Conditions: ER+ and AR+ Breast Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 136
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine if GTx-024 at different dosages (9 mg or 18 mg) is effective and safe in the treatment of patients with metastatic or locally advanced Estrogen Receptor (ER)+ and Androgen Receptor (AR)+ breast cancer in postmenopausal women.

Detailed description:

Arms:
arm 1: Drug: GTx-024 GTx-024 softgel capsules will be administered once daily to a total dose of 9 mg arm 2: Drug: GTx-024 GTx-024 softgel capsules will be administered once daily to a total dose of 18 mg

Interventions: intervention 1: GTx-024
Intervention descriptions: intervention 1: To determine whether either or both doses result in an acceptable clinical benefit rate.

Protocol document:
Prot_SAP_000.pdf: 
 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 1 of 121 
 
A Phase 2 Open Label, Multi-Center, Multinational, Randomized, Parallel 
Design Study Investigating The Efficacy and Safety Of GTx-024 On Metastatic 
or Locally Advanced ER+/AR+ Breast Cancer (BC) in Postmenopausal Women 
 
 
GTx Protocol Number: G200802 
IND Number: 125281 
EudraCT Number: 2015-001012-35 
Principal Investigator: 
Beth A. Overmoyer, MD 
Susan Smith Center for Women’s Cancers, Dana-Farber Cancer Institute 
450 Brookline Avenue, Boston, MA 02215 
Tel: 617-632-2175 
Fax: 617-632-1930 
E-mail: Beth_Overmoyer@DFCI.HARVARD.EDU 
GTx Program Official: 
Michael DeSordi, BS, MBA 
Senior Director, Clinical Operations 
GTx, Inc. 
175 Toyota Plaza, 7th Floor, Memphis, TN 38103 
Tel: (901) 261-3795 
Fax: (901) 271-8679 
E-mail: mdesordi@gtxinc.com   
Medical Monitor: 
Nikolay Grechko, MD 
Medical Monitor 
Cmed Clinical Services 
Holmwood, Broadlands Business Campus 
Langhurstwood Road 
Horsham, West Sussex, RH12 4QP, United Kingdom 
T: +44 (0)1403 758249 
M: +44 (0)7917 665632 
 
Version Number: 1.0 
26 May 2015 
Protocol Amendment Number: N/A 
This template is adapted from the ICH guidance document E6 (Good Clinical 
Practice), Section 6. 
 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 2 of 121 
 
CONFIDENTIALITY STATEMENT 
All information and data contained within this document are the property of 
GTx, Inc., and are considered confidential. Acceptance of this document 
constitutes the agreement by the recipient that no information contained herein 
may be divulged or disclosed to third parties without prior written approval from 
GTx, Inc., except to the extent necessary to obtain informed consent from subjects 
who participate in this study. Do not copy this protocol without the express written 
permission of GTx, Inc. 
 
 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 3 of 121 
 
STATEMENT OF COMPLIANCE 
The study will be carried out in accordance with Good Clinical Practice (GCP) as 
required by the following: 
 United States (US) Code of Federal Regulations (CFR) applicable to clinical 
studies (45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, and 21 CFR Part 312) 
 International Conference on Harmonization (ICH) E6; 62 Federal Register 25691 
(May 9, 1997)  
 European Union (EU) Clinical Trial Directive 2001/20/EC 
 Relevant regulations from all countries where the clinical study will be conducted 


G
Protocol: A Phase 2 Open Label, Multi-Center,
Multinational,
Randomized,
Parallel Design Study
Investigating The Efficacy and Safety Of GTx-024 On
Metastatic or Locally Advanced
ER+/AR+ Breast Cancer
(Be) in Postmenopausal
Women
Compound No.: GTx-024
Author: Nancy Milligan
PROTOCOL SIGNATURE PAGE
Study Principal
Investigator
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GTx ER+/AR+
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Cmed Clinical Services
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26May2015
CONFIDENTIAL
Page 4 of 121


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 5 of 121 
 
INVESTIGATOR SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and the attachments, 
and provides the necessary assurances that this trial will be conducted according to 
all stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable US federal 
regulations and ICH guidelines. 
Site Investigator: 
 
Signed: 
 
Date: 
 
 
Name 
Title 
 
 
 
 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 6 of 121 
 
TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE 
3 
PROTOCOL SIGNATURE PAGE 
4 
INVESTIGATOR SIGNATURE PAGE 
5 
TABLE OF CONTENTS 
6 
LIST OF TABLES 
9 
LIST OF FIGURES 
10 
LIST OF ABBREVIATIONS 
11 
PROTOCOL SUMMARY 
14 
1 
Roles and responsibilities 
30 
2 
Introduction: Background Information and Scientific Rationale 
33 
2.1 Background Information 
33 
2.2 Rationale 
37 
2.3 Potential Risks and Benefits 
39 
2.3.1 
Potential Risks 
39 
2.3.2 
Potential Benefits 
41 
3 
Objectives 
43 
3.1 Study Objectives 
43 
3.2 Study Outcome Measures 
44 
3.2.1 
Primary Efficacy Outcome Measures 
44 
3.2.2 
Secondary Efficacy Outcome Measures 
45 
3.2.3 
Tertiary Efficacy Outcome Measures 
45 
3.2.4 
Safety Outcome Measures 
46 
3.2.5 Pharmacokinetic outcome measures 
46 
4 
Study Design 
47 
4.1 Substudies (if applicable) 
49 
4.2  Safety Monitoring Committee 
50 
5 
Study Enrollment and Withdrawal 
51 
5.1 Subject Inclusion Criteria 
51 
5.2 Subject Exclusion Criteria 
53 
5.3 Strategies for Recruitment, Retention, and to Improve Adherence to Intervention Protocols54 
5.4 Treatment Assignment Procedures 
55 
5.4.1 
Randomization Procedures 
55 
5.4.2 
Masking Procedures 
55 
5.4.3 
Reasons for Withdrawal 
55 
5.4.4 
Handling of Withdrawals 
56 
5.4.5 
Termination of Study 
56 
6 
Study Intervention/Investigational Product 
58 
6.1 Study Product Description 
58 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 7 of 121 
 
6.1.1 
Acquisition 
58 
6.1.2 
Formulation, Packaging, and Labelling 
58 
6.1.3 
Product Storage and Stability 
59 
6.2 Dosage, Preparation, and Administration of Study Investigational Product 
59 
6.3 Modification of Study Investigational Product for a Subject 
59 
6.4 Accountability Procedures for the Study Investigational Product(s) 
60 
6.5 Assessment of Subject Compliance with Study Investigational Product 
60 
6.6 Concomitant Medications/Treatments 
61 
7 
Study Schedule 
63 
7.1 Screening 
63 
7.2 Randomization/Baseline 
64 
7.3 Treatment Phase 
65 
7.4 End of Treatment (EOT) Visit 
67 
7.5 Post-treatment Follow-up 
68 
7.6 Early Termination Visit 
68 
7.7 Unscheduled Visit 
69 
8 
Study Procedures/Evaluations 
70 
8.1 Clinical Evaluations 
70 
8.2 Laboratory Evaluations 
73 
8.2.1 
Clinical Laboratory Evaluations 
73 
8.2.2 
Special Assays or Procedures 
76 
8.2.3 
Specimen Preparation, Handling, and Shipping 
77 
9 
Assessment of Safety 
78 
9.1 Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters 
78 
9.1.1 
Adverse Events 
78 
9.1.2 
Intensity of Event: 
79 
9.1.3 
Drug–Adverse Event Relationship 
80 
9.1.4 Serious Adverse Events 
81 
9.1.5 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values or 
Abnormal Clinical Findings 
82 
9.2 Reporting Procedures 
82 
9.2.1 
Serious Adverse Events 
82 
9.2.2 
Regulatory Reporting 
84 
9.2.3 
Other Adverse Events 
85 
9.2.4 
Reporting of Pregnancy 
86 
9.3 Type and Duration of Follow-up of Subjects after Adverse Events 
87 
9.4  Halting Rules 
87 
9.5 Safety Oversight 
88 
10 
Clinical Monitoring 
90 
11 
Statistical Considerations 
91 
11.1 Study Hypotheses 
91 
11.2 Sample Size Considerations 
91 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 8 of 121 
 
11.3 Planned Interim Analyses (if applicable) 
92 
11.4 Final Analysis Plan 
92 
11.4.1 
Analysis sets 
92 
11.4.2 
Definition of analysis endpoints; primary, secondary, tertiary, exploratory, safety 
93 
12 
Source Documents and Access to Source Data/Documents 
100 
13 
Quality Control and Quality Assurance 
101 
14 
Ethics/Protection of Human Subjects 
102 
14.1 Ethical Standard 
102 
14.2 Institutional Review Board/Independent Ethics Committee 
102 
14.3 Pre-study Documentation 
103 
14.4 Informed Consent Process 
103 
14.4.1 
Informed Consent/Assent Process (in Case of a Minor) 
104 
14.5 Subject Confidentiality 
104 
14.6 Protocol Adherence 
105 
14.7 Permission to Review Subjects’ Source Records 
105 
14.8 Protocol Amendments 
105 
14.9 Change in Investigator 
106 
14.10 Study Discontinuation 
106 
14.11 Future Use of Stored Specimens 
106 
14.12 Indemnity 
107 
15 
Data Handling and Record Keeping 
108 
15.1 Data Capture Methods 
108 
15.2 Study Site Responsibilities 
109 
15.3 Data Management Responsibilities 
109 
15.4 Timing/Reports 
109 
15.5 Study Records Retention 
109 
15.6 Protocol Deviations 
110 
16 
Publication Policy 
112 
17 
Literature References 
113 
APPENDIX A: SCHEDULE OF EVENTS 
115 
APPENDIX B: ECOG PERFORMANCE STATUS 
121 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 9 of 121 
 
LIST OF TABLES 
Table 1: Clinical Laboratory Tests ............................................................................ 75 
Table 2: Description of Grades According to the NCI-CTCAE ................................. 79 
 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 10 of 121 
 
LIST OF FIGURES 
Figure 1: Flow chart of Study Plan ........................................................................... 49 
 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 11 of 121 
 
LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
AI 
Aromatase Inhibitor 
ALT 
Alanine Transaminase 
ANC 
Absolute Neutrophil Count 
aPTT 
Activated Partial Thromboplastin Time 
AR 
Androgen Receptor 
AST 
Aspartate Aminotransferase 
BC 
Breast Cancer 
BCRP 
Breast Cancer Resistance Protein 
BMI 
Body Mass Index 
BOR 
Best Overall Response 
CB 
Clinical Benefit 
CBR 
Clinical Benefit Rate 
CD-ROM 
Compact Disk-Read Only Memory 
CFR 
Code of Federal Regulations 
CIN 
Cervical Intraepithelial Neoplasia 
CNS 
Central Nervous System 
CR 
Complete Response 
CRA 
Clinical Research Associate 
CT 
Computerized Tomography 
CTCs 
Circulating Tumor Cells 
CYP2C9 
Cytochrome P450 2C9 
CYP3A 
Cytochrome P450, Family 3, Subfamily A 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EDTA 
Ethylenediaminetetraacetic acid 
EOT 
End Of Treatment 
ER 
Estrogen Receptor 
ER+/AR+ 
Estrogen Receptor Positive and Androgen Receptor Positive 
EU 
European Union 
FAS 
Full Analysis Set 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 12 of 121 
 
FDA 
Food and Drug Administration 
FISH 
Fluorescence In Situ Hybridization 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl Transferase 
HBcAb 
Hepatitis B core Antibody 
HBsAb 
Hepatitis B surface Antibody 
HBsAg 
Hepatitis B surface Antigen 
HBV 
Hepatitis B Virus 
HBV-DNA 
Hepatitis B Virus-Deoxyribonucleic Acid 
HCV 
Hepatitis C Virus 
HDL 
High-Density Lipoprotein 
HER2 
Human Epidermal Growth Factor Receptor 2 
Hgb 
Hemoglobin 
HIV 
Human Immunodeficiency Virus 
HPF 
High Power Field 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 
IMP 
Investigational Medicinal Product 
IN 
Investigator Notification 
IND 
Investigational New Drug Application 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ISH 
In situ hybridization 
LBM 
Lean Body Mass 
LDH 
Lactate Dehydrogenase 
LDL 
Low-Density Lipoprotein 
LH-RH 
Luteinizing Hormone-Releasing Hormone 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
mRNA 
Messenger Ribonucleic Acid 
NCI-CTCAE 
 
National Cancer Institute-Common Terminology Criteria for Adverse 
Events 
NYHA 
New York Heart Association 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 13 of 121 
 
ORR 
Objective Response Rate 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PI 
Principal Investigator 
PO 
Per Os (oral) 
PPS 
Per Protocol Set 
PR 
Partial Response 
PSA 
Prostate Specific Antigen 
QoL 
Quality of Life 
QTCB 
QT interval corrected for heart rate according to Bazett’s formula 
RBC 
Red Blood Cells 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RNA-PCR 
Ribonucleic Acid-Polymerase Chain Reaction 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SARM 
Selective Androgen Receptor Modulator 
SAS 
Safety Analysis Set 
SD 
Stable Disease 
SERM 
Selective Estrogen Receptor Modulator 
SHBG 
Sex Hormone Binding Globulin 
SMC 
Safety Monitoring Committee 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TNBC 
Triple Negative Breast Cancer 
TTP 
Time To Progression 
UGT2B7 
UDP-Glucuronosyltransferase-2B7 
ULN 
Upper Limit of the Normal Range 
US 
United States 
VAS 
Visual Analog Scale 
WBC 
White Blood Cells 
α 
Alpha 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 14 of 121 
 
PROTOCOL SUMMARY 
Title: 
A Phase 2 Open Label, Multi-Center, Multinational, 
Randomized, Parallel Design Study Investigating The Efficacy 
and Safety Of GTx-024 On Metastatic or Locally Advanced 
ER+/AR+ Breast Cancer (BC) in Postmenopausal Women 
Sponsor: 
GTx, Inc. 
Indication: 
Metastatic or locally advanced estrogen receptor positive and 
androgen receptor positive (ER+/AR+) BC 
Study design: 
This is an open label, multicenter, multinational, randomized, 
parallel design Phase 2 study to assess the efficacy and 
safety of GTx-024 in postmenopausal subjects with ER+/AR+ 
BC. Subjects will be randomized to receive either GTx-024 
9 mg or 18 mg given orally (PO) daily for up to 24 months. 
Each dose arm will be treated independently and each 
assessed for efficacy using Simon’s two-stage design1. 
Randomization will be 1:1 and stratified so as to balance 
subjects presenting with bone only metastases and all other 
subjects, and setting of immediately preceding therapy 
(adjuvant setting or metastatic setting). There is no intent to 
statistically compare the two dose arms, but to determine 
whether either or both doses result in an acceptable clinical 
benefit rate (CBR), defined as the proportion of evaluable 
subjects (i.e., subjects with centrally confirmed AR+ and who 
receive at least one dose of study drug) with either complete 
response (CR), partial response (PR), or stable disease (SD), 
by Response Evaluation Criteria in Solid Tumors [RECIST], 
Version 1.12, at week 24, consistent with 30% while 
maintaining an acceptable safety profile. Given such a result, 
future exploration of GTx-024 in ER+/AR+ BC would be 
warranted.  
Thirty-six to eighty-eight (36–88) subjects with centrally 
confirmed AR+ who receive at least one dose of study drug 
(evaluable subjects) will be needed for primary efficacy 
analysis purposes and will be a subset of the Full Analysis 
Set (FAS). Thirty-six to one hundred and eighteen (36–118) 
subjects, including replacement subjects, will be randomized 
in a 1:1 fashion to receive a daily PO dose of either GTx-024 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 15 of 121 
 
9 mg or 18 mg. Thirty of the aforementioned subjects may be 
considered replacement subjects to account for lack of 
centrally confirmed AR+ status, or for the rare subject who is 
randomized but does not receive study drug. The trial will test 
for an unacceptably low CBR of ≤ 10% versus a CBR more 
consistent with ≥ 30%. The first stage in each study arm will 
be assessed among the first 18 evaluable subjects. If at least 
3/18 subjects achieve clinical benefit (CB) at week 24, then 
the trial arm will proceed to the second stage of recruitment of 
up to a total of 44 evaluable subjects in the FAS in that arm. 
Otherwise, the arm will be discontinued for lack of efficacy.  
Subjects who are not confirmed AR+ may remain on the trial, 
but will not be part of the primary efficacy analysis – these 
subjects will contribute to secondary and tertiary analyses as 
noted in Section 11 
Statistical Considerations. 
Subjects on the 18 mg treatment arm who experience an 
adverse event (AE) with Grade ≥ 3 intensity (National Cancer 
Institute-Common Terminology Criteria for Adverse Events 
[NCI-CTCAE], Version 4.0) and/or intolerance may have a 
dose reduction from 18 mg to 9 mg per day or a drug 
interruption based on the medical judgment of the Investigator 
and after confirmation by the study Medical Monitor. The drug 
interruption may last for a period of up to 5 days after which 
the subject must be rechallenged with study drug (18 mg or 
9 mg) or discontinued from the study. In the case of a dose 
reduction, once the AE has resolved or reduced in intensity to 
Grade 1, the subject may be rechallenged with 18 mg or 
maintained at 9 mg at the discretion of the Investigator.  
Subjects on the 9 mg treatment arm who experience an AE 
with Grade ≥ 3 intensity (NCI-CTCAE 4.0) and/or intolerance 
may have a drug interruption based on the medical judgment 
of the Investigator and after confirmation by the study Medical 
Monitor. The drug interruption may last for a period of up to 
5 days after which the subject must be rechallenged with 
study drug (9 mg) or discontinued from the study.  
In the event of hepatotoxicity, please also refer to Section 9.4 
 
Halting Rules. 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 16 of 121 
 
The subjects who demonstrate CB from the treatment will be 
treated for up to 24 months from the date of randomization 
(as long as they continue to demonstrate CB from the 
treatment during these 24 months). Subjects who continue to 
demonstrate a CB from the study treatment at 24 months will 
be offered to continue in a safety extension study under a 
separate protocol.  
For safety purposes, all subjects will be followed-up for one 
month after the last dose of GTx-024 is received. 
In order to protect the safety of the subjects, a Safety 
Monitoring Committee (SMC) will be established for the study 
to review the safety data on an ongoing basis. The SMC will 
consist of, as a minimum, the Medical Monitor, a Safety 
Reviewer with an oncology background, a statistician, and 
two GTx, Inc. representatives, consistent with the SMC 
charter. 
Objectives: 
The primary efficacy objective of this trial is to estimate the 
CBR at 24 weeks (defined as CR, PR, or SD) (by 
RECIST 1.1) of GTx-024 9 mg and of GTx-024 18 mg given 
PO daily in subjects with ER+/AR+ BC who have centrally 
confirmed AR+ status. 
Secondary efficacy objectives: 
 
Estimate the CBR at 24 weeks (by RECIST 1.1) of 
GTx-024 9 mg and 18 mg in all subjects randomized who 
receive at least one dose of study medication (the FAS) 
regardless of AR status as determined by the central 
laboratory 
The following secondary efficacy objectives apply to both 
centrally confirmed AR+ subjects (the evaluable subset of the 
FAS) as well as to all subjects in the FAS: 
 
Estimate the objective response rate (ORR; defined as 
CR or PR) (by RECIST 1.1) of GTx-024 9 mg and 18 mg 
at 24 weeks 
 
Estimate the best overall response rate (BOR) of 
GTx-024 9 mg and 18 mg  


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 17 of 121 
 
 
Estimate the progression free survival (PFS) of subjects 
receiving GTx-024 9 mg and 18 mg 
 
Estimate the time to progression (TTP) of subjects 
receiving GTx-024 9 mg and 18 mg 
 
Estimate duration of response (time from documentation 
of tumor response to disease progression or death) of 
subjects receiving GTx-024 9 mg and 18 mg 
Tertiary objectives: 
The following tertiary efficacy objectives apply to both 
centrally confirmed AR+ subjects (the evaluable subset of the 
FAS) as well as to all subjects in the FAS: 
 
Assess the effect of GTx-024 9 mg and 18 mg on serum 
prostate specific antigen (PSA) 
 
Assess the effect of GTx-024 9 mg and 18 mg on Quality 
of Life (QoL) as measured by EQ-5D-5L3  
 
Assess the effect of GTx-024 9 mg and 18 mg on 
circulating tumor cells (CTCs) 
 
Assess the impact of duration of prior CB on outcome 
 
Assess the impact of time from diagnosis of metastases 
to randomization on outcome 
 
Describe the effect of GTx-024 9 mg and 18 mg on tumor 
volumetrics 
 
Assess the effect of plasma concentrations of GTx-024 
and GTx-024 glucuronide on CBR at 24 weeks 
Safety objective: 
To describe the safety profile of GTx-024 9 mg and 18 mg PO 
daily in subjects with ER+/AR+ BC with centrally confirmed 
AR+ as well as in all subjects randomized and treated. 
Pharmacokinetic objective: 
To describe the plasma concentrations of GTx-024 and 
GTx-024 glucuronide at each of the assessed time points. 
Target Population: 
Adult postmenopausal women with metastatic or recurrent 
locally advanced ER+/AR+ BC. 
Subject Inclusion criteria: Subjects eligible for inclusion in 
this study must meet all of the following criteria:  
1. Adult women (≥ 18 years of age) with metastatic or 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 18 of 121 
 
recurrent locally advanced BC, not amenable to curative 
treatment by surgery or radiotherapy, with objective 
evidence of disease progression. 
 
