be 
available to enable testing of archival tissue for AR expression before initiating other 
screening activities. Patients must sign the separate prescreening consent form if archival 
tissue is to be analyzed before the protocol screening period (i.e., 28 days before day 1). 


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Subjects will not be allowed to undergo a biopsy for the sole purpose of determining 
eligibility for this study.  For subjects who are known AR+ per local pathology report, a fresh 
biopsy can only be done, per Investigator’s discretion, to obtain tissue for central AR 
confirmation if the archival specimen is insufficient or unavailable.   
Furthermore, patients must be informed that analysis of tissue will not guarantee eligibility 
for this study, as patients found to have AR+ disease must meet all other eligibility criteria at 
the time of enrollment.  
5.3 
Efficacy Assessment 
5.3.1 
Radiographic Disease Assessment 
Disease assessment will be based on RECIST v.1.1 criteria [Eisenhauer et al, 2009]. Disease 
assessment will be performed by the Investigator. Radiographic imaging technique will be 
dependent on the location and degree of disease, and must be performed using either diagnostic 
computed tomography (CT) scan, magnetic resonance imaging (MRI), and/or bone scan or 
skeletal survey. Imaging may be performed at any time to confirm suspected progression of 
disease. Assessment will include tumor measurements for target lesions, nontarget lesions, and 
assessment for any new lesions. An overall assessment will be characterized for each time 
point evaluation. At the end of study for that subject, the overall best response to the study 
regimen will be characterized. Refer to Appendix 12.6 RECIST Criteria for more detail.  
5.3.2 
Disease Assessment Methods  
Baseline evaluations (with the exception of bone imaging) will be performed within 4 weeks 
prior to day 1.  Results from CT/MRI assessments performed prior to consent and within 
28 days of day 1 may be used for screening if available. All patients should have bone 
imaging to assess metastasis to the bone within 6 months prior to the Day 1 visit. 
Postbaseline evaluations including chest/abdominal/pelvic imaging will be performed every 
8 weeks through 49, and then every 12 weeks thereafter. If a definitive new lesion is 
identified, remaining imaging is not required (for example, a CT of the chest, abdomen, and 
pelvis is not required if a new lesion is identified in the brain).  
PR and CR require confirmation with equivalent or improved assessment no less than 
4 weeks after the date of scan that PR or CR was first observed. 
5.3.2.1 Chest/Abdominal/Pelvic Imaging and Other Measurements 
Diagnostic CT, MRI, clinical measurement by caliper, and cytology/histology may be used to 
assess disease. CT/MRI of the chest/abdomen/pelvis as well as any other anatomical region 
appropriate for that subject’s disease will be performed. CT or MRI with contrast should be used 
unless contraindicated. The same method of assessment should be used throughout the study.  
NOTE: PET scans may not be used to assess response or progression; if PET-CT was 
performed, the CT component may be used if CT was obtained per RECIST 1.1 guidelines for 
gap thickness.  


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5.3.2.2 Brain Imaging 
Brain imaging is required at Screening for all subjects to rule out central nervous system 
disease. A brain MRI with contrast enhancement is required unless it cannot be performed 
within 2 weeks prior to Day 1 due to feasibility or subject-specific contraindications. A head 
CT may be performed in these situations after discussion with the medical monitor or 
designee. Results from brain imaging performed prior to consent and within 28 days of Day 1 
may be used for screening if available. Additional imaging to rule out CNS metastases should 
be performed as clinically indicated. 
5.3.2.3 Bone Imaging 
All subjects should have bone imaging to assess metastasis to the bone within 6 months prior 
to the Day 1 visit. Thereafter, subjects without bone metastasis will have bone scans only if 
clinically indicated. Subjects with suspected bone-only, measurable lesions must have bone 
lesions assessed by CT with bone windows or by MRI within 12 weeks before Day 1. 
Thereafter, measureable lytic lesions should be followed as target lesions according to 
RECIST 1.1 using the same method. Subjects with suspected bone-only, nonmeasurable 
disease should have had a bone assessment (e.g., scintigraphy or skeletal survey) performed 
within 12 weeks before Day 1. Thereafter, imaging of nonmeasurable, evaluable disease 
should be performed as clinically indicated, with a required assessment at Week 24.   
5.3.2.4 Cutaneous and Subcutaneous Lesions 
Cutaneous and subcutaneous lesions should be assessed by physical examination with digital 
photographs that must include a metric ruler in the image. Photographs should be obtained in 
such a manner to protect subject privacy. 
5.4 
Safety Assessment 
5.4.1 
Height and Weight 
Height and weight will be measured using standard Institution practice and equipment.  
5.4.2 
Vital Signs 
Vital signs will include systolic and diastolic blood pressure measured with standard 
sphygmo-manometer (mmHg), radial pulse (beats/min), and temperature (per institution 
standards). All vital signs will be measured with the subject in the sitting or supine position. 
5.4.3 
Adverse Events 
See Section 5.5 Adverse Events and Other Safety Aspects for information regarding AE 
collection and data handling.  
5.4.3.1 Adverse Events of Possible Hepatic Origin 
See Appendix 12.2 Liver Safety Monitoring and Assessment for detailed information on liver 
abnormalities, monitoring and assessment, if the AE for a subject enrolled in a study and 
receiving study drug is accompanied by increases in liver function testing (LFT) (e.g., AST, 
ALT, bilirubin, etc.) or is suspected to be due to hepatic dysfunction.  


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5.4.4 
Laboratory Assessments 
Routine laboratory assessments for hematology, chemistry, coagulation, urinalysis, and urine 
pregnancy test will be collected and analyzed at the Institution’s local laboratory. The local 
laboratory must be accredited to perform the protocol required tests and a certificate of 
accreditation and laboratory normal ranges must be provided to the Sponsor. Please refer to 
Appendix 12.7 Laboratory Assessments for a listing of analytes to be assessed. 
5.4.5 
Physical Examination 
Standard, full physical examinations will be performed at Screening and Day 1 per 
Investigator’s standard practice.   
After Day 1, a brief symptom directed physical examination may be performed. 
New or worsening clinically significant findings on physical exam will be recorded as AEs if 
they meet the criteria in Section 5.5.1 Definition of Adverse Events. 
5.4.6 
Electrocardiogram (ECG) 
A 12-lead ECG will be performed on all subjects at the Institution and interpreted by the 
Institution’s medically trained staff. Parameters that include heart rate, PR interval, RR 
interval, QRS interval, QT interval will be collected. Abnormalities and clinical significance as 
judged by the Investigator will be reported as well. It is recommended that ECG reports are 
printed in duplicate and photocopied to prevent fading. 
ECG should be obtained after the subject has rested quietly and is awake in a fully supine 
position or semi-recumbent, if supine not tolerated) for 10 minutes. 
All on-treatment ECGs will be obtained prior to drug administration. Whenever a study 
procedure coincides with the scheduled time point for an ECG, the study activities are ideally 
undertaken in a fixed sequence: ECG first, vital signs (blood pressure and heart rate) second, 
and any type of blood draws as the last assessment. 
5.4.7 
Echocardiogram/MUGA 
Echocardiogram/MPS/MUGA will be used to measure LVEF. The same method used at 
baseline for each subject must be used throughout the study. 
5.4.8 
Performance Status 
The ECOG scale [Oken et al, 1982] will be used to assess performance status. Refer to 
Appendix 12.5 ECOG Performance Status Scale. 
5.5 
Adverse Events and Other Safety Aspects 
5.5.1 
Definition of Adverse Events (AEs) 
An AE is defined as any untoward medical occurrence in a subject administered a study drug 
or has undergone study procedures and which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unintended sign (including an abnormal 


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laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product.  
AEs are events that begin or worsen from the time of informed consent through the 30 Day 
Follow-up period. Treatment emergent adverse events (TEAEs) are events that begin or 
worsen from the date of first study drug administration through the 30 Day Follow-up period 
or start of subsequent treatment of an anti-neoplastic, whichever occurs first. 
An abnormality identified during a medical test (e.g., laboratory parameter, vital sign, ECG 
data, physical exam) should be defined as an AE only if the abnormality meets one of the 
following criteria: 
● 
Induces clinical signs or symptoms 
● 
Requires active intervention 
● 
Requires interruption or discontinuation of study medication 
● 
The abnormality or investigational value is clinically significant in the opinion of the 
Investigator. 
In the case of clinically disease progression, individual signs and symptoms that are secondary 
to disease progression will be collected as AEs.  If disease progression is the cause of death, 
then “breast cancer progression” should be listed as the AE term with outcome as fatal.  
5.5.2 
Definition of Serious Adverse Events 
An AE is considered “serious” if, in the view of either the Investigator or Sponsor, it results 
in any of the following outcomes:  
● 
Results in death 
● 
Is life threatening (an AE is considered “life-threatening” if, in the view of either the 
Investigator or Sponsor, its occurrence places the subject at immediate risk of death. It 
does not include an AE that, had it occurred in a more severe form, might have caused 
death) 
● 
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions  
● 
Results in congenital anomaly, or birth defect 
● 
Requires inpatient hospitalization or leads to prolongation of hospitalization 
(hospitalization for treatment/observation/examination caused by AE is to be considered 
as serious)  
● 
Other medically important events 
Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. These events, including those that may result in disability/incapacity, 
should also usually be considered serious. Examples of such events are intensive treatment in 
an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
that do not result in hospitalization; or development of drug dependency or drug abuse.  


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Safety events of interest on the medicinal products administered to the subject as part of the 
study (e.g., study drug, comparator, background therapy) that may require expedited 
reporting and/or safety evaluation include, but are not limited to: 
● 
Overdose of the medicinal product(s) 
● 
Suspected abuse/misuse of the medicinal product(s) 
● 
Inadvertent or accidental exposure to the medicinal product(s) 
● 
Medication error involving the medicinal product(s) (with or without subject/patient 
exposure to the Sponsor medicinal product, e.g., name confusion) 
All of the events of interest noted above should be recorded on the electronic case report 
form ([e]CRF). Any situation involving these events of interest that also meets the criteria for 
an SAE should be recorded on the AE page of the (e)CRF and marked ‘serious’ and the SAE 
worksheet. 
The Sponsor has a list of events that they classify as “always serious” events. If an 
AE is reported that is considered to be an event per this classification as 
“always serious,” additional information on the event may be requested. 
5.5.3 
Criteria for Causal Relationship to the Study Drug 
Causal relationship will be assessed for enzalutamide and trastuzumab. Separate assessments 
for each agent will be obtained. 
AEs that fall under either "Possible" or "Probable" should be defined as "AEs whose 
relationship to the study drugs could not be ruled out". 
Causal 
relationship to the 
study drug 
Criteria for causal relationship 
Not Related 
A clinical event, including laboratory test abnormality, with a 
temporal relationship to drug administration which makes a causal 
relationship improbable, and/or in which other drugs, chemicals or 
underlying disease provide plausible explanations. 
Possible 
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, but which 
could also be explained by concurrent disease or other drugs or 
chemicals. Information on drug withdrawal may be lacking or 
unclear. 
Probable 
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, unlikely to 
be attributed to concurrent disease or other drugs or chemicals, and 
which follows a clinically reasonable response on re- administration 
(rechallenge) or withdrawal (dechallenge). 


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5.5.4 
Criteria for Defining the Severity of an Adverse Event 
AEs, including abnormal clinical laboratory values, will be graded using the NCI CTCAE 
(Version 4.03) [CTEP, 2010]. For terms not specified within NCI CTCAE, the following 
guidelines should be used to determine grade: 
Grade Assessment Standard 
1 
Mild; Asymptomatic, or mild symptoms, clinical or diagnostic observations 
noted; intervention not indicated. 
2 
Moderate; 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 prolonged hospitalization indicated; disabling; limiting self-
care activities of daily living. 
4 
Life threatening consequences, urgent intervention indicated 
5 
Death related to AE 
5.5.5 
Reporting of Serious Adverse Events 
In the case of an SAE, the Investigator must contact the Sponsor by telephone or fax 
immediately (within 24 hours of awareness). 
The Investigator should complete and submit an SAE Worksheet containing all information 
that is required by the Regulatory Authorities to the Sponsor by fax immediately (within 
24 hours of awareness). If the faxing of an SAE Worksheet is not possible or is not possible 
within 24 hours, the local drug safety contact should be informed by phone.  
For contact details, see Section II Contact Details of Key Sponsor's Personnel.  
If there are any questions, or if clarification is needed regarding the SAE, please contact the 
Sponsor's Medical Monitor/Expert or his/her designee (see Section II Contact Details of Key 
Sponsor’s Personnel).  
Follow-up information for the event should be sent promptly (within 7 days of the initial 
notification). 
Full details of the SAE should be recorded on the medical records and on the (e)CRF. 
The following minimum information is required: 
● 
ISN/Study number,  
● 
Subject number, sex and age, 
● 
The date of report, 
● 
A description of the SAE (event, seriousness of the event), and 
● 
Causal relationship to the study drug. 
The Sponsor or Sponsor's designee will submit expedited safety reports (i.e., Investigational 
New Drug (IND) Safety Reports) to the regulatory agencies (i.e., FDA) as necessary, and will 
inform the Investigators of such regulatory reports. Investigators must submit safety reports 


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as required by their IRB/IEC within timelines set by regional regulations (i.e., EU, electronic 
common technical document [eCTD], FDA). Documentation of the submission to and receipt 
by the IRB/IEC of expedited safety reports should be retained by the site. 
The Sponsor will notify all Investigators responsible for ongoing clinical studies with the 
study drug of all SAEs which require submission per local requirements IRB/IEC/head of the 
study site. 
The Investigator should provide written documentation of IRB/IEC notification for each 
report to the Sponsor. 
You may contact the Sponsor's Medical Monitor/Expert for any other problem related to the 
safety, welfare, or rights of the subject. 
5.5.6 
Follow-up of Adverse Events 
All AEs occurring during the study (through the 30 Day Follow-up period or start of 
subsequent treatment of an anti-neoplastic, whichever occurs first) are to be followed until 
resolved or judged to be no longer clinically significant, or until they become chronic to the 
extent that they can be fully characterized.  
If during AE follow-up, the AE progresses to an "SAE," or if a subject experiences a new 
SAE, the Investigator must immediately report the information to the Sponsor.  
Please refer to Appendix 12.2 Liver Safety Monitoring and Assessment for detailed 
instructions on Drug Induced Liver Injury (DILI). 
5.5.7 
Monitoring of Common Serious Adverse Events 
Common SAEs are SAEs commonly anticipated to occur in the study population independent 
of drug exposure. SAEs classified as “common” are provided in Appendix 12.3 Common 
Serious Adverse Events for your reference. The list does NOT change your reporting 
obligations or prevent the need to report an AE meeting the definition of an SAE as detailed 
above.  
The purpose of this list is to alert you that some events reported as SAEs may not require 
expedited reporting by the Sponsor to the regulatory authorities based on the classification of 
“common SAEs” as specified in Appendix 12.3 Common Serious Adverse Events. The 
Sponsor will monitor these events throughout the course of the study for any change in 
frequency. Any changes to this list will be communicated to the participating investigational 
sites. Investigators must report individual occurrences of these events as stated in 
Section 5.5.5 Reporting of Serious Adverse Events.  
5.5.8 
Procedure in Case of Pregnancy 
If a subject becomes pregnant during the study dosing period, study medication should be 
discontinued.  If a subject becomes pregnant during the study dosing period or within 
6 months from the discontinuation of dosing, the Investigator should report the information to 
the Sponsor as if it is an SAE. The expected date of delivery or expected date of the end of 


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the pregnancy, last menstruation, estimated conception 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. 
The Investigator should report the outcome of the pregnancy (independent of outcome, e.g., 
full term delivery, preterm delivery, spontaneous abortion, induced abortion, stillbirth, death 
of newborn, congenital anomaly (including anomaly in a miscarried fetus), in accordance 
with the same reporting procedure as for SAEs. The date of outcome of the pregnancy, 
gestational age, date of birth and neonatal data, etc., should be included in this information. 
Additional information regarding the outcome of a pregnancy (which is categorized as an 
SAE) is mentioned below. 
● 
"Spontaneous abortion" includes miscarriage, abortion and missed abortion 
● 
Death of an infant within 1 month after birth should be reported as an SAE regardless of 
its relationship with the study drug 
● 
If an infant dies more than 1 month after the birth, it should be reported if a relationship 
between the death and intrauterine exposure to the study drug is judged as "possible" by 
the Investigator 
● 
In the case of a delivery of a living newborn, the "normality" of the infant is evaluated at 
the birth 
● 
Unless a congenital anomaly are identified prior to spontaneous abortion or miscarriage, 
the embryo or fetus should be assessed for congenital defects by visual examination 
5.5.9 
Emergency Procedures and Management of Overdose 
If an overdose of enzalutamide occurs, the Medical Monitor must be contacted. An overdose 
is defined as at least 2 daily doses of study drug taken on the same calendar day. In the event 
of an overdose, stop treatment with study drug and initiate general supportive measures 
taking into consideration the enzalutamide t1/2 of 5.8 days. The medical monitor must be 
contacted in the event of a study drug overdose. 
Neither the effects of overdose of enzalutamide nor an antidote to overdose are known. 
Subjects may be at increased risk of seizures following an overdose of enzalutamide. 
In the event of suspected trastuzumab overdose, refer to the approved Package Insert, 
Summary of Product Characteristics (SPC), or local product information supplied by the 
manufacturer. 
5.5.10 Supply of New Information Affecting the Conduct of the Study 
When new information becomes available that is necessary for conducting the clinical study 
properly, the Sponsor will inform all Investigators involved in the clinical study as well as the 
regulatory authorities. Investigators should inform the IRB/IEC of such information when 
needed.  


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5.5.11 Urgent Safety Measures  
An Urgent Safety Measure (USM) is an intervention, which is not defined by the protocol 
and can be put in place with immediate effect without needing to gain prior approval by the 
sponsor, relevant Competent Authorities, IRB/IEC, where applicable, in order to protect 
study participants from any immediate hazard to their health and/or safety. Either the 
Investigator or the sponsor can initiate an USM. The cause of an USM can be safety, product 
or procedure related.  
5.5.12 Reporting Urgent Safety Measures 
In the event of a potential USM, the Investigator must contact the Astellas Study Physician 
(within 24 hours of awareness).  Full details of the potential USM are to be recorded in the 
subject’s medical records.  The sponsor may request additional information related to the 
event to support their evaluation.  
If the event is confirmed to be an USM the sponsor will take appropriate action to ensure the 
safety and welfare of the patients. These actions may include but are not limited to a change 
in study procedures or study treatment, halting further enrollment in the trial, or stopping the 
study in its entirety. The sponsor or sponsor's designee will notify Competent Authorities and 
concerned Ethics Committee within the timelines required per current local regulations, and 
will inform the Investigators as required. When required, Investigators must notify their 
IRB/IEC within timelines set by regional regulations. 
5.6 
Test Drug Concentration 
5.6.1 
Pharmacokinetic Assessments 
Plasma samples will be analyzed to determine enzalutamide and N-desmethyl enzalutamide 
concentrations and serum samples will be analyzed to determine trastuzumab concentrations 
in all subjects treated in the study. PK samples will be obtained before enzalutamide and 
trastuzumab dosing in the clinic. Blood samples will be collected from a vein or port that is 
not used for drug infusions. Blood sampling, processing, storage and shipment instructions 
are provided in a lab manual. Samples will be shipped to and analyzed by a Sponsor 
designated analytical laboratory.  
Subjects will keep a diary to record date and time of enzalutamide doses before PK visit days.  
The date and time that the subject took the previous 2 doses of study drug must be recorded 
at each PK sample collection visit. The PK sample will be collected even if the subject 
inadvertently took her daily dose of study drug earlier the same day.  When this occurs, the 
dose that was taken on the same day will be recorded as one of the previous doses, and the 
subject will take no additional study drug that day.   


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5.7 
Other Measurements, Assessments or Methods 
5.7.1 
Pharmacodynamic Assessments 
5.7.1.1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.7.2 
Sample for the Analysis of Genes Related to Pharmacokinetics, Efficacy, and/or 
Safety 
Knowledge of polymorphisms in the AR gene may help understand/explain observed 
differences in PK profiles, efficacy, and/or safety. After enrollment (see Schedule of 
Assessments), two 2 mL whole blood samples for the analysis of these genes will be collected 
into ethylenediaminetetraacetic acid (EDTA) containing polypropylene tubes. The first sample 
will be analyzed for polymorphisms of the AR gene. The second sample will be stored and 
may further be used for the exploratory analysis of relevant metabolism, transporter, PD and/or 
safety genes.  Sample labels should uniquely identify each sample and contain at least: protocol 
number; subject ID; “genotyping” and biological matrix. The samples should be stored at -
20ºC or colder in the freezer or on dry ice for immediate shipment. For detailed sample 
collection, sample labeling and sample shipment procedures refer to the laboratory manual. All 
CCI


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samples will be transferred to the analytical laboratory. Samples will be analyzed using 
appropriate validated methods. The extracted deoxyribonucleic acid (DNA) will be stored at 
the analytical laboratory. A pharmacogenomics (PGx) analysis plan may be prepared, if 
necessary, and exploratory analysis will be carried out before the completion of the study. PGx 
samples will be disposed after the completion of the study. Genetic information which has an 
established relevance to an individual for prescription of approved medicines can be disclosed 
to subjects upon their request.  
5.7.3 
Blood Sample for Future Pharmacogenomic Analysis (Retrospective 
Pharmacogenomic Analysis) 
PGx research may be conducted in the future to analyze or determine genes of relevance to 
clinical response, PK, and toxicity/safety issues. After enrollment (see Schedule of 
Assessments), a 5 mL sample of whole blood for possible retrospective PGx analysis will be 
collected using a vacutainer tube containing EDTA. After collection, gently invert the blood 
sample 8 to 10 times. The blood collection tube may either be stored upright at 4°C for up to 
5 days prior to shipment or stored frozen at -20°C or below at the site for extended storage. 
Samples will be shipped to a Sponsor designated banking contract research organization 
(CRO). 
Labels should uniquely identify each sample and contain at least: 
● 
Protocol number (9785-CL-1121), 
● 
Subject number, and 
● 
Purpose and biological matrix (i.e., “biobanking,” “whole blood”). 
Details on sample collection, labeling, storage and shipment procedures will be provided in a 
separate laboratory manual. 
The results of the Retrospective PGx analysis will not be provided to any Investigators or 
subjects, nor can the results be requested at a later date. 
See Appendix 12.4, Retrospective Pharmacogenomic Sub-study for further details on the 
banking procedures. 
5.8 
Total Amount of Blood 
The total amount of blood for each subject will vary depending on the course of their disease, 
how long they stay on treatment, and local laboratory requirements. At any time during the 
study, if any laboratory abnormalities are found for a subject, additional blood may be drawn 
for monitoring.  
The maximum amount of blood estimated for collection over any 1 month period is from 
Screening through the Week 4 visit where approximately 65mL may be drawn. The maximum 
amount of blood estimated over any approximate 3 month period is from Day 1 through 
Week 13 where approximately 106 mL may be drawn. 


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6 
DISCONTINUATION 
6.1 
Discontinuation of Individual Subject(s)  
A discontinuation is a subject who enrolled in the study and for whom study treatment is 
permanently discontinued for any reason. 
The subject is free to withdraw from the study treatment and/or study for any reason and at 
any time without giving reason for doing so and without penalty or prejudice. The 
Investigator is also free to terminate a subject's involvement in the study at any time if the 
subject's clinical condition warrants it. 
If a subject is discontinued from the study with an ongoing AE or an unresolved laboratory 
result that is significantly outside of the reference range, the Investigator will attempt to 
provide follow-up until the condition stabilizes or no longer is clinically significant.  
Discontinuation Criteria from Treatment for Individual Subjects: 
● 
Disease progression per RECIST 1.1; 
● 
Subject develops an unacceptable AE including, but not limited to: 
o seizure 
o persistent (> 8 weeks) LVEF decline or for suspension of trastuzumab dosing on 
more than 3 occasions for cardiomyopathy 
o severe or life-threatening infusion reaction to trastuzumab 
o anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress 
syndrome due to trastuzumab 
● 
Subject is lost to follow-up despite reasonable efforts by the Investigator to locate the 
subject 
● 
Subject withdraws consent for further treatment 
● 
Subject becomes pregnant 
Discontinuation of treatment should be considered if: 
● 
The subject experiences severe hepatic abnormalities as described in Appendix 12.2. 
● 
There is a significant protocol violation or noncompliance that occurs with a subject that 
compromises study objectives or subject safety.  
Discontinuation Criteria from Posttreatment Follow-up for Individual Subjects: 
● 
Subject is lost to follow-up despite reasonable efforts by the Investigator to locate the 
subject 
● 
Subject withdraws consent for further treatment 
● 
Death 
● 
2 years has passed from the last dose 
6.2 
Discontinuation of the Site 
If an Investigator intends to discontinue participation in the study, the Investigator must 
immediately inform the Sponsor. 


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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. 
7 
STATISTICAL METHODOLOGY 
The statistical analysis will be coordinated by the responsible biostatistician of APGD. A 
Statistical Analysis Plan (SAP) will be written to provide details of the analysis, along with 
specifications for tables, listings and figures to be produced. The SAP will be drafted before 
first subject enrolled and finalized before the database soft lock. Any changes from the 
analyses planned in SAP will be justified in the Clinical Study Report (CSR). 
Prior to Database Lock, a Final Review of Data and Tables, Listings and Figures (TLFs) 
Meeting will be held to allow a review of the clinical trial data and to verify the data that will 
be used for analysis set classification. If required, consequences for the statistical analysis 
will be discussed and documented. A meeting to determine analysis set classifications may 
also be held prior to database lock. 
In general, all data will be summarized with descriptive statistics (number of subjects, mean, 
median, standard deviation, minimum, and maximum) for continuous endpoints, and 
frequency and percentage for categorical endpoints. 
7.1 
Sample Size 
The sample size is sufficient to determine the absence or presence of an efficacy signal. The 
sample sizes for the first and second stage were determined using Simon’s 2-stage design. 
The null hypothesis that the true CBR is 10% will be tested against a 1-sided alternative at a 
5% significance level. In the first stage, 21 evaluable AR+ subjects will be evaluated; the 
study will stop if < 3 evaluable subjects show confirmed CR or PR per RECIST 1.1, or 
prolonged SD (≥ 24 weeks). Otherwise, the study will continue to enroll up to 66 evaluable 
AR+ subjects. This design has a statistical power of 90% when the true CBR is 25% (East 
version 5.4, Cytel Inc). To illustrate the precision with a total of 66 subjects: if the observed 
CBR is 40%, then the 90% confidence interval will be within the 30% to 50% range.  
Taking into account the number of nonevaluable subjects, approximately 80 subjects were 
planned to be enrolled to get 66 evaluable AR+ subjects.  
7.2 
Analysis Set 
Detailed criteria for analysis sets will be laid out in Classification Specifications and the 
allocation of subjects to analysis sets will be determined prior to database hard-lock.  
The All Enrolled Subjects (AES) consists of all subjects who are found to be eligible for 
treatment and enrolled using the IRT at the day 1 visit. 


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7.2.1 
Full Analysis Set (FAS) 
The FAS is defined as all enrolled subjects who have centrally assessed AR+ breast cancer 
(defined as ≥ 10% of tumor cells with nuclear expression), and received at least 1 dose of 
study drug.  
7.2.2 
Efficacy Evaluable Set (EES) 
The Efficacy Evaluable Set (EES) is a subset of the FAS defined as all enrolled subjects who 
have centrally assessed AR+ (defined as > 10% of tumor cells with nuclear expression), 
received at least 1 dose of study drug, and have at least 1 available post baseline tumor 
assessment. 
7.2.3 
Per Protocol Set (PPS) 
PPS is not defined for this study and separate analyses will not be performed on a PPS. 
7.2.4 
Safety Analysis Set (SAF) 
For the statistical summary of the safety data, the safety analysis set (SAF) will be used. The 
SAF is defined as all subjects who have received at least partial or full dose of study drug. 
7.2.5 
Pharmacokinetic Analysis Set (PKAS) 
The pharmacokinetic analysis set (PKAS) consists of the subset of the SAF population for 
which at least 1 quantifiable enzalutamide, N-desmethyl enzalutamide, or trastuzumab 
concentration value after Week 4 is available. Additional subjects may be excluded from the 
PKAS at the discretion of the pharmacokineticist. Any formal definitions for exclusion of 
subjects or time-points from the PKAS will be documented.  
7.2.6 
Pharmacodynamic Analysis Set (PDAS) 
The pharmacodynamic analysis set (PDAS) will include the subjects from the SAF 
population for whom sufficient PD measurements (a baseline and at least 1 postbaseline 
sample after Week 4) were collected. The PDAS will be used for all analyses of PD data. 
7.3 
Demographics and Other Baseline Characteristics  
Demographics and other baseline characteristics will be summarized for the SAF. Descriptive 
statistics will include number of subjects, mean, standard deviation, minimum, median and 
maximum for continuous endpoints, and frequency and percentage for categorical endpoints.  
7.4 
Analysis of Efficacy  
The primary analyses will be done in the EES, while all efficacy analyses will be done in 
both the EES and FAS. If more than 5 subjects are enrolled into the study but had less than 
10% of tumor cells with nuclear expression, and received at least 1 dose of study drug, the 
efficacy analyses will also be conducted in this subset of FAS.  Further details will be 
presented in the statistical analysis plan. 
The totality of evidence from all primary and secondary efficacy variables on the EES will be 
used to evaluate the biologic activity of enzalutamide in combination with trastuzumab. 


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Subjects whose disease is not confirmed to be AR+ upon central review may stay on study; 
however, they will not contribute to the primary and secondary efficacy analyses. 
7.4.1 
Analysis of Primary Endpoint  
7.4.1.1 Primary Analysis 
The primary efficacy endpoint, (confirmed CR or PR according to RECIST 1.1 criteria or SD 
≥ 24 weeks) will be presented using descriptive statistics and will be summarized including 
95% 2-sided exact confidence intervals.  
7.4.1.2 Secondary Analysis 
A secondary analysis is not planned. 
7.4.1.3 Subgroup Analysis 
A subgroup analysis will be conducted for the ER-/PgR- subjects. The details of any 
subgroup analyses will be included in the SAP.  
7.4.2 
Analysis of Secondary Endpoints  
All variables will be presented as descriptive statistics. ORR, and BORR will be summarized 
including 95% 2-sided exact confidence intervals. 
Kaplan-Meier methods will be used to estimate PFS, TTP, TTR, and DOR. 
7.4.3 
Analysis of Exploratory Endpoints  
All variables will be presented as descriptive statistics.  
7.5 
Analysis of Safety 
Safety analyses will be conducted using the SAF. The SAF is defined as all subjects who 
have initiated at least 1 or partial dose of study drug. The treatment emergent period will be 
defined as the period of time from the first dose date of study drug to 30 days after the last 
dose date of study drug or the start of subsequent treatment (whichever is first). Safety will be 
assessed through descriptive statistics for the frequency of AEs by system organ class (SOC), 
preferred term (PT), and NCI CTCAE grade, the frequency of treatment discontinuations due 
to AEs, vital signs, ECG, LVEF, and laboratory evaluations.  
7.5.1 
Adverse Events 
The severity of all AEs is to be evaluated by the Investigator based on the NCI CTCAE, 
version 4.03. All AEs will be coded to preferred term and system organ class using Medical 
Dictionary for Regulatory Activities (MedDRA). The number and percentage of subjects 
with TEAEs will be presented by MedDRA system organ class and preferred term, 
relationship to study treatment, and NCI CTCAE grade. A subject reporting the same AE 
more than once is counted once and at the maximum severity or strongest relationship to 
study drug treatment, when calculating incidence.  