Women must have received ≥ 1 prior hormonal 
treatment(s) in the metastatic or adjuvant setting 
 
If the most recent hormonal treatment was in 
the metastatic setting, duration of response 
(tumor regression or stabilization of disease) 
to this specific course of therapy must be 
≥ 6 months 
 
If the most recent hormonal treatment was in 
the adjuvant setting, duration of response 
(disease free) to this specific course of 
therapy must be ≥ 3 years 
2. Histological or cytological confirmation of ER+ BC as 
assessed by a local laboratory using slides, paraffin 
blocks, or paraffin sample or by medical history: ER+ 
(confirmed as ER expression more than or equal to 1% 
positive tumor nuclei)  
3. Human epidermal growth factor receptor 2 (HER2)-
negative tumor by local laboratory testing 
(immunohistochemistry [IHC] 0, 1+ regardless of 
fluorescence in situ hybridization [FISH] ratio; IHC 2+ with 
FISH ratio lower than 2.0 or HER2 gene copy less than 
6.0; FISH ratio of 0, indicating gene deletion, when 
positive and negative in situ hybridization [ISH] controls 
are present) 
4. Availability of paraffin embedded or formalin fixed tumor 
tissue; OR, a minimum of 10 and up to 20 slides of 
archived tumor tissue for central laboratory confirmation of 
AR status and molecular subtyping. Metastatic tumor 
tissue is preferred when possible 
5. Postmenopausal women. Postmenopausal status is 
defined by the National Comprehensive Cancer Network 
as either:  
 
Age ≥ 55 years and one year or more of amenorrhea  
 
Age < 55 years and one year or more of amenorrhea, 
with an estradiol assay < 20 pg/mL  


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 19 of 121 
 
 
Age < 55 years and surgical menopause with bilateral 
oophorectomy  
a. Note: Ovarian radiation or treatment with 
a luteinizing hormone-releasing hormone 
(LH-RH) agonist (goserelin acetate or 
leuprolide acetate) is not permitted for 
induction of ovarian suppression  
6. Radiological or clinical evidence (bone scan, 
computerized tomography [CT], and magnetic resonance 
Imaging [MRI]) of recurrence or progression within 
30 days before randomization 
7. Subject must have either measurable disease or 
bone-only non-measurable disease, evaluable according 
to RECIST 1.1 
8. Adequate organ function as shown by:  
 
Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3  
 
Platelet count ≥ 100,000 cells/mm3  
 
Hemoglobin (Hgb) ≥ 9.0 g/dL  
 
Serum aspartate aminotransferase (AST) and alanine 
transaminase (ALT) ≤ 2.5 upper limit of the normal 
range (ULN) (or ≤ 5 if hepatic metastases are present) 
 
Total serum bilirubin ≤ 2.0 × ULN (unless the subject 
has documented Gilbert Syndrome)  
 
Alkaline phosphatase levels ≤ 2.5 × ULN (≤ 5 × ULN in 
subjects with liver metastasis) 
 
Serum creatinine ≤ 2.0 mg/dL or 177 µmol/L 
 
International normalized ratio (INR) or activated partial 
thromboplastin (aPTT) < 1.5 × ULN (unless on 
anticoagulant treatment at screening) 
9. Subject has an Eastern Cooperative Oncology Group 
(ECOG) performance status4 0 or 1 
10. Subject is able to swallow capsules  
11. Able and willing to give voluntary, written and signed 
informed consent before any screening procedure and 
according to local guidelines  
Exclusion criteria: Subjects eligible for this study must 
not meet any of the following criteria:  


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 20 of 121 
 
1. Previously received > 1 course of chemotherapy (not 
including immunotherapies or targeted therapies) for the 
treatment of metastatic BC 
a. Note: Subjects may have received 1 course of 
chemotherapy prior to surgery for the treatment of 
locally advanced disease and 1 course of 
chemotherapy for the treatment of metastatic BC; 
however, if surgery could not be performed, this 
will count as the 1 chemotherapy course allowed 
prior to study 
2. Known hypersensitivity to any of the GTx-024 
components or subjects previously received treatment 
with Selective Androgen Receptor Modulator (SARM)  
3. Subjects with radiographic evidence of central nervous 
system (CNS) metastases as assessed by CT or MRI that 
are not well-controlled (symptomatic or requiring control 
with continuous corticosteroid therapy [e.g., 
dexamethasone])  
a. Note: Subjects with CNS metastases are permitted 
to participate in the study if the CNS metastases 
are medically well-controlled and stable for at least 
28 days after receiving local therapy (irradiation, 
surgery, etc.) 
4. Radiotherapy within 14 days prior to randomization except 
in case of localized radiotherapy for analgesic purpose or 
for lytic lesions at risk of fracture, which can then be 
completed within 7 days prior to randomization. Subjects 
must have recovered from radiotherapy toxicities prior to 
randomization 
5. Currently receiving hormone replacement therapy, unless 
discontinued prior to screening  
6. Subjects positive for Human Immunodeficiency Virus 
(HIV) 
7. Subject has a concomitant medical condition that 
precludes adequate study treatment compliance or 
assessment, or increases subject risk, in the opinion of 
the Investigator, such as but not limited to: 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 21 of 121 
 
 
Myocardial infarction or arterial thromboembolic 
events within 6 months prior to Baseline or severe or 
unstable angina, New York Heart Association (NYHA) 
Class III or IV disease, or a QTCB (corrected 
according to Bazett’s formula) interval > 470 msec  
 
Serious uncontrolled cardiac arrhythmia grade II or 
higher according to NYHA  
 
Uncontrolled hypertension (systolic > 150 and/or 
diastolic > 100 mm Hg) 
 
Acute and chronic, active infectious disorders and 
non-malignant medical illnesses that are uncontrolled 
or whose control may be jeopardized by the 
complications of this study therapy  
 
Impairment of gastrointestinal function or 
gastrointestinal disease that may significantly alter the 
absorption of study drugs (e.g., ulcerative disease, 
uncontrolled nausea, vomiting, diarrhea, 
malabsorption syndrome)  
 
Another active cancer (excluding adequately treated 
basal cell carcinoma or cervical intraepithelial 
neoplasia [CIN]/cervical carcinoma in situ or 
melanoma in situ). Prior history of other cancer is 
allowed as long as there is no active disease within 
the prior 5 years 
8. Major surgery within 28 days before randomization 
9. Positive hepatitis B virus (HBV) and/or hepatitis C virus 
(HCV) infection at screening  
10. History of non-compliance to medical regimens  
11. Subjects unwilling to or unable to comply with the protocol  
12. Subject is currently receiving treatment with any agent 
listed on the prohibited medication list (See Section 6.6
 
Concomitant Medications/Treatments for complete list) 
13. Treatment with any investigational product within 
< 4 half-lives for each individual investigational product 
OR within 28 days prior to randomization 
Phase: 
2 
Number of Sites: 
The study will be conducted primarily in 20 sites in the United 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 22 of 121 
 
States (US) and Europe.  
Study Duration: 
The study duration is estimated at 3 years.   
Subject Participation 
Duration: 
It is expected the subjects will remain in the study for 
approximately two (2) years. There will be a screening period 
of up to 28 days and a follow-up period of 1 month. 
Description of Agent or 
Intervention: 
Three (3) GTx-024 3.0 mg softgels for a 9 mg daily dose or 
six (6) GTx-024 3.0 mg softgels for an 18 mg daily dose will 
be taken PO with water at approximately the same time each 
day, with or without food. 
Estimated Time to 
Complete Enrolment: 
It is anticipated the time to complete enrollment will be 
12 months. 
Statistical Considerations 
This trial will employ a Simon’s two-stage (optimal) design 
independently for each dose arm, 9 mg and 18 mg. The 
assumptions for the design are as follows: 
 
H0: CBR ≤ 0.10  
 
H1: CBR ≥ 0.30 
 
Alpha (α) = 0.025 (one-sided) 
 
Power = 90%. 
Based on the above assumptions, a sample size of N = 44 
centrally confirmed AR+ subjects who have received at least 
one dose of study medication (evaluable subjects) are 
needed for each arm to proceed to completion of the second 
stage. An arm will proceed to the second stage if at least 
3 subjects among the first 18 evaluable subjects randomized 
in stage 1 achieve CB, defined as CR, PR, or SD, as per 
RECIST 1.1 as determined by central review. Otherwise, the 
arm will be closed due to lack of efficacy. If an arm proceeds 
to the second stage, the efficacy criteria favoring further 
evaluation of the dose arm(s) in future trials will require at 
least 9/44 subjects to achieve CB; i.e., the null hypothesis of 
an unacceptably low rate of CB, ≤ 10.0%, can be rejected in 
favor of the alternative hypothesis that indicates the higher 
rate, ≥ 30%, is more likely. 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 23 of 121 
 
Over-enrollment: Subjects who are not centrally confirmed 
AR+ will be replaced by an over-enrollee in order to accrue 
the 44 subjects of the evaluable subset of the FAS. Subjects 
who are randomized but not centrally confirmed AR+ may, at 
the discretion of the Investigator, be maintained on the study, 
but these subjects will not be part of the evaluable subset of 
the FAS used for the primary analysis. However, these 
subjects are part of the FAS and will contribute to analysis as 
specified in Section 11 
Statistical Considerations. 
Subjects who are randomized but do not receive treatment 
will also be replaced by an over-enrollee. Subjects who do not 
receive any study medication will not be included in any 
efficacy analyses. These two conditions may result in up to an 
additional 30 subjects being randomized (assumes 25% of 
enrolled subjects are not evaluable for the primary efficacy 
analysis). 
 


 
Protocol: A Phase 2 Open Label, Multi-Center, Multinational, Randomized, Parallel 
Design Study Investigating The Efficacy and Safety Of GTx-024 On Metastatic or Locally 
Advanced ER+/AR+ Breast Cancer (BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 24 of 121 
 
Schedule of Events  
Periods 
Screening 
Randomization/ 
Baseline 
Treatment phase1 
(from randomization to EOT) 
EOT/ 
Early 
termination 
FU post 
treatment 
Day –28  
to –1 
 
Day 1 
 
 
 
 
Confirmation 
of CR or PR 
As required if 
still on 
treatment 
 
 
Visit number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V82– V13 
VEOT 
VFU 
Week/Day 
 
 
Week 6 
Week 12 
Week 18 
Week 24 
Week 28 
Every 
12 weeks 
(± 7  
days) 
3 days after 
the last dose 
of GTx-024 
28 days 
(± 2 days) 
after the 
last dose of 
GTx-024 
Procedure 
 
 
Day 42 
(± 7 
days) 
Day 84  
(± 7 
days) 
Day 126  
(± 7  
days) 
Day 168  
(± 7  
days) 
Day 196  
(± 7  
days) 
Obtain ICF 
X 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
check 
X 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Prior anticancer 
treatment 
X 
X 
 
 
 
 
 
 
 
 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Diagnosis and extent 
of BC
X 
 
 
 
 
 
 
 
 
 


 
Protocol: A Phase 2 Open Label, Multi-Center, Multinational, Randomized, Parallel 
Design Study Investigating The Efficacy and Safety Of GTx-024 On Metastatic or Locally 
Advanced ER+/AR+ Breast Cancer (BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 25 of 121 
 
Periods 
Screening 
Randomization/ 
Baseline 
Treatment phase1 
(from randomization to EOT) 
EOT/ 
Early 
termination 
FU post 
treatment 
Day –28  
to –1 
 
Day 1 
 
 
 
 
Confirmation 
of CR or PR 
As required if 
still on 
treatment 
 
 
Visit number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V82– V13 
VEOT 
VFU 
Week/Day 
 
 
Week 6 
Week 12 
Week 18 
Week 24 
Week 28 
Every 
12 weeks 
(± 7  
days) 
3 days after 
the last dose 
of GTx-024 
28 days 
(± 2 days) 
after the 
last dose of 
GTx-024 
Procedure 
 
 
Day 42 
(± 7 
days) 
Day 84  
(± 7 
days) 
Day 126  
(± 7  
days) 
Day 168  
(± 7  
days) 
Day 196  
(± 7  
days) 
Hormonal receptor 
status (ER+) and 
HER23 
X 
 
 
 
 
 
 
 
 
 
AR status3 
X 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
Vital signs 
X 
X4 
X 
X 
X 
X 
 
X 
X 
X 
ECOG performance 
status 
X 
X4 
X 
X 
X 
X 
 
X 
X 
X 
Eye examination5 
X 
As clinically indicated 
X 
 


 
Protocol: A Phase 2 Open Label, Multi-Center, Multinational, Randomized, Parallel 
Design Study Investigating The Efficacy and Safety Of GTx-024 On Metastatic or Locally 
Advanced ER+/AR+ Breast Cancer (BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 26 of 121 
 
Periods 
Screening 
Randomization/ 
Baseline 
Treatment phase1 
(from randomization to EOT) 
EOT/ 
Early 
termination 
FU post 
treatment 
Day –28  
to –1 
 
Day 1 
 
 
 
 
Confirmation 
of CR or PR 
As required if 
still on 
treatment 
 
 
Visit number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V82– V13 
VEOT 
VFU 
Week/Day 
 
 
Week 6 
Week 12 
Week 18 
Week 24 
Week 28 
Every 
12 weeks 
(± 7  
days) 
3 days after 
the last dose 
of GTx-024 
28 days 
(± 2 days) 
after the 
last dose of 
GTx-024 
Procedure 
 
 
Day 42 
(± 7 
days) 
Day 84  
(± 7 
days) 
Day 126  
(± 7  
days) 
Day 168  
(± 7  
days) 
Day 196  
(± 7  
days) 
Hematology 
X 
X4 
X 
X 
X 
X 
 
X 
X 
X 
Biochemistry 
X 
X4 
X 
X 
X 
X 
 
X 
X 
X 
HIV screening 
X 
 
 
 
 
 
 
 
 
 
HBV screening6 
X 
 
 
 
 
 
 
 
 
 
HCV screening 
X 
 
 
 
 
 
 
 
 
 
Serum lipid profile 
 
X 
X 
X 
X 
X 
 
X 
X 
 
Coagulation status 
X 
 
X 
X 
X 
X 
 
X 
X 
 
Serum hormones 
 
X 
X 
X 
X 
X 
 
X 
X 
 
PSA 
X 
X4 
X 
X 
X 
X 
 
X 
X 
X 


 
Protocol: A Phase 2 Open Label, Multi-Center, Multinational, Randomized, Parallel 
Design Study Investigating The Efficacy and Safety Of GTx-024 On Metastatic or Locally 
Advanced ER+/AR+ Breast Cancer (BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 27 of 121 
 
Periods 
Screening 
Randomization/ 
Baseline 
Treatment phase1 
(from randomization to EOT) 
EOT/ 
Early 
termination 
FU post 
treatment 
Day –28  
to –1 
 
Day 1 
 
 
 
 
Confirmation 
of CR or PR 
As required if 
still on 
treatment 
 
 
Visit number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V82– V13 
VEOT 
VFU 
Week/Day 
 
 
Week 6 
Week 12 
Week 18 
Week 24 
Week 28 
Every 
12 weeks 
(± 7  
days) 
3 days after 
the last dose 
of GTx-024 
28 days 
(± 2 days) 
after the 
last dose of 
GTx-024 
Procedure 
 
 
Day 42 
(± 7 
days) 
Day 84  
(± 7 
days) 
Day 126  
(± 7  
days) 
Day 168  
(± 7  
days) 
Day 196  
(± 7  
days) 
CTC enumeration 
 
X 
 
X 
 
X 
 
X 
X 
 
CTC gene expression 
 
X 
 
 
 
 
 
 
X 
 
Urine analysis 
X 
As clinically indicated 
Radiological 
evaluation: CT/MRI7  
X 
 
 
X 
 
X 
X8 
X 
X 
 
Radiological 
evaluation: bone 
scan9 
X 
 
 
X 
 
X 
X10 
X 
X 
 
Pharmacokinetic 
samples11 
 
X 
X 
 
X 
X 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 


 
Protocol: A Phase 2 Open Label, Multi-Center, Multinational, Randomized, Parallel 
Design Study Investigating The Efficacy and Safety Of GTx-024 On Metastatic or Locally 
Advanced ER+/AR+ Breast Cancer (BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 28 of 121 
 
Periods 
Screening 
Randomization/ 
Baseline 
Treatment phase1 
(from randomization to EOT) 
EOT/ 
Early 
termination 
FU post 
treatment 
Day –28  
to –1 
 
Day 1 
 
 
 
 
Confirmation 
of CR or PR 
As required if 
still on 
treatment 
 
 
Visit number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V82– V13 
VEOT 
VFU 
Week/Day 
 
 
Week 6 
Week 12 
Week 18 
Week 24 
Week 28 
Every 
12 weeks 
(± 7  
days) 
3 days after 
the last dose 
of GTx-024 
28 days 
(± 2 days) 
after the 
last dose of 
GTx-024 
Procedure 
 
 
Day 42 
(± 7 
days) 
Day 84  
(± 7 
days) 
Day 126  
(± 7  
days) 
Day 168  
(± 7  
days) 
Day 196  
(± 7  
days) 
AEs 
X 
X 
X 
X 
X 
X 
 
X 
X 
To be 
followed up 
to 28 days 
post 
treatment 
Serum Pregnancy 
Test 
X 
 
 
 
 
 
 
 
 
 
GTx-024 9 mg or 
18 mg dispensing/ 
administration 
 
X12 
X 
X 
X 
X13 
 
X13 
 
 
GTx-024 9 mg or 
18 mg accountability 
 
 
X 
X 
X 
X 
 
X 
X 
 
QoL EQ-5D-5L 
 
X 
X 
X 
X 
X 
 
X 
X 
 
1 Subjects with clinical benefit at 24 weeks will continue on therapy for up to 24 months (as long as they still benefit from the treatment during these 24 months). If so, the subjects 
will be asked to come for a visit every 3 months and undergo the assessments for the treatment period.  
2 Visit 8 should occur at Week 36; i.e., 12 weeks after Visit 6 (Week 24). 


 
Protocol: A Phase 2 Open Label, Multi-Center, Multinational, Randomized, Parallel 
Design Study Investigating The Efficacy and Safety Of GTx-024 On Metastatic or Locally 
Advanced ER+/AR+ Breast Cancer (BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 29 of 121 
 
3 ER and HER2 as per medical record will be used to determine subject eligibility. ER status will be confirmed by a local laboratory if not available in the subject’s medical history. 
AR status will be confirmed by a central laboratory. 
4 These medical procedures and assessments do not have to be repeated if done at screening within 7 days before randomization. 
5 Eye examination including best corrected distance visual acuity with refraction, intraocular pressure, slit lamp examination, and dilated fundus photography must be completed 
between Day –28 and Day –1, as clinically indicated during the treatment phase, and at EOT. 
6 HBV screening will be done as HBsAg. 
7 Imaging study (CT, MRI) is recommended to be performed within 7 days prior to randomization. The imaging studies will be assessed by both a local imaging facility and a blinded 
central reader. Subject eligibility will be based on local reading of the imaging studies. Medical decisions will be based on the local assessments. 
At screening, week 12 (Visit 4), and week 24 (Visit 6), tumor volumetric assessments will be done for the subjects undergoing CT scanning. 
8 In compliance with RECIST 1.1 guidelines, subjects who have CR or PR at week 24 (Visit 6) require confirmation within a month as follows: 
 
For subjects with measureable lesions, subjects will undergo CT/MRI based on the Investigator’s medical judgment  
9 Bone scans will be performed at screening and then every 12 weeks whilst subjects receive treatment (Visits 4, 6, and thereafter) in only those subjects with baseline bone 
metastases, or if clinically indicated. 
10 In compliance with RECIST 1.1 guidelines, subjects who have CR or PR at week 24 (Visit 6) require confirmation within a month as follows: 
 
For subjects with non-measurable lesions, subjects will undergo X-ray or bone-scanning based on the Investigator’s medical judgment and location of disease. 
11 Blood sampling for pharmacokinetic assessment. The exact time (hh:mm) and date of the blood sample should be recorded on the eCRF. At the baseline visit, the blood 
sample should be collected before the subject is given their first dose of GTx-024. At visits 3 (week 6), 5 (week 18), and 6 (week 24), the date and approximate time of the 
last dose of GTx-024 prior to the blood sample should also be recorded; i.e., it should be documented whether the subject took the previous dose that morning or the evening 
before.  
12 First dose to be given at site during this visit. 
13 At Visits 6, 8, 9, 10, 11, 12, and 13, in order to accommodate the visit schedule of every 12 weeks (± 7 days), the subjects will receive two carton boxes of study drug (each 
containing 7 blisters) to cover study treatment for 14 weeks. 
Abbreviations: AR = Androgen Receptor, BC = Breast Cancer, CR = Complete Response; CT = Computerized Tomography, CTCs = Circulating Tumor Cells, 
ECG = Electrocardiogram, ECOG = Eastern Cooperative Oncology Group, eCRF = electronic Case Report Form, EOT = End of Treatment, ER = Estrogen Receptor, 
FU = Follow-up, HBsAg = Hepatitis B surface Antigen, HBV = hepatitis B virus, HCV = hepatitis C virus, HIV = Human Immunodeficiency Virus, ICF = Informed Consent Form, 
IHC = Immunohistochemistry, MRI = Magnetic Resonance Imaging, PR = Partial Response; QoL = Quality of Life, PSA = Prostate Specific Antigen, V = Visit. 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 30 of 121 
 
1 ROLES AND RESPONSIBILITIES 
Principal Investigator 
Beth A. Overmoyer, MD 
Susan Smith Center for Women’s Cancers, Dana-Farber Cancer Institute 
450 Brookline Avenue 
Boston, MA 02215 
Tel: 617-632-2175 
Fax: 617-632-1930 
E-mail: Beth_Overmoyer@DFCI.HARVARD.EDU 
 
GTx, Inc. 
Michael DeSordi, BS, MBA 
Senior Director, Clinical Operations 
GTx, Inc. 
175 Toyota Plaza, 7th Floor 
Memphis, TN 38103 
Tel: (901) 261-3795 
Fax: (901) 271-8679 
E-mail: mdesordi@gtxinc.com 
 
Mayzie Johnston, PharmD 
Vice President, Medical Affairs and Clinical Operations 
GTx, Inc. 
175 Toyota Plaza, 7th Floor 
Memphis, TN 38103 
Tel: (901) 261-3858 
Fax: (901) 271-8677 
E-mail: mjohnston@gtxinc.com 
 
Jeff Hesselberg, MBA  
Vice President, Regulatory Affairs, Corporate Quality & Drug Safety 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 31 of 121 
 