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7.5.2 
Laboratory Assessments 
Laboratory data consist of hematology, chemistry, coagulation, and urine dipstick laboratory 
test results. Where applicable, NCI CTCAE version 4.03 will be used to categorize toxicity 
grades for the laboratory parameters. Laboratory shift tables compared to baseline results for 
each subsequent visit will be produced. For each laboratory parameter, the baseline 
laboratory value is defined as the last laboratory value collected on or prior to the first dose 
date of enzalutamide. 
7.5.3 
Vital Signs  
Descriptive statistics will be used to summarize vital sign results and changes from baseline 
by time point. Vital signs data will be displayed in listings. 
7.5.4 
ECGs 
The 12-lead ECG results will be summarized by time point. 
7.5.5 
LVEF 
Descriptive statistics will be used to summarize vital sign LVEF and changes from baseline 
by time point. 
7.6 
Analysis of Pharmacokinetics 
PK analyses will be conducted using the PKAS.  
The enzalutamide, N-desmethyl enzalutamide, and trastuzumab concentration-time data will 
be summarized by descriptive statistics at each visit. Additional model-based analyses may 
be performed and will be described in a separate population PK analysis plan. 
7.6.1 
Estimation of Pharmacokinetic Parameters  
Enzalutamide and N-desmethyl enzalutamide concentration-time data may be incorporated in 
a population PK model.  The analysis plan and results would be reported separately from the 
clinical study report. Similar analysis may be done on the trastuzumab levels, which will be 
reported separately too. 
7.6.2 
Concentration-Response Relationship Analysis 
An exploratory population PK-PD analysis may be performed to investigate the relationship 
of enzalutamide and N-desmethyl enzalutamide exposure on circulating hormone 
concentrations, efficacy measures, and possibly safety endpoints. The details of the analysis 
would be provided in a separate population PK-PD analysis plan and the results will be 
reported separately from the clinical study report. 
7.7 
Analysis of Pharmacodynamics 
7.7.1 
Pharmacodynamic Analyses 
 
 
CCI


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Additional model-based analyses to explore PK-PD relationships may be performed. 
 
 
 
 
 
 
 
 
7.8 
Protocol Deviations and Other Analyses 
Protocol deviations as defined in Section 8.1.6 Protocol Deviations will be summarized for 
all enrolled subjects by site. A data listing will be provided by site and subject. 
The protocol deviation criteria will be uniquely identified in the summary table and listing. 
The unique identifiers will be as follows: 
PD1 - Entered into the study even though they did not satisfy entry criteria,  
PD2 - Developed withdrawal criteria during the study and was not withdrawn, 
PD3 - Received wrong treatment or incorrect dose, 
PD4 - Received excluded concomitant treatment. 
7.9 
Interim Analysis (and Early Discontinuation of the Clinical Study) 
Recruitment will continue if there are 3 or more subjects with clinical benefit in the first 
21 evaluable AR+ subjects from the evaluable set. If there are less than 3 subjects who 
demonstrate a confirmed CR or PR per RECIST 1.1, or prolonged SD of ≥ 24 weeks (using 
all available data), recruitment will be stopped.  If the study is terminated early for reasons 
other than safety, and the subject is receiving clinical benefit per Investigator’s judgment, the 
subject may continue on study medication until they have disease progression as defined per 
RECIST.  
Tumor response will be monitored continuously throughout Stage 1, therefore it is expected 
that the decision to expand enrollment using the CBR after 24 weeks will be made before the 
21st subject is evaluated.  
7.10 
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information 
As a general principle, no imputation of missing data will be done. Exceptions are the start and 
stop dates of AEs and concomitant medication. The imputed dates will be used to allocate the 
concomitant medication and AEs to a treatment period, in addition to determining whether an 
AE is/is not treatment emergent. Listings of the AEs and concomitant medications will present 
the actual partial dates; imputed dates will not be shown. 
See the SAP for details of the definitions for windows to be used for analyses by visit. 
CCI


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8 
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS 
8.1 
Procedure for Clinical Study Quality Control 
8.1.1 
Data Collection 
The Investigator or site designee will enter data collected using an Electronic Data Capture 
(EDC) system. The Investigator or site designee is responsible to ensure that all data in the 
(e)CRFs and queries are accurate and complete and that all entries are verifiable with source 
documents. These documents should be appropriately maintained by the site. 
The monitor should verify the data in the (e)CRFs with source documents and confirm that 
there are no inconsistencies between them. 
For Screen failures the demographic data, reason for failing, informed consent, inclusion and 
exclusion criteria and AEs will be collected in the eCRF. 
Analytical laboratory tests for PK and PD measures will be collected and managed by 
Sponsor-designated vendors during the study. Data will be transferred electronically to the 
Sponsor at predefined intervals during the study. The external data vendors may provide the 
Data Manager with a complete and clean copy of the data, accompanied by a Quality Control 
statement. 
8.1.2 
Specification of Source Documents 
Source data must be available at the site to document the existence of the study subjects and 
to substantiate the integrity of study data collected. Source data must include the original 
documents relating to the study, as well as the medical treatment and medical history of the 
subject. Source data may be in paper or electronic format. 
Source documents will generally be in the institution’s standard record format to avoid 
duplicate source. The sponsor may provide (or site can create) supplemental source tools to 
ensure all data elements are captured for assessments such as AEs (relationship, action taken, 
outcome, etc.) and disease assessment. 
Source documents – whether paper or electronic must be: 
● 
Attributable (distinguishable)  
● 
Legible 
● 
Contemporaneous (happening at the same period in time) 
● 
Accurate 
● 
Original (copies verified as identical, can replace the original) 
A certified copy is a copy of original information that has been verified, as indicated by a dated 
signature, as an exact copy having all of the same attributes and information as the original. A 
certified copy of electronic records may be used for monitoring purposes. 


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The following information should be included in the source medical records: 
● 
Demographic data (age, sex, race, ethnicity, height and body weight) 
● 
Target disease history. Photocopies or fax documents of original records are acceptable if 
obtained from an outside institution 
● 
Inclusion and exclusion criteria details 
● 
Participation in study and original signed and dated informed consent forms  
● 
Visit dates 
● 
Medical history and physical examination details 
● 
Key efficacy and safety data, if applicable (as specified in the protocol) 
● 
AEs and concomitant medication  
● 
Results of relevant examinations (e.g., ECG charts, X-ray films, photographs, etc.) 
● 
Laboratory results 
● 
Dispensing and return of study drug details 
● 
Reason for premature discontinuation (if applicable) 
● 
Subject number 
● 
Staff notes and subject contact records 
● 
Significant medical records from other departments or hospitals, including discharge 
summaries, correspondence, etc., during the time the subject is on study. Photocopies or 
fax documents of original records are acceptable if obtained from an outside department 
or 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/Subinvestigator 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.  


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8.1.4 
Direct Access to Source Data/Documents 
The Investigator and the study site must accept monitoring and auditing by the Sponsor or 
delegated CRO as well as inspections from the IRB/IEC and relevant regulatory authorities. 
In these instances, they must provide all study-related records, such as source documents 
(refer to Section 8.1.2 "Specification of Source Documents") when they are requested by the 
Sponsor monitors and auditors, the IRB/IEC, or regulatory authorities. The confidentiality of 
the subject's identities shall be well protected consistent with local and national regulations 
when the source documents are subject to direct access. 
8.1.5 
Data Management 
Data Management will be coordinated by the Global Data Science department of the Sponsor 
in accordance with the standard operating procedures (SOPs) for data management. All study 
specific processes and definitions will be documented by Data Management. (e)CRF 
completion will be described in the (e)CRF instructions. Coding of medical terms and 
medications will be performed using MedDRA and World Health Organization (WHO) Drug 
Dictionary respectively. 
8.1.6 
Protocol Deviations 
A protocol deviation is generally an unplanned excursion from the protocol that is not 
implemented or intended as a systematic change. The Investigator is responsible for ensuring 
the study is conducted in accordance with the procedures and evaluations described in this 
protocol and must protect the rights, safety, and welfare of subjects. The Investigator should 
not implement any deviation from, or changes of, the protocol, unless it is necessary to 
eliminate an immediate hazard to trial subjects.   
A protocol waiver is a documented prospective approval of a request from an Investigator to 
deviate from the protocol.  Protocol waivers are strictly prohibited. 
For the purposes of this protocol, deviations requiring notification to 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 one of the above deviations 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 


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communications to the IRB/IEC and applicable regulatory authorities will be provided to the 
Sponsor and maintained within the Trial Master File (TMF). 
NOTE: Other deviations outside of the categories defined above that are required to be 
reported by the IRB/IEC in accordance with local requirements will be reported, as 
applicable.  
8.1.7 
End of Trial in All Participating Countries 
The end of trial in all participating countries is defined as the Last Subject’s Last Visit 
(including follow-up contact if applicable). 
8.2 
Ethics and Protection of Subject Confidentiality  
8.2.1 
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC)/Competent Authorities (CA) 
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol amendments, 
the Investigator’s Brochure, the informed consent and all other forms of subject information 
related to the study (e.g., advertisements used to recruit subjects) and any other necessary 
documents be reviewed by an IEC/IRB. The IEC/IRB will review the ethical, scientific and 
medical appropriateness of the study before it is conducted. IEC/IRB approval of the 
protocol, informed consent and subject information and/or advertising, as relevant, will be 
obtained prior to the authorization of drug shipment to a study site. 
Any substantial amendments to the protocol will require IEC/IRB approval prior to 
implementation of the changes made to the study design at the site.  The Investigator will be 
required to submit, maintain and archive study essential documents according to ICH GCP. 
Any SAEs that meet reporting criteria, as dictated by local regulations, will be reported to 
both responsible Ethics Committees and Regulatory Agencies, as required. During the 
conduct of the study, the Investigator should promptly provide written reports (e.g., ICH 
Expedited Reports, and any additional reports required by local regulations) to the IEC/IRB 
of any changes that affect the conduct of the study and/or increase the risk to subjects. 
Written documentation of the submission to the IEC/IRB should also be provided to Sponsor. 
If required by local regulations, the Investigator shall make accurate and adequate written 
progress reports to the IEC/IRB at appropriate intervals, not exceeding 1 year. The 
Investigator shall make an accurate and adequate final report to the IRB/IEC within 90 days 
after the close-out visit for APGD-sponsored studies. 
8.2.2 
Ethical Conduct of the Study 
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing clinical study conduct and the ethical principles that 
have their origin in the Declaration of Helsinki.  


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8.2.3 
Informed Consent of Subjects 
8.2.3.1 Subject Information and Consent 
The Investigator or his/her representative will explain the nature of the study to the subject or 
his/her guardian or legal representative, and answer all questions regarding this study. Prior 
to any study-related screening procedures being performed on the subject, the informed 
consent statement will be reviewed and signed and dated by the subject or his/her guardian or 
legal representative, the person who administered the informed consent and any other 
signatories according to local requirements. A copy of the signed informed consent form will 
be given to the subject and the original will be placed in the subject’s medical record. An 
entry must also be made in the subject’s dated source documents to confirm that informed 
consent was obtained prior to any study-related procedures and that the subject received a 
signed copy. A prescreening consent form may be used to allow for testing of archival tissue 
samples for AR expression prior to the screening period (See Section 5.2.4 for details). 
The signed consent forms will be retained by the Investigator and made available (for review 
only) to the study monitor and auditor regulatory authorities and other applicable individuals 
upon request. 
8.2.3.2 Supply of New and Important Information Influencing the Subject’s Consent 
and Revision of the Written Information 
The Investigator or his/her representative will immediately inform the subject orally 
whenever new information becomes available that may be relevant to the subject’s consent or 
may influence the subject’s willingness to continue to participate in the study (e.g., report of 
serious drug adverse drug reaction). The communication must be documented in the subject’s 
medical records and must document whether the subject is willing to remain in the study or 
not. 
The Investigator must update their ICF and submit it for approval to the IRB/IEC. The 
Investigator or his/her representative must obtain written informed consent from the subject 
on all updated ICFs throughout their participation in the study. The Investigator or his/her 
designee must re-consent subjects with the updated ICF even if relevant information was 
provided orally. The Investigator or his/her representative who obtained the written informed 
consent and the subject should sign and date the informed consent form. A copy of the signed 
informed consent form will be given to the subject and the original will be placed in the 
subject’s medical record. An entry must be made in the subject’s records documenting the 
re-consent process. 
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 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., Health Insurance Portability and 
Accountability Act [HIPAA]).  
8.3 
Administrative Matters 
8.3.1 
Arrangement for Use of Information and Publication of the Clinical Study 
Information concerning the study drug, patent applications, processes, unpublished scientific 
data, the Investigator's Brochure and other pertinent information is confidential and remains 
the property of the Sponsor. Details should be disclosed only to the persons involved in the 
approval or conduct of the study. The Investigator may use this information for the purpose 
of the study only. It is understood by the Investigator that the Sponsor will use the 
information obtained during the clinical study in connection with the development of the drug 
and therefore may disclose it as required to other clinical Investigators or to regulatory 
agencies. In order to allow for the use of the information derived from this clinical study, the 
Investigator understands that he/she has an obligation to provide the Sponsor with all data 
obtained during the study. 
Publication of the study results is discussed in the Clinical Study Agreement. 
8.3.2 
Documents and Records Related to the Clinical Study 
The Investigator will archive all study data (e.g., Subject Identification Code List, source 
data, case report forms (CRFs), and Investigator's File) and relevant correspondence. These 
documents are to be kept on file for the appropriate term determined by local regulation (for 
US sites, 2 years after approval of the New Drug Application (NDA) or discontinuation of 
the IND). The Sponsor will notify the site/Investigator if the NDA/Marketing Authorisation 
Application (MAA)/Japanese New Drug Application (J-NDA) is approved or if the 
Investigational New Drug application (IND)/Investigational Medical Product Dossier 
(IMPD)/Clinical Trial Notification (Chiken-Todoke) 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 the (e)CRFs supplied 
for each subject.  


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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 nonsubstantial amendments. 
Depending on the nature of the amendment, either IRB/IEC, Competent Authority approval 
or notification may be required. The changes will become effective only after the approval of 
the Sponsor, the Investigator, the regulatory authority, and the IRB/IEC (if applicable). 
Amendments to this protocol must be signed by the Sponsor and the Investigator. Written 
verification of IRB/IEC approval will be obtained before any amendment is implemented 
which affects subject safety or the evaluation of safety, and/or efficacy. Modifications to the 
protocol that are administrative in nature do not require IRB/IEC approval, but will be 
submitted to the IRB/IEC for their information, if required by local regulations. 
If there are changes to the Informed Consent, written verification of IRB/IEC approval must 
be forwarded to the Sponsor. An approved copy of the new Informed Consent must also be 
forwarded to the Sponsor. 
8.3.4 
Insurance of Subjects and Others 
The Sponsor has covered this study by means of an insurance of the study according to national 
requirements. The name and address of the relevant insurance company, the certificate of 
insurance, the policy number and the sum insured are provided in the Investigator's File.  
8.3.5 
Signatory Investigator for Clinical Study Report 
ICH E3 guidelines recommend and EU Directive 2001/83/EC requires that a final study 
report which forms part of a marketing authorization application be signed by the 
representative for the Coordinating Investigator(s) or the Principal Investigator(s). The 
representative for the Coordinating Investigator (s) or the Principal Investigator(s) will have 
the responsibility to review the final study results to confirm to the best of his/her knowledge 
it accurately describes the conduct and results of the study. The representative for 
Coordinating Investigator(s) or the Principal Investigator(s) will be selected from the 
participating Investigators by the Sponsor prior to database lock. 
9 
QUALITY ASSURANCE 
The Sponsor is implementing and maintaining quality assurance and quality control systems 
with written SOPs to ensure that trials are conducted and data are generated, documented, 
recorded, and reported in compliance with the protocol, GCP, and applicable regulatory 
requirement(s).  
The Sponsor or Sponsor's designee may arrange to audit the clinical study at any or all 
investigational sites and facilities. The audit may include on-site review of regulatory 
documents, case report forms, and source documents. Direct access to these documents will 
be required by the auditors.  


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10 
STUDY ORGANIZATION 
10.1 
Independent Data-Monitoring Committee (IDMC) | Data and Safety 
Monitoring Board (DSMB)  
Not applicable. The study will undergo regular, data review by the internal study teams 
including but not limited to data management, clinical, medical, safety, etc. 
10.2 
Other Study Organization 
Not applicable. 


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11 
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Hu R, Dawood S, Holmes MD, Collins LC, Schnitt SJ, Cole K, et al. Androgen Receptor expression 
and breast cancer survival in postmenopausal women. Clin Cancer Res. 2011;17(7):1867-1874. 
Leyland-Jones B, Gelman K, Ayoub J, Arnold A, Verma S, Dias R, et al. Pharmacokinetics, Safety, and 
Efficacy of Trastuzumab Administered Every Three Weeks in Combination with Paclitaxel. 
J Clin Oncol. 2003;21(1):3965-71. 
Lin NU, Bellon JR, Winer EP. CNS Metastases in Brain Cancer. J Clin Oncol 2004; 22(17):3608-3617. 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 
[CTEP, 2010]. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf 
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast 
Cancer. 2012. 


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Ni M, Chen Y, Lim E, Wimberly H, Bailey ST, Imai Y, et al. Targeting Androgen Receptor in Estrogen 
Receptor-Negative Breast Cancer. Cancer Cell 2011;20(1):119-131. 
Niemeier LA, Dabbs DJ, Beriwal S, Striebel JM, Bhargava R. Androgen receptor in breast cancer: 
expression in estrogen receptor-positive tumors and in estrogen receptor-negative tumors with 
apocrine differentiation. Mod Pathol. 2010;23(2):205-12. 
Oken MM, Creech RH, Tormey DC, Horton, J, Davis TE, McFadden ET, et al. Toxicity and Response 
Criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655. 
Park S, Koo J, Park HS, Kim JH, Cho SY, Lee JH, et al. Expression of androgen receptors in primary 
breast cancer. Ann Oncol. 2010;21(3):488-492. 
Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of 
human breast tumours. Nature. 2000;406(6797):747-52. 
Siegel R, Ward E, Brawley O, Jemal A. Cancer Statistics, 2011. The impact of eliminating 
socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin. 
2011;61(4):212-236. 
Sørlie T. Molecular portraits of breast cancer: tumour subtypes as distinct disease entities. Eur J Cancer. 
2004;40(18):2667-75. 
Swain SM, Kim, SB, Cortés J, Ro J, Semiglazov V, Campone M, et al. Pertuzumab, trastuzumab, and 
docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival 
results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 
2013;14(6):461-71.  


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12 
APPENDICES 
12.1 
List of Excluded Concomitant Medications 
The following medications or therapies are prohibited during the receipt of study drug: 
● 
Medications, including herbal therapies, with an antitumor effect (Use of LHRH agonist 
used to induce menopause in women of child-bearing potential is permitted). 
● 
Any investigational agent 
● 
AR antagonists (e.g., bicalutamide, flutamide, nilutamide) 
● 
5-α reductase inhibitors (e.g., finasteride, dutasteride) 
● 
Systemic androgens and estrogens  
● 
Megestrol acetate for appetite stimulation may be used at Investigator’s discretion.  


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12.2 
Liver Safety Monitoring and Assessment 
Any subject enrolled in a clinical study with active drug therapy and reveals an increase of 
serum aminotransferases (AT) to > 3 × ULN (to > 5 × ULN in subjects with liver metastases), 
or bilirubin > 2 × ULN, should undergo detailed testing for liver enzymes (including at least 
ALT, AST, alkaline phosphatase (ALP), and total bilirubin [TBL]). 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 severe 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 severe where ULN: 
 
ALT or AST 
 
Total Bilirubin 
Moderate 
> 3 x ULN (in patients without liver 
metastases), > 5 x ULN (in patients with liver 
metastases) 
or 
> 2 x ULN 
Severe* 
> 3 x ULN 
and 
> 2 x ULN 
In addition, the subject should be considered to have severe hepatic abnormalities for any of 
the following: 
● 
ALT or AST > 8 × ULN 
● 
ALT or AST > 5 × ULN for more than 2 weeks (in the absence of liver metastases) 
● 
ALT or AST > 3 × ULN and INR > 1.5 (If INR testing is applicable/evaluated) 
● 
ALT or AST > 3 × 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 severe abnormalities and require additional monitoring and 
follow-up. 
Follow-up Procedures 
Confirmed moderate and severe 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) that has been developed globally and can be activated for any study or 
appropriate document. Subjects with confirmed abnormal liver function testing should be 
followed as described below.  
Confirmed moderately abnormal LFTs should be repeated 2 to 3 times weekly then weekly or 
less if abnormalities stabilize or the study drug has been discontinued and the subject is 
asymptomatic. 
Severe hepatic liver function abnormalities as defined above, in the absence of another etiology 
may be considered an important medical event and may be reported as an SAE. The Sponsor 


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should be contacted and informed of all subjects for whom severe 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 ‘AEs’ on the AE page of 
(e)CRF. Illnesses and conditions such as hypotensive events, and decompensated 
cardiac disease that may lead to secondary liver abnormalities should be noted. 
Nonalcoholic 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 
predates study enrollment that may be relevant in assessing hepatic function. 
● 
Obtain a history of concomitant drug use (including nonprescription 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 the (e)CRF. Information on alcohol, other substance use, and diet 
should be entered on the LA-CRF or an appropriate document. 
● 
Obtain a history of exposure to environmental chemical agents. 
● 
Based on the subject’s history, other testing may be appropriate including:  
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 LFT’s, such as viral hepatitis, preexisting or 
acute liver disease, presence of liver metastases, 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 should be considered if: 
● 
ALT or AST > 8 × ULN 
● 
ALT or AST > 5 × ULN for more than 2 weeks (in subjects without liver metastases) 
● 
ALT or AST > 3 × ULN and TBL > 2 × ULN or INR > 1.5 (if INR testing is 
applicable/evaluated) 
● 
ALT or AST > 5 × ULN and (TBL > 2 × ULN in patients with liver metastases) 
● 
ALT or AST > 3 × 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 severe hepatic laboratory tests 
is not possible, drug should be discontinued. 


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*Hy’s Law Definition-Drug-induced jaundice caused by hepatocellular injury, without a 
significant obstructive component, has a high rate of bad outcomes, from 10 to 50% 
mortality (or transplant).” The 2 “requirements” for Hy’s Law are:1. Evidence that a drug 
can cause hepatocellular-type injury, generally has shown by an increase in transaminase 
elevations higher 3 times the upper limit of normal (“2 x ULN elevations are too common in 
treated and untreated patients to be discriminating”). 2. Cases of increased bilirubin (at least 
2 x ULN) with concurrent transaminase elevations at least 3 x ULN and no evidence of 
intra- or extra-hepatic bilirubin obstruction (elevated alkaline phosphatase)or Gilbert’s 
syndrome [Temple R. Hy's law: predicting serious hepatotoxicity. Pharmacoepidemiol Drug 
Saf. 2006 Apr;15(4):241-3]. 
Reference 
Guidance for Industry titled “Drug-Induced Liver Injury: Premarketing Clinical Evaluation” issued by 
FDA on July 2009. 


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12.3 
Common Serious Adverse Events 
The following is a list of SAEs that the Sponsor considers to be associated with the disease 
state being studied. The list does NOT change your reporting obligations or prevent the need 
to report an AE meeting the definition of an SAE as detailed in Section 5.5.2 Definition of 
Serious Adverse Events. The purpose of this list is to alert you that some events reported as 
SAEs may not require expedited reporting to the regulatory authorities based on the 
classification of “common SAEs”. You are required to follow the requirements detailed in 
Section 5.5.5 Reporting of Serious Adverse Events. 
For IND safety reporting, single occurrences of the following events may be excluded from 
expedited reporting to the FDA. If aggregate analyses of these events indicate they occur 
more frequently with study drug, an expedited IND safety report may be submitted to the 
FDA. 
● Anorexia  
● Asthenia/Fatigue 
● Dyspnea 
● Metastases to brain 
● Metastases to bone  
● Metastases to lung  
● Metastases to liver  
● Spinal cord compression 
● Nausea  
● Bone Pain  
● Metastatic breast cancer  
● Vomiting 


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12.4 
Retrospective Pharmacogenomic Sub-Study 
INTRODUCTION 
PGx research aims to provide information regarding how naturally occurring changes in a 
subject’s gene and/or expression based on genetic variation may impact what treatment options 
are best suited for the subject. Through investigation of PGx by technologies such as 
genotyping, gene sequencing, statistical genetics and Genome-Wide Association Studies 
(GWAS), the relationship between gene profiles and a drug’s kinetics, efficacy or toxicity may 
be better understood. As many diseases may be influenced by 1 or more genetic variations, 
PGx research may identify which genes are involved in determining the way a subject may or 
may not respond to a drug. 
OBJECTIVES 
The PGx research that may be conducted in the future with acquired blood samples is 
exploratory. The objective of this research will be to analyze or determine genes of relevance 
to clinical response, pharmacokinetics, and toxicity/safety issues. 
By analyzing genetic variations, it may be possible to predict an individual subject’s response 
to treatment in terms of efficacy and/or toxicity. 
SUBJECT PARTICIPATION 
Subjects who have consented to participate in this study may participate in this PGx sub-
study. As part of this sub-study, subjects must provide separate written consent prior to 
providing any blood samples that may be used at a later time for genetic analysis. 
SAMPLE COLLECTION AND STORAGE 
Subjects who consent to participate in this sub-study will provide one 5 ml tube of whole blood 
per Astellas’ instructions. Each sample will be identified by the unique subject number (first 
code). Samples will be shipped frozen to a designated banking CRO either directly from site or 
via a central laboratory as directed by Astellas. 
BANKING CRO STORAGE AND SAMPLE CODING  
Once received at the banking CRO, the samples will be assigned a unique sample code (second 
code) and stored frozen. A table linking the subject number (first code) with the 
newly-assigned sample code (second code) will be kept by the banking CRO. PGx analysis 
will be conducted using the second code only. 
PGx ANALYSIS 
Details on the potential PGx analysis cannot be established yet. Astellas may initiate the PGx 
analysis in case evidence suggests that genetic variants may be influencing the drug’s kinetics, 
efficacy and/or safety. Prior to initiating any analysis on the banked samples, the Astellas 
ethical committee (AREC) must approve the analysis plan. 


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DISPOSAL OF PGx SAMPLES/DATA 
All PGx samples collected will be stored for a period of up to 15 years following study 
database hardlock. If there is no requirement for analysis, the whole blood sample will be 
destroyed after the planned storage period. The subject has the right to withdraw consent at any 
time. When a subject’s withdraw notification is received, the PGx sample will be destroyed. 
The results of any PGx analysis conducted on a sample prior to its withdrawal will be retained 
at Astellas indefinitely. 
INFORMATION DISCLOSURE TO THE SUBJECTS 
Exploratory PGx analysis may be conducted following the conclusion of the clinical study, if 
applicable. The results of the genetic analysis will not be provided to any Investigators or 
subjects, nor can the results be requested at a later date. Any information that is obtained from 
the PGx analysis will be the property of Astellas.  


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12.5 
ECOG Performance Status 
Grade 
Description 
0 
Fully active, able to carry on all predisease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed 
or chair 
5 
Dead 
 


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12.6 
RECIST 1.1 Criteria 
The following is a summary of RECIST 1.1 criteria to be used for the study. Refer to 
Eisenhauer et al, 2009 for further details. 
Baseline Evaluations 
Assessment must occur during the Screening period. 
● 
Measurable lesions at baseline: tumor lesions must be accurately measured in at least one 
dimension and have a minimum diameter of 10 mm by CT scan when slice thickness is 
5 mm or less OR twice the slice thickness of scan if slice thickness is greater than 5 mm. 
A lesion that is 10 mm by caliper measurement by clinical exam may be considered 
measurable. Lymph nodes must have a minimum diameter of 15 mm in the short axis by 
CT scan when slice thickness is 5 mm or less. 
● 
Target Lesions: a maximum of 5 lesions and maximum of 2 lesions per organ 
representative of all organs can be recorded. 
● 
Nontarget lesions: all other lesions. 
Assessment methods: 
● 
CT, MRI: CT slice thickness should be 5 mm or less, however if it is greater than 5 mm, 
the minimum size of a measurable lesion at baseline is twice the slice thickness of the 
baseline scans. 
● 
Clinical lesions: considered measurable at baseline if they are superficial and ≥ 10 mm in 
diameter. For cutaneous and subcutaneous lesions, digital photographs with a metric 
ruler in the image must be available. Photographs must be obtained in such a manner to 
protect subject privacy. 
● 
Cytology, histology: may be used to determine if effusions are neoplastic in origin. 
Special consideration is to be given for bone lesion: 
● 
Bone scan, positron emission tomography (PET) scan or plain films are not considered 
adequate imaging techniques to measure bone lesions. However, these techniques can be 
used to confirm the presence or disappearance of bone lesions. 
● 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as CT or 
MRI can be considered as measurable lesions if the soft tissue component meets the 
definition of measurability above. 
● 
Blastic bone lesions are not measurable. 
Time Point Evaluations 
Each lesion identified at baseline must be continually tracked at each time point evaluation. 
The longest diameter for that lesion will be measured at each time point evaluation (with the 
exception of lymph nodes for which the short axis will be used in the sum of diameters). The 
sum of diameters will be recorded at each time point measurement. Lesions that become too 
small to measure must still have a numerical measurement provided. Lesions that disappear 
completely with no residual disease are to be recorded as 0 mm. Lymph nodes identified as 


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target lesions should always have the actual short axis measurement recorded (measured in the 
same anatomical plane as the baseline examination), even if the nodes regress to below 10 mm 
on study. If a lesion is still present but cannot be measured, then a default of 5 mm is to be 
recorded. If a lesion is less than 5 mm but can be measured, then the actual measurement is to 
be recorded. 
Table 3 
Evaluation of Target Lesions 
Response 
Definitions 
Complete Response (CR) 
Disappearance of all target lesions. Pathologic lymph nodes must have 
reduction in short axis to < 10 mm. 
Partial Response (PR) 
≥ 30% decrease in sum of diameters from baseline sum of target lesions. 
Stable Disease (SD) 
Neither PR nor PD. 
Progressive Disease (PD) 
≥ 20% increase in the sum of diameters from the smallest sum on study 
AND sum of diameters must be at least 5 mm increase from smallest sum 
on study. 
 