GTx, Inc. 
175 Toyota Plaza, 7th Floor 
Memphis TN 38103 
Tel: (901) 523-9700 
Fax: (901) 271-8707 
E-mail: jhesselberg@gtxinc.com 
 
Michael L. Hancock, MS 
Director, Biostatistics 
GTx, Inc. 
175 Toyota Plaza, 7th Floor 
Memphis TN 38103 
Tel: (901) 271-8700 
Fax: (901) 271-8677 
E-mail: mhancock@gtxinc.com 
 
Cmed Clinical Research 
Joanna Sagar RGN, RM, Senior Project Manager 
Cmed Clinical Services 
Holmwood, Broadlands Business Campus 
Langhurstwood Road 
Horsham, West Sussex, RH12 4QP 
United Kingdom 
Tel: +44 (0)1282 866881 
Fax: +44 (0)1282 866881 
E-mail: jsagar@cmedresearch.com 
 
Asya Tsaneva, MD, Associate Director, Regulatory Operations 
Cmed Clinical Services 
Holmwood, Broadlands Business Campus 
Langhurstwood Road 
Horsham, West Sussex, RH12 4QP 
United Kingdom 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 32 of 121 
 
Tel: +359 885 017070 
Fax: +44 (0)1403 755051 
E-mail: atsaneva@cmedresearch.com 
 
Sarah Lilley, Principal Biostatistician 
Cmed Clinical Services 
Holmwood, Broadlands Business Campus 
Langhurstwood Road 
Horsham, West Sussex, RH12 4QP 
United Kingdom 
Tel: +44 (0)1403 755601 
Fax: +44 (0)1403 755051 
E-mail: slilley@cmedresearch.com 
 
Daniel Hyde, Drug Safety Associate 
Cmed Clinical Services 
Holmwood, Broadlands Business Campus 
Langhurstwood Road 
Horsham, West Sussex, RH12 4QP 
United Kingdom 
Tel: +44 (0)1403 758279 
Fax: +44 (0)1403 755051 
E-mail: dhyde@cmedresearch.com 
 
Julia Surber, Biometrics Project Manager 
Cmed Clinical Services 
4620 Creekstone Drive 
Suite 160 
Durham, North Carolina, 27703, United States 
Tel: +1 919 595 1112 
Fax: +1 919 595 6901 
E-mail: jsurber@cmedresearch.com 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 33 of 121 
 
2 
INTRODUCTION: BACKGROUND INFORMATION AND 
SCIENTIFIC RATIONALE 
2.1 
Background Information 
Breast cancer (BC) is the most commonly diagnosed cancer in women, and one in 
eight women will develop invasive BC in their lifetime. In 2012, 1.7 million women were 
diagnosed with BC, and there were 6.3 million women alive who had been diagnosed 
with BC in the previous five years. Since 2008, BC incidence has increased by more 
than 20%, while mortality has increased by 14%. BC is the most common cause of 
cancer death among women, representing 522,000 deaths in 2012 and the most 
frequently diagnosed cancer among women in 140 of 184 countries worldwide. 
BC is a highly heterogeneous disease with diverse clinical (tumor size, histological 
subtype and grade, and lymph node status) and molecular characteristics. Clinical 
assessment of BC includes routine characterization of receptor status including the 
presence or absence of estrogen receptor (ER), progesterone receptor, and human 
epidermal growth factor receptor 2 (HER2) in the tumor tissue. Receptor status is used 
to assess metastatic potential as well as to guide treatment decisions. Hormonal 
manipulation with selective estrogen receptor modulators (SERMs) or aromatase 
inhibitors (AIs) is the standard treatment given to subjects with tumors that are positive 
for the ER (ER+). For those subjects with tumors overexpressing HER2, targeted 
therapy against HER2 is typically used with chemotherapy. 
While ER, progesterone receptor, and HER2 are oncogenic in BC, another member of 
the steroid hormone receptor family, the androgen receptor (AR), has historically been 
considered anti-proliferative and beneficial, and expression of AR is prognostically 
favorable. Until the 1970s, BC was treated mostly with non-aromatizable androgens 
such as dihydrotestosterone or fluoxymesterone. AR is the most highly expressed 
receptor in BC with more than 75–95% of ER-positive and 10–35% of triple negative 
breast cancers (TNBC) expressing AR. Evidence also suggests that the AR target 
gene, prostate specific antigen (PSA), is a favorable prognostic marker in BC. A study 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 34 of 121 
 
conducted with 156 BC samples to histologically determine AR and PSA expression 
showed that 72% of the samples expressed the two proteins with significant positive 
correlation between them. 
Despite evidence of benefit, therapeutic efforts using androgens for the treatment of 
BC preceded knowledge regarding AR expression. Subsequently, the use of these 
agents fell from favor due to virilizing side effects, fears of aromatization to estrogen, 
and the advent of tamoxifen. Selective androgen receptor modulators (SARMs) are a 
new class of drugs under development for a variety of diseases due to their high 
specificity for AR, selective anabolic activity, lack of virilizing side effect, and ability to 
extend androgen therapy to women. 
GTx-024 is an oral (PO) nonsteroidal SARM that is being developed for clinical use 
because of its selectivity for anabolic activity with minimal androgenic activity 
(i.e., tissue selectivity). GTx-024 binds to the AR with similar affinity as testosterone. 
However, GTx-024 is a nonsteroidal ligand that does not bind or activate ER or 
progesterone receptor and, unlike testosterone and other steroidal androgens, cannot 
be aromatized to estrogenic metabolites. The underlying hypothesis regarding the 
selectivity of GTx-024 is that this nonsteroidal molecule induces slight conformational 
changes in the AR upon binding. The altered conformational change in AR changes 
the interaction of AR with specific coactivator and corepressor proteins that exist in 
different tissues thereby resulting in a different mix of genes being turned on and off 
and conferring more selective anabolic activities. Differences in intracellular signaling 
pathways (i.e., non-genomic effects) and/or interactions with steroid biosynthetic 
enzymes (e.g., 5 alpha [α]-reductase) between GTx-024 and the steroids may also 
contribute to differences in selectivity. GTx-024 is an anabolic agonist in muscle and 
bone while acting neutral or antagonistic in androgenic tissues like the skin. 
Various preclinical models have demonstrated that non-aromatizable AR agonists are 
anti-proliferative in BC cells. GTx-024 and its closely related analog, GTx-027, were 
tested in models of ER-positive BC. GTx-027 binds to and activates AR at comparable 
concentrations and, structurally, GTx-027 is comparable to GTx-024 with a difference 
of only one atom. The growth of MCF-7 ER-positive BC cells over-expressing AR 
(MCF-7-AR) and endogenously AR-expressing cells (ZR-75-1) were inhibited by AR 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 35 of 121 
 
agonists, but not by antagonists or structurally similar non-binders. Furthermore, the 
growth of MCF-7-AR tumors in nude mice was completely inhibited by SARMs. 
Microarray analyses with tumors obtained from xenograft studies indicated that 
GTx-027 inhibited the expression of messenger ribonucleic acid (mRNA) for 
oncogenes and induced tumor suppressor genes. GTx-027 up- and down- regulated 
(725 vs. 641) a similar number of genes with BC pathway genes being the most 
regulated disease pathway. Several anti-proliferative genes increased (TIMP3, AHR, 
KLK3) and an equal number of proliferative genes (MTR, XRCC1, and progesterone 
receptor) decreased. GTx-027 not only increased most of the well-known 
AR-regulated genes, such as KLK3, SNAI2, and MUC1, but also inhibited several ER 
target genes such as progesterone receptor, ER, and pS2. Overall, these studies 
clearly establish the importance of androgens and the AR in the treatment of BCs. 
Ongoing and Completed Clinical Trials with GTx-024 
Twenty-one Phase 1, 2, and 3 clinical trials have been completed or are ongoing with 
GTx-024. These include: 
1. Protocol G100401, a Phase 1 single ascending dose study in 96 healthy, 
young, male volunteers; 
2. Protocol G100402, a Phase 1 multiple ascending dose study in 50 healthy, 
young, male volunteers, and 23 elderly male volunteers with truncal obesity; 
3. Protocol G100503, a Phase 1 single dose pharmacokinetic study to assess the 
effect of a dosage regimen that simulates a sustained release formulation to an 
immediate release formulation in 18 healthy, young male volunteers and 
18 postmenopausal women; 
4. Protocol G100506, a Phase 1 single dose pharmacokinetic study to assess the 
relative bioavailability of a 3 mg hard shell capsule formulation to be used 
during continued clinical development and to assess the effect of food on the 
pharmacokinetics of the 3 mg softgel formulation in 27 healthy, young, male 
volunteers; 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 36 of 121 
 
5. Protocol 006, a Phase 1 single dose and multiple dose pharmacokinetic study 
in 24 postmenopausal, Japanese women; 
6. Protocol G200501, a Phase 2 study in 60 postmenopausal women and 60 
elderly men to assess lean body mass (LBM) and physical function; 
7. Protocol 003, a Phase 1b study in 44 postmenopausal women; 
8. Protocol G200502, a Phase 2b study in 159 men and postmenopausal women 
with cancer to assess LBM and physical function; 
9. Protocol G100511, a Phase 1 study to assess the effect of severe renal 
impairment on the pharmacokinetics of GTx-024; 
10. Protocol G100508, a Phase 1 study to assess the effect of mild and moderate 
hepatic impairment on the pharmacokinetics of GTx-024; 
11. Protocol G100509, a Phase 1 mass balance study of GTx-024 in healthy 
volunteers; 
12. Protocol G100507, a Phase 1 study to assess the pharmacokinetics and 
absolute PO bioavailability of GTx-024 in Caucasian and African American men 
and women;  
13. Protocol G100510, a single-dose, randomized, double-blind, comparative, 
positive and placebo-controlled, four-period crossover Phase 1 study to define 
the electrocardiogram (ECG) effects of GTx-024, at therapeutic and 
supratherapeutic doses, in healthy male and female subjects: a thorough ECG 
trial;  
14. Protocol G100512, a Phase 1 study to assess the effect of ketoconazole 
(Cytochrome P450, Family 3,Subfamily A [CYP3A4] inhibitor) on the 
pharmacokinetics of GTx-024; 
15. Protocol G100513, a Phase 1 study to assess the effect of rifampin (CYP3A4 
inducer) on the pharmacokinetics of GTx-024; 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 37 of 121 
 
16. Protocol G100514, a Phase 1 study to assess the pharmacokinetic drug:drug 
interaction of GTx-024 and celecoxib (CYP2C9); 
17. Protocol G100515, a Phase 1 study to assess the pharmacokinetic drug:drug 
interaction of GTx-024 and probenecid (UGT2B7); 
18. Protocol G100516, a Phase 1 study to assess the pharmacokinetic drug:drug 
interaction of GTx-024 and rosuvastatin (breast cancer resistance protein 
[BCRP]); 
19.  Protocol G300504, a Phase 3 randomized, double-blind, placebo-controlled 
study of the effect of GTx-024 on muscle wasting in 321 subjects with non-small 
cell lung cancer receiving first line platinum plus a taxane chemotherapy; 
20.  Protocol G300505, a Phase 3 randomized, double-blind, placebo-controlled 
study of the effect of GTx-024 on muscle wasting in 320 subjects with non-small 
cell lung cancer receiving first line platinum plus a non-taxane chemotherapy; 
21.  Protocol G200801, an ongoing, Phase 2, open label study to examine AR 
status and the activity of GTx-024 hormonal therapy in 22 women with ER 
positive metastatic BC who have previously responded to hormone therapy. 
2.2 
Rationale 
GTx-024 has been evaluated in 21 completed and ongoing clinical studies enrolling 
over 1,500 total subjects. GTx-024 has been generally well-tolerated, including single 
doses up to 100 mg and multiple doses up to 30 mg once daily for up to 14 days. In 
longer studies, GTx-024 has also been generally well-tolerated, including 1, 3, and 
9 mg daily doses for up to 184 days.  
Previous clinical studies demonstrated that daily doses up to 30 mg of GTx-024 were 
well-tolerated in healthy male volunteers. Both 10 mg and 30 mg daily doses were 
evaluated in Protocol G100402 for up to 14 days. Elevated alanine transaminase 
(ALT) (any elevation outside the upper limit of the normal range [ULN]) was the most 
common adverse event (AE) experienced. None of the subjects in the 10 mg dose 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 38 of 121 
 
group were discontinued from the study due to ALT elevations. Six out of 71 subjects 
experienced ALT increases above two times the ULN. 
GTx-024 3 mg given daily was evaluated in two completed Phase 3 trials, in over 
600 subjects, for the prevention and treatment of muscle wasting (cachexia) in 
subjects with advanced non-small cell lung cancer receiving chemotherapy. GTx-024 
3 mg increased LBM in both studies and was safe and well-tolerated. Subjects in the 
GTx-024 and placebo groups experienced similar AEs, and these AEs were consistent 
with the background chemotherapy regimen. 
Although GTx-024 3 mg was chosen for its anabolic activity in muscle for the 
completed Phase 3 program, a dose of 9 mg once daily was selected for hormonal 
therapy in the ongoing Phase 2 trial in ER+/AR+ metastatic BC in order to achieve a 
higher exposure that is both safe and more likely to be efficacious in women with 
advanced BC. Seven out of twenty-two subjects with advanced, heavily pretreated 
(hormonal therapy, radiation, and chemotherapy) BC demonstrated clinical benefit 
(CB) (stable disease [SD]) at 6 months. In one subject with SD (by Response 
Evaluation Criteria in Solid Tumors [RECIST], Version 1.12), tumor regression of 27% 
in a single target lesion was demonstrated. Consistent with the previous studies, 
GTx-024 remained safe and well-tolerated.  
 
Reductions in sex hormone binding globulin (SHBG) have been identified as one of 
the most sensitive serum biomarkers for AR signaling in healthy volunteers and 
patients. SHBG was reduced by 15.1%, 15.6%, 18.2%, and 18.4% in young, healthy 
volunteers who received PO GTx-024 1 mg, 3 mg, 10 mg, and 30 mg daily for 
14 days, respectively, in Protocol G100402, suggesting that doses of 10 mg and 
above maximally stimulate AR activity.  
 
Dosing GTx-024 at 15–20 mg per day may provide therapeutic benefit in hormone 
receptor positive BC by two separate mechanisms: activating AR and inhibiting 
progesterone receptor, thereby increasing potential efficacy. Progesterone receptor 
expression in cancer stem cells has been shown to be involved in proliferation of 
cancer epithelial cells, and inhibiting progesterone receptor’s activity is now 
considered a novel approach to treating BC. Hence, enobosarm at higher doses might 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 39 of 121 
 
provide dual anti-proliferative effects in BC. Doses of 15–20 mg per day should 
provide saturation of the AR potentially providing better efficacy as opposed to a lower 
dose with partial occupancy of the AR and absence of any progesterone receptor 
inhibitory effect. 
 
Based on the safety data collected to date in both preclinical and clinical settings, the 
company expects the 18 mg dose will be safe and generally well tolerated. However, 
in the event that a subject has a Grade 3 or greater toxicity, the 18 mg dose may be 
reduced to 9 mg until the AE resolves or for the remainder of treatment based on the 
Investigator’s discretion. The 9 mg dose has been previously studied in 
postmenopausal women with metastatic BC and was safe and well tolerated.  
 
Proof of concept was demonstrated in ER+ BC patients at a 9 mg dose with no 
serious adverse events (SAEs) and over 70% of AEs reported as Grade 1. The 
efficacy at 9 mg was modest with a 35% clinical benefit rate (CBR). The purpose of 
the 9 mg dose arm in the present investigation is to confirm the safety and efficacy 
findings of the prior proof of concept study in a larger population of ER+/AR+ BC 
patients, while the purpose of the 18 mg dose arm is to explore the safety and efficacy 
of this dosage in a similar patient population without compromising subject safety. By 
increasing the dose to 18 mg, there is potential for greater efficacy in ER+ patients 
due to the dual mechanism of action; AR agonist and progesterone receptor 
antagonist. In the event that safety and efficacy is demonstrated in both dosing arms, 
the data from this study will be informative in the design of any potential future trials 
comparing both doses of GTx-024 to an active comparator determining the most 
efficacious dose of GTx-024 with an acceptable safety profile in the treatment of 
ER+/AR+ BC patients. 
2.3 
Potential Risks and Benefits 
2.3.1 
Potential Risks 
GTx-024 has generally been well-tolerated in clinical trials conducted to date. Certain 
AEs associated with GTx-024 may occur. The most commonly reported side effects 
for GTx-024 in the previous 21 clinical studies include: 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 40 of 121 
 
 
Headache 
 
Back pain 
 
Diarrhea 
 
Pain in arm or leg 
 
Upset stomach 
 
Constipation 
 
Fatigue (tiredness) 
 
Dizziness 
 
Increases in liver enzymes 
 
Flu-like symptoms 
 
Anemia (decrease in red blood cells) 
 
Reduction in high density lipoproteins (HDL) 
 
Visual disturbances 
These side effects were based on information obtained from other clinical studies 
using GTx-024 in doses ranging from 0.1 mg to 3 mg. These studies suggest that side 
effects associated with the study drug resolve after GTx-024 is stopped. 
 
In a Phase 2 clinical study using GTx-024 in cancer subjects, the following SAEs 
occurred in at least 2% but less than 10% of subjects. These SAEs are also consistent 
with the subject’s cancer therapy and the severity of the illness, and, therefore, may 
have resulted from the GTx-024 or from the cancer progression and/or the cancer 
treatment: 
 
Febrile neutropenia 
 
Pneumonia 
An AE that appears related to GTx-024 in clinical trials has been a dose-dependent, 
transient, asymptomatic increase in ALT. However, these increases were modest at 
doses up to 10 mg per day. Most of the subjects studied to date had ALT levels that 
remained within normal limits. One subject was discontinued for an ALT > 3 times the 
ULN. The ALT levels returned to normal with continued exposure to GTx-024 in most 
cases and, further, in instances when dosing was not continued, levels returned to 
normal. No significant increases in total bilirubin, gamma-glutamyl transferase (GGT), 
alkaline phosphatase, or lactate dehydrogenase (LDH) have been observed in 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 41 of 121 
 
subjects with elevated ALT levels. Consistent with the effects of other PO 
administered anabolic agents, GTx-024 causes a dose dependent reduction in HDL, 
the clinical significance of which is unknown at this time. The proposed mechanism for 
reduction in HDL is due to stimulation of reverse cholesterol transport and increased 
HDL catabolism by hepatic lipase. Reductions in HDL are temporary and typically 
return to baseline 12 months after treatment initiation5,6,7,8,9. 
 
There were no other consistent, clinically relevant, dose-related effects of GTx-024 on 
ECGs or vital signs measurements (blood pressure or heart rate).  
 
Investigators should be aware that blood levels of the tumor marker, CA27.29, have 
been shown to be modulated by compounds with androgenic activity as a result of the 
marker binding to the androgen regulated protein MUC-1. As a result, administration of 
GTx-024 has the potential to result in increases in CA27.29 that are not necessarily 
reflective of disease progression10,11.  
 
The drug used in this research study may affect a fetus. Subjects should not become 
pregnant nor breastfeed a baby while participating in this research study. All subjects 
in this study are required to be confirmed as postmenopausal; however, a serum 
pregnancy test will be obtained at screening as a standard safety precaution. 
2.3.2 
Potential Benefits 
GTx-024 9 mg once daily has been studied in 22 postmenopausal women with 
metastatic ER+ BC who have previously responded to hormonal therapy. The primary 
endpoint was assessed in 17 AR positive subjects. Six of these 17 subjects 
demonstrated CB (SD) at six months. In one subject with SD (RECIST 1.1), tumor 
regression of 27% in a single target lesion was demonstrated. Seven subjects in total 
(one subject with indeterminate AR status) achieved CB at six months. Among the 
seven subjects who achieved CB at six months, time to progression (TTP) was 
estimated as 10.2 months. The results also demonstrated that, after a median duration 
on study of 81 days, 41 percent of all subjects (9/22) achieved CB as best response 
and also had increased PSA, which appears to be an indicator of AR activity. As of the 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 42 of 121 
 
finalization of this protocol, the study is still ongoing with one subject whose disease 
remains stable beyond 336 days.  
Preclinical data with GTx-024 suggests that it is also anabolic in bone and decreases 
bone turn over markers. Treatment with GTx-024 may decrease bone turn over as 
compared with other hormonal therapies for the treatment of hormone receptor 
positive BC. Stronger bone microenvironment may decrease metastases to bone or 
delay time to skeletal related events. 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 43 of 121 
 
3 
OBJECTIVES 
3.1 
Study Objectives 
The primary efficacy objective of this trial is to estimate the CBR at 24 weeks  
(defined as complete response [CR], partial response [PR], or SD) (by RECIST 1.1) of 
GTx-024 9 mg and of GTx-024 18 mg given PO daily in subjects with estrogen 
receptor positive and androgen receptor positive (ER+/AR+) BC who have centrally 
confirmed AR+ status. 
Secondary efficacy objectives: 
 Estimate the CBR at 24 weeks (by RECIST 1.1) of GTx-024 9 mg and 18 mg in all 
subjects randomized who receive at least one dose of study medication (the full 
analysis set [FAS]) regardless of AR status as determined by the central laboratory 
The following secondary efficacy objectives apply to both centrally confirmed AR+ 
subjects (the evaluable subset of the FAS) as well as to all subjects in the FAS: 
 Estimate the objective response rate (ORR; defined as CR or PR) (by RECIST 1.1) 
of GTx-024 9 mg and 18 mg at 24 weeks 
 Estimate the best overall response rate (BOR) of GTx-024 9 mg and 18 mg  
 Estimate the progression free survival (PFS) of subjects receiving GTx-024 9 mg 
and 18 mg 
 Estimate the TTP of subjects receiving GTx-024 9 mg and 18 mg 
 Estimate duration of response (time from documentation of tumor response to 
disease progression or death) of subjects receiving GTx-024 9 mg and 18 mg 
Tertiary objectives: 
The following tertiary efficacy objectives apply to both centrally confirmed AR+ 
subjects (the evaluable subset of the FAS) as well as to all subjects in the FAS: 
 Assess the effect of GTx-024 9 mg and 18 mg on serum PSA 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 44 of 121 
 
 Assess the effect of GTx-024 9 mg and 18 mg on Quality of Life (QoL) as 
measured by EQ-5D-5L3  
 Assess the effect of GTx-024 9 mg and 18 mg on circulating tumor cells (CTCs) 
 Assess the impact of duration of prior CB on outcome 
 Assess the impact of time from diagnosis of metastases to randomization on 
outcome 
 Describe the effect of GTx-024 9 mg and 18 mg on tumor volumetrics 
 Assess the effect of plasma concentrations of GTx-024 and GTx-024 
glucuronide on CBR at 24 weeks 
Safety objective: 
To describe the safety profile of GTx-024 9 mg and 18 mg PO daily in subjects with 
ER+/AR+ BC with centrally confirmed AR+ as well as in all subjects randomized and 
treated. 
Pharmacokinetic objective: 
To describe the plasma concentrations of GTx-024 and GTx-024 glucuronide at each 
of the assessed time points. 
3.2 
Study Outcome Measures 
3.2.1 
Primary Efficacy Outcome Measures 
Response of CB at 24 weeks, in a subject with centrally confirmed AR+ status.  
 