Table 4 
Evaluation of Nontarget Lesions 
Response 
Definitions 
Complete Response (CR) 
Disappearance of all non-target lesions. AND lymph nodes all  
< 10 mm in short axis. 
Non-CR/Non-PD 
Persistence of any nontarget lesions. 
Progressive Disease (PD) 
Unequivocal progression of nontarget lesions. 
 
Table 5 
Evaluation of New Lesions 
Response 
Definitions 
Unequivocal New Lesion 
Not attributable to scanning technique, imaging modality, or necrosis. 
Equivocal New Lesion 
Small lesion requiring follow-up scan, biopsy, or fluorodeoxyglucose 
positron emission tomography (FDG-PET) to confirm. 
Absent 
No new malignant lesions identified. 
 
Table 6 
Time Point Response 
Target 
Nontarget 
New  
Overall Response 
CR 
CR 
Absent 
CR 
CR 
Non-CR/Non-PD 
Absent 
PR 
CR 
Not evaluated 
Absent 
PR 
PR 
Non-PD OR not all evaluated. 
Absent 
PR 
SD 
Non-PD OR not all evaluated. 
Absent  
SD 
Not all evaluated 
Non-PD 
Absent 
NE 
PD 
Any 
Any 
PD 
Any 
PD 
Any 
PD 
Any 
Any 
Unequivocally present 
PD 
CR=complete response, PR=partial response, SD = stable disease, PD=progressive disease, NE=not evaluated.  


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Best Overall Response 
Best overall response will be assessed at the end of study for a given subject and is the best 
response across all time points. PR and CR require confirmation with equivalent or improved 
assessment no less than 4 weeks after the date of scan that PR or CR was first observed. SD 
requires confirmation with equivalent or improved assessment no less than 8 weeks after 
enrollment. 
Table 7 
Best Overall Response  
Overall Response 
First Time point 
Overall Response 
Subsequent Time point 
BEST Overall Response 
CR 
CR 
CR 
CR 
PD 
SD if ≥ 8 weeks after enrollment. 
Otherwise, PD. 
CR 
NE 
SD if ≥ 8 weeks after enrollment. 
Otherwise, NE. 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD if ≥ 8 weeks after enrollment. 
Otherwise, PD. 
PR 
NE 
SD if ≥ 8 weeks after enrollment. 
Otherwise, NE. 
NE 
NE 
NE 
CR and PR require minimum of 4 weeks duration to be considered a confirmed response. 
Stable Disease requires a minimum of 8 weeks after enrollment above to be considered a confirmed response. 
The only valid responses following an initial CR is CR, PD, and NE; otherwise the responses require review. 
Date of Progression 
Date of progression for all primary and secondary analyses will be the earliest date (either 
scan date or visit date) that PD has been documented by objective assessment. Clinical 
progression date will be collected (if applicable or if objective assessment is not available) 
for sensitivity analyses. 


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12.7 
Laboratory Assessments 
Panel/Assessment 
Parameters to be Analyzed 
Hematology 
Red blood cell count 
Hemoglobin 
Hematocrit 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin concentration 
Mean corpuscular volume 
White blood cell count 
Platelet count 
White blood cell count differential includes lymphocytes, monocytes, 
eosinophils, neutrophils, and basophils. ANC will be recorded. 
Follicle Stimulating Hormone (required at screening for 
postmenopausal women < 55 years of age) 
Biochemistry 
Albumin 
Alkaline phosphatase 
Alanine aminotransferase 
Aspartate aminotransferase 
Bicarbonate 
Blood urea nitrogen/Blood urea 
Serum Creatinine 
Calcium 
Chloride 
Glucose 
Lactate dehydrogenase 
Magnesium 
Phosphorus 
Potassium 
Sodium 
Total bilirubin (including direct and indirect if available) 
Total protein 
Uric acid 
Coagulation Studies 
International normalization ratio (with prothrombin time/prothrombin 
time percent if reported, or partial thromboplastin time ratio if 
reported) 
Activated partial thromboplastin time or partial thromboplastin time 
Urinalysis – Standard 
dipstick urinalysis 
Color 
Appearance 
Specific gravity 
pH 
Bilirubin 
Blood 
Glucose 
Ketones 
Leukocyte esterase 
Nitrite 
Protein 
Urobilinogen 
Pregnancy test - urine 
Human chorionic gonadotropin (hCG) 
 


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13 
ATTACHMENT 1:  NONSUBSTANTIAL AMENDMENT 2 
I.  The purpose of this amendment is: 
Nonsubstantial Changes 
1. Update Key Sponsor Personnel 
DESCRIPTION OF CHANGE:  
Contact details for the medical monitor/medical expert and clinical research contact are 
updated. 
 
RATIONALE: 
These revisions are made based on changes to study personnel. 
 
2. Update Planned Study Period 
DESCRIPTION OF CHANGE: 
The completion date of the study is changed from 1Q2023 to 1Q2025. 
 
RATIONALE: 
The study period is updated to reflect the expected study completion date.  
 
II.  Amendment Summary of Changes: 
IIA. Nonsubstantial Changes 
II Contact Details of Key Sponsor’s Personnel 
 
WAS: 
Medical Monitor/ 
Medical Expert: 
 
 
Astellas Pharma Global Development, Inc. 
 
 
 
 
PPD
PPD


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IS AMENDED TO: 
Medical Monitor/ 
Medical Expert: 
 
 
Astellas Pharma Global Development, Inc. 
 
 
 
 
Astellas Pharma Global Development, Inc. 
 
 
 
 
WAS: 
Clinical Research 
Contact: 
 
 
Astellas Pharma Inc 
 
 
 
IS AMENDED TO: 
Clinical Research 
Contact: 
 
 
Astellas Pharma, Inc. 
 
 
 
 
Astellas Pharma Inc 
 
 
 
IV Synopsis, Planned Study Period 
 
WAS: 
From 2Q2014 to 1Q2023 
 
IS AMENDED TO: 
From 2Q2014 to 1Q2023 1Q2025 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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14 
SPONSOR’S SIGNATURE 
Required sponsor signatures as required by ICH GCP 4.5.1 are located in the second 
attachment. 
Attachment 2 
Electronic Sponsor Signatures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SAP_003.pdf: 
Sponsor: Astellas Pharma Inc.
SAP Version 3.0
ISN/Protocol 9785-CL-1121
23-Mar-2017
Astellas
Page 1 of 34
STATISTICAL ANALYSIS PLAN
Version 3.0, dated 23-Mar-2017
A Phase 2, Multicenter, Open-label Study to Assess the Efficacy 
and Safety of Enzalutamide with Trastuzumab in Subjects with 
HER2+ AR+ Metastatic or Locally Advanced Breast Cancer
ISN/Protocol: 9785-CL-1121
EudraCT number: 2013-000093-29
IND number: 113,339
Astellas Pharma Global Development, Inc. (APGD)
1 Astellas Way,
Northbrook, IL 60062
This confidential document is the property of the sponsor.  No unpublished information 
contained in this document may be disclosed without prior written approval of the sponsor.


Sponsor: Astellas Pharma Inc.
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Table of Contents
I.
LIST OF ABBREVIATIONS AND KEY TERMS··········································· 5
1
INTRODUCTION·················································································· 8
2
FLOW CHART AND VISIT SCHEDULE···················································· 9
3
STUDY OBJECTIVE(S) AND DESIGN······················································12
3.1
Study Objective(s) ············································································12
3.1.1
Primary Objective ·······································································12
3.1.2
Secondary Objectives···································································12
3.1.3
Exploratory Objectives ·································································12
3.2
Study Design···················································································12
3.3
Randomization·················································································13
4
SAMPLE SIZE ····················································································13
5
ANALYSIS SETS ·················································································14
5.1
All Enrolled Subjects (AES)·································································14
5.2
Full Analysis Set (FAS) ······································································14
5.3
Efficacy Evaluable Set (EES)································································14
5.4
Low AR Expression Set (LARES)··························································14
5.5
Per Protocol Set (PPS)········································································15
5.6
Safety Analysis Set (SAF) ···································································15
5.7
Pharmacokinetics Analysis Set (PKAS)····················································15
5.8
Pharmacodynamic Analysis Set (PDAS)···················································15
6
ANALYSIS VARIABLES ·······································································15
6.1
Efficacy Endpoints············································································15
6.1.1
Primary Efficacy Endpoint(s)··························································15
6.1.2
Secondary Efficacy Endpoints·························································15
6.1.3
Other Efficacy Variables ·······························································16
6.2
Safety Variables···············································································16
6.3
Exploratory Endpoints········································································16
6.3.1
Pharmacokinetic Variables·····························································16
6.3.2
Pharmacodynamic Variables···························································16
6.3.3
Other Variables ··········································································17
7
STATISTICAL METHODOLOGY ···························································17


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7.1
General Considerations·······································································17
7.2
Study Population ··············································································17
7.2.1
Disposition of Subjects ·································································17
7.2.2
Protocol Deviations ·····································································18
7.2.3
Demographic and Other Baseline Characteristics ···································18
7.2.4
Previous and Concomitant Medications ··············································19
7.3
Study Drugs····················································································19
7.3.1
Exposure··················································································19
7.3.2
Treatment Compliance··································································20
7.4
Analysis of Efficacy ··········································································20
7.4.1
Analysis of Primary Endpoint ·························································20
7.4.2
Analysis of Secondary Endpoints ·····················································20
7.4.3
Analysis of Exploratory Endpoints····················································22
7.5
Analysis of Safety·············································································23
7.5.1
Adverse Events ··········································································23
7.5.2
Clinical Laboratory Evaluation ························································25
7.5.3
Vital Signs················································································25
7.5.4
Electrocardiograms (ECGs)····························································26
7.5.5
Pregnancies···············································································27
7.5.6
Other Safety-Related Observations ···················································27
7.6
Analysis of PK·················································································27
7.7
Analysis of PD·················································································27
7.7.1
Pharmacodynamic Analyses ···························································27
7.8
Subgroups of Interest ·········································································27
7.9
Interim Analysis (and Early Discontinuation of the Clinical Study)····················28
7.10
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········28
7.10.1
Missing Data ·············································································28
7.10.2
Outliers ···················································································29
7.10.3
Visit Windows ···········································································29
8
DOCUMENT REVISION HISTORY·························································30
9
REFERENCES ····················································································32
10
APPENDICES ·····················································································33
10.1
Appendix 1: Definition of Progression-Free Survival ····································33


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10.2
Appendix 2: Signatures·······································································34


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I.
LIST OF ABBREVIATIONS AND KEY TERMS
List of Abbreviations
Abbreviations
Description of abbreviations
AE
Adverse event
AR
Androgen receptor
AUC
Area under the concentration curve
BOR
Best overall response
BORR
Best overall response rate
CBR
Clinical Benefit Rate
CI
Confidence Interval
CR
Complete response
CSR
Clinical study report
CT
Computed tomography
Ctrough
Trough concentration
DHT
Dihydrotestosterone
DOR
Duration of response
ECG
Electrocardiogram
Echo
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
EOT
End of treatment
ER
Estrogen receptor
FAS
Full Analysis Set
GD
Global Development
FSH
Follicle stimulating hormone
HER2
or HER2/neu
Human epidermal growth factor receptor 2
ICF
Informed Consent Form
ICH 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IND
Investigational New Drug
IRT
Interactive response technology
ISN
International Study Number
LH
Luteinizing hormone
LVEF
Left ventricular ejection fraction
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic resonance imaging
MUGA
Multi-gated acquisition scan
N/A
Not applicable
NCI CTCAE
National Cancer Institute Common Toxicity Criteria for Adverse Events
OPT
Optional
ORR
Overall response rate
PD
Pharmacodynamic or progressive disease
PDAS
Pharmacodynamic analysis set


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Abbreviations
Description of abbreviations
PFS
Progression free survival
PgR
Progesterone Receptor
PK
Pharmacokinetic
PKAS
Pharmacokinetic Analysis Set
PPS
Per Protocol Set
PR
Partial response
PT
Preferred term
RECIST
Response evaluation criteria in solid tumors
SAF
Safety analysis set
SAP
Statistical analysis plan
SD
Stable disease
SHBG
Sex hormone binding globulin
SOC
System organ class
TEAE
Treatment emergent adverse event
TLF
Tables listings figures
TTP
Time to Progression
TTR
Time to Response
UNSCH
Unscheduled
W
Week
WHO
World health organization


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List of Key Terms
Terms
Definition of terms
Baseline
Observed values/findings which are regarded observed starting point for 
comparison. For this study, unless otherwise specified, Baseline finding are the 
findings observed just prior to the first dose of study drug (enzalutamide or 
trastuzumab).
Enroll
To enter into a clinical trial in order to begin treatment. Informed consent 
precedes enrollment.
Screening
Process for checking the eligibility of subjects usually done during the 
Screening Period and prior to Enrollment.
Screen failure
Subject that was screened but did not fulfill protocol inclusion and/or 
exclusion criteria and failed to receive study treatment, or decided not to 
participate anymore (withdrew consent) prior to completing pre-investigational 
period.
Study drug
Agents given as part of the clinical trial. In this study, enzalutamide and 
trastuzumab are study drugs.
Study period
Period of time beginning with the first subject consented through to the last 
observation collected for the study.
Variable
Any quantity, attribute, phenomenon or event that can have different 
qualitative or quantitative values.


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


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2
FLOW CHART AND VISIT SCHEDULE
Flow Chart
AR+ = androgen receptor positive, BORR = best overall response rate, CBR = clinical benefit rate, CT = computed tomography, CTx = chemotherapy, D = day, DOR = duration of response,  Echo = 
echocardiogram, EOT = end of treatment,  HER2+ = human epithelial growth factor receptor positive, LABC = locally advanced breast cancer, M = month, MBC = metastatic breast cancer, MRI = 
magnetic resonance imaging, MUGA = multi-gated acquisition scan, ORR = overall response rate, PFS = progression free survival, PK = pharmacokinetics, Q = every, TTP = time to progression, Tx = 
treatment, W = week, %ΔTM = percent change in tumor measurements.


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Assessments
Prescreen
Screen
Treatment
Follow-up
Study Week/Visit
Prior to 
screen
-4 
to -1
1
4
7
10
13
16
25 
34
40
49 and 
Q12W
UNSCH
EOT
30D FU1
Study Day
N/A
-28 
to -1
1
22
43
64
85
106
169
232
274
337+
N/A
≤ 7D 
after last 
dose
30D after 
last dose
Window (days)
N/A
N/A
0
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
+/-7
N/A
N/A
+7
Informed Consent
X
X
Initial AR expression testing2
X
Inclusion/Exclusion Criteria
X
X
Return and/or Dispense Enzalutamide
X
X
X
X
X
X
X
X
X
X
X [OPT]
X
Trastuzumab administration
To be administered Q3W
Concomitant Medications3
X
X
X
X
X
X
X
X
X
X
X
X
X
Demographics, Medical and Disease History 
X
Radiographic Disease Assessment4
X
To be performed Q8W (+/- 10 D)
X
X [OPT]
Brain Imaging5
X
X [OPT]
Height
X
Weight
X
X
X
X
X
X
X
X [OPT]
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X [OPT]
X
Adverse Events6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Laboratory Tests7
X8
X9
X
X
X
X
X
X
X
X
X
X [OPT]
X
Urine Pregnancy Test10
X
X
X
X
X
X
X
X
X
X [OPT]
X
X
Physical Examination11
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECG12
X
To be performed Q12W (+/- 14D) or according to local guidelines
X [OPT]
X
Echocardiogram/MUGA/MPS
X
To be performed Q12W (+/- 14D) or according to local guidelines
X [OPT]
ECOG PS
X
X
X
X
X
X
X
X
X
X
X
X [OPT]
X
Circulating Endocrine and Other Protein 
Markers13
X
X
X
X
X
X
X
X
X
X
X
PK Samples14
X
X
X
X
X
X
X [OPT]
Dosing Diary Review15
X
X
X
X
X
X
Tumor Tissue Collection for Central Testing16
X
Blood Sample for Genotype Analysis17
X
Optional PGx Sample18
X
Footnotes appear on next page


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1. Phone call may be conducted only if subject is unable to return to the clinic. Follow-up visit should occur approximately 30 days following the last dose of study drug, or before 
initiation of subsequent treatment (whichever is first). Subjects who discontinue treatment for a reason other than disease progression will continue to have tumor assessment 
performed according to the protocol schedule until progression, initiation of new therapy, or withdrawal of consent 
2. Testing of archival tissue for AR expression can be done before initiation of other screening activities under a separate pre-screen consent form. Results for AR expression from 
local pathology can be used for enrollment.  
3. Medications taken within 14 days before the Screening visit and up to 30 Day-Follow-up visit will be collected.
4. CT/MRI of the chest/abdomen/pelvis as well as any other anatomical region appropriate for that subject’s disease must be performed within 28 days prior to day 1. Results from 
CT/MRI assessments performed prior to consent and within 28 days of day 1 may be used for screening if available. All patients should have a bone imaging assess metastasis to 
the bone within 6 months prior to the Day 1 visit. Thereafter, subjects without bone metastasis will have bone scans only if clinically indicated. PR and CR require confirmation 
with equivalent or improved assessment no less than 4 weeks after the date of scan that PR or CR was first observed.
5. Brain imaging is required at Screening for all subjects to rule out central nervous system disease.A brain MRI with contrast enhancement is required unless it cannot be performed 
within 2 weeks prior to Day 1due to feasibility or subject-specific contraindications. A head CT may be performed in these situations after discussion with the medical monitor or 
designee.
6. Adverse Events will be collected from the time of informed consent through 30 days following last dose of study drug or through the day prior to initiation of alternate treatment 
(whichever occurs first). 
7. Clinical Laboratory Assessments include hematology, chemistry, and local urine dipstick. Coagulation panel will be performed at Screening for all subjects and only at each visit if 
subject is on anti-coagulant therapy.
8. Local FSH testing is required at screening for postmenopausal women who are < 55 years of age.
9. Day 1 clinical laboratory tests do not need to be repeated if Screening labs were performed within 7 days prior to Day 1.
10.Urine pregnancy test will be performed in women of child-bearing potential. Testing at treatment visits must occur prior to study drug administration. 
11.Physical exam performed prior to ICF and within 7 days of the screening visit may be used for screening if available.
12.All on-treatment ECGs will be obtained prior to drug administration. In addition, whenever a study procedure coincides with the scheduled time point for an ECG, the study 
activities should be undertaken in a fixed sequence if possible: ECGs first, vital signs second, and any type of blood draw as the last assessment.
13.Blood samples to measure circulating endocrine levels and other protein markers will be obtained. Blood sample should be obtained prior to study drug administration at the Day 1 
visit and at approximately the same time of day at each following visit.
14.Pre-dose plasma PK samples will be collected prior to enzalutamide intake and will be analyzed for enzalutamide and N-desmethyl enzalutamide. Pre-dose serum PK samples will 
be collected prior to the start of the trastuzumab infusion and will be analyzed for trastuzumab. Enzalutamide and trastuzumab will be administered in clinic on PK days. 
15.A dosing diary will be dispensed to the subject on Day 1. Date and time of enzalutamide dose will be recorded in the diary by the subject for the 2 days prior to each PK sample.
16.All subjects are required to have tissue sample available to send for central lab confirmation of AR expression at screening visit. 
17.A blood sample is taken to allow evaluation of potential AR mutations and another sample is taken to allow for genotype analysis of relevant metabolism, transporter, PD, and/or 
safety genes, in the event of unusual PK/PD patterns or safety findings.
18. Optional exploratory retrospective, PGx for those subjects who consent to the sub-study.


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3
STUDY OBJECTIVE(S) AND DESIGN
3.1
Study Objective(s)
3.1.1
Primary Objective
To evaluate the efficacy of enzalutamide with trastuzumab in evaluable subjects with human 
epidermal growth factor receptor 2 positive (HER2+), androgen receptor positive (AR+), 
metastatic or locally advanced breast cancer, as measured by Clinical Benefit Rate (CBR24),
defined as the proportion of evaluable subjects with best objective response of confirmed CR 
or PR per RECIST 1.1, or prolonged SD (≥ 24 weeks).
3.1.2
Secondary Objectives
●
To evaluate the following efficacy measures:
o
Best Overall Response Rate (BORR)
o
Overall Response Rate (ORR) at 24 weeks
o
Progression Free Survival (PFS)
o
Time to Progression (TTP)
o
Duration of Response (DOR) 
o
Time to Response (TTR)
●
To evaluate the safety and tolerability.
3.1.3
Exploratory Objectives
●
 
 
 
 
 
3.2
Study Design
This is a multinational, multicenter, open-label, single-arm, two-stage, Phase 2 study 
evaluating the efficacy, safety, and tolerability of enzalutamide with trastuzumab. The study 
population includes female subjects with HER2+, AR+, metastatic or locally advanced breast 
cancer who have progressed on at least 1 prior line of anti-HER2 therapy in the metastatic or 
advanced setting. Subjects may be either ER/PgR positive or negative according to the local 
assessment for hormone receptor diagnostic. A line of therapy is defined as a course of 
treatment at the end of which there was disease progression, toxicity, or in the investigator’s 
opinion, maximum benefit has been achieved. Approximately 50 centers in North America 
and Europe will conduct the study. Approximately 80 subjects will be enrolled to reach 66 
evaluable AR+ subjects.
A Simon’s two-stage design is implemented to allow for early termination if < 3 of 21 
evaluable AR+ subjects show clinical benefit [confirmed complete response (CR), partial 


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response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1,
criteria or prolonged stable disease (SD) ≥ 24 weeks] at the analysis of the first stage. If ≥ 3 
of 21 evaluable AR+ subjects show clinical benefit, then a second stage will continue to 
enroll a total of 66 evaluable AR+ subjects.
Subjects will enter the screening period up to 28 days prior to treatment start. Subjects will be 
allowed to pre-screen under a separate consent form to enable testing of archival tissue for 
AR expression before initiation of other screening activities. After completion of screening 
assessments, eligible subjects will enter into the treatment phase to receive enzalutamide with 
trastuzumab. Study visits will take place every 3 weeks until week 16, then at weeks 25, 34, 
40, and 49, and then every 12 weeks thereafter until the subject meets discontinuation criteria 
or the study ends. Tumor assessments will be performed every 8 weeks through week 49, 
and then every 12 weeks thereafter. Subjects will continue on treatment until disease 
progression, unacceptable toxicity, or any other discontinuation criteria are met. Subjects 
who discontinue study drug for a reason other than disease progression will continue to have 
tumor assessments performed, when possible, according to the protocol schedule until
disease progression, initiation of new therapy, or withdrawal of consent. Upon 
discontinuation of study drug, subjects will enter the follow-up period. An end of treatment 
visit will be performed within 7 days of the last dose of enzalutamide. The Follow-up Visit 
will be performed 30 days after the last dose of enzalutamide or before initiation of 
subsequent treatment (whichever occurs first); this visit may be conducted by phone call if 
the subject is unable to return to the clinic. The treatment emergent period will be defined as 
the period of time from the first dose date of study drug to 30 days after the last dose date of 
study drug or the start of subsequent treatment (whichever occurs first). All adverse events 
that occur during the collection period are to be followed up until resolved or judged to be no 
longer clinically significant, or until they become chronic to the extent that they can be fully 
characterized.
If the study is terminated early for reasons other than safety, and the subject is receiving 
clinical benefit per investigator judgment, the subject may continue on study medication until 
they have disease progression as defined per RECIST.  
3.3
Randomization
This is a single arm study. All subjects will receive the same treatment. An Interactive 
Response Technology (IRT) system will be used to register subjects and to assign specific 
enzalutamide containers by packaging lot to subjects. Specific procedures for the IRT are 
contained in a separate IRT procedures manual.
4
SAMPLE SIZE
The sample size is sufficient to determine the absence or presence of an efficacy signal. The 
sample sizes for the first and second stage were determined using optimal Simon’s two-stage 
design. The null hypothesis that the true CBR is 10% will be tested against a one-sided 
alternative at a 5% significance level. In the first stage, 21 evaluable subjects will be 
evaluated; the study will stop if < 3 evaluable subjects show CR, PR, or SD ≥ 24 weeks. 


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Otherwise, the study will continue to enroll up to 66 evaluable subjects. This design has a 
statistical power of 90% when the true CBR is 25% (East version 5.4, Cytel Inc).  To 
illustrate the precision with a total of 66 subjects: if the observed CBR is 40%, then the 90% 
confidence interval will be within the 30% to 50% range.
Taking into account the number of non-evaluable subjects, approximately 80 subjects will be 
enrolled to get 66 evaluable subjects.
5
ANALYSIS SETS
In accordance with International Conference on Harmonization (ICH) recommendations in 
guidelines E3 and E9, the following analysis sets will be used for the analyses.
Detailed criteria for analysis sets will be laid out in Classification Specifications (CS) and the 
allocation of subjects to analysis sets will be determined prior to database hard lock.
For the determination of the percentage tumor cells with nuclear expression, the Ventana 
assay will be used.
5.1
All Enrolled Subjects (AES)
The All Enrolled Subjects (AES) consists of all subjects who are found to be eligible for 
treatment and enrolled using the IRT at the Day 1 visit.
5.2
Full Analysis Set (FAS)
The Full Analysis Set (FAS) consists of all enrolled subjects who have centrally assessed 
AR+ breast cancer (defined as >10% of tumor cells with nuclear expression), and received at 
least one dose of study drug.
5.3
Efficacy Evaluable Set (EES)
The Efficacy Evaluable Set (EES) is a subset of the FAS defined as all enrolled subjects who 
have centrally assessed AR+ breast cancer (defined as >10% of tumor cells with nuclear 
expression), received at least one dose of study drug, and have at least one available post 
baseline tumor assessment.
The selection of subjects for the FAS and EES will be confirmed in the Analysis Set 
Classification Meeting (ASCM).
The primary analyses will be done on the EES, while all efficacy analyses will be done on 
both the EES and FAS. 
5.4
Low AR Expression Set (LARES)
In the event that more than 5 subjects have a central assessment of AR+ expression less than 
10%, an additional analysis set will be defined for the primary efficacy end-point.
The Low AR Expression Set (LARES) consists of enrolled subjects who received at least one 
dose of study drug, and had central assessment of AR+ expression <10%.


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5.5
Per Protocol Set (PPS)
PPS is not defined for this study and separate analyses will not be performed on a PPS.
5.6
Safety Analysis Set (SAF)
The Safety Analysis Set (SAF) consists of all subjects who have received at least 1 or partial 
dose of study drug.
The SAF will be used for the statistical summary of the safety data.
5.7
Pharmacokinetics Analysis Set (PKAS)
The pharmacokinetic analysis set (PKAS) consists of the subset of the SAF population for 
which at least one quantifiable enzalutamide, N-desmethyl enzalutamide, or trastuzumab
concentration value is available. Additional subjects may be excluded from the PKAS at the 
discretion of the pharmacokineticist. Any formal definitions for exclusion of subjects or 
time-points from the PKAS will be documented in the Classification Specifications.
The PKAS will be used for all tables and graphical summaries of the PK data.
5.8
Pharmacodynamic Analysis Set (PDAS)
The pharmacodynamic analysis set (PDAS) will include the subjects from the SAF 
population for whom sufficient pharmacodynamic measurements (a baseline and at least one 
post-baseline sample) were collected. The PDAS will be used for all analyses of 
pharmacodynamic data.
Any formal definitions for exclusion of subjects from the PDAS will be documented in the 
Classification Specifications.
The PDAS will be used for all analyses of pharmacodynamic data.
6
ANALYSIS VARIABLES
6.1
Efficacy Endpoints
6.1.1
Primary Efficacy Endpoint(s)
The Primary Efficacy Endpoint is Clinical Benefit Rate (CBR). CBR is defined as the 
proportion of evaluable subjects with best objective response of confirmed CR, PR per 
RECIST 1.1, or prolonged SD (≥ 24 weeks).  
6.1.2
Secondary Efficacy Endpoints
The Secondary Efficacy Endpoints include:
●
Overall response rate (CR or PR) according to RECIST 1.1 criteria.
●
Best overall response rate according to RECIST 1.1.
●
PFS, defined as the time from the date of first dose of enzalutamide until the date of 
disease progression per RECIST 1.1 or death from any cause on study (death within 
168 days after treatment discontinuation), whichever occurs first.


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●
TTP, defined as the time from the first date of enzalutamide treatment until the date of 
disease progression per RECIST 1.1.
●
DOR, defined as the time from the date of first documentation of response (CR or PR) 
until the date of disease progression per RECIST 1.1.
●
TTR, defined as the time from the first date of enzalutamide treatment to initial CR or 
PR.
6.1.3
Other Efficacy Variables
Percent change of tumor diameter in target lesions based on the smallest value post-baseline.
6.2
Safety Variables
Safety will be assessed by evaluation of the following variables:
●
Treatment-emergent adverse events (TEAEs; any, CTCAE grade, seriousness, action 
taken and relationship to study drug).
●
Clinical laboratory variables (hematology, biochemistry including liver tests, coagulation 
parameters and urinalysis)
●
Vital signs (systolic and diastolic blood pressure and pulse rate)
●
12-lead electrocardiogram (ECG)
●
Left ventricular ejection fraction (LVEF) by echocardiogram or multi-gated acquisition 
scan (MUGA).
TEAE is defined as an adverse event observed during the treatment emergent period, which 
is from the first dose date of study drug to 30 days after the last dose date of study drug or the 
start of subsequent treatment or date of death, whichever is first. If the adverse event occurs 
on Day 1 and the onset check box is marked “Onset after first dose of study drug” or the 
onset check box is left blank, then the adverse event will be considered treatment emergent. 
If the adverse event occurs on Day 1 and the onset check box is marked “Onset before first 
dose of study drug”, then the adverse event will not be considered treatment emergent.
A drug-related TEAE is defined as any TEAE with at least possible relationship to study 
treatment as assessed by the investigator or with missing assessment of the causal 
relationship.
6.3
Exploratory Endpoints
6.3.1
 
6.3.2
 
 


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6.3.3
 
 
 
  
7
STATISTICAL METHODOLOGY
7.1
General Considerations
Prior to database lock, a Final Review of Data and Tables, Listings and Figures (TLFs)
meeting will be held to allow a review of the clinical trial data and to verify the data that will 
be used for analysis set classification. If required, consequences for the statistical analysis 
will be discussed and documented.  A meeting to determine analysis set classifications may 
also be held prior to database lock.
In general, all data will be summarized with descriptive statistics (number of subjects, mean, 
median, standard deviation, minimum, and maximum) for continuous endpoints, and 
frequency and percentage for categorical endpoints.
For continuous variables, descriptive statistics will include the number of subjects (n), mean, 
standard deviation, median, minimum and maximum. When needed, the use of other 
percentiles (e.g. 10%, 25% [Q25], 75% [Q75], and 90%) will be mentioned in the relevant 
section. Frequencies and percentages will be displayed for categorical data. Percentages by 
categories will be based on the number of subjects with no missing data, i.e. will add up to 
100%.
All data processing, summarization, and analyses will be performed using SAS® Version 9.3
or higher on Unix. Specifications for tables, figures, and data listing formats can be found in 
the TLF specifications for this study.
7.2
Study Population
7.2.1
Disposition of Subjects
Number and percentage of subjects screened, discontinued before enrollment, and enrolled 
will be presented for all subjects screened.
The following subject data will be presented for the AES:
●
Number and percentage of subjects in each analysis set;
●
Number and percentage of subjects discontinued treatment, by primary reason for 
treatment discontinuation;
●
Number and percentage of subjects discontinued study, by primary reason for treatment 
discontinuation;
●
Number and percentage of subjects completed the study. 