CB is defined as a CR, a PR, or SD as measured by RECIST 1.1 and confirmed by a 
central image-reading facility blinded to the GTx-024 dose received. 
 
For subjects with non-measurable (non-target) disease only at baseline, SD is defined 
as those with non-CR/non-progressive disease (PD) combined response.  


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 45 of 121 
 
3.2.2 
Secondary Efficacy Outcome Measures 
 
Response of CB in a subject at 24 weeks regardless of central confirmation of AR 
status (FAS)  
The following secondary efficacy outcome measures apply to both the evaluable 
subset of the FAS as well as to the FAS: 
 
OR at week 24. OR is defined as attainment of a CR or PR at 24 weeks as 
measured by RECIST 1.1 
 
BOR as measured by RECIST 1.1 and defined as: the best response recorded 
from the start of the study treatment until the end of treatment taking into account 
any requirement for confirmation. For a subject with non-measurable (non-target) 
disease only at baseline, SD will be defined as those with non-CR/non-PD 
combined response 
 
PFS defined as the time elapsed between randomization and tumor progression as 
measured by RECIST 1.1 or death due to any cause 
 
TTP defined as the time elapsed between randomization and tumor progression as 
measured by RECIST 1.1 or death due to disease progression 
 
Duration of response (time from documentation of tumor response to disease 
progression or death) 
3.2.3 
Tertiary Efficacy Outcome Measures 
The following tertiary efficacy outcome measures apply to both the evaluable subset of 
the FAS as well as to the FAS: 
 
Serum PSA at each assessment, changes from baseline to each assessment, and 
percentage change from baseline of serum PSA at each assessment 
 
Subject reported QoL (EQ-5D-5L questionnaire) at each assessment and changes 
from baseline to each assessment 
 
CTCs at each assessment and changes from baseline to each assessment 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 46 of 121 
 
 
Impact of duration of prior CB on outcome (CB response at week 24, PFS, TTP, 
duration of response) 
 
Impact of time from diagnosis of metastases to randomization on outcome (CB 
response at week 24, PFS, TTP, duration of response) 
 
Tumor volume at each assessment and change from baseline to each assessment 
 
Plasma concentrations of GTx-024 and GTx-024 glucuronide on outcome (CB 
response at week 24) 
3.2.4 Safety Outcome Measures 
The following safety outcome measures apply to both the evaluable subset of the FAS 
as well as to all subjects enrolled and treated: 
 
AEs and concomitant medications 
 
Laboratory examinations (clinical chemistry, hematology, and urinalysis) 
 
Physical examinations  
 
Vital signs 
 
ECOG performance status 
 
Eye examinations 
3.2.5 Pharmacokinetic outcome measures 
 
Plasma concentrations of GTx-024 and GTx-024 glucuronide at each of the 
assessed time points  
 
 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 47 of 121 
 
4 
STUDY DESIGN 
This is an open label, multicenter, multinational, randomized, parallel design Phase 2 
study to assess the efficacy and safety of GTx-024 in postmenopausal subjects with 
ER+/AR+ BC. Subjects will be randomized to receive either GTx-024 9 mg or 18 mg 
given PO daily for up to 24 months. Each dose arm will be treated independently and 
each assessed for efficacy using Simon’s two-stage (optimal) design1. Subjects will be 
randomized in a 1:1 fashion to one of the two dose arms. Randomization will be 
stratified by subjects presenting with bone only metastases and all other subjects, and 
further by setting of immediately preceding therapy (adjuvant setting or metastatic 
setting) in order to balance the proportion of subjects with these presenting features in 
each dose arm. There is no intent to statistically compare the two dose arms, but to 
determine whether either or both doses result in an acceptable CBR, defined as the 
proportion of evaluable subjects (i.e., subjects with centrally confirmed AR+ and who 
receive at least one dose of study drug) with either CR, PR, or SD by RECIST 1.1 at 
week 24, consistent with 30% while maintaining an acceptable safety profile. Given 
such a result, future exploration of GTx-024 in ER+/AR+ BC would be warranted at 
that dose level. 
 
Thirty-six to 88 (36–88) subjects with centrally confirmed AR+ who receive at least one 
dose of study drug (evaluable subjects) will be needed for primary efficacy analysis 
purposes and will be a subset of the FAS. Thirty-six to one hundred and eighteen  
(36–118) subjects, including replacement subjects, will be randomized in a 1:1 fashion 
to receive a daily PO dose of either GTx-024 9 mg or 18 mg. Thirty of the 
aforementioned subjects may be considered replacement subjects to account for lack 
of centrally confirmed AR+ status or for the rare subject who is randomized but does 
not receive study drug (assumes 25% of enrolled subjects are not evaluable for the 
primary efficacy analysis). Other statistical parameters that are part of the sample size 
calculation are α = 0.025 (one-sided) and power = 90%. The first stage in each study 
arm will be assessed among the first 18 evaluable subjects. If at least 3/18 subjects 
achieve CB (defined as CR, PR, or SD) at week 24, the arm will proceed to the 
second stage of recruitment up to a total of 44 evaluable subjects per arm. Otherwise, 
the arm will be discontinued for lack of efficacy. Statistical significance, i.e., rejection of 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 48 of 121 
 
the null hypothesis of an unacceptably low CBR of ≤ 10% in favor of the alternative 
hypothesis that indicates the higher rate, ≥ 30%, is more likely, will be declared if at 
least 9/44 subjects achieve CB at week 24 in that arm. 
 
Subjects who are not centrally confirmed AR+ may remain on the trial, but will not be 
part of the primary efficacy analysis – these subjects will contribute to secondary and 
tertiary analyses as noted in Section 11 Statistical Considerations. 
 
Subjects on the 18 mg treatment arm who experience an AE with Grade ≥ 3 intensity 
(National Cancer Institute-Common Terminology Criteria for Adverse Events 
[NCI-CTCAE], Version 4.0) and/or intolerance may have a dose reduction from 18 mg 
to 9 mg per day or a drug interruption based on the medical judgment of the 
Investigator and after confirmation by the study Medical Monitor. The drug interruption 
may last for a period of up to 5 days after which the subject must be rechallenged with 
study drug (18 mg or 9 mg) or discontinued from the study. In the case of a dose 
reduction, once the AE has resolved or reduced in intensity to Grade 1, the subject 
may be rechallenged with 18 mg or maintained at 9 mg at the discretion of the 
Investigator.  
 
Subjects on the 9 mg treatment arm who experience an AE with Grade ≥ 3 intensity 
(NCI-CTCAE 4.0) and/or intolerance may have a drug interruption based on the 
medical judgment of the Investigator and after confirmation by the study Medical 
Monitor. The drug interruption may last for a period of up to 5 days after which the 
subject must be rechallenged with study drug (9 mg) or discontinued from the study. 
 
In the event of hepatotoxicity, please also refer to Section 9.4  
Halting Rules. 
 
For safety analysis, subjects will be analyzed in the treatment arm in which they are 
initially dosed. For efficacy analysis, subjects will be analyzed according to the 
treatment arm to which they were randomized. 
 
The subjects who demonstrate CB will be treated for up to 24 months from the date of 
randomization (as long as they continue to demonstrate CB from the treatment during 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 49 of 121 
 
these 24 months). Subjects who continue to demonstrate a CB from the study 
treatment at 24 months will be offered to continue in a safety extension study under a 
separate protocol. For safety purposes, all subjects will be followed-up for one month 
after the last dose of GTx-024 is received. 
 
A flow chart of the study is shown in Figure 1 below. 
 
Figure 1: Flow chart of Study Plan 
 
Possible pause in enrollment: The implementation of Simon’s two-Stage design could 
cause a pause in enrollment of the trial prior to proceeding to the second stage. For 
example, if the required 18 evaluable subjects in the first stage of an arm are enrolled 
and 15 have either terminated the trial or been assessed as not achieving CBR at 
24 weeks, it will be necessary to pause enrollment in that arm until the remaining three 
evaluable subjects are fully assessed for CBR, i.e., either withdraw prior to week 24 or 
have the week 24 RECIST 1.1 assessment. 
4.1 
Substudies (if applicable) 
Not applicable. 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 50 of 121 
 
4.2  Safety Monitoring Committee 
In order to protect the safety of the subjects, a Safety Monitoring Committee (SMC) 
will be established for the study to review the safety data on an ongoing basis. The 
SMC will consist of, as a minimum, the Medical Monitor, a Safety Reviewer with an 
oncology background, a statistician, and two GTx, Inc. representatives, consistent with 
the SMC charter. 
The first safety review meeting will occur approximately one to two weeks following the 
enrollment of first 5 subjects in the study. Additionally, the SMC chairman or GTx, Inc. 
may call an unscheduled review of the study by the SMC if there is a concern for 
subject safety. Following the meetings, the SMC chairperson is responsible for 
communicating one of the following recommendations to GTx, Inc.: 
 
Continue the study without modification 
 
Continue the study with modifications (to be specified); or 
 
Stop the study due to safety (specific safety concern[s] to be specified) 
 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 51 of 121 
 
5 
STUDY ENROLLMENT AND WITHDRAWAL 
5.1 
Subject Inclusion Criteria 
Subjects eligible for inclusion in this study must meet all of the following criteria:  
1. Adult women (≥ 18 years of age) with metastatic or recurrent locally advanced BC, 
not amenable to curative treatment by surgery or radiotherapy, with objective 
evidence of disease progression. 
 Women must have received ≥ 1 prior hormonal treatment(s) in the metastatic or 
adjuvant setting 
 If the most recent hormonal treatment was in the metastatic setting, 
duration of response (tumor regression or stabilization of disease) to this 
specific course of therapy must be ≥ 6 months 
 If the most recent hormonal treatment was in the adjuvant setting, 
duration of response (disease free) to this specific course of therapy 
must be ≥ 3 years 
2. Histological or cytological confirmation of ER+ BC as assessed by a local 
laboratory using slides, paraffin blocks, or paraffin sample or by medical history: 
ER+ (confirmed as ER expression more than or equal to 1% positive tumor nuclei) 
3. Human epidermal growth factor receptor 2 (HER2)-negative tumor by local 
laboratory testing (immunohistochemistry [IHC] 0, 1+ regardless of fluorescence in 
situ hybridization [FISH] ratio; IHC 2+ with FISH ratio lower than 2.0 or HER2 gene 
copy less than 6.0; FISH ratio of 0, indicating gene deletion, when positive and 
negative in situ hybridization [ISH] controls are present) 
4. Availability of paraffin embedded or formalin fixed tumor tissue; OR, a minimum of 
10 and up to 20 slides of archived tumor tissue for central laboratory confirmation 
of AR status and molecular subtyping. Metastatic tumor tissue is preferred when 
possible 
5. Postmenopausal women. Postmenopausal status is defined by the National 
Comprehensive Cancer Network as either:  


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 52 of 121 
 
 Age ≥ 55 years and one year or more of amenorrhea  
 Age < 55 years and one year or more of amenorrhea, with an estradiol assay 
< 20 pg/mL  
 Age < 55 years and surgical menopause with bilateral oophorectomy  
a. Note: Ovarian radiation or treatment with a luteinizing hormone-
releasing hormone (LH-RH) agonist (goserelin acetate or leuprolide 
acetate) is not permitted for induction of ovarian suppression  
6. Radiological or clinical evidence (bone scan, computerized tomography [CT], and 
magnetic resonance Imaging [MRI]) of recurrence or progression within 30 days 
before randomization 
7. Subject must have either measurable disease or bone-only non-measurable 
disease, evaluable according to RECIST 1.1 
8. Adequate organ function as shown by:  
 Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3  
 Platelet count ≥ 100,000 cells/mm3  
 Hemoglobin (Hgb) ≥ 9.0 g/dL  
 Serum aspartate aminotransferase (AST) and alanine transaminase (ALT) ≤ 2.5 
upper limit of the normal range (ULN) (or ≤ 5 if hepatic metastases are present) 
 Total serum bilirubin ≤ 2.0 × ULN (unless the subject has documented Gilbert 
Syndrome)  
 Alkaline phosphatase levels ≤ 2.5 × ULN (≤ 5 × ULN in subjects with liver 
metastasis) 
 Serum creatinine ≤ 2.0 mg/dL or 177 µmol/L 
 International normalized ratio (INR) or activated partial thromboplastin (aPTT) 
< 1.5 × ULN (unless on anticoagulant treatment at screening) 
9. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status4 
0 or 1 
10. Subject is able to swallow capsules  
11. Able and willing to give voluntary, written and signed informed consent before any 
screening procedure and according to local guidelines  


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 53 of 121 
 
5.2 
Subject Exclusion Criteria  
Subjects eligible for this study must not meet any of the following criteria: 
1. Previously received > 1 course of chemotherapy (not including immunotherapies or 
targeted therapies) for the treatment of metastatic BC 
a. Note: Subjects may have received 1 course of chemotherapy prior to 
surgery for the treatment of locally advanced disease and 1 course of 
chemotherapy for the treatment of metastatic BC; however, if surgery could 
not be performed, this will count as the 1 chemotherapy course allowed prior 
to study 
2. Known hypersensitivity to any of the GTx-024 components or subjects previously 
received treatment with SARM 
3. Subjects with radiographic evidence of central nervous system (CNS) metastases 
as assessed by CT or MRI that are not well-controlled (symptomatic or requiring 
control with continuous corticosteroid therapy [e.g., dexamethasone])  
a. Note: Subjects with CNS metastases are permitted to participate in 
the study if the CNS metastases are medically well-controlled and 
stable for at least 28 days after receiving local therapy (irradiation, 
surgery, etc.) 
4. Radiotherapy within 14 days prior to randomization except in case of localized 
radiotherapy for analgesic purpose or for lytic lesions at risk of fracture, which can 
then be completed within 7 days prior to randomization. Subjects must have 
recovered from radiotherapy toxicities prior to randomization 
5. Currently receiving hormone replacement therapy, unless discontinued prior to 
screening  
6. Subjects positive for Human Immunodeficiency Virus (HIV) 
7. Subject has a concomitant medical condition that precludes adequate study 
treatment compliance or assessment, or increases subject risk, in the opinion of 
the Investigator, such as but not limited to: 
 Myocardial infarction or arterial thromboembolic events within 6 months prior to 
Baseline or severe or unstable angina, New York Heart Association (NYHA) 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 54 of 121 
 
Class III or IV disease, or a QTCB (corrected according to Bazett’s formula) 
interval > 470 msec  
 Serious uncontrolled cardiac arrhythmia grade II or higher according to NYHA  
 Uncontrolled hypertension (systolic > 150 and/or diastolic > 100 mm Hg) 
 Acute and chronic, active infectious disorders and non-malignant medical 
illnesses that are uncontrolled or whose control may be jeopardized by the 
complications of this study therapy  
 Impairment of gastrointestinal function or gastrointestinal disease that may 
significantly alter the absorption of study drugs (e.g., ulcerative disease, 
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome)  
 Another active cancer (excluding adequately treated basal cell carcinoma or 
cervical intraepithelial neoplasia [CIN]/cervical carcinoma in situ or melanoma in 
situ). Prior history of other cancer is allowed as long as there is no active 
disease within the prior 5 years 
8. Major surgery within 28 days before randomization 
9. Positive hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection at 
screening  
10. History of non-compliance to medical regimens  
11. Subject unwilling to or unable to comply with the protocol  
12. Subject is currently receiving treatment with any agent listed on the prohibited 
medication list (See Section 6.6 
Concomitant Medications/Treatments for 
complete list) 
13. Treatment with any investigational product within < 4 half-lives for each individual 
investigational product OR within 28 days prior to randomization 
5.3 
Strategies for Recruitment, Retention, and to Improve 
Adherence to Intervention Protocols 
No special strategies or activities will be employed for recruitment and retention.  


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 55 of 121 
 
5.4 
Treatment Assignment Procedures 
5.4.1 
Randomization Procedures 
Eligible subjects will be randomized in a 1:1 ratio to GTx-024 9 mg daily or GTx-024 
18 mg daily. If based on halting rules (Section 9.4  
Halting Rules) or for any other 
reason the 18 mg arm is terminated, randomization will end and all future enrollees will 
be enrolled on the 9 mg arm. 
5.4.2 
Masking Procedures 
Treatment periods will be open label.  
Tumor lesions will be assessed using RECIST 1.1 at the site based on the local 
reading facility; however, scans will also be sent to the central imaging facility, blinded 
to the GTx-024 dose, for final efficacy outcomes analysis. 
5.4.3 
Reasons for Withdrawal 
Subjects are free to withdraw from the study at any time for any reason.  
In addition, subjects may be withdrawn from the study by the Principal Investigator (PI) 
in consultation with GTx, Inc. for the following reasons: 
 AEs that require treatment with a forbidden medication or procedure 
 Development of any condition that may pose an additional risk to the subject or 
PI decision that this is in the best interest of the subject 
 Sponsor’s decision 
 Subject unable to follow Investigators’ instructions and comply with the study 
procedures 
 Protocol deviation 
 Disease progression 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 56 of 121 
 
The clinical study report will include reasons for all subject withdrawals from treatment 
as well as details relevant to violations of Study Prohibitions and Concomitant 
Therapy. 
5.4.4 
Handling of Withdrawals 
Every effort will be made to ensure that subjects who withdraw (for whatever reason) 
from the study will still be asked to continue scheduled evaluations and participate in 
the follow-up evaluation. Subjects who withdraw due to an AE or SAE will be given 
appropriate care under medical supervision until the symptoms of any AE resolve or 
the subject’s condition becomes stable. 
Subjects who are randomized but do not go on to receive study drug will be replaced; 
otherwise, subjects who receive at least one dose of study drug and who withdraw 
from the study will not be replaced. 
5.4.5 
Termination of Study  
The Sponsor can stop this study at any time, for any reason. This study may be 
prematurely terminated if, in the opinion of the Investigator or the Sponsor, there is 
sufficient reasonable cause to stop the study at the clinical site. Written notification, 
documenting the reason for study termination, will be provided to the Investigator or 
Sponsor by the terminating party. 
Circumstances that may warrant termination include, but are not limited to: 
 
Determination of unexpected, significant, or unacceptable risk to subjects 
 
Insufficient adherence to protocol requirements 
 
Data that are not sufficiently complete and/or evaluable  
 
Plans to modify, suspend, or discontinue the development of the study drug 
If the study is prematurely terminated or suspended, the Sponsor will promptly inform 
the Investigators/institutions, and the regulatory authority(ies) of the termination or 
suspension and the reason(s) for the termination or suspension. The Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC) will also be informed 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 57 of 121 
 
promptly and provided the reason(s) for the termination or suspension by the Sponsor 
or by the Investigator/institution, as specified by the applicable regulatory 
requirement(s). 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 58 of 121 
 
6 
STUDY INTERVENTION/INVESTIGATIONAL PRODUCT 
6.1 
Study Product Description 
6.1.1 
Acquisition 
GTx-024 3.0 mg softgel capsules will be supplied by GTx, Inc. 
6.1.2 
Formulation, Packaging, and Labelling 
GTx-024 3.0 mg Softgels will be supplied as opaque, white to off-white, size 5, oval 
Softgel capsules with “GTx” imprinted in black ink on the outer shell containing 3.0 mg 
of GTx-024. The liquid Softgel fill is composed of GTx-024 dissolved in polyethylene 
glycol 400. GTx-024 3.0 mg Softgels will be packaged in blister packs. Each blister 
pack will contain sufficient study drug for one (1) week of dosing. At randomization 
(Visit 2) and at Visits 3, 4, and 5), subjects will be provided with a carton of study drug 
containing 7 blister packs, equivalent to 7 weeks of dosing. At Visits 6, 8, 9, 10, 11, 12, 
and 13, in order to accommodate the visit schedule of every 12 weeks (± 7 days), the 
subjects will receive two carton boxes of study drug (each containing 7 blisters) to 
cover study treatment for 14 weeks. Subjects will be requested to bring with them the 
carton box with all blister packs at every visit. 
Each blister pack will be comprised of an appropriate number of blister strips (1 blister 
for the 9 mg treatment arm and 2 blisters for the 18 mg treatment arm) encased in a 
child-resistant heat-sealed card. The blister strips are composed of a PVC/ACLAR 
base and an aluminum foil/PVC/PVAC copolymer and polymethacrylate (product 
contact) lidding. Perforations on the back of the heat-seal card overlay the foil 
lidding. To remove the study drug, subjects will release the appropriate perforation by 
depressing a release button on the inside of the card. Once released, the perforation 
can be removed and the study drug pushed through the foil. 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 59 of 121 
 
Dosing instructions will be provided on the study drug label and in the subject 
information sheet. 
6.1.3 
Product Storage and Stability 
Recommended storage will be at controlled room temperature 15°C–25°C (59°F–
77oF), with excursions permitted to 30°C (86°F), protected from moisture. 
6.2 
Dosage, Preparation, and Administration of Study 
Investigational Product 
Three (3) GTx-024 3.0 mg softgels for a 9 mg daily dose or six (6) GTx-024 3.0 mg 
softgels for an 18 mg daily dose will be taken PO with water at approximately the 
same time each day, with or without food.  
6.3 
Modification of Study Investigational Product for a Subject 
Subjects on the 9 mg treatment arm who experience an AE with Grade ≥ 3 intensity 
(NCI-CTCAE 4.0) and/or intolerance may have a drug interruption based on the 
medical judgment of the Investigator and after confirmation by the study Medical 
Monitor. The drug interruption may last for a period of up to 5 days after which the 
subject must be rechallenged with study drug (9 mg) or, as appropriate, subjects 
should be discontinued from study. 
Subjects in the 18 mg treatment group who experience an AE with Grade ≥ 3 intensity 
(NCI-CTCAE 4.0) and/or intolerance may have a dose reduction from 18 mg to 9 mg 
per day or a drug interruption based on the medical judgment of the Investigator and 
after confirmation by the study Medical Monitor. The drug interruption may last for a 
period of up to 5 days after which the subject must be rechallenged with study drug 
(18 mg or 9 mg) or discontinued from the study. In the case of a dose reduction, once 
the AE has resolved or reduced in intensity to Grade 1, the subject may be 
rechallenged with 18 mg or maintained at 9 mg at the discretion of the Investigator.  
In the event of hepatotoxicity, please also refer to Section 9.4  
Halting Rules. 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 60 of 121 
 
6.4 
Accountability Procedures for the Study Investigational 
Product(s) 
The Investigator is responsible for the correct storage of study medication according to 
GTx, Inc. recommendations. The study medication made available for this clinical trial 
must be used in accordance with the protocol and dispensed only under the 
supervision of the Investigator and documented sub-Investigators. The Investigator 
must maintain complete and accurate records, showing the receipt and disposition of 
all supplies of the study medication delivered by the GTx, Inc., authorized 
representative. These records must include a master record which lists the date of 
receipt of all study medication shipments, batch numbers, expiration date, and 
quantities received. In addition, a dispensing record which includes all quantities 
dispensed, identification of the person to whom study medication was dispensed, the 
date of each dispensing, and the identification of the dispenser will also be 
maintained. The master dispensing records are separate from records kept for 
individual trial subjects. 
It is the Investigator’s responsibility to ensure that study medication used by trial 
subjects plus unused study medication equal the total amount received from the 
GTx, Inc., authorized representative. Damaged and/or contaminated packets must 
also be accounted for in the dispensing records. All discrepancies must be explained 
in writing. The study personnel responsible for study medication administration to the 
subject will record the date and time the initial treatment is given to the subject. In 
addition, the Drug Accountability electronic case report form (eCRF) will document any 
treatment interruptions or discontinuations. 
6.5 
Assessment of Subject Compliance with Study Investigational 
Product  
Subjects should be instructed to return all unused study medication and containers at 
clinic Visits 3, 4, 5, and 6; Visits 8–13 if still on treatment after week 24; and end of 
treatment (EOT) during the clinical trial period so that drug accountability can be 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 61 of 121 
 
performed. The dispensing pharmacy is required to count all returned study capsules 
and record this on the eCRF.  
All study medication returned by subjects must be accounted for and verified by the 
GTx, Inc., study monitor. After verification of all study medication, return of used 
packages and unused study medication must be authorized by the study monitor 
before being returned to GTx, Inc., or authorized representative. 
6.6 
Concomitant Medications/Treatments 
Forbidden medications and treatments during the study include:  
 Major surgery within 28 days before randomization 
 Testosterone, methyltestosterone, oxandrolone (Oxandrin®), oxymetholone, 
danazol, fluoxymesterone (Halotestin®), testosterone-like agents (such as 
dehydroepiandrosterone, androstenedione, and other androgenic compounds, 
including herbals), or antiandrogens. Previous therapy with testosterone and 
testosterone-like agents is acceptable with a 28-day washout (if previous 
testosterone therapy was long-term depot within the past 6 months, the site 
should contact the Medical Monitor) 
 Treatment with any of the following hormone replacement therapies, unless 
discontinued at least 28 days prior to randomization 
o Estrogens 
o Megesterol acetate 
 Treatment with any investigational agent within < 4 half-lives for each individual 
investigational product OR within 28 days prior to randomization 
 Local palliative radiation within 7 days before randomization 
 Radiotherapy within 14 days prior to randomization, except in case of 
localized radiotherapy for analgesic purpose or for lytic lesions at risk of 
fracture which can then be completed within 7 days prior to randomization. 
Subjects must have recovered from radiotherapy toxicities prior to 
randomization 
 All other anticancer treatments (including, but not limited to, all SERMs, AIs, 
and fulvestrant) 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 62 of 121 
 
 Caution should be exercised when administering potent CYP3A4 inducers, 
UDP inhibitors, and substrates of BCRP with GTx-024. Drug-drug interaction 
studies conducted with GTx-024 3 mg have demonstrated that concomitant 
use of CYP3A4 inducers may decrease the rate and extent of exposure of 
GTx-024 and its glucuronide metabolite. UDP inhibitors may increase 
GTx-024 and glucuronide exposure. Concomitant administration of GTx-024 
with BCRP substrates may lead to increased exposure of the BCRP 
substrate. 
 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 63 of 121 
 
7 
STUDY SCHEDULE 
Subjects with CB at 24 weeks (Visit 6) will continue on therapy as long as they are still 
benefitting from the treatment. Treatment may continue for up to 24 months from the 
date of randomization (as long as they continue to demonstrate CB from the treatment 
during these 24 months). 
 
Subjects who continue to demonstrate a CB from the study treatment at 24 months will 
be offered to continue in a safety extension study under a separate protocol.  
 
All visits may be scheduled within a time window of ± 7 days. 
7.1 
Screening 
Screening assessments must occur within 28 days prior to randomization for 
determination of subject’s overall eligibility. Informed consent will be obtained from the 
subjects before any other study procedure or test. AEs will be collected from the 
signing of the informed consent form (ICF). The following tests and procedures will be 
performed during the screening visit (Visit 1): 
 
Eligibility criteria check 
 
Subject medical history (current and past)  
 
Demography (age, gender, race)  
 
Diagnosis and extent of cancer  
 
Review of prior/concomitant medications, including previous and current anticancer 
treatment  
 
Physical examination, including height, weight, and vital signs (heart rate, 
respiratory rate, body temperature, blood pressure in a sitting position)  
 
ECOG performance status  
 
ECG 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 64 of 121 
 
 
Blood sampling for: screening for HIV, HBV, and HCV 
 
Blood sampling for: hematology, biochemistry, coagulation status, and serum 
pregnancy test  
 
Blood sampling for specific blood tests: PSA 
 
Urine analysis 
 
AE collection (from the moment of ICF signing) 
 
Radiological evaluation of the BC (as applicable CT/MRI/bone scan). Imaging 
results will be confirmed by a central imaging facility blinded to the dose of 
GTx-024 to be received, although a subject will be enrolled based on the local 
imaging and Investigator’s assessment. The central imaging facility will also 
perform tumor volumetric assessment for the subjects undergoing CT scanning. It 
is recommended these procedures are done as close to the randomization visit 
(Visit 2) as possible (if possible within 7 days prior to randomization) 
 
Review of medical history to confirm the hormonal receptor status of the tumor 
(ER, HER2). ER status will be confirmed by a local laboratory if not available in the 
subject’s medical history. AR status will be confirmed at a central laboratory  
 
Eye examination including best corrected distance visual acuity with refraction, 
intraocular pressure, slit lamp examination, and dilated fundus photography (must 
be completed between Day –28 and Day –1) 
7.2 
Randomization/Baseline 
The following tests and procedures will be performed during the 
randomization/baseline visit (Visit 2), or results checked and confirmed: 
 
Eligibility criteria checked; prior to randomization 
 
Review of prior/concomitant medications, including previous and current anticancer 
treatment 
 
Vital signs (heart rate, respiratory rate, body temperature, blood pressure in a 
sitting position), if not done within the last 7 days 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 65 of 121 
 
 
ECOG performance status, if not done within the last 7 days 
 
Blood sampling for: hematology, biochemistry, and PSA, if not done within the last 
7 days; and serum lipid profile, serum hormones, and CTCs (enumeration and 
gene expression)  
 
Urine analysis, if clinically indicated 
 
AE collection 
 
Subjects will be asked to complete a QoL questionnaire (EQ-5D-5L; before 
initiation of treatment) 
 
Randomization 
 
The first dose of study drug will be administered at this visit. Subjects will be given 
a carton box of 7 blister packs containing GTx-024 
 
Blood sample for pharmacokinetic assessment. The baseline blood sample should 
be collected before the subject is given their first dose of GTx-024. The exact time 
(hh:mm) and date of the blood sample will be recorded on the eCRF.  
7.3 
Treatment Phase 
The first dose of study drug will be administered on the day of randomization (Visit 2). 
GTx-024 will be administered daily for up to 24 months from randomization or until 
disease progression (whichever is sooner), subject’s withdrawal of consent, or 
intolerability.  
During the study treatment phase, the subjects will be scheduled for a visit every 
6 weeks. Visit 7 at week 28 will only take place in subjects who have CR or PR at 
Visit 6 (week 24; see below). 
The following tests and procedures will be performed during Visits 3, 4, 5, and 6 
(weeks 6, 12, 18, and 24) in the treatment phase: 
 
Review concomitant medications 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 66 of 121 
 
 
Physical examination, including weight and vital signs (heart rate, respiratory rate, 
body temperature, blood pressure in a sitting position)  
 
ECOG performance status 
 
Blood sampling for: hematology, biochemistry, serum lipid profile, coagulation 
status, serum hormones, and PSA 
 
Urine analysis, if clinically indicated  
 
AE collection 
 
Subjects will be asked to complete a QoL questionnaire (EQ-5D-5L) 
 
GTx-024 drug accountability/dispensation 
 
Radiologic assessments for anti-tumor effect will be done every 12 weeks whilst 
subjects receive treatment (Visits 4, 6, and thereafter). The same imaging technique 
must be used throughout the study in a given subject. Bone scans will be performed at 
screening and then every 12 weeks whilst subjects receive treatment (Visits 4, 6, and 
thereafter) in only those subjects with baseline bone metastases, or if clinically 
indicated. In addition, if any subject has CR or PR at Visit 6 (week 24), in compliance 
with RECIST 1.1 guidelines, a confirmation of the CR or PR (CT/MRI/bone scan) 
should be done 4 weeks later (Visit 7; week 28). The central imaging facility will also 
perform tumor volumetric assessment for the subjects undergoing CT scanning during 
Visits 4 and 6 (weeks 12 and 24). Blood sampling for CTC enumeration will be done at 
the same visits as the radiological assessments during the treatment phase; i.e., every 
12 weeks whilst subjects receive treatment (Visits 4 and 6), but not at the confirmation 
of the CR or PR visit (Visit 7; week 28) or at Visits 8–13.  
 
Dispensing of GTx-024 will be done at all study visits (except Visit 7) during the 
treatment phase (every 6 weeks at Visits 3, 4, and 5). At Visits 6, 8, 9, 10, 11, 12, and 
13, in order to accommodate the visit schedule of every 12 weeks (± 7 days), the 
subjects will receive two carton boxes of study drug (each containing 7 blisters) to 
cover study treatment for 14 weeks. 
 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 67 of 121 
 
At any time point during the treatment period, if clinically indicated, an eye examination 
including any or all of the following procedures will be performed based on medical 
judgment: best corrected distance visual acuity with refraction, intraocular pressure, 
slit lamp examination, and dilated fundus photography. 
 
Blood samples for pharmacokinetic assessment will be collected at Visit 3 (week 6), 
Visit 5 (week 18), and Visit 6 (week 24). The exact time (hh:mm) and date of each 
blood sample will be recorded on the eCRF. The date and approximate time of the last 
dose of GTx-024 prior to the blood sample should also be recorded; i.e., it should be 
documented whether the subject took the previous dose that morning or the evening 
before. 
7.4 
End of Treatment (EOT) Visit 
For all subjects the EOT visit should happen as soon as possible after the last dose of 
GTx-024 has been taken and no later than 3 days after that. The following tests and 
procedures will be performed during the EOT visit: 
 
Review of concomitant medications 
 
Physical examination, including weight and vital signs (heart rate, respiratory rate, 
body temperature, blood pressure in a sitting position) 
 
ECOG performance status  
 
Blood sampling for: hematology, biochemistry, serum lipid profile, coagulation 
status, and serum hormones  
 
Blood sampling for specific blood tests: PSA and CTCs (enumeration and gene 
expression) 
 
Urine analysis, if clinically indicated  
 
AE collection 
 
Radiological evaluation of the BC (as applicable CT/MRI/bone scan). Imaging 
results will be confirmed by a central imaging facility blinded to the GTx-024 dose. 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 68 of 121 
 
The same imaging technique must be used throughout the study in a given 
subject.  
 
Subjects will be asked to complete a QoL questionnaire (EQ-5D-5L) 
 
GTx-024 drug accountability 
 
Eye examination including best corrected distance visual acuity with refraction, 
intraocular pressure, slit lamp examination, and dilated fundus photography 
7.5 
Post-treatment Follow-up 
Subjects will be followed up for 1 month after the last dose of GTx-024. They will 
undergo the following procedures: 
 
Review of concomitant medications 
 
Physical examination, including weight and vital signs (heart rate, respiratory rate, 
body temperature, blood pressure in a sitting position) 
 
ECOG performance status 
 
Blood sampling for: hematology and biochemistry 
 
Blood sampling for PSA 
 
Urine analysis, if clinically indicated 
 
AE collection 
7.6 
Early Termination Visit 
An early termination visit will happen in case of: 
 
A subject withdrawing from the study at their discretion 
 
GTx, Inc. terminating the study in the interest of subject welfare 
 
Investigator withdrawing the subject from the study  
Subjects will be asked to attend a final visit so that the procedures for the EOT (see 
above) may be performed. 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 69 of 121 
 
7.7 
Unscheduled Visit  
A page will be included in the eCRF that asks about whether any unscheduled visits 
have taken place and provides space for the recording of any collected data, including 
unscheduled vital signs, ECGs, and laboratory results on the unscheduled visit eCRF 
page. Early/late planned visits will not be considered to be unscheduled visits. 
 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 70 of 121 
 
8 
STUDY PROCEDURES/EVALUATIONS 
Please see the APPENDIX A: SCHEDULE OF EVENTS for an outline of the timing of 
the study procedures/evaluations. 
8.1 
Clinical Evaluations 
All treatment decisions will be based on Investigator assessments, including 
determination of PD. 
Imaging Assessments: 
CT with contrast of the chest, abdomen, and pelvis including the liver and the adrenals 
will be performed to assess tumor status. If contrast is contraindicated, CT without 
contrast for chest and pelvis and MRI of the abdomen should be performed. 
Whichever imaging method is selected should be used for all study assessments in a 
given subject. 
Bone scintigraphy (bone scans) will be performed to assess bone metastases. Bone 
scans will be performed at screening and then every 12 weeks whilst subjects receive 
treatment (Visits 4, 6, and thereafter) in only those subjects with baseline bone 
metastases, or if clinically indicated.   
Tumor lesions will be assessed using RECIST 1.1 at the site based on the local 
reading facility. Scans will be sent to the central imaging facility, blinded to the 
GTx-024 dose, for final efficacy outcomes analysis. 
In compliance with RECIST 1.1, if any subject has CR or PR at Visit 6 (week 24), a 
confirmation of the CR or PR (CT/MRI/bone scan) should be done 4 weeks later 
(Visit 7; week 28).  
Tumor volumetrics will be performed by the assigned central vendor only for subjects 
who have CT scans at screening and then at weeks 12 and 24 (Visits 4 and 6). Tumor 
volumetrics will be performed by an independent 3rd party vendor who is masked to 
individual subject treatment and outcomes. 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 71 of 121 
 
Medical History and Medication History: 
The medical history of the subject will be obtained by the PI from the subject’s medical 
record. The medical history will include a review of the hormonal status of the BC (ER, 
HER2). 
Medication history will include all medications currently being taken (rather than the 
lifelong medication history) and will include both prescription and over-the-counter 
medicines (also including nutritional supplements or herbal treatments). This will 
include prior cancer treatments taken.  
Demographics: 
The following demographic data will be collected: age, gender, and race. 
Physical Examination: 
Physical examination will include organ palpation, lymph nodes palpation, skin turgor, 
and muscle weakness measurement.  
Height and weight will also be measured as outlined in the schedule of events.  
AEs will be followed-up to resolution, and while further physical examinations may 
take place, they will not be mandatory. 
Vital Signs: 
Vital signs at scheduled visits will include body temperature, respiratory rate, blood 
pressure, and heart rate. Vital signs may be taken at any other times. Blood pressure 
and heart rate measurements will be performed with subjects in a seated position.  
ECOG Performance Status: 
ECOG performance status will also be measured (see APPENDIX B: ECOG 
PERFORMANCE STATUS). 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 72 of 121 
 
ECG: 
A standard 12-lead ECG will be performed at screening. Tracings must be dated and 
signed by the Investigator (or his/her designee) and filed with the subject’s source 
documentation. Results from 12-lead ECG should be captured on the ECG Evaluation 
eCRF. Significant findings must be recorded as Relevant Medical History/Current 
Medical Conditions (if present before treatment). ECG may be repeated at the 
discretion of the Investigator at any time during the study and as clinically indicated; 
any clinically relevant findings should be added to the AE eCRF.  
Interpretation of the tracing must be made by a qualified physician. Each ECG tracing 
should be labeled with the study number, subject initials (where regulations permit), 
subject number, and date, and kept in the source documents at the study site. 
Clinically significant abnormalities present when the subject signed informed consent 
should be reported on the Medical History eCRF page. Clinically significant findings 
must be discussed with the Medical Monitor prior to randomizing the subject in the 
study. The PI will take the final decision if any observed deviations in the ECG are 
sufficient to require that the subject be excluded from the study. 
Eye examination: 
An eye examination will be performed at screening, as clinically indicated during the 
treatment phase, and at EOT. The eye examination should include best corrected 
distance visual acuity with refraction, intraocular pressure, slit lamp examination, and 
dilated fundus photography. 
QoL (EQ-5D-5L): 
Subjects will complete the EQ-5D-5L at the time points as per the schedule of events.  
The EQ-5D-5L is a standardized instrument to measure health outcome. It is 
applicable to a wide range of health conditions and treatments, and provides a simple 
descriptive profile and a single index value for health status. The EQ-5D-5L takes only 
a few minutes to complete. Instructions to respondents are included in the 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 73 of 121 
 
questionnaire. An EQ-5D-5L self-complete version was designed to increase 
sensitivity and reduce ceiling effects. This is available in paper format. 
8.2 
Laboratory Evaluations 
8.2.1 
Clinical Laboratory Evaluations  
All tests listed below (Table 1) will be performed by a central laboratory as per 
APPENDIX A: SCHEDULE OF EVENTS. In addition, laboratory safety tests may be 
performed at various unscheduled time points, if deemed necessary by the PI. 
Hematological and biochemistry tests will be performed at screening, at baseline (only 
if screening was done longer than 7 days before start of the treatment), at each visit 
during the treatment phase (except Visit 7), or as medically necessary, and at the 
discontinuation from study treatment (within 3 days after discontinuation).  
A serum lipid profile includes: total cholesterol, low-density lipoprotein (LDL), HDL, and 
triglycerides. This assessment will be performed at baseline; at Visits 3, 4, 5, and 6 
(weeks 6, 12, 18, and 24) and Visits 8–13 (every 12 weeks ± 7 days if still on 
treatment after week 24) during the treatment phase; and at EOT. 
INR and aPTT are examined as coagulation assessments. They will be performed at 
screening (and checked at the baseline visit only if screening was done longer than 
7 days before start of the treatment); at Visits 3, 4, 5, and 6 (weeks 6, 12, 18, and 24) 
and Visits 8–13 (every 12 weeks ± 7 days if still on treatment after week 24) during the 
treatment phase; and at EOT. 
Serum hormones include: testosterone, estradiol, and SHBG. This assessment will be 
performed at baseline; at Visits 3, 4, 5, and 6 (weeks 6, 12, 18, and 24) and Visits 8–
13 (every 12 weeks ± 7 days if still on treatment after week 24) during the treatment 
phase; and at EOT.  
Any particular clinical findings seen before taking study treatments must be 
documented in the Relevant Medical History/Current Medical Conditions eCRF. 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 74 of 121 
 
Findings compatible with AEs after taking study treatment must be documented in the 
AE eCRF.  
Urinalysis includes macroscopic and microscopic examinations. Macroscopic 
examination includes: specific gravity, pH, protein, glucose, bilirubin, ketones, blood 
cells, and leukocytes. Microscopic examination includes: white blood cells (WBC)/high 
power field (HPF), red blood cells (RBC)/HPF and any additional findings. Urinalysis 
will be performed only at screening and if medically indicated.  
Significant findings must be recorded as Relevant Medical History/Current Medical 
Conditions (if present before treatment). Urinalysis may be repeated at the discretion 
of the Investigator at any time during the study and as clinically indicated; any clinically 
relevant findings should be added to the AE eCRF.  
The categories of subjects listed in Section 5 
Study Enrollment and Withdrawal 
should be tested for hepatitis B serologic markers and viral load at screening: 
HBV-DNA, HBsAg, HBcAb, and HBsAb. Subjects with hepatitis C risk factors and 
additional subjects at the discretion of the Investigator should be tested for HCV 
ribonucleic acid-polymerase chain reaction (RNA-PCR) test at screening. For a list of 
hepatitis C risk factors, refer to Section 5.  
HIV, HBV, and HCV screening will be performed at screening for all subjects. If a 
subject test is positive for HIV, HBV, or HCV, she will be considered ineligible for the 
study according to the Exclusion Criteria. Please note that subjects whose test is 
negative for HBV-DNA, HBsAg, and HBcAb but positive for HBsAb with prior history of 
vaccination against Hepatitis B will be eligible. The fact that the subject had been 
vaccinated should be entered into the subject’s Medical History eCRF. Results will not 
be reported in the eCRF.  


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 75 of 121 
 
Table 1: Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
 
Hemoglobin 
 
Hematocrit 
 
Total and differential leukocyte 
count 
 
RBC count 
 
Platelet count 
 
Blood Urea Nitrogen 
 
Bilirubin (total and direct) 
 
Alkaline phosphatase 
 
AST 
 
ALT 
 
Albumin 
 
Sodium 
 
Potassium 
 
Creatinine 
Urinalysis 
Additional Tests 
 
pH 
 
Specific gravity 
 
Protein* 
 
Glucose 
 
Ketones 
 
Bilirubin 
 
Blood* 
 
Nitrite* 
 
Urobilinogen 
 
Leukocyte esterase* 
 
HIV test 
 
HBV-DNA 
 
HBsAg 
 
HBcAb 
 
HBsAb 
 
HCV 
 
Serum lipid panel (total cholesterol, LDL, 
HDL, triglycerides) 
 
Coagulation tests (INR, aPTT) 
 
Serum pregnancy test 
 
PSA 
 
Hormonal status of the tumor (AR) 
 
CTCs 
 
Blood hormone levels, including testosterone, 
estradiol, SHBG 
* If urinalysis is positive for protein, blood, nitrite, and/or leukocyte esterase, a microscopic 
examination (for RBC, WBC, bacteria, casts, and epithelial cells) will be performed. 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 76 of 121 
 
8.2.2 
Special Assays or Procedures 
Pharmacokinetic assessment: 
Blood samples for pharmacokinetic assessment will be collected at baseline 
(pre-dose), Visit 3 (week 6), Visit 5 (week 18), and Visit 6 (week 24). One blood 
sample will be collected in a 6 mL K2-ethylenediaminetetraacetic acid (EDTA) blood 
collection tube on each of these days. The exact time (hh:mm) and date that each 
blood sample is collected will be recorded on the eCRF. At the baseline visit, the blood 
sample should be collected before the subject is given their first dose of GTx-024. At 
visits 3 (week 6), 5 (week 18), and 6 (week 24), the date and approximate time of the 
last dose of GTx-024 prior to the blood sample should be recorded; i.e., it should be 
documented whether the subject took the previous dose that morning or the evening 
before. Immediately after collection, the tubes will be gently inverted several times to 
mix the anticoagulant with the blood sample. 
Blood samples will be kept on wet ice (ice packs in a water bath is also acceptable) for 
up to 20 minutes until processed. The plasma fraction will be separated by placing the 
collection tube into a centrifuge for 10 minutes at 1,500 x g. The plasma fraction will be 
withdrawn by pipette and divided into two 2 mL polypropylene transfer vials (with each 
tube receiving approximately equal aliquots). 
All sample collection and freezing tubes will be clearly labeled in a fashion which 
identifies the subject, the study number, the visit number, and freezing tube aliquot 
letter. Labels will be fixed to freezing tubes in a manner that will prevent the label from 
becoming detached after freezing. Samples will be stored in a freezer at –20°C or 
lower. Samples will be shipped in a thermal insulated container with sufficient dry ice 
to assure they remain frozen. 
Any remaining plasma samples after completion of the protocol outlined 
pharmacokinetic analysis may be used to identify and quantify the metabolites of 
GTx-024. 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 77 of 121 
 
Circulating Tumor Cells (CTCs): 
Blood samples will be collected for CTC enumeration at Visits 2, 4, 6, 8, and EOT and 
for gene expression at Visit 2 and EOT. 
The enumeration sample will be collected in a 10 mL CellSave tube. 
The gene expression sample will be collected in a 10 mL EDTA blood collection tube. 
All CTC samples are to be stored under ambient conditions and shipped on the same 
day of collection.  CTC enumeration testing is to be completed within 96 hours of 
collection and gene expression within 36 hours of collection.   
8.2.3 
Specimen Preparation, Handling, and Shipping 
As a central laboratory will be used for specimen analysis, the PI and all members of 
the investigational team will be instructed to follow the instructions of the central 
laboratory manual provided by the central laboratory concerning specimen 
preparation, handling, storage, and shipment.  
 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 78 of 121 
 
9 
ASSESSMENT OF SAFETY 
9.1 
Methods and Timing for Assessing, Recording, and Analyzing 
Safety Parameters 
9.1.1 
Adverse Events 
ICH E6 guidelines define an AE as any untoward medical occurrence in a subject or 
clinical investigation subject administered a pharmaceutical product regardless of its 
causal relationship to the study treatment. An AE can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of medicinal (investigational) product, whether or 
not considered related to the medicinal (investigational) product.  
 
The occurrence of an AE may come to the attention of study personnel during study 
visits and interviews of a study subject presenting for medical care, or upon review by 
a study monitor.  
The period of observation for which AEs are to be collected begins after the subject 
has signed the ICF, throughout the study intervention period, and for 28 days post 
treatment.   
 
All AEs, whether reported by the subject or noted by study personnel, will be recorded 
in the subject’s medical record and captured on the appropriate eCRF. 
Information to be collected includes event description, time of onset, Investigator’s 
assessment of severity, Investigator’s assessment of relationship to study drug, and 
time of resolution/stabilization of the event. All AEs occurring while on study must be 
documented appropriately regardless of relationship to study drug. All AEs will be 
followed to adequate resolution as per Section 9.3 
Type and Duration of Follow-up 
of Subjects after Adverse Events. 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 79 of 121 
 
Any medical condition that is present at the time that the subject is screened will be 
considered as baseline and not reported as an AE. However, if the condition 
deteriorates at any time during the study, it will be recorded as an AE. 
All AEs must be graded for intensity and relationship to study drug.  
9.1.2 Intensity of Event:  
All AEs will be assessed by the Investigator according to NCI-CTCAE 4.0. For any AE 
that is not specifically covered in NCI-CTCAE 4.0, the criteria from Table 2 should be 
used: 
 
Table 2: Description of Grades According to the NCI-CTCAE  
Grade 
Description 
0 
No AE or within normal limits 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention 
indicated; limiting age-appropriate instrumental activities of 
daily living 
3 
Severe or medically significant but not immediately 
life-threatening; hospitalization or prolongation of 
hospitalization indicated; disabling; limiting self-care activities 
of daily living 
4 
Life-threatening consequences; urgent intervention indicated 
5 
Death related to AE 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 80 of 121 
 
If the intensity changes within a day, the maximum intensity should be recorded. If the 
intensity changes over a longer period of time, the changes should be recorded as 
separate events (having separate onset and stop dates for each change in intensity). 
Changes in the intensity of an AE will be documented to allow an assessment of the 
duration of the event at each level of intensity to be performed. AEs characterized as 
intermittent require documentation of onset and duration of each episode. 
9.1.3 
Drug–Adverse Event Relationship 
The causal relationship of the study drug to the AE will be assessed by the 
Investigator. 
 
 
If there is a reasonable suspected causal relationship to the study treatment, i.e., there 
are facts (evidence) or arguments to suggest a causal relationship, the drug-event 
relationship should be assessed as related.  
The following criteria should be considered by the Investigator to assess the 
relationship (or association) of each AE to the study drug: 
 
Related - There is a reasonable causal relationship to the study treatment, i.e., 
there is evidence or arguments to suggest a causal relationship. The following 
criteria should be considered in order to assess the relationship as related: 
- 
Reasonable temporal association with drug administration 
- 
It may or may not have been produced by the subject’s clinical state, 
environmental or toxic factors, or other modes of therapy administered to the 
subject 
- 
Known response pattern to suspected drug 
- 
Disappears or decreases on cessation or reduction in dose 
- 
Reappears on rechallenge 
 
Not related - This category applies to any AE that does not appear to have a 
reasonable relationship to the use of study drug (see above guidelines) 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 81 of 121 
 
9.1.4 Serious Adverse Events 
An SAE is defined as an AE that meets one of the following conditions: 
 
Death 
 
Life-threatening event (defined as a subject at immediate risk of death at the time 
of the event) 
 
An event requiring inpatient hospitalization or prolongation of existing 
hospitalization  
 
Results in congenital anomaly or birth defect 
 
Results in a persistent or significant disability/incapacity 
 
Any other important medical event that may not result in death, be life threatening, 
or require hospitalization, may be considered a serious adverse experience when, 
based upon appropriate medical judgment, the event may jeopardize the subject 
and may require medical or surgical intervention to prevent one of the outcomes 
listed above. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse 
All SAEs will be: 
 
Recorded on the appropriate eCRF 
 
Reported to the designated Safety department/pharmacovigilance contractor using 
a SAE Report Form within 24 hours of awareness 
 
Followed through resolution by a study Investigator 
 
Reviewed and evaluated by a study Investigator 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 82 of 121 
 
9.1.5 
Procedures to be Followed in the Event of Abnormal 
Laboratory Test Values or Abnormal Clinical Findings 
Clinical laboratory values will be listed with abnormal values flagged. Clinically 
significant laboratory values will be reported as an AE. The AE will be followed to 
resolution as per Section 9.3 
Type and Duration of Follow-up of Subjects after 
Adverse Events. 
9.2 
Reporting Procedures 
9.2.1 
Serious Adverse Events 
All SAEs, including death due to any cause, which occur after the subject signs the 
ICF and within 28 days following the last administration of study drug, whether or not 
related to the study drug, must be reported immediately to the designated Safety 
Department/pharmacovigilance contractor within 24 hours by e-fax, e-mail, or 
telephone (see contact information below). At the very least, the following information 
must be reported: 
 
Date and time of report 
 
Reporter’s name and phone number 
 
Investigator’s name and site number 
 
Subject number 
 
SAE information: event term, onset date, causal relationship 
 
Study drug: start date of study drug and whether or not study drug has been 
withheld or discontinued 
SAE Reporting Contact Information:  
UK Safety E-Fax Line: 0044 (0)1403 330459 
UK Safety Unmanned Hotline: 0044 (0)1403 758462 
US Safety Toll-Free E-Fax Line: 001 866 966 2970 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 83 of 121 
 
US Safety Toll-Free Unmanned Hotline: 001 866 966 8429 
Cmed Safety E-mail: sae@cmedresearch.com  
Information about all SAEs is collected and recorded on the SAE Report Form. The 
Investigator must assess the relationship of any SAE to study drug, complete the SAE 
Report Form in English, and send the completed, signed form by e-fax or e-mail within 
24 hours to the assigned drug safety group. As a back-up, the site may report SAEs 
using the unmanned safety hotline, with a completed SAE Report Form forwarded to 
the assigned drug safety group within 24 hours following notification on the hotline. 
The original copy of the SAE Report Form and the e-fax confirmation sheet must be 
kept with the case report form documentation at the study site.  
Follow-up information must also be sent to the same assigned drug safety group by 
e-fax or e-mail using a either new SAE Report Form stating that this is a follow-up to 
the previously reported SAE (giving the date of the original report), or by using a 
follow-up query form.  
If an SAE is not previously documented (new occurrence) in the Investigator’s 
Brochure (IB) and is thought to be related to the relevant Investigational Medicinal 
Product (IMP), the assigned drug safety group may urgently require further information 
from the Investigator for regulatory authority reporting. The drug safety group may 
need to issue an Investigator Notification (IN) to inform all Investigators involved in any 
study with the same drug that this SAE has been reported. Suspected Unexpected 
Serious Adverse Reactions (SUSARs) will be collected and reported to the 
regulatory/competent authorities and relevant IRBs/IECs in accordance with Food and 
Drug Administration (FDA) regulations 21 Code of Federal Regulations (CFR) 312.32, 
ICH guidelines, and European Clinical Trials Directive 2001/20/EC, or as per national 
regulatory requirements in participating countries. Adequate documentation must be 
maintained showing that regulatory authorities and IRBs/IECs have been properly 
notified. 
SAEs must be reported within 24 hours, regardless of relationship, on a SAE 
Report Form to allow the Sponsor to take appropriate measures to address potential 
new risks in a clinical trial. The Investigator must report such events to the Sponsor 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 84 of 121 
 
immediately; under no circumstances should reporting take place more than 24 hours 
after the Investigator learns of the event. 
The term sudden death should be used only when the cause is of a cardiac origin as 
per standard definition. The terms death and sudden death are clearly distinct and 
must not be used interchangeably. The study will comply with all local regulatory 
requirements and adhere to the full requirements of the ICH Guideline for Clinical 
Safety Data Management, Definitions and Standards for Expedited Reporting, Topic 
E2. 
The SAE Report Form must be signed by the PI or assigned designee.  
Other supporting documentation of the event may be requested by the Safety 
Department/pharmacovigilance contractor and should be provided as soon as 
possible. 
All SAEs will be followed until satisfactory resolution as per Section 9.3 
Type and 
Duration of Follow-up of Subjects after Adverse Events. 
9.2.2 
Regulatory Reporting  
Suspected (considered related to the study drug) and unexpected (not previously 
described in the reference safety document) serious adverse reactions (SUSARs) will 
be reported in an expedited manner by GTx, Inc. to regulatory authorities, 
EudraVigilance, IECs, IRBs and Investigators in compliance with FDA regulations 21 
CFR 312.32, ICH guidelines, the European Clinical Trials Directive 2001/20/EC, the 
European Commission’s “Detailed guidance on the collection, verification, and 
presentation of adverse event/reaction reports arising from clinical trials on medicinal 
products for human use” (CT-3, June 2011) and other applicable local regulations and 
guidelines. The timelines stipulated by applicable national regulations and guidelines 
shall be adhered to, typically death and life-threatening SUSARs shall be reported 
within 7 days and all other SUSARs shall be reported within 15 days. 
Additionally, events may occur during a clinical trial which do not fall within the 
definition of a SUSAR and thus are not subject to the reporting requirements for 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 85 of 121 
 
SUSARs, even though they may be relevant in terms of subject safety. Examples are 
new events related to the conduct of a trial or the development of an IMP likely to 
affect the safety of subjects such as:  
 
An SAE which could be associated with the trial procedures and which could 
modify the conduct of the trial  
 
A significant hazard to the subject population such as lack of efficacy of an IMP 
used for the treatment of a life-threatening disease  
 
A major safety finding from a newly completed animal study (such as 
carcinogenicity)  
 
A temporary halt of a trial for safety reasons if the trial is conducted with the same 
IMP in another country by the same Sponsor, recommendations of the SMC, if any, 
where relevant for the safety of subjects 
These events/observations are not to be reported as SUSARs, but they might require 
other action, such as urgent safety measures and their notification, substantial 
amendments, or early termination of the trial, and shall be reported in accordance with 
applicable local regulations and guidelines. 
All serious events designated as expected and/or “not related” to study drug(s), will be 
reported to the applicable regulatory authorities and IECs/IRBs at least annually in a 
summary format. 
9.2.3 
Other Adverse Events 
Progression of Underlying Malignancy 
If progression of underlying malignancy is clearly consistent with the suspected 
progression of the underlying cancer as defined by RECIST 1.1, or other criteria as 
determined by the protocol, it should not be reported as an AE. Similarly, 
hospitalization due exclusively to the progression of underlying malignancy should 
NOT be reported as an SAE. Clinical symptoms of progression may be reported as 
AEs if the symptom cannot be determined as solely due to the progression of the 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 86 of 121 
 
underlying malignancy, or does not meet the expected pattern of progression for the 
disease under study. 
If there is any uncertainty about an AE being due only to the disease 
under study, it should be reported as an AE or SAE. 
Liver Toxicity Management 
Elevated ALT or AST (> 3 × ULN) in combination with either an elevated total bilirubin 
(> 2 × ULN) or clinical jaundice in the absence of cholestasis or other causes of 
hyperbilirubinemia is considered to be an indicator of severe liver injury. Therefore, 
Investigators must report the occurrence of either of the following as an SAE: 
 
Treatment-emergent ALT or AST > 3 × ULN in combination with total bilirubin 
> 2 × ULN (of which 35% is direct bilirubin) 
 
Treatment-emergent ALT or AST > 3 × ULN in combination with clinical jaundice 
For subjects with liver metastasis and elevated ALT or AST of > 3 × ULN at baseline, 
the values will not be reported as an SAE if ≤ 5 × ULN. 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the eCRF and reported to the Sponsor within 
24 hours after learning of the event, as per Section 9.2 
Reporting Procedures. 
9.2.4 
Reporting of Pregnancy 
If a subject becomes pregnant during the study, she must be instructed to stop taking 
the study drug and immediately inform the Investigator. The Investigator must report 
all pregnancies within 24 hours to the Sponsor as per Section 9.2 Reporting 
Procedures, regardless of seriousness. The Investigator should counsel the subject 
and discuss the risks of continuing with the pregnancy and the possible effects on the 
fetus. Monitoring of the subject should continue until conclusion of the pregnancy. The 
clinical outcome of the pregnancy should be documented. Specifically, the estimated 
date of conception, expected date of delivery, actual date of delivery, date of last 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 87 of 121 
 
menstrual period, and details of contraceptives should be documented. The 
pregnancy course should be described in full. If the subject gives birth, the weight and 
length of the child, Apgar scores (with explanation of score < 10), and congenital 
abnormalities should be documented. Concomitant drugs and medical history of the 
mother should be documented. Smoking status and alcohol intake during pregnancy 
and illicit drug use prior to and during pregnancy should be recorded. Pregnancy will 
be followed until completion. If the new-born is healthy, additional follow-up is not 
necessary. 
9.3 
Type and Duration of Follow-up of Subjects after Adverse 
Events 
AEs will be collected up until 28 days after the last dose of study treatment, and will 
continue to be followed up until one of the following occurs: 
 Resolved or improved to baseline 
 Death 
 Start of new anticancer regimen 
 Investigator confirms that no further improvement can be expected 
9.4  Halting Rules 
If in the opinion of the Investigator, the participation in the study is or is becoming 
detrimental to the well-being of a particular subject, this issue should be discussed 
with the Medical Monitor for this study and a determination made regarding dose 
reduction, interruption, or withdrawal of the subject from the study. 
Dose reduction, interruption, or withdrawal of the subject from the study should be 
considered if: 
 
ALT or AST > 8 × ULN 
 
ALT or AST > 5 × ULN for more than 2 weeks 
 
ALT or AST > 3 × ULN and (total bilirubin > 2 × ULN or INR > 1.5) 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 88 of 121 
 
 
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%) 
For subjects with known liver metastasis and elevated ALT or AST of ≤ 5 × ULN at 
baseline, discontinuation of treatment should be considered if: 
 
ALT or AST > 5 × ULN and total bilirubin > 2 × ULN 
All subjects discontinued from dosing should be followed until abnormal values return 
to normal.  
ALL DISCONTINUATIONS SHOULD BE DISCUSSED WITH THE MEDICAL 
MONITOR PRIOR TO DISCONTINUATION. 
If any 2 out of the first 10 subjects enrolled in the 18 mg arm meet the above 
hepatotoxicity criteria, or if a total of 5 subjects ever meet these criteria in the 18 mg 
arm, the 18 mg dose will be reduced to 9 mg for all subjects; the 18 mg arm will be 
permanently halted and all subjects will be enrolled into the 9 mg arm.  
If a total of 5 subjects in the 9 mg arm ever meet the above hepatotoxicity criteria, the 
study will be halted. 
9.5 
Safety Oversight  
In order to protect the safety of the subjects, an SMC will be established for the study 
to review the safety data on an ongoing basis. The SMC will consist of, as a minimum, 
the Medical Monitor, a Safety Reviewer with an oncology background, a statistician, 
and two GTx, Inc. representatives, consistent with the SMC charter. 
 
The Medical Monitor will be a physician with relevant expertise whose primary 
responsibility is to provide independent safety monitoring in a timely fashion through 
review of AEs, immediately after they occur or are reported, with follow-up through to 
resolution. The Medical Monitor will evaluate individual and cumulative participant data 
when making recommendations regarding the safe continuation of the study.  
 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 89 of 121 
 
The Medical Monitor will be selected based on relevant study-related or therapeutic 
expertise and participation is for the duration of the study. The Medical Monitor will be 
able to readily access participant records in real time. 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 90 of 121 
 
10 
CLINICAL MONITORING 
The purpose of the site monitoring visit is to ensure that the study is being conducted 
in accordance with the protocol (and any subsequent amendments), current ICH 
Guideline on Good Clinical Practice (GCP) requirements, and applicable IRB/IEC and 
regulatory requirements.  
An authorized study monitor (clinical research associate [CRA]) will visit the site prior 
to initiation and at periodic intervals to review the study records (including ICFs, 
inventory of study drug, and eCRFs), and assess compliance with the study protocol. 
The monitor(s) will also visit at conclusion of the study to help resolve any remaining 
data queries and close out all record keeping. 
It is the responsibility of the Investigator to make sure all necessary source 
documentation and records are available to the CRA during his/her visit and to provide 
a suitable space for the CRA to review these documents. Additionally, the Investigator 
must also be available as needed during the monitoring visit. It is the CRA’s 
responsibility to arrange the visits with the unit in advance and to notify the unit of the 
documentation that he/she will need during the visit. 
All findings resulting from monitoring visits will be documented and shared with the 
Investigator and Sponsor via follow-up letters and monitoring reports. As much as 
possible, issues/discrepancies should be resolved during the monitoring visits, but 
those remaining at the end of the visit will be followed through until resolution. 
 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 91 of 121 
 
11 
STATISTICAL CONSIDERATIONS 
This section is an overview of the statistical design and its rationale. A separate 
Statistical Analysis Plan (SAP) will provide further detail of statistical tests, handling of 
missing data, and various methods for imputing time-to-event to account for the 
difference between the last known event free time and the subsequent first event date, 
as well as specifications of tables, figures, and listings. 
11.1 Study Hypotheses 
This trial will employ a Simon’s two-stage (optimal) design independently for each 
dose arm, 9 mg and 18 mg. The assumptions for the design are as follows: 
 
H0: CBR ≤ 0.10 
 
H1: CBR ≥ 0.30 
 
α = 0.025 (one-sided) 
 
Power = 90% 
11.2 Sample Size Considerations 
Based on the above assumptions, a sample size of N = 44 ER+/AR+ BC subjects with 
centrally confirmed AR+ status who receive at least one dose of study treatment 
(evaluable subjects) are needed for each arm that proceeds to the second stage. An 
arm will proceed to the second stage if at least 3 subjects among the first 18 evaluable 
subjects randomized achieve CB, defined as CR, PR, or SD as per RECIST 1.1, as 
determined by central review. If an arm proceeds to the second stage, a statistical 
success that favors further evaluation of the dose arm(s) in future trials will require at 
least 9/44 subjects to achieve CB at week 24, i.e., the null hypothesis of an 
unacceptably low rate of CB, ≤ 10.0%, can be rejected in favor of the alternative 
hypothesis that indicates the higher rate, ≥ 30.0%, is more likely. The lower limit of the 
exact 95% confidence interval at exactly 9 CBs, 11.0%, exceeds 10.0%12.  


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 92 of 121 
 
At any time during the first stage, if 3 evaluable subjects in any one arm achieve CB at 
week 24, that arm will proceed to the second stage; otherwise, it will be halted for lack 
of efficacy. If at any time, 9 evaluable subjects in an arm achieve CB at week 24, the 
efficacy criteria for that arm has been met; however, the arm should proceed to full 
accrual of 44 evaluable subjects in the successful arm(s) in order to better 
characterize the CB rate, evaluate secondary endpoints, and describe the safety 
profile of the dose level(s). To reiterate, the intent of the trial is not to statistically 
compare the CB rate between the two dose arms and the trial is not powered to do so.  
Subjects whose AR+ status is not centrally confirmed will be replaced in order to 
accrue the necessary number of evaluable AR+ subjects to be included in the primary 
analysis. Subjects who are not confirmed AR+ may remain on the trial, but will not be 
part of the primary efficacy analysis – these subjects will contribute to secondary and 
tertiary analyses as noted below. Subjects who are randomized but never receive 
study drug will be replaced as well. Assuming that 25% of subjects enrolled are not 
evaluable for the primary efficacy analysis for the reasons noted above, up to 30 
additional subjects may need to be randomized. 
11.3 Planned Interim Analyses (if applicable) 
No interim analysis is planned.  
11.4 Final Analysis Plan 
11.4.1 Analysis sets 
Full Analysis set (FAS): All subjects who are randomized and receive at least one 
dose of study drug. 
Evaluable subjects: Subjects in the FAS who have centrally confirmed AR+ status; 
these subjects are the subjects in the primary efficacy analysis. 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 93 of 121 
 
Per protocol set (PPS): All subjects with centrally confirmed AR+ who have baseline 
scans, receive at least 80% of the anticipated doses, and complete the week 24 
RECIST 1.1 evaluation, and have no major protocol deviations. 
Safety analysis set (SAS): All subjects who are randomized and receive at least one 
dose of study drug. 
Safety analysis subjects will be analyzed in the treatment arm in which they are initially 
dosed. Efficacy analysis subjects will be analyzed according to the treatment arm to 
which they were randomized. 
11.4.2 Definition of analysis endpoints; primary, secondary, tertiary, 
exploratory, safety 
Primary efficacy endpoint 
Tumor response in terms of clinical benefit will be assessed by RECIST 1.1 criteria 
from centrally read CT scans obtained at the 24 week assessment. Tumor response is 
judged relative to baseline tumor assessments. An evaluable subject will be 
considered to have a response of CB if the assessment indicates CR, PR, or SD. The 
primary assessment is among evaluable subjects in the FAS at 24 weeks in each of 
the 9 mg and 18 mg arms. An evaluable subject who does not have a week 24 
assessment for any reason remains in the evaluable subset of the FAS and is 
considered a failure to achieve CB (CR, PR, or SD). 
Secondary efficacy endpoints 
 CBR in the FAS and PPS at 24 weeks in each of the 9 mg and 18 mg arms 
The following secondary efficacy endpoints will be assessed among subjects in each 
of the 9 mg and 18 mg arms among the evaluable subjects, the FAS, and the PPS:   
 
ORR (CR or PR assessed by RECIST 1.1 criteria) at 24 weeks 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 94 of 121 
 
 
Best (confirmed) overall response rate (BOR). BOR is defined as the best 
observed response for each subject up to and including the EOT. Reponses of CR 
or PR should be confirmed by a repeat assessment at least 4 weeks later. 
 
PFS: PFS is defined as the time from randomization until objective tumor 
progression or death due to any cause. Subjects who have no PFS events will be 
censored at the date of the last adequate tumor assessment. If the subject has no 
post-baseline tumor assessments, they will be censored at the time of 
randomization 
 
TTP: TTP is defined as the time from randomization until objective tumor 
progression or death due to disease progression. Subjects who have not 
progressed will be censored at the date of the last adequate tumor assessment. If 
the subject has no post-baseline tumor assessments but is known to be alive, they 
will be censored at the time of randomization 
 
Duration of response: Duration of response, in responders, is defined as the period 
from the date of initial CR or PR until the date of disease progression or death from 
any cause. Only subjects with BOR of CR or PR (i.e., responders) will be included 
in the analysis of duration of response. Subjects with no documented progression 
or death after CR or PR will be censored at the last date at which they are known 
to have had the CR or PR 
Tertiary efficacy endpoints 
The following tertiary efficacy endpoints will be assessed among subjects in each of 
the 9 mg and 18 mg arms among the evaluable set of subjects and among the FAS: 
 
PSA: PSA will be obtained during routine laboratory assessments and results at 
each scheduled assessment will be compared with baseline along with percentage 
change from baseline 
 
QoL: QoL will be obtained using the EQ-5D-5L, with each scheduled assessment 
compared with baseline 
 
CTCs: The number of CTCs will be obtained at each scheduled assessment and 
compared with baseline 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 95 of 121 
 
 
Duration of prior CB: The impact of duration of prior CB on outcome (CB response 
at week 24, PFS, TTP, duration of response) 
 
Time from diagnosis of metastases to randomization: The impact of time from 
diagnosis of metastases to randomization on outcome (CB response at week 24, 
PFS, TTP, duration of response) 
 
Tumor volume and change from baseline in tumor volume 
 
Pharmacokinetics: GTx-024 and GTx-024 glucuronide plasma concentrations and 
outcome (CBR at weeks 16 and/or 24) 
Safety endpoints 
The following safety endpoints will be assessed among evaluable subjects as well as 
all subjects enrolled and treated: 
 
AEs and concomitant medications 
 
Laboratory examinations (clinical chemistry, hematology, and urinalysis) 
 
Physical examinations  
 
Vital signs 
 
ECOG performance status 
 
Eye examinations 
Pharmacokinetic endpoints 
 
Plasma concentrations of GTx-024 18 mg and GTx-024 glucuronide at each 
assessment 
11.4.3 Statistical methodology  
 11.4.3.1 Demographic data 
Continuous demographic data (i.e., age, weight, height, and body mass index [BMI]) 
will be summarized by descriptive statistics (arithmetic mean, standard deviations, 
median, minimum, maximum, and total number of subjects). Categorical demographic 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 96 of 121 
 
data (i.e., gender, race, ethnicity, and ECOG performance status) will also be listed 
and tabulated in frequency counts and percentage. 
11.4.3.2 Primary efficacy analysis 
The primary efficacy analysis is based on rules as set forth in Simon’s two stage 
(optimal) design as previously described, and is based on the proportion of evaluable 
subjects in the FAS who achieve CB at 24 weeks. At least 3/18 evaluable subjects 
must achieve CB in order for the arm to proceed to the second stage. If an arm 
proceeds to the second stage, ≥ 9/44 subjects must have CB at 24 weeks to deem the 
efficacy criteria to have been met in that arm. This is the minimum number of 
successes needed to rule out an unacceptably low, 10%, CB rate (lower limit of the 
95% confidence interval). The exact 95% confidence intervals about the CBR at 
week 24 will be constructed. 
11.4.3.3 Second efficacy analysis 
 
The exact 95% confidence intervals about the CBR at week 24 among subjects in 
the FAS and PPS in each of the 9 mg and 18 mg arms will be constructed 
The following secondary efficacy analyses will be performed in subjects in each of the 
9 mg and 18 mg arms among the evaluable subjects, the FAS, and the PPS:   
 
The exact 95% confidence interval about the ORR (CR or PR) will be constructed 
at week 24 
 
The exact 95% confidence interval about the BOR will be constructed at week 24 
 
PFS: Median PFS and 95% confidence intervals will be estimated by the 
Kaplan-Meier method and the survival function and associated 95% confidence 
intervals will be constructed at key time points 
 
TTP: Median TTP and 95% confidence intervals will be estimated by the 
Kaplan-Meier method and the survival function and associated 95% confidence 
intervals will be constructed at key time points 
 
Duration of response: Median duration of response and 95% confidence intervals 
will be estimated by the Kaplan-Meier method and the survival function and 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 97 of 121 
 
associated 95% confidence intervals will be constructed at key time points for 
responders 
11.4.3.4 Tertiary efficacy analysis 
The following tertiary efficacy analyses will be performed in subjects in each of the 
9 mg and 18 mg arms among the evaluable subjects and among the FAS: 
 
PSA changes from baseline to each scheduled assessment will be described and 
tested for a significant change from baseline. Percentage change from baseline will 
be summarized and analyzed as well 
 
QoL: The EQ visual analog scale (VAS) will be summarized by descriptive 
statistics at baseline and each assessment. Mean changes from baseline will also 
be summarized using descriptive statistics and 95% confidence intervals. 
EQ-5D-5L single item scale scores (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression) will be summarized by means of 
frequency counts at baseline and at each assessment 
 
CTCs: Changes in the number of CTCs from baseline to each scheduled 
assessment will be described and tested for a significant change from baseline 
 
Duration of prior CB: The impact of duration of prior CB on the current CB 
response will be explored in an exploratory way using logistic regression models 
with and without other covariates. The impact of duration of prior CB on PFS, TTP, 
and duration of response outcomes will be assessed in a Cox proportional hazards 
model with and without other covariates 
 
Time from diagnosis of metastases to randomization: The impact of time from 
diagnosis of metastases to randomization on the current CB outcome will be 
explored in an exploratory way using logistic regression models with and without 
other covariates. The impact of time from diagnosis of metastases to 
randomization on PFS, TTP, and duration of response outcomes will be assessed 
in a Cox proportional hazards model with and without other covariates 
 
Tumor volumetrics: The effect of GTx-024 9 mg and 18 mg on tumor volume will be 
described visually using waterfall plots 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 98 of 121 
 
 
GTx-024 and GTx-024 glucuronide plasma concentrations will be assessed for 
their association with CBR at week 24 using logistic regression by creating binary 
variables for the concentrations by dichotomizing at the median concentration at 
week 24 
11.4.3.5 Safety; AEs/labs/study drug exposure/vitals/other 
Routine safety assessments for AEs, laboratory variables (clinical chemistry, 
hematology, and urinalysis), physical examinations, vital signs, ECOG performance 
status, and eye examinations will be done. 
Safety analyses will be conducted among the SAS. AEs will be coded according to the 
current version of the Medical Dictionary for Regulatory Activities (MedDRA®). AEs, 
laboratory outcomes, and results from physical examinations will be graded according 
to NCI-CTCAE 4.0.  
The results of the eye examinations will be summarized. 
Summaries of safety data will be presented for subjects in the FAS with centrally 
confirmed AR+ status as well as in all subjects enrolled and treated (SAS and FAS). 
11.4.3.6 Pharmacokinetic analyses 
 
Descriptive statistics will be used to summarize the plasma concentrations of 
GTx-024 9 mg and 18 mg and GTx-024 glucuronide at each assessment 
11.4.3.7 Missing data/Outliers/Dropout considerations 
No imputation for missing data will be carried out other than to complete partial dates 
using standard imputation techniques as per the Contract Research Organization’s 
standard. 
No evaluable subject will have missing data for the primary efficacy analysis because 
subjects who have the week 24 assessment will be classified as having CB or not, and 
those who do not have a week 24 assessment will classified as not having CB. 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 99 of 121 
 
With regards to missing start and stop dates for AEs and medications, imputation rules 
will be provided in the SAP. In addition, rules to determine in which period each AE 
belongs for the summary tables will also be provided in the SAP. 
11.4.3.8 Other statistical analysis considerations 
Additionally, sensitivity analysis and exploratory analysis of the data may be 
performed and will be described in the SAP. 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 100 of 121 
 
12 
SOURCE DOCUMENTS AND ACCESS TO SOURCE 
DATA/DOCUMENTS 
Access to study-specific eCRFs will be provided to all sites. Source documents are all 
documents, data, and reports from which the subject’s eCRF data is obtained. This 
includes, but is not limited to, hospital records, clinical and office charts, laboratory and 
pharmacy records, laboratory reports, microfiches, radiographs, and correspondence. 
The Investigator and the study staff are responsible for maintaining a comprehensive 
and centralized filing system of study related documentation, available for inspection 
at any time by representatives from GTx, Inc. or their designee, all applicable 
regulatory authorities, and all applicable ethics committees. Elements should include: 
 
Study files containing signed ICFs and subject identification lists 
 
Study files containing the protocol, all amendments, IB, copies of pre-study 
documentation (if applicable), and all correspondence to and from the IEC, 
competent authorities, and GTx, Inc. 
 
Investigational product accountability records and drug-related correspondence 
In addition, all source documents supporting entries in the eCRFs and the safety 
database must be maintained and be readily available for at least 15 years after the 
completion or the discontinuation of the study. After that period of time, the documents 
may be destroyed subject to local regulations. 
Should the Investigator wish to assign the study records to another party or another 
location, GTx, Inc. must be notified. 
If the Investigator cannot guarantee this archiving requirement at the investigational 
site for any or all of the documents, special arrangements must be made between the 
Investigator and GTx, Inc. to store these in a sealed container(s) outside of the site so 
that they can be returned sealed to the Investigator in case of a regulatory audit. 
Where source documents are required for the continued care of the subject, 
appropriate copies should be made for storing outside of the site. 
Each eCRF will be reviewed and electronically signed by the PI.  
ICH GCP guidelines require that the eCRF will in no case be considered source data. 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 101 of 121 
 
13 
QUALITY CONTROL AND QUALITY ASSURANCE 
Standard operating procedures are available for all activities relevant to the quality of 
this study. Designated personnel will be responsible for implementing and maintaining 
quality assurance and quality control systems to ensure that the study is conducted, 
and that data are generated, documented, and reported in compliance with the study 
protocol, GCP, and Good Laboratory Practice requirements as well as applicable 
regulatory requirements and local laws, rules, and regulations relating to the conduct 
of the clinical study. 
An authorized Quality Assurance auditor will audit the study data and procedures at 
periodic intervals as indicated. Domestic or foreign regulatory authorities, the IRB/IEC, 
and a Sponsor-authorized auditor may request access to all study documentation for 
an on-site inspection or audit. The Investigator must notify GTx, Inc. of any regulatory 
authority inspections and forward copies of the inspection report to GTx, Inc. 
Electronic data systems will be in accordance with applicable aspects of 21 CFR 
Part 11, ICH Guidelines, GCP, local laws and legislation, and the Health Insurance 
Portability and Accountability Act.  
On-site Audits 
At any time, quality assurance representatives of the Sponsor and/or regulatory bodies 
may visit the unit to carry out an audit of the study in compliance with regulatory 
guidelines and company policy. Such audits will require access to study records, 
documentation, and regulatory files. At all times, subject privacy will be of utmost 
importance and respected. Typically, sufficient notice will be given to the Investigator 
to prepare for the visit. 
 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 102 of 121 
 
14 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
14.1 Ethical Standard 
This clinical study was designed, shall be implemented and reported in 
accordance with the ICH Harmonized Tripartite Guidelines for GCP, with applicable 
local regulations (including European Directive 2001/20/EC and US CFR Title 21), 
and with the ethical principles laid down in the Declaration of Helsinki. 
14.2 Institutional Review Board/Independent Ethics Committee 
The protocol and the proposed ICF will be reviewed and approved by a properly 
constituted IRB/IEC before the study start. A signed and dated statement that the 
protocol and informed consent have been approved by the IRB/IEC will be given to 
GTx, Inc. or their designee before study initiation. The signed IRB/IEC approval letter 
must identify the documents approved (i.e., list the Investigator’s name, the protocol 
number and title, the date of the protocol, and the date of approval of the protocol and 
the informed consent document). Any advertisements used to recruit subjects must 
also be reviewed by the IRB/IEC. Clinical supplies will not be shipped to a site until a 
signed approval letter from the IRB/IEC has been received and a contractual 
agreement has been signed by both parties. 
Prior to study start, the Investigator will be required to sign a protocol signature page 
confirming his/her agreement to conduct the study in accordance with these 
documents and all of the instructions and procedures found in this protocol and to give 
access to all relevant data and records to GTx, Inc. monitors, auditors, GTx, Inc. 
Clinical Quality Assurance representatives, designated agents of GTx, Inc., 
IRBs/IECs/Research Ethics Boards, and regulatory authorities as required. 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 103 of 121 
 
14.3 Pre-study Documentation 
The Investigator must provide GTx, Inc. or its designee with the following documents 
prior to the enrollment of any subjects: 
 
Copy of the signed Investigator Agreement page 
 
Copy of the IRB/IEC approval letter for protocol and informed consent  
 
Completed, signed, and dated Form FDA 1572 
 
Current curricula vitae, licenses, and financial disclosures for the Investigator(s) 
and sub Investigators listed on the 1572 
 
Where applicable, list of IRB/IEC committee members and a statement of 
adherence to GCP 
 
Copy of approved site-specific informed consent document 
 
Executed clinical trial agreement  
 
Name, location, certification number, and date of certification of the laboratory to 
be used for laboratory assays and those of other facilities conducting tests. GTx, 
Inc. or its designee must be notified if the central laboratory is changed or if any 
additional laboratory is to be used 
 
List of normal laboratory values (i.e., reference ranges and units of measure) for 
each central laboratory to be used during the study. GTx, Inc. or its designee must 
be notified if normal values change 
14.4 Informed Consent Process 
Eligible subjects will only be included in the study after providing written (witnessed, 
where required by law or regulation), IRB/IEC-approved informed consent.  
The informed consent documents must be reviewed and approved by GTx, Inc. or its 
designee and the investigative site IRB/IEC prior to the initiation of the study. 
Each subject will receive an IRB/IEC approved informed consent document with study 
information. Subjects should be given ample time to read the information and the 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 104 of 121 
 
opportunity to ask questions. Informed consent must be obtained from each subject 
prior to performing any protocol-specific evaluations. The signed ICF will be retained 
with the study records and the subject will receive a copy of the signed informed 
consent for his/her records. The process of obtaining informed consent will be 
documented in the subject source documents.  
The date when a subject’s Informed Consent was actually obtained will be captured in 
their eCRFs. 
The Investigator (or designated staff) will explain the nature of the study as well as its 
risks and benefits to the subject.  
14.4.1 Informed Consent/Assent Process (in Case of a Minor) 
Not applicable. 
14.5 Subject Confidentiality 
Subject confidentiality is strictly held in trust by the participating Investigators, their 
staff, and the Sponsor(s) and their agents. This confidentiality is extended to cover 
testing of biological samples and genetic tests (if applicable) in addition to the clinical 
information relating to participating subjects as provided under each subject’s ICF. 
The study protocol, documentation, data, and all other information generated will be 
held in strict confidence. No information concerning the study or the data will be 
released to any unauthorized third party without prior written approval of the Sponsor. 
The study monitor or other authorized representatives of the Sponsor may inspect all 
documents and records required to be maintained by the Investigator, including but 
not limited to, medical records (office, clinic, or hospital) and pharmacy records for the 
subjects in this study. The clinical study site will permit access to such records. 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 105 of 121 
 
14.6 Protocol Adherence 
By signing the Form FDA 1572, the Investigator agrees to conduct the study according 
to the protocol and the FDA regulations set forth in 21 CFR Parts 50, 54, 56, and 312. 
14.7 Permission to Review Subjects’ Source Records 
The Investigator agrees to allow the FDA and other regulatory agencies, individuals 
delegated by the IRB/IEC and competent authorities, and the Sponsor or its designee 
to have access to all the original documentation of the study, including the ICFs 
signed by the subjects enrolled into the study and the relevant subject medical files. 
The individuals who are given access to the documentation must take every 
reasonable precaution to keep the identity of the subjects and the proprietary 
information of the Sponsor as confidential information in accordance with relevant 
applicable legislation. 
14.8 Protocol Amendments 
All amendments to the study protocol must be submitted to the IRB/IEC and 
competent authorities/regulatory agencies for written approval. The approval letter 
must refer specifically to the Investigator, the protocol number and protocol title, the 
protocol amendment number, and the date of the protocol amendment. A copy of the 
approval letter and revised informed consent document (if applicable) must be sent to 
GTx, Inc. or its designee. A protocol amendment may be implemented only after it has 
been approved by the IRB/IEC and has been approved by the appropriate regulatory 
authority. In the case of a protocol change intended to eliminate an apparent 
immediate hazard to subjects, the change may be implemented immediately, but the 
change must then be documented in a protocol amendment and approved as 
described above. 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 106 of 121 
 
14.9 Change in Investigator 
If any Investigator retires, relocates, or withdraws from an investigation during the 
conduct of the study the responsibility for conduct of the study may be transferred to 
another appropriately qualified Investigator at the investigative site. GTx, Inc. or its 
designee must be notified. An updated Form FDA 1572 must be submitted to GTx, 
Inc. or its designee. 
14.10 Study Discontinuation 
GTx, Inc. reserves the right to discontinue this study under the conditions specified in 
the clinical study agreement. Specific conditions for terminating the study are outlined 
in Section 5.4.5 
Termination of Study. 
14.11 Future Use of Stored Specimens 
Left over biospecimens (for example, blood and tissue samples) after analyses may 
be stored for future research uses from subjects who have consented and provided it 
is not prohibited by local laws and Ethics Committees. No additional samples will be 
collected except for those listed above. The samples will be stored for up to 10 years 
and destroyed after that. The samples may undergo genetic tests, tests for 
biomarkers, and other uses as described in the informed consent, including tests 
specific for the indication. It is the responsibility of the Investigator, or a person 
designated by the Investigator (if acceptable under local regulations), to obtain written 
informed consent from each individual who has consented to have their biospecimens 
stored for future research. Subjects must receive an explanation that they are 
completely free to refuse long-term storage of their samples for future research and 
may withdraw their sample at any time and for any reason during the 10 year storage 
period of the specimen(s) unless their sample has been retained in an anonymized 
manner (in which case it can no longer be identified as relating to the subject). 
The informed consent for optional specimen donation will be incorporated as a specific 
section into the main clinical trial ICF or provided as a separate document based on 
the local legislation requirements.  


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 107 of 121 
 
14.12 Indemnity 
The Sponsor certifies that it has taken out a liability insurance policy that is consistent 
with the requirements within the countries in which the study is being conducted. This 
insurance policy is in accordance with local laws and requirements. An insurance 
certificate will be provided to the PI in countries requiring this document. The 
insurance of the Sponsor does not relieve the PI and the collaborators of any 
obligation to maintain their own liability insurance policy as required by applicable law. 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 108 of 121 
 
15 
DATA HANDLING AND RECORD KEEPING 
The Investigator is responsible to ensure the accuracy, completeness, legibility, and 
timeliness of the source data. All source documents should be completed in a neat, 
legible manner to ensure accurate interpretation of data. Dark ink is required to ensure 
clarity of reproduced copies. When making changes or corrections, cross out the 
original entry with a single line, and initial and date the change. DO NOT ERASE, 
OVERWRITE, OR USE CORRECTION FLUID OR TAPE ON THE ORIGINAL. 
Copies of the eCRF will be provided for use as source documents and maintained for 
recording data for each subject enrolled in the study. Data reported in the eCRF 
derived from source documents should be consistent with the source documents or 
the discrepancies should be explained. 
GTx, Inc. and/or its designee will provide guidance to Investigators on making 
corrections to the source documents and eCRFs. 
Cmed will serve as the Statistical and Data Coordinating Center for this study and will 
be responsible for data management, quality review, analysis, and reporting of the 
study data. 
15.1 Data Capture Methods 
Clinical data (including AEs, concomitant medications, and expected adverse 
reactions data) and clinical laboratory data will be entered into a 21 CFR Part 11-
compliant data capture system provided by Data Management. The data system 
includes password protection and internal quality checks, such as automatic range 
checks, to identify data that appear inconsistent, incomplete, or inaccurate. Clinical 
data will be entered directly from the source documents. 
Cmed personnel will be responsible for the training of Investigator designated site staff 
on the correct use of the Electronic Data Capture (EDC) system. Authorized study 
staff will only be given access once they have received training. 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 109 of 121 
 
15.2 Study Site Responsibilities 
All data requested on the eCRF must be recorded. Data will be transcribed by 
authorized personnel at the study site from the source documents into the eCRF for 
enrolled subjects. All information on the eCRF must be traceable to these source 
documents. All electronic entries (including any changes or updates) will be traceable 
through the system. Only the PI or authorized staff may enter or modify data in the 
database using their unique password. The Investigator must certify that the data 
entered in the eCRFs are complete and accurate by electronically signing the eCRF. 
15.3 Data Management Responsibilities 
The Cmed Biometrics department will serve as the Statistical and Data Management 
center for this study and will be responsible for data management, quality review, 
analysis, and reporting of the study data. 
Data management staff at Cmed will review the data in the eCRFs according to their 
internal standard operating procedures and systematically validate the data using 
appropriate electronic checks in addition to relevant manual checks.  For any errors 
identified in the data, Cmed will generate a formal query to be addressed by the 
investigational site staff within the EDC system. 
For classification purposes, concomitant medications, AEs, and medical history 
entered into the eCRF will be coded using relevant medication and medical term 
dictionaries. These will be specified in the study-specific Data Management Plan. 
15.4 Timing/Reports 
A final report for the study will be completed upon completion of the study and the 
analysis of data. Please see for information concerning publication policy. 
15.5 Study Records Retention 
After the trial is completed, the Investigator will receive a Compact Disk-Read Only 
Memory (CD-ROM) with the eCRFs of the subject data for the site for archiving at the 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 110 of 121 
 
investigational study site. Study documents, including the CD-ROM, must be retained 
for a minimum of 2 years after the last approval of a marketing application in an ICH 
region and until there are no pending or contemplated marketing applications in an 
ICH region or until at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product. These documents will be retained 
for a longer period, however, if required by local regulations. No records will be 
destroyed without the written consent of GTx, Inc., if applicable. It is the responsibility 
of GTx, Inc. to inform the PI when these documents are no longer need to be retained. 
15.6 Protocol Deviations 
A protocol deviation is any non-compliance with the clinical trial protocol that affects a 
subject’s safety and primary efficacy, GCP, or Manual of Procedures requirements. 
The non-compliance may be either on the part of the subject, the PI, or the study site 
staff. As a result of deviations, corrective actions are to be developed by the site and 
implemented promptly.  
These practices are consistent with ICH E6: 
4.5 
Compliance with Protocol, Sections 4.5.1, 4.5.2, and 4.5.3 
5.1 
Quality Assurance and Quality Control, Section 5.1.1 
5.20 Non-compliance, Sections 5.20.1 and 5.20.2 
It is the responsibility of the site to use continuous vigilance to identify and report 
deviations within 5 working days of identification of the protocol deviation, or within 
5 working days of the scheduled protocol-required activity. All deviations must be 
promptly reported to the appropriate project manager responsible for the conduct of 
the study. 
All deviations from the protocol must be addressed in study subject source 
documents. A completed copy of the Protocol Deviation Form will be maintained in the 
regulatory file, as well as in the subject’s source document. Protocol deviations will be 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 111 of 121 
 
sent to the local IRB/IEC per their guidelines. The PI/study staff are responsible for 
knowing and adhering to their IRB/IEC requirements. 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 112 of 121 
 
16 
PUBLICATION POLICY 
Following completion of the study, it is expected some Investigators will publish the 
results of this research in scientific journal(s). Publication rights are governed by each 
investigatory site’s clinical trial agreement with GTx, Inc. The Investigator may request 
to publish this study in a scientific journal, but must have written authorization of 
GTx, Inc.   
The data generated by this study are confidential information and the property of 
GTx, Inc. This confidential information may be published only in collaboration with 
participating personnel from GTx, Inc. or upon GTx’s written consent, or otherwise 
under terms of the investigatory site’s clinical trial agreement with GTx, Inc.  All 
unpublished information provided by GTx, Inc. to vendors and investigatory teams 
shall not be published or disclosed to any third parties without the prior written consent 
of GTx, Inc. 
The International Committee of Medical Journal Editors member journals have 
adopted a trials-registration policy as a condition for publication. This policy requires 
that all clinical trials be registered in a public trials registry such as ClinicalTrials.gov, 
which is sponsored by the U.S. National Library of Medicine. It is GTx’s responsibility 
to register this trial in an acceptable registry.  


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 113 of 121 
 
17 
LITERATURE REFERENCES 
1. Simon R. Optimal two-stage designs for Phase 2 clinical trials. Controlled Clinical 
Trials 1989;10:1–10. 
2. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey 
J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, 
Lacombe D, Verweij J. New response evaluation criteria in solid tumors: revised 
RECIST guideline (version 1.1). Eur J Cancer 2009;45(2):228–247. 
3. Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, Bonsel G, Badia X. 
Development and preliminary testing of the new five-level version of EQ-5D 
(EQ-5D-5L). Qual Life Res 2011;20(10):1727–36. 
4. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone 
PP. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am 
J Clin Oncol 1982;5:649–655. 
5. Achar S, Rostamian A, Narayan SM. Cardiac and metabolic effects of anabolic-
androgenic steroid abuse on lipids, blood pressure, left ventricular dimensions, and 
rhythm. Am J Cardiol 2010;106(6):893–901. 
6. Kelly DM, Jones TH. Testosterone: a metabolic hormone in health and disease. J 
Endocrinol 2013;217(3):R25–45.  
7. Rader DJ, deGoma EM. Approach to the patient with extremely low HDL-
cholesterol. J Clin Endocrinol Metab 2012;97(10):3399–407.  
8. von Eckardstein A, Nofer JR, Assmann G. High density lipoproteins and 
arteriosclerosis. Role of cholesterol efflux and reverse cholesterol transport. 
Arterioscler Thromb Vasc Biol 2001;21(1):13–27.  
9. Wu FC, von Eckardstein A. Androgens and coronary artery disease. Endocr Rev 
2003;24(2):183–217.  
10. Rajabi H, Joshi MD, Jin C, Ahmad R, Kufe D. Androgen receptor regulates 
expression of the MUC1-C oncoprotein in human prostate cancer cells. Prostate 
2011;71(12):1299–308. 


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 114 of 121 
 
11. Gion M, Mione R, Leon AE, Lüftner D, Molina R, Possinger K, Robertson JF. 
CA27.29: a valuable marker for breast cancer management. A confirmatory 
multicentric study on 603 cases. Eur J Cancer 2001;37(3):355–63. 
12. Blyth C, Still H. Binomial confidence intervals. Journal of American Statistical 
Association 1983;78:108–116. 
 
 
 


 
Protocol: A Phase 2 Open Label, Multi-Center, Multinational, Randomized, Parallel 
Design Study Investigating The Efficacy and Safety Of GTx-024 On Metastatic or Locally 
Advanced ER+/AR+ Breast Cancer (BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 115 of 121 
 
APPENDIX A: SCHEDULE OF EVENTS 
Periods 
Screening 
Randomization
/ 
Treatment phase1 
(from randomization to EOT) 
EOT/ 
Early 
termination 
FU post 
treatment 
Day –28  
to –1 
 
Day 1 
 
 
 
 
Confirmation 
of CR or PR 
As required 
if still on 
treatment 
 
 
Visit number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V82– V13 
VEOT 
VFU 
Week/Day 
 
 
Week 
6 
Week 12 
 
Week 18 
Week 24 
Week 28 
Every 
12 weeks 
(± 7  
days) 
3 days after 
the last dose 
of GTx-024 
28 days 
(± 2 days) 
after the 
last dose 
of GTx-024 
Procedure 
 
 
Day 42 
(± 7 
days) 
Day 84  
(± 7 
days) 
Day 126  
(± 7  
days) 
Day 168  
(± 7  
days) 
Day 196  
(± 7  
days) 
Obtain ICF 
X 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
check 
X 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Prior anticancer 
treatment 
X 
X 
 
 
 
 
 
 
 
 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Diagnosis and 
extent of BC 
X 
 
 
 
 
 
 
 
 
 


 
Protocol: A Phase 2 Open Label, Multi-Center, Multinational, Randomized, Parallel 
Design Study Investigating The Efficacy and Safety Of GTx-024 On Metastatic or Locally 
Advanced ER+/AR+ Breast Cancer (BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 116 of 121 
 
Periods 
Screening 
Randomization
/ 
Treatment phase1 
(from randomization to EOT) 
EOT/ 
Early 
termination 
FU post 
treatment 
Day –28  
to –1 
 
Day 1 
 
 
 
 
Confirmation 
of CR or PR 
As required 
if still on 
treatment 
 
 
Visit number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V82– V13 
VEOT 
VFU 
Week/Day 
 
 
Week 
6 
Week 12 
 
Week 18 
Week 24 
Week 28 
Every 
12 weeks 
(± 7  
days) 
3 days after 
the last dose 
of GTx-024 
28 days 
(± 2 days) 
after the 
last dose 
of GTx-024 
Procedure 
 
 
Day 42 
(± 7 
days) 
Day 84  
(± 7 
days) 
Day 126  
(± 7  
days) 
Day 168  
(± 7  
days) 
Day 196  
(± 7  
days) 
Hormonal receptor 
status (ER+) and 
HER23 
X 
 
 
 
 
 
 
 
 
 
AR status3 
X 
 
 
 
 
 
 
 
 
 
Physical 
examination 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
Vital signs 
X 
X4 
X 
X 
X 
X 
 
X 
X 
X 
ECOG performance 
status 
X 
X4 
X 
X 
X 
X 
 
X 
X 
X 
Eye examination5 
X 
As clinically indicated 
X 
 


 
Protocol: A Phase 2 Open Label, Multi-Center, Multinational, Randomized, Parallel 
Design Study Investigating The Efficacy and Safety Of GTx-024 On Metastatic or Locally 
Advanced ER+/AR+ Breast Cancer (BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 117 of 121 
 
Periods 
Screening 
Randomization
/ 
Treatment phase1 
(from randomization to EOT) 
EOT/ 
Early 
termination 
FU post 
treatment 
Day –28  
to –1 
 
Day 1 
 
 
 
 
Confirmation 
of CR or PR 
As required 
if still on 
treatment 
 
 
Visit number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V82– V13 
VEOT 
VFU 
Week/Day 
 
 
Week 
6 
Week 12 
 
Week 18 
Week 24 
Week 28 
Every 
12 weeks 
(± 7  
days) 
3 days after 
the last dose 
of GTx-024 
28 days 
(± 2 days) 
after the 
last dose 
of GTx-024 
Procedure 
 
 
Day 42 
(± 7 
days) 
Day 84  
(± 7 
days) 
Day 126  
(± 7  
days) 
Day 168  
(± 7  
days) 
Day 196  
(± 7  
days) 
Hematology 
X 
X4 
X 
X 
X 
X 
 
X 
X 
X 
Biochemistry 
X 
X4 
X 
X 
X 
X 
 
X 
X 
X 
HIV screening 
X 
 
 
 
 
 
 
 
 
 
HBV screening6 
X 
 
 
 
 
 
 
 
 
 
HCV screening 
X 
 
 
 
 
 
 
 
 
 
Serum lipid profile 
 
X 
X 
X 
X 
X 
 
X 
X 
 
Coagulation status 
X 
 
X 
X 
X 
X 
 
X 
X 
 
Serum hormones 
 
X 
X 
X 
X 
X 
 
X 
X 
 
PSA 
X 
X4 
X 
X 
X 
X 
 
X 
X 
X 


 
Protocol: A Phase 2 Open Label, Multi-Center, Multinational, Randomized, Parallel 
Design Study Investigating The Efficacy and Safety Of GTx-024 On Metastatic or Locally 
Advanced ER+/AR+ Breast Cancer (BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 118 of 121 
 
Periods 
Screening 
Randomization
/ 
Treatment phase1 
(from randomization to EOT) 
EOT/ 
Early 
termination 
FU post 
treatment 
Day –28  
to –1 
 
Day 1 
 
 
 
 
Confirmation 
of CR or PR 
As required 
if still on 
treatment 
 
 
Visit number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V82– V13 
VEOT 
VFU 
Week/Day 
 
 
Week 
6 
Week 12 
 
Week 18 
Week 24 
Week 28 
Every 
12 weeks 
(± 7  
days) 
3 days after 
the last dose 
of GTx-024 
28 days 
(± 2 days) 
after the 
last dose 
of GTx-024 
Procedure 
 
 
Day 42 
(± 7 
days) 
Day 84  
(± 7 
days) 
Day 126  
(± 7  
days) 
Day 168  
(± 7  
days) 
Day 196  
(± 7  
days) 
CTC enumeration 
 
X 
 
X 
 
X 
 
X 
X 
 
CTC gene 
expression 
 
X 
 
 
 
 
 
 
X 
 
Urine analysis 
X 
As clinically indicated 
Radiological 
evaluation: CT/MRI7  
X 
 
 
X 
 
X 
X8 
X 
X 
 
Radiological 
evaluation: bone 
scan9 
X 
 
 
X 
 
X 
X10 
X 
X 
 
Pharmacokinetic 
samples11 
 
X 
X 
 
X 
X 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 


 
Protocol: A Phase 2 Open Label, Multi-Center, Multinational, Randomized, Parallel 
Design Study Investigating The Efficacy and Safety Of GTx-024 On Metastatic or Locally 
Advanced ER+/AR+ Breast Cancer (BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 119 of 121 
 
Periods 
Screening 
Randomization
/ 
Treatment phase1 
(from randomization to EOT) 
EOT/ 
Early 
termination 
FU post 
treatment 
Day –28  
to –1 
 
Day 1 
 
 
 
 
Confirmation 
of CR or PR 
As required 
if still on 
treatment 
 
 
Visit number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V82– V13 
VEOT 
VFU 
Week/Day 
 
 
Week 
6 
Week 12 
 
Week 18 
Week 24 
Week 28 
Every 
12 weeks 
(± 7  
days) 
3 days after 
the last dose 
of GTx-024 
28 days 
(± 2 days) 
after the 
last dose 
of GTx-024 
Procedure 
 
 
Day 42 
(± 7 
days) 
Day 84  
(± 7 
days) 
Day 126  
(± 7  
days) 
Day 168  
(± 7  
days) 
Day 196  
(± 7  
days) 
AEs 
X 
X 
X 
X 
X 
X 
 
X 
X 
To be 
followed up 
to 28 days 
post 
treatment 
Serum Pregnancy 
Test 
X 
 
 
 
 
 
 
 
 
 
GTx-024 9 mg or 
18 mg dispensing/ 
administration 
 
X12 
X 
X 
X 
X13 
 
X13 
 
 
GTx-024 9 mg or 
18 mg accountability 
 
 
X 
X 
X 
X 
 
X 
X 
 
QoL EQ-5D-5L 
 
X 
X 
X 
X 
X 
 
X 
X 
 
1 Subjects with clinical benefit at 24 weeks will continue on therapy for up to 24 months (as long as they still benefit from the treatment during these 24 months). If so, 
the subjects will be asked to come for a visit every 3 months and undergo the assessments for the treatment period.  
2 Visit 8 should occur at Week 36; i.e., 12 weeks after Visit 6 (Week 24). 


 
Protocol: A Phase 2 Open Label, Multi-Center, Multinational, Randomized, Parallel 
Design Study Investigating The Efficacy and Safety Of GTx-024 On Metastatic or Locally 
Advanced ER+/AR+ Breast Cancer (BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 120 of 121 
 
3 ER and HER2 as per medical record will be used to determine subject eligibility. ER status will be confirmed by a local laboratory if not available in the subject’s 
medical history. AR status will be confirmed by a central laboratory. 
4 These medical procedures and assessments do not have to be repeated if done at screening within 7 days before randomization. 
5 Eye examination including best corrected distance visual acuity with refraction, intraocular pressure, slit lamp examination, and dilated fundus photography must be 
completed between Day –28 and Day –1, as clinically indicated during the treatment phase, and at EOT. 
6 HBV screening will be done as HBsAg. 
7 Imaging study (CT, MRI) is recommended to be performed within 7 days prior to randomization. The imaging studies will be assessed by both a local imaging facility 
and a blinded central reader. Subject eligibility will be based on local reading of the imaging studies. Medical decisions will be based on the local assessments. 
At screening, week 12 (Visit 4), and week 24 (Visit 6), tumor volumetric assessments will be done for the subjects undergoing CT scanning. 
8 In compliance with RECIST 1.1 guidelines, subjects who have CR or PR at week 24 (Visit 6) require confirmation within a month as follows: 
 
For subjects with measureable lesions, subjects will undergo CT/MRI based on the Investigator’s medical judgment  
9 Bone scans will be performed at screening and then every 12 weeks whilst subjects receive treatment (Visits 4, 6, and thereafter) in only those subjects with baseline 
bone metastases, or if clinically indicated. 
10 In compliance with RECIST 1.1 guidelines, subjects who have CR or PR at week 24 (Visit 6) require confirmation within a month as follows: 
 
For subjects with non-measurable lesions, subjects will undergo X-ray or bone-scanning based on the Investigator’s medical judgment and location of 
disease. 
11 Blood sampling for pharmacokinetic assessment. The exact time (hh:mm) and date of the blood sample should be recorded on the eCRF. At the baseline visit, 
the blood sample should be collected before the subject is given their first dose of GTx-024. At visits 3 (week 6), 5 (week 18), and 6 (week 24), the date and 
approximate time of the last dose of GTx-024 prior to the blood sample should also be recorded; i.e., it should be documented whether the subject took the 
previous dose that morning or the evening before.  
12 First dose to be given at site during this visit. 
13 At Visits 6, 8, 9, 10, 11, 12, and 13, in order to accommodate the visit schedule of every 12 weeks (± 7 days), the subjects will receive two carton boxes of study drug 
(each containing 7 blisters) to cover study treatment for 14 weeks. 
Abbreviations: AR = Androgen Receptor, BC = Breast Cancer, CR = Complete Response; CT = Computerized Tomography, CTCs = Circulating Tumor Cells, 
ECG = Electrocardiogram, ECOG = Eastern Cooperative Oncology Group, eCRF = electronic Case Report Form, EOT = End of Treatment, ER = Estrogen 
Receptor, FU = Follow-up, HBsAg = Hepatitis B surface Antigen, HBV = hepatitis B virus, HCV = hepatitis C virus, HIV = Human Immunodeficiency Virus, ICF = 
Informed Consent Form, IHC = Immunohistochemistry, MRI = Magnetic Resonance Imaging, PR = Partial Response; QoL = Quality of Life, PSA = Prostate 
Specific Antigen, V = Visit.


 
Protocol: A Phase 2 Open Label, Multi-Center, 
Multinational, Randomized, Parallel Design Study 
Investigating The Efficacy and Safety Of GTx-024 On 
Metastatic or Locally Advanced ER+/AR+ Breast Cancer 
(BC) in Postmenopausal Women 
Compound No.: GTx-024 
Author: Nancy Milligan 
 
GTx ER+/AR+ Protocol; Version 1.0 
26May2015 
CONFIDENTIAL  
Page 121 of 121 
 
APPENDIX B: ECOG PERFORMANCE STATUS 
 
ECOG PERFORMANCE STATUS4 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature; e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair 
5 
Dead