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Number and percentage of subjects enrolled in each country and site will be presented for the 
All Enrolled Subjects Set.
The duration from date of first intake/administration of study drug to date of permanent 
treatment discontinuation due to any primary reason will be analyzed by Kaplan-Meier 
method for SAF. For subjects in whom no event occurs within the reporting period the 
censoring date will be date of last medication intake. The number of subjects who already 
experienced a treatment discontinuation due to any reason, the number of subjects still at risk 
and Kaplan-Meier estimates with two-sided 95% CI of cumulative incidence will be 
presented at the following time points: Days 22, 43, 64, 85, 106, 169, 232, 274, 337 and 
thereafter every 84 days as appropriate.
7.2.2
Protocol Deviations
Protocol deviations as defined in the study protocol (Section 7.8 Protocol Deviations) will be 
assessed for the AES.  The number and percentage of subjects meeting any criteria will be 
summarized for each criterion and overall as well as by study site. Subjects deviating from a 
criterion more than once will be counted once for the corresponding criterion. Any subjects 
who have more than one protocol deviation will be counted once in the overall summary. A 
data listing will be provided by site and subject.
The protocol deviation 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
Demographic and Other Baseline Characteristics
Demographic and disease history will be summarized by descriptive statistics for the SAF, 
FAS, EES and LARES.
For demographics table, descriptive statistics will be presented for age, weight, body mass 
index (BMI) and height at study entry.  Frequency tabulations for ethnicity, age group (≤ 65, 
66-75, and >75 yr) and race will be presented. Descriptive statistics will include number of 
subjects, mean, standard deviation, minimum, median and maximum for continuous 
endpoints, and frequency and percentage for categorical endpoints.
For disease history table, descriptive statistics will be presented for time from initial 
diagnostis. Frequency tabulations will be presented for histopathology at diagnosis, 
histologic grade, anatomic staging, primary tumor stage, regional lymph node stage 
(clinical/pathological), distant metastasis, HER2 Status, HER2 testing method confirming 
HER2 status, ER status, PgR status, AR+ status (Nuclear staining by Ventana), and number 
of lines of prior therapy. Two scatter plots will be made to access the correlation of the 


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percentage of AR+ between Ventana and Dako, for 1) Nuclear staining, and 2) cytoplasmic 
staining.
Prior cancer procedures treatment will be summarized for the SAF.
Medical history is coded in MedDRA, and will be summarized by System Organ Class 
(SOC) and Preferred Term (PT) as well as by PT alone, for the SAF.
7.2.4
Previous and Concomitant Medications
Previous medications are coded with WHO-DD, and will be summarized by therapeutic 
subgroup (ATC 2nd level) and chemical subgroup (ATC 4th level) and preferred WHO name 
for the SAF. 
As with previous medication, concomitant medication will be summarized by therapeutic 
subgroup (ATC 2nd level) and chemical subgroup (ATC 4th level) and preferred WHO name 
for the SAF. Subjects taking the same medication multiple times will be counted once per 
medication and investigational period. A medication which can be classified into several 
chemical and/or therapeutic subgroups is presented in all chemical and therapeutic subgroups.
7.3
Study Drugs
7.3.1
Exposure
7.3.1.1 Enzalutamide
The following information on drug exposure will be presented for the SAF:
●
Descriptive statistics for cumulative amount of the drug a subject was exposed to and 
average daily dose; and
●
Number and percent of subjects with dose decreases or interruptions.
Duration of exposure will be summarized in two ways:
●
Summary statistics, including quantiles, will be presented for subjects in the SAF.
●
Exposure time will be categorized according to the following categories by study drug:
○
less than 3 months
○
at least 3 months and less than 6 months
○
at least 6 months.
Counts and percentages of subjects in each of these categories will be summarized for 
the SAF.
7.3.1.2 Trastuzumab
Summaries for the following data will be provided for Trastuzumab:
●
Number of Infusion Started
●
Number of Completed Infusion Administration
●
Number of Incomplete Infusion Administration
●
Reason for dose interruption/discontinuation.


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Summary statistics, including quantiles, will be provided for each of these variables for 
subjects in the SAF.
7.3.2
Treatment Compliance
Overall compliance with the dosing schedule will be examined for subjects in the SAF whose 
total study drug count and first and last days of treatment are known.
Percent overall compliance for Enzalutamide and Trastuzumab will be summarized in two 
ways for the SAF:
●
Descriptive statistics will be presented by study drug.
●
Percent compliance will be categorized according to the following categories by study 
drug:
○
less than 80%
○
at least 80%, less or equal to 90%
○
greater than 90%
and also as:
○
less than 80%
○
greater or equal than 80%

Treatment compliance of enzalutamide is defined as:
(Total amount of study drug actually consumed per subject) / (Amount of study drug that 
should have been taken [=number of days on study drug x 4 capsules] per subject) * 100
●
Treatment compliance of trastuzumab is defined as the percentage of the number of 
completed infusions per patient over total infusions per patient * 100. Total infusion is 
the number of completed, incomplete or missed infusion administrations.
7.4
Analysis of Efficacy 
The primary analyses will be done in the EES, while all efficacy analyses will be done in 
both the EES and FAS. If more than 5 subjects are enrolled into the study but had less than 
10% of tumor cells with nuclear expression, and received at least one dose of study drug, the 
efficacy analyses will also be conducted on this analysis set (LARES).
7.4.1
Analysis of Primary Endpoint
The primary efficacy endpoint, CBR, will be presented using descriptive statistics and will be 
summarized including 95% two-sided exact confidence intervals (CIs).  Clopper-Pearson 
method will be used for exact intervals.
The primary analysis will be done on the EES. Same analysis will also be done on FAS, and 
on LARES (analysis set with AR+ less than 10%, if more than 5 subjects enrolled, took at 
least one dose of study medication, and had central assessment of AR expression <10%).
Analysis will also be done on the data from the combined FAS and LARES.
7.4.2
Analysis of Secondary Endpoints
All variables will be presented as descriptive statistics. ORR, and BORR will be summarized 
including 95% two-sided exact CIs (Clopper Pearson Method).  Kaplan-Meier curves will be 


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calculated to estimate the median (95% CI), Q25 and Q75 times for duration (DOR), 
progression free times (PFS), and times to Progression (TTP) and to Response (TTR).
7.4.2.1 Overall Response Rate
Overall response rate (CR or PR) is defined according to RECIST 1.1 criteria.
7.4.2.2 Best Overall Response Rate
Best overall response rate is defined according to RECIST 1.1. Two sets of analysis will be 
conducted: one with confirmed PR/CR, and one without confirmation.  Sponsor-derived Best 
Overall Response (BOR) will be used in the analysis. If there is a discrepancy between the 
investigator rated BOR and sponsor-derived BOR, a sensitivity analysis will be done using 
investigator rated BOR.  Both derived and investigator rated BOR will be presented in 
listing.
7.4.2.3 Progression-Free Survival
PFS is defined as the time from the date of first dose of enzalutamide until the date of disease 
progression per RECIST 1.1, or death from any cause on study (death within 168 days after 
treatment discontinuation), whichever occurs first. For analysis data will be used up to and 
including the cut-off date. The following subjects will be censored at the date of the last 
radiological assessment showing no progression: 1) subjects who initiated another anti-tumor 
therapy before documented PD or death, 2) subjects who progressed or died after missing 
two or more consecutive radiological assessments. Subjects are considered to have missed 
two or more consecutive radiological assessments if duration between two consecutive 
imaging scans are more than 20 weeks while on treatment or more than 30 weeks off-
treatment. Subjects who have no valid post-baseline tumor assessment will be censored at 
first dose of enzalutamide.
A sensitivity analysis will be done with the rule listed above, except that initiation of another 
anti-tumor therapy will be considered as an event.
7.4.2.4 Time to Progression
TTP is defined as the time from the first date of enzalutamide treatment until the date of 
disease progression per RECIST 1.1. The following subjects will be censored at the date of 
the last radiological assessment showing no progression: 1) subjects who initiated another 
anti-tumor therapy before documented PD; 2) subjects who progressed after missing two or 
more consecutive radiological assessments; 3) subjects who died before disease progression.  
Subjects are considered to have missed two or more consecutive radiological assessments if 
duration between two consecutive imaging scans are more than 20 weeks while on treatment 
or more than 30 weeks off-treatment. Subjects who have no valid post-baseline tumor 
assessment will be censored at first dose of enzalutamide.
7.4.2.5 Duration of Response
DOR is defined as the time from the date of first documentation of response (CR or PR) until 
the date of disease progression per RECIST 1.1. DOR is defined for subjects who achieved 


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BOR of CR or PR only. The following subjects will be censored at the date of the last 
radiological assessment showing no progression: 1) subjects who initiated another anti-tumor 
therapy before documented PD; 2) subjects who progressed after missing two or more 
consecutive radiological assessments; 3) subjects who died before disease progression.  
Subjects are considered to have missed two or more consecutive radiological assessments if 
duration between two consecutive imaging scans are more than 20 weeks while on treatment 
or more than 30 weeks off-treatment. Subjects who have no valid post-baseline tumor 
assessment will be censored at first dose of enzalutamide.
For subjects with confirmed CR or confirmed PR, duration of response will be analyzed 
using Kaplan-Meier estimates, and the median with corresponding two-sided 95% CI will 
also be reported.
7.4.2.6 Time to Response
TTR is defined as the time from the first date of enzalutamide treatment to initial CR or PR.
For subjects with a confirmed CR or confirmed PR, simple descriptive statistics will be 
presented.
7.4.3
Analysis of Exploratory Endpoints
Waterfall plot will be done for percent change of tumor diameter in target lesions.
7.4.3.1
 
 
 
 
 
 
 
 
n 


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7.4.3.2
 
 
 
 
 
 
7.4.3.3
 
 
 
7.5
Analysis of Safety
Safety will be assessed on an ongoing basis by physical examination, measurement of vital 
signs, laboratory assessments, 12-lead ECGs, left ventricular ejection fraction (LVEF) by 
echocardiogram or multi-gated acquisition scan (MUGA), and evaluation of adverse 
events/serious adverse events.
Safety analyses will be conducted using the SAF and restricted to the treatment emergent 
period. The SAF is defined as all subjects who have initiated at least 1 or partial dose of 
study drug. The treatment emergent period will be defined as the period of time from the first 
dose date of study drug to 30 days after the last dose date of study drug or the start of 
subsequent treatment (whichever is first). Only data within this period will be summarized in 
safety analysis. Safety will be assessed through descriptive statistics for the frequency of 
adverse events by system organ class (SOC), preferred term (PT), and NCI CTCAE grade, 
the frequency of treatment discontinuations due to adverse events, vital signs, ECG, LVEF, 
and laboratory evaluations.
7.5.1
Adverse Events
The severity of all adverse events is to be evaluated by the Investigator based on the NCI 
CTCAE, version 4.03. All adverse events will be coded to preferred term and system organ 
class using Medical Dictionary for Regulatory Activities (MedDRA).
The number and percentage of subjects with treatment emergent adverse events will be 
presented by MedDRA system organ class and preferred term, relationship to study 
treatment, and NCI CTCAE grade. A subject reporting the same adverse event more than 


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once is counted once and at the maximum severity or strongest relationship to study drug 
treatment, when calculating incidence.
The coding dictionary for this study will be MedDRA. It will be used to summarize AEs by 
SOC and PT.
An overview table will include the following details:
●
Number of TEAEs,
●
Number and percentage of subjects with TEAEs,
●
Number of drug related TEAEs,
●
Number and percentage of subjects with drug related TEAEs,
●
Number of serious TEAEs,
●
Number and percentage of subjects with serious TEAEs,
●
Number of serious drug related TEAEs,
●
Number and percentage of subjects with serious drug related TEAEs,
●
Number of TEAEs leading to permanent discontinuation of study drug,
●
Number and percentage of subjects with TEAEs leading to permanent discontinuation of 
study drug, 
●
Number of drug related TEAEs leading to permanent discontinuation of study drug,
●
Number and percentage of subjects with drug related TEAEs leading to permanent 
discontinuation of study drug, 
●
Number of deaths,
●
Number and percentage of subjects with TEAEs leading to dose reduction,
●
Number and percentage of subjects with TEAEs leading to interruption.
The number and percentage of subjects with TEAEs, as classified by SOC and PT will be 
summarized. Summaries will be provided for:
●
TEAEs,
●
Drug related TEAEs,
●
Grade 3 or higher TEAEs.
●
Serious TEAEs, 
●
Drug related serious TEAEs,
●
TEAEs leading to dose reduction of enzalutamide, 
●
Drug related TEAEs leading to dose reduction enzalutamide, 
●
TEAEs leading to permanent discontinuation of study drug,
●
Drug related TEAEs leading to permanent discontinuation of study drug,
●
Common TEAEs that equal to or exceed a threshold of 5% of the subjects,
●
TEAEs of interest. 
TEAEs and the number and percentage of subjects with TEAEs, as classified by SOC and PT 
will also be summarized by grade and by relationship to study drug. If an adverse event 
changes in grade or relationship, then the subject will be counted only once with the 
maximum grade and highest degree of relationship. The adverse event however will be 
presented in each category they were classified to. If a subject has an event more than once 


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with missing grade/relationship and with non-missing grade/relationship, then the subject 
will be counted as missing. Drug related TEAEs will be presented in a similar way by grade
only.
The Always Serious Terms (AST) List is a list of AEs that a Sponsor determines regardless 
of Investigator assessment are to be captured as serious. Serious TEAEs table will include 
both investigator reported and Astellas upgraded ones according to AST list.  In the listing 
they will be presented with different flag.
The number and percentage of subjects with treatment-emergent adverse events of interest, as 
classified by SOC and PT will also be summarized.  The list of adverse events of interest to 
be summarized may change during the course of the study due to ongoing pharmacovigilance.  
It will be finalized before the database hard lock.
7.5.2
Clinical Laboratory Evaluation
For selected quantitative laboratory parameter, summary statistics of change from baseline 
value by visit will be presented. The baseline laboratory value is defined as the last 
laboratory value collected on or prior to the first dose date of enzalutamide or trastuzumab.
Using the definitions provided in the NCI-CTCAE Version 4.03, lab values will be classified 
as Grade 1 through 4, where possible.  For each lab parameter at each scheduled collection 
time point, the number and percentage of subjects who have lab values within the categories 
defined by each of the grades will be displayed.  If a subject has multiple lab values that fall 
into more than one NCI-CTCAE grade, the highest NCI-CTCAE grade will be displayed for 
that subject. In the event the NCI-CTCAE grade is listed as > ULN or < LLN, the normal 
ranges of local labs will be used for the purposes of comparison.  These values are 
maintained by the Data Management group using the New England Journal of Medicine SI 
Unit Conversion Guide as a reference.
Shift tables will be created for each of the lab parameters after classifying by NCI-CTCAE
criteria.  Shift from baseline to the highest NCI-CTCAE grade will be presented. Shift tables 
for high and low abnormalities will be summarized separately.
Grade 3 and higher lab abnormalities will also be summarized by number and percent, by 
visit and overall during the study.
7.5.2.1 Liver Tests 
The number and percentage of subjects with potentially clinically significant values in liver 
tests will be presented.  A drug induced liver injury (DILI) table will also be generated.
7.5.3
Vital Signs
Vital signs (systolic blood pressure, diastolic blood pressure, and pulse rate) will be 
summarized using n, mean, standard deviation, minimum, maximum and median by visit. 
Additionally, a within-subject change will be calculated as the post-baseline measurement 
minus the baseline measurement and summarized by visit.


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The number and proportion of subjects experiencing potentially clinically significant 
abnormalities during the treatment-emergent period will be summarized.  The definitions of 
potentially clinically significant abnormalities are provided in the table below.
Parameter
Criteria for Potentially Clinically Significant Abnormalities
Systolic blood 
pressure
Absolute result > 180 mm Hg and increase from baseline > 40 mm Hg
Absolute result < 90 mm Hg and decrease from baseline > 30 mm Hg
Final visit or 2 consecutive visits results ≥20 mm Hg change from baseline
Most extreme post baseline result ≥140 mm Hg
Most extreme post baseline result ≥180 mm Hg
Most extreme result ≥180 mm Hg and ≥20 mm Hg change from baseline
Most extreme result ≥140 mm Hg and ≥20 mm Hg change from baseline
Diastolic blood 
pressure
Absolute result > 105 mm Hg and increase from baseline >30 mm Hg
Absolute result < 50 mm Hg and decrease from baseline >20 mm Hg
Final visit or 2 consecutive visits results ≥15 mm Hg change from baseline
Most extreme post-baseline result ≥90 mm Hg
Most extreme post-baseline result ≥105 mm Hg
Most extreme result ≥105 mm Hg and ≥15 mm Hg change from baseline
Most extreme result ≥90 mm Hg and ≥15 mm Hg change from baseline
Pulse Rate
Absolute result >120 bpm and increase from baseline >30 bpm
Absolute result < 50 bpm and decrease from baseline >20 bpm
bpm, beats per minute; mm Hg, millimeters of mercury.
7.5.4
Electrocardiograms (ECGs)
Number and percent of subjects with normal, not clinically significant abnormal, and 
clinically significant abnormal results for the 12-lead ECG will be tabulated by visit.
The QTc interval will be summarized using frequency tables for each time point for values of 
clinical importance using the range criteria below.
QTc Interval Criteria Values
Normal
Borderline
Prolonged
Clinically significant
≤ 450 msec
> 450  and ≤480 msec
> 480  and ≤500 msec
> 500 msec
QT data using Fredericia’s (QTcF) and Bazett’s (QTcB) correction will be used for the 
categorization:
●
QTcF: QT interval corrected for heart rate using Fridericia's formula = QT/√

.
●
QTcB: QT interval corrected for heart rate using Bazett's formula = QT/√

Note: for the calculations the value of RR should be in seconds (not milliseconds).
The QTc interval (QTcF and QTcB) will also be summarized by the frequencies of subjects 
with a change from baseline of clinical importance using the criteria identified below. These 
summaries will be provided for each time point. 


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Variable
Change from Baseline
QTc Interval (msec)
<0 msec
≥ 0   and  ≤30 msec
> 30 and  ≤60 msec
> 60 msec
7.5.5
Pregnancies
A detailed listing of all pregnancies will be provided.
7.5.6
Other Safety-Related Observations
7.5.6.1 Physical Examination
All clinically significant abnormal findings will be recorded as baseline conditions or adverse 
events and graded using NCI-CTCAE guidelines. There will be no separate summary report 
for physical exams. Instead, any findings from physical exams will be summarized and 
reported as part of baseline conditions or adverse events.
7.5.6.2 LVEF
Descriptive statistics will be used to summarize LVEF data and changes from baseline data 
by time point.
7.5.6.3 ECOG
Descriptive statistics will be used to summarize ECOG data and changes from baseline data 
by time point.
7.6
Analysis of PK
Pharmacokinetic analyses will be conducted using the PKAS.
The enzalutamide, N-desmethyl enzalutamide, and trastuzumab concentration-time data will 
be summarized by descriptive statistics at each visit.  Additional model-based analyses may 
be performed and will be described in a separate population PK analysis plan.
7.7
Analysis of PD
7.7.1
Pharmacodynamic Analyses
Circulating hormones and protein markers will be expressed as the change in absolute value 
and percent change from baseline at each visit and presented using descriptive statistics.
Additional model-based analyses to explore PK-PD relationships may be performed and will 
be described in separate PK analysis plan.
7.8
Subgroups of Interest
Subgroup analysis will be done on the primary endpoint based on number of lines of prior 
therapy (1-2, 3-4 or >4) in the metastatic or locally advanced disease setting, and ER/PgR 
status of the subjects. The latter implies that the subgroup analysis will be done on:
●
Subjects with negative ER status and negative PgR status, and 
●
Subjects positive ER and/or positive PgR status.


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Analyses will be done on the EES.
7.9
Interim Analysis (and Early Discontinuation of the Clinical Study)
Recruitment will continue if there are 3 or more subjects with clinical benefit in the first 
21 evaluable subjects from the evaluable set. If there are less than three subjects who 
demonstrate CBR, recruitment will be stopped.
Tumor response will be monitored continuously throughout Stage 1, therefore it is expected 
that the decision to expand enrollment using the CBR after 24 weeks will be made before the 
21st subject is evaluated.
Once the 21st evaluable subject reaches week 24, a data cut will be applied for stage one data.  
Planned efficacy and safety analysis will be done on stage 1 data for EES, FAS, and SAF.
7.10
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information
As a general principle, no imputation of missing data will be done. Exceptions are the start 
and stop dates of AEs and concomitant medication. The imputed dates will be used to allocate 
the concomitant medication and AEs to a treatment period, in addition to determining whether 
an AE is/is not treatment emergent. Listings of the AEs and concomitant medications will 
present the actual partial dates; imputed dates will not be shown.
7.10.1
Missing Data
Subjects who do not satisfy the criteria to be counted as responders or have insufficient data 
to determine or confirm a response per the RECIST 1.1 Criteria will be considered as 
non-responders in the primary final analysis of response rates.  No imputation of data will be 
done to determine individual subject response.
For continuous variables (e.g., clinical laboratory measurement, vital signs), subjects with 
missing baseline variable will be excluded from the analysis of change from baseline.
Missing end of treatment information will be imputed by last observation carried forward, if 
applicable.  Visit-by-visit analyses of data will exclude subjects who did not provide data at 
the visit in question. Missing ECOG performance status at end of treatmentwill be imputed 
by last observation carried forward, unless the subject is known to have died (Grade 5). For 
visit by visit summary of ECOG, no imputation will be made.
The imputed dates will be used to allocate the relative study day of the concomitant 
medication and AEs to treatment, in addition to determining whether an AE is/is not 
treatment emergent.  Imputation on missing non-prostate cancer related concomitant 
medication dates (to categorize them as previous medications or concomitant medications) 
and adverse event dates (to categorize them as TEAE or not) will be done as follows:
●
Incomplete Start Day: use the later of (first day of the month, first dosing day if first
dosing month)


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Imputation on missing date of initial diagnosis (cancer duration) and cancer treatment 
history, including prior prostate cancer drug therapies, (start date, stop date, or date of 
procedure) will be done as follows:
●
Incomplete Day: use the 15th day of the month
●
Incomplete Month: use 1st of July if the Year is before Year of dosing, otherwise
missing
For all analyses other than PK analysis, all values will be included in the analyses.  For 
analysis of PK data, only samples for which the time of sampling relative to the dose and the 
exact dose is known will be included.
7.10.2
Outliers
All values will be included in the analyses.
7.10.3
Visit Windows
Analyses will not exclude any subject’s data due to the subject’s failure to comply with the 
visit schedule.  Labs, vital signs, weight, ECOG, ECG, and LVEF will be analyzed based on 
the following visit window.
Visit (study day)
Lab, Vital signs, ECOG
Weight
ECG, LVEF
Baseline (1)
<= 1
<= 1
<= 1
Week 4 (22)
>=2 – <33
NA
NA
Week 7 (43)
>=33 – < 54
NA
NA
Week 10 (64)
>=54 – <75
NA
NA
Week 13 (85)
>=75 – <96
>=2 – < 128
>=2 – <128
Week 16 (106)
>=96 – <138
NA
NA
Week 25 (169)
>=138 – < 201
>=128 – <201
>=128 – < 210
Week 34 (232)
>=201 – <254
>=201 – <254
NA
Week 37 (253)
NA
NA
>= 210 – <292
Week 40 (274)
>=254 – <310
>=254 – <306
NA
Week 49 (337)
>=310 – <380
>=306 - <380
>=292 – <380
Week 61 (421)
>=380 – <468
>=380 – <468
>=380 – <468
Week 73 (505)
>=468 – <554
>=468 – <554
>=468 – <554
Week 85 (589)
>=554 – <640
>=554 – <640
>=554 – <640
Q12W…
If data available at Day 640 or later, then adapt table accordingly.
If more than 1 assessment occurs within a given visit window, the assessment closest to the 
target date will be used in summaries for the given visit.  If 2 assessments are equally close to 
the target day, the earlier assessment will be used.


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8
DOCUMENT REVISION HISTORY
Version
Change
1.1
Update changes from protocol amendment 4.
2.0
Update changes from protocol amendment 5., making SAP consistent with the 
statistical analysis conducted for the same study in TNBc studies (MDV3100-11)
Removal of the OS as an endpoint
Clarification in the summary of treatment compliance and exposure for 
enzalutamide and trastuzumab
Added summary for adverse events of interests
Clarification in time to response analysis
Additional AE summaries
Clarification in windowing algorithm
3.0
Added two abbreviations (CI, and ICF) to List of Abbreviations
Section 4: Added “optimal” before “Simon’s two-stage design”in first sentence
Section 5: Added”for clarification “”For the determination of the percentage 
tumor cells with nuclear expression, the Ventana assay will be used.”
Added Section 5.4 Low AR Expression Set (LARES)
Section 6.1.2 & 7.4.2.1: Overall Response Rate: deleted “at 24 weeks”, CR or PR 
instead of CR+PR 
Section 6.1.2: Ädded “(death within 168 days after treatment discontinuation)
Section 7.1 Deleted “Summaries based on FAS and EES (e.g. baseline and 
efficacy data) will be presented, unless specifically stated otherwise. Safety 
analysis and other summaries based on SAF will be presented.”
Section 7.2.1: Text regarding treatment discontinuation and Kaplan-Meier 
updated
Section 7.2.3: Deleted in 3rd paragraph “This will be done for the SAF, FAS and 
EES populations.”
Section 7.2.3; version number of MedDRA deleted
Section 7.2.4: Text “Prior cancer procedures treatment will also be summarized 
for the SAF.”moved to Section 7.2.3.
Section 7.3.1.1: 1st bullet, text updated after “Duration of exposure will be 
summarized in two ways”
Section 7.3.2: 2nd bullet, changed -80% to 80%. 3rd bullet, format updated
3rd bullet: added “[=number of days on study drug x 4 capsules]”
Section 7.4: last sentence “in this subset of FAS” replaced by “on this analysis 
set (LARES)”
Section 7.4.1: second paragraph, “subset” replace by analysis set”
Added text: Analysis will also be done on the data from the combined FAS 
and LARES
Text on subgroup analysis deleted
Section 7.4.2: 2nd sentence, added (Clopper Pearson Method).
Text regarding Kaplan Meier method rewritten
Section 7.4.2.3: Added after the first sentence: For analysis data will be used up 
to and including the cut-off date
Section 7.4.3: Added text
Section 7.5.1: Added “TEAEs leading to” to the text related to dose reduction 
and interruption.
Section 7.5.1: CTCAE instead of CTC
Section 7.5.2:1 Liver Tests instead of Liver Function Tests
Section 7.5.3: In table “Heart rate” replaced by “Pulse rate”


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Version
Change
Section 7.5.4: Text regarding QTc interval inserted
Section 7.5.6.2 & 7.5.6.3: text adapted
Section 7.7.2.1: Added Section on Biomarker Analyses
Section 7.8: subgroup analysis for ER-/PgR- subjects is specified. 
Added: “Analyses will be done on the EES.”
Section 7.10.1: changed study into treatment in sentence describing missing 
ECOG performance status. 3rd paragraph end of treatment instead of end of 
study
Section 7.10.3: replaced MUFA by LVEF
Extended the “window visit” table. Deleted “PE” from sentence above table 
and from 2nd column header of the table


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9
REFERENCES
ICH Harmonized Tripartite Guideline E 3. Structure and Content of Clinical Study Reports, 
November 1995. (www.ich.org; Guidelines; "Efficacy" Topics)
ICH Harmonized Tripartite Guideline E 9. Statistical Principles for Clinical Trials, February 1998. 
(www.ich.org; Guidelines; "Efficacy" Topics)
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al.: New Response 
Evaluation Criteria in Solid Tumours: Revised RECIST guideline (Version 1.1). Eur J Cancer. 
2009; 45(2):228-247.


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10
APPENDICES
10.1
Appendix 1: Definition of Progression-Free Survival
Progression free survival (PFS) is defined as the time interval from the date of the first dose 
of enzalutamide to the date of disease progression as determined by the investigator using 
RECIST 1.1 or the date of on-study death due to any cause, whichever occurs first. Patients 
who die after receiving the first dose of enzalutamide without post baseline tumor 
assessments evaluable using RECIST 1.1, will be considered to have a PFS event on the date 
of death. The censoring rules for the primary and sensitivity analyses of PFS are summarized 
in the following table. The earliest of the following censoring times will be used:
Analysis
Censoring Rules
Date of Censoring
Primary analysis of PFS
Patients with no post baseline 
assessments
Date of first dose of 
enzalutamide +1
Patients who had no disease 
progression per RECIST 1.1 or 
died before data cutoff date
Date of the last tumor 
assessment before data cutoff 
date
Patients who had no disease 
progression per RECIST 1.1 died 
before initiating use of a new 
antitumor treatment 
Date of the last tumor 
assessment before use of a 
new antitumor treatment
Patients who had no disease 
progression per RECIST 1.1 
before treatment discontinuation 
for reason ‘lost to follow-up’
Date of the last available 
tumor assessment when 
patient was known to be 
progression free
Sensitivity PFS 
Patients who discontinued study 
treatment for disease progression 
not by RECIST 1.1 (e.g. end of 
trial)
This is an EVENT (not 
censoring) occurring at the 
date of treatment 
discontinuation
Patients who received a new 
antitumor treatment 
(antineoplastic or investigational 
therapy) without documented 
disease progression per RECIST 
1.1
This is an EVENT (not 
censoring) occurring at the 
date of initiation of the new 
antitumor treatment